U.S. patent application number 12/468494 was filed with the patent office on 2010-04-01 for phenyl or pyridinyl substituted indazoles derivatives.
Invention is credited to Markus Berger, Jan Dahmen, Karl Edman, Thomas Hansson, Martin Hemmerling, Nafizal Hossain, Henrik Johanssson, Matti Lepisto, Stinabritt Nilsson, Hartmut Rehwinkel.
Application Number | 20100080786 12/468494 |
Document ID | / |
Family ID | 41340347 |
Filed Date | 2010-04-01 |
United States Patent
Application |
20100080786 |
Kind Code |
A1 |
Berger; Markus ; et
al. |
April 1, 2010 |
Phenyl or Pyridinyl Substituted Indazoles Derivatives
Abstract
A compound of formula Ia: ##STR00001## The present invention
relates to novel indazolyl derivatives, to pharmaceutical
compositions comprising such derivatives, to processes for
preparing such novel derivatives and to the use of such derivatives
as medicaments
Inventors: |
Berger; Markus; (Berlin,
DE) ; Rehwinkel; Hartmut; (Berlin, DE) ;
Dahmen; Jan; (Lund, SE) ; Hansson; Thomas;
(Lund, SE) ; Hossain; Nafizal; (Lund, SE) ;
Johanssson; Henrik; (Lund, SE) ; Lepisto; Matti;
(Lund, SE) ; Nilsson; Stinabritt; (Lund, SE)
; Hemmerling; Martin; (Lund, SE) ; Edman;
Karl; (Molndal, SE) |
Correspondence
Address: |
FISH & RICHARDSON P.C.
P.O BOX 1022
MINNEAPOLIS
MN
55440-1022
US
|
Family ID: |
41340347 |
Appl. No.: |
12/468494 |
Filed: |
May 19, 2009 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
61054616 |
May 20, 2008 |
|
|
|
61080312 |
Jul 14, 2008 |
|
|
|
61144776 |
Jan 15, 2009 |
|
|
|
Current U.S.
Class: |
424/94.1 ;
514/254.06; 514/333; 514/338; 514/392; 514/406; 544/371; 546/256;
546/275.7; 548/311.7; 548/361.1 |
Current CPC
Class: |
A61P 9/10 20180101; A61P
25/24 20180101; A61P 13/12 20180101; C07D 231/56 20130101; C07D
405/10 20130101; A61P 13/02 20180101; A61P 11/08 20180101; A61P
19/02 20180101; A61P 7/10 20180101; A61P 17/14 20180101; C07D
403/10 20130101; C07D 405/14 20130101; A61P 5/00 20180101; A61P
17/00 20180101; A61P 25/04 20180101; C07D 401/12 20130101; A61P
7/04 20180101; A61P 25/22 20180101; A61K 31/416 20130101; A61P 3/10
20180101; A61P 17/02 20180101; A61P 11/06 20180101; A61P 43/00
20180101; A61P 7/00 20180101; A61P 35/02 20180101; C07D 407/14
20130101; A61P 5/46 20180101; A61P 37/00 20180101; C07D 409/14
20130101; A61P 9/06 20180101; C07D 413/12 20130101; A61P 9/00
20180101; A61P 11/16 20180101; A61P 27/02 20180101; A61P 11/00
20180101; A61P 7/06 20180101; A61P 9/12 20180101; C07D 403/12
20130101; A61P 25/00 20180101; A61P 25/18 20180101; A61P 17/04
20180101; A61P 37/02 20180101; A61P 21/00 20180101; A61P 35/00
20180101; C07D 401/14 20130101; A61P 5/14 20180101; A61P 11/02
20180101; A61P 17/06 20180101; A61P 1/08 20180101; A61P 3/04
20180101; A61P 37/06 20180101; A61P 17/10 20180101; C07D 405/12
20130101; A61K 31/4439 20130101; A61K 45/06 20130101; A61P 1/04
20180101; A61P 9/04 20180101; A61P 19/10 20180101; A61P 37/08
20180101; C07D 409/12 20130101; A61P 25/28 20180101; A61P 29/00
20180101; A61P 1/16 20180101; A61P 27/16 20180101 |
Class at
Publication: |
424/94.1 ;
548/361.1; 514/406; 514/392; 548/311.7; 544/371; 514/254.06;
514/338; 546/275.7; 546/256; 514/333 |
International
Class: |
A61K 38/55 20060101
A61K038/55; C07D 403/10 20060101 C07D403/10; A61K 31/416 20060101
A61K031/416; A61K 31/4166 20060101 A61K031/4166; A61K 31/496
20060101 A61K031/496; A61K 31/4427 20060101 A61K031/4427; C07D
401/10 20060101 C07D401/10; C07D 401/14 20060101 C07D401/14; A61P
11/06 20060101 A61P011/06 |
Claims
1. A compound of formula Ia: ##STR00063## wherein: A is
C.sub.1-6alkyl, C.sub.1-6alkoxy, C.sub.3-7cycloalkyl,
C.sub.1-6haloalkyl, C.sub.1-6alkylthio, C.sub.1-6alkylC(O)--,
C.sub.1-6alkyloxyC(O)--, NR.sup.5R.sup.6,NR.sup.5R.sup.6C(O)-- or
C.sub.5-10heteroaryl, all optionally substituted by one or more
substituents independently selected from halo, cyano, hydroxyl,
C.sub.1-4alkyl, C.sub.1-4alkoxy and C.sub.1-4haloalkyl; R.sup.5 and
R.sup.6 are independently selected from hydrogen, C.sub.1-6alkyl,
C.sub.3-7cycloalkyl, C.sub.1-6alkylC(O)-- and
C.sub.3-7cycloalkylC(O)--, or R.sup.5 and R.sup.6 might form a ring
with the nitrogen to which they are attached; R.sup.1 is hydrogen,
C.sub.1-4alkyl, C.sub.1-4hydroxyalkyl-,
C.sub.1-4alkylOC.sub.1-4alkyl-, C.sub.1-4alkylthioC.sub.1-4alkyl-
or C.sub.1-4haloalkyl; R.sup.3 is C.sub.5-10aryl,
C.sub.5-10arylC.sub.1-4alkyl-, C.sub.5-10arylO-,
C.sub.5-10arylC.sub.1-4alkoxy-, C.sub.5-10aryloxyC.sub.1-4alkyl-,
C.sub.5-10heteroaryl-, C.sub.5-10heteroarylC.sub.1-4alkyl-,
C.sub.5-10heteroarylC.sub.1-4alkoxy- or
C.sub.5-10heteroaryoxyC.sub.1-4alkyl-, all of which are
unsubstituted or optionally substituted by one or more substituents
independently selected from B; B is hydroxyl, halo, cyano,
C.sub.1-4alkyl, C.sub.1-4alkoxy, C.sub.1-3hydroxyalkyl-,
C.sub.1-4alkoxyC.sub.1-4alkyl-,
C.sub.3-6cycloalkyloxyC.sub.1-4alkyl-, C.sub.3-6cycloalkylO-,
C.sub.3-6cycloalkylthioC.sub.1-4alkyl-, C.sub.3-6cycloalkylthio-,
C.sub.1-3alkylS(O).sub.kC.sub.1-4alkyl-,
C.sub.1-3alkylS(O).sub.k--, C.sub.1-4haloalkyl or
C.sub.1-4haloalkoxy-, or B is one of the following groups which are
linked to adjacent carbons on an aryl or heteroaryl ring
(CH.sub.2).sub.tOC.sub.1-4alkylenylO(CH.sub.2).sub.v-- or
(CH.sub.2).sub.tO(CH.sub.2).sub.v--; k is 0, 1; t and v are,
independently, 0, 1, 2 or 3, and t and v are not both 0; X is O or
NH; W is phenyl substituted by one or more substituents
independently selected from --(CH.sub.2).sub.nC(O)NR.sup.7R.sup.8,
--(CH.sub.2).sub.nNR.sup.9C(O)R.sup.8 or
--(CH.sub.2).sub.nC(O)NR.sup.9(CR.sup.14R.sup.15)C(O)NR.sup.7R.sup.8;
and W is optionally further substituted by halogen or
C.sub.1-4alkyl; R.sup.7 is hydrogen or C.sub.1-4alkyl; R.sup.8 and
R.sup.9 are, independently, hydrogen, C.sub.1-4 alkyl (optionally
substituted by one or two groups selected from hydroxyl, C.sub.1-4
alkoxy, NH.sub.2, oxo, --C(O)NR.sup.10R.sup.11,
--NR.sup.10C.sub.1-4alkyl, --C(O)NR.sup.10C.sub.1-4alkyl,
--NR.sup.10C(O)C.sub.1-4 alkyl, C.sub.1-4 alkylthio,
C.sub.5-10heterocyclyl, C.sub.5-10aryl or C.sub.5-10heteroaryl),
C.sub.3-7 cycloalkyl (optionally substituted by --C(O)NH.sub.2),
C.sub.5-10heterocyclyl, C.sub.5-10aryl, C.sub.5-10heteroaryl or
--C(O)NR.sup.10R.sup.11; whereby C.sub.5-10aryl or
C.sub.5-10heteroaryl are optionally substituted by halogen,
C.sub.1-4 alkyl, C.sub.1-4alkoxy, CF.sub.3, --OCF.sub.3, hydroxy or
cyano; and whereby any heterocyclyl is optionally substituted by
C.sub.1-4 alkyl, --C.sub.1-4 alkoxy(C.sub.1-4 alkyl), oxo or
hydroxyl; or R.sup.7 and R.sup.8, together with the nitrogen to
which the are attached, form a 5- or 6-membered ring optionally
comprising a second ring-nitrogen atom, the ring being optionally
substituted by one or two groups selected from oxo, hydroxyl,
C.sub.1-4hydroxyalkyl-, C.sub.1-4 alkyl, --C.sub.1-4
alkoxy(C.sub.1-4 alkyl) or --(CH.sub.2).sub.pC(O)NR.sup.12R.sup.13;
R.sup.10, R.sup.11, R.sup.12 and R.sup.13 are, independently,
hydrogen or C.sub.1-4 alkyl; n and p are, independently, 0, 1, 2, 3
or 4; and Y is hydrogen, halo, C.sub.1-4alkyl or
C.sub.1-4haloalkyl; or a pharmaceutically acceptable salt
thereof.
2. The compound according to claim 1, wherein: A is
C.sub.3-7cycloalkyl, C.sub.1-6haloalkyl optionally substituted by
cyano; R.sup.1 is C.sub.1-4alkyl or C.sub.1-4hydroxyalkyl; R.sup.3
is C.sub.5-10aryl or C.sub.5-10heteroaryl optionally substituted by
C.sub.1-4alkoxy; X is O; W is phenyl substituted by
--C(O)NR.sup.7R.sup.8; R.sup.7 is hydrogen; R.sup.8 is C.sub.1-4
alkyl (optionally substituted by one or two groups selected from
hydroxyl, --C(O)NR.sup.10R.sup.11, --NR.sup.10C(O)C.sub.1-4 alkyl,
C.sub.5-40heterocyclyl, C.sub.5-10aryl or C.sub.5-10heteroaryl),
C.sub.3-7 cycloalkyl, C.sub.5-10heterocyclyl or
C.sub.5-10heteroaryl, whereby any heterocyclyl is optionally
substituted by C.sub.1-4 alkyl or oxo; or R.sup.7 and R.sup.8,
together with the nitrogen to which the are attached, form a 5- or
6-membered ring optionally comprising a second ring-nitrogen atom,
the ring being optionally substituted by one or two groups selected
from oxo, hydroxyl, C.sub.1-4hydroxyalkyl or
--C(O)NR.sup.12R.sup.13; R.sup.10, R.sup.11, R.sup.12 and R.sup.13
are hydrogen; and Y is hydrogen; or a pharmaceutically acceptable
salt thereof.
3. The compound according to claim 1 or 2, wherein A is
difluoroethyl or cyclopropyl substituted with cyano; R.sup.1 is
methyl or hydroxymethyl; R.sup.3 is phenyl or pyridyl substituted
with methoxy.
4. The compound according to any one of claims 1 to 3, wherein W is
phenyl substituted by --C(O)NR.sup.7R.sup.8; R.sup.7 is hydrogen;
and R.sup.8 is hydroxymethyl, hydroxyethyl, hydroxypropyl,
hydroxybutyl, aminooxomethyl, aminooxoethyl, aminooxopropyl,
aminomethyloxomethyl, aminomethyloxoethyl, cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, acetylaminomethyl, acetylaminoethyl,
oxoimidazolidinylmethyl, oxoimidazolidinylethyl,
oxopyrrolidinylmethyl, oxopyrrolidinylethyl,
oxidotetrahydrothiophenyl, dioxidotetrahydrothiophenyl,
oxotertahydrofuranyl, tertahydrofuranyl,
methyldioxooxazolidinylmethyl, dimethyldioxooxazolidinylmethyl,
methyldioxooxazolidinylethyl, dimethyldioxooxazolidinylethyl,
indazolylmethyl, indazolylethyl, aminooxophenylmethyl,
aminooxophenylethyl, pyridinyl, pyrimidyl, pyrazinyl, pyridazinyl,
pyridinylmethyl, pyridinylethyl, indazolylmethyl or
indazolylethyl.
5. The compound according to any one of claims 1 to 3, wherein W is
phenyl substituted by --C(O)NR.sup.7R.sup.8; and R.sup.7 and
R.sup.8, together form pyrrolidinyl, oxopyrrolidinyl,
carbamoylpyrrolidinyl, hydroxymethylpyrrolidinyl,
hydroxypyrrolidinyl, prolinamide, hydroxyprolinamide, piperidinyl,
hydroxypiperidinyl, oxopiperidinyl, imidazolidinyl, piperazinyl,
hydroxypiperazinyl, oxopiperazinyl, tetrahydrothiophenyl,
oxidotetrahydrothiophenyl, dioxidotetrahydrothiophenyl,
oxotertahydrofuranyl or tertahydrofuranyl.
6. Compounds selected from
1-({3-[5-({(1R,2S)-2-[(2,2-difluoropropanoyl)amino]-1-phenylpropyl}oxy)-1-
H-indazol-1-yl]phenyl}carbonyl)-D-prolinamide,
N-[(1S,2R)-2-{[1-(3-{[(2R)-2-carbamoylpyrrolidin-1-yl]carbonyl}phenyl)-1H-
-indazol-5-yl]oxy}-1-methyl-2-phenylethyl]ethanediamide,
3-[5-({(1R,2S)-2-[(2,2-difluoropropanoyl)amino]-1-phenylpropyl}oxy)-1H-in-
dazol-1-yl]-N-(2-hydroxyethyl)benzamide,
N-(2-amino-2-oxoethyl)-3-[5-({(1R,2S)-2-[(2,2-difluoropropanoyl)amino]-1--
phenylpropyl}oxy)-1H-indazol-1-yl]benzamide,
N-[(1S)-2-amino-1-methyl-2-oxoethyl]-3-[5({(1R,2S)-2-[(2,2-difluoropropan-
oyl)amino]-1-phenylpropyl}oxy)-1H-indazol-1-yl]benzamide,
N-[2-(acetylamino)ethyl]-3-[5-({(1R,2S)-2-[(2,2-difluoropropanoyl)amino]--
1-phenylpropyl}oxy)-1H-indazol-1-yl]benzamide,
3-[5-({(1R,2S)-2-[(2,2-difluoropropanoyl)amino]-1-phenylpropyl}oxy)-1H-in-
dazol-1-yl]-N-[2-(2-oxoimidazolidin-1-yl)ethyl]benzamide,
2,2-difluoro-N-[(1S,2R)-2-{[1-(3-{[(2R)-2-(hydroxymethyl)pyrolidin-1-yl]c-
arbonyl}phenyl)-1H-indazol-5-yl]oxy}-1-methyl-2-phenylethyl]propanamide,
2,2-difluoro-N-[(1S,2R)-2-{[1-(3-{[(3R)-3-hydroxypyrrolidin-1-yl]carbonyl-
}phenyl)-1H-indazol-5-yl]oxy}-1-methyl-2-phenylethyl]propanamide,
3-[5-({(1R,2S)-2-[(2,2-difluoropropanoyl)amino]-1-phenylpropyl}oxy)-1H-in-
dazol-1-yl]-N-[(3R)-2-oxotetrahydrofuran-3-yl]benzamide,
1-({3-[5-({(1R,2S)-2-[(2,2-difluoropropanoyl)amino]-1-phenylpropyl}oxy)-1-
H-indazol-1-yl]phenyl}carbonyl)-L-prolinamide,
2,2-difluoro-N-{(1S,2R)-1-methyl-2-[(1-{3-[(3-oxopiperazin-1-yl)carbonyl]-
phenyl}-1H-indazol-5-yl)oxy]-2-phenylethyl}propanamide,
3-[5({(1R,2S)-2-[(2,2-difluoropropanoyl)amino]-1-phenylpropyl}oxy)-1H-ind-
azol-1-yl]-N-[2-(2-oxopyrrolidin-1-yl)ethyl]benzamide,
3-[5-({(1R,2S)-2-[(2,2-difluoropropanoyl)amino]-1-phenylpropyl}oxy)-1H-in-
dazol-1-yl]-N-[2-(5,5-dimethyl-2,4-dioxo-1,3-oxazolidin-3-yl)ethyl]benzami-
de,
3-[5-({(1R,2S)-2-[(2,2-difluoropropanoyl)amino]-1-phenylpropyl}oxy)-1H-
-indazol-1-yl]-N-(1,1-dioxidotetrahydrothiophen-3-yl)benzamide,
3-[5-({(1R,2S)-2-[(2,2-difluoropropanoyl)amino]-1-phenylpropyl}oxy)-1H-in-
dazol-1-yl]-N-(1H-indazol-3-ylmethyl)benzamide,
N-[(1R)-2-amino-2-oxo-1-phenylethyl]-3-[5-({(1R,2S)-2-[(2,2-difluoropropa-
noyl)amino]-1-phenylpropyl}oxy)-1H-indazol-1-yl]benzamide,
N-(2-amino-2-oxoethyl)-3-[5-({(1R,2S)-2-[(2,2-difluoropropanoyl)amino]-1--
phenylpropyl}oxy)-1H-indazol-1-yl]-N-methylbenzamide,
N-(3-amino-3-oxopropyl)-3-[5-({(1R,2S)-2-[(2,2-difluoropropanoyl)amino]-1-
-phenylpropyl}oxy)-1H-indazol-1-yl]benzamide,
(4R)-1-({3-[5-({(1R,2S)-2-[(2,2-difluoropropanoyl)amino]-1-phenylpropyl}o-
xy)-1H-indazol-1-yl]phenyl}carbonyl)-4-hydroxy-L-prolinamide,
1-{[3-(5-{[(1R,2S)-2-{[(1-cyanocyclopropyl)carbonyl]amino}-1-phenylpropyl-
]oxy}-1H-indazol-1-yl)phenyl]carbonyl}-D-prolinamide,
N-cyclopentyl-3-(5-{[(1R,2S)-2-[(2,2-difluoropropanoyl)amino]-1-(6-methox-
ypyridin-3-yl)propyl]oxy}-1H-indazol-1-yl)benzamide,
3-(5-{[(1R,2S)-2-[(2,2-difluoropropanoyl)amino]-1-(6-methoxypyridin-3-yl)-
propyl]oxy}-1H-indazol-1-yl)-N-pyridin-3-ylbenzamide,
3-(5-{[(1R,2S)-2-[(2,2-difluoropropanoyl)amino]-1-(6-methoxypyridin-3-yl)-
propyl]oxy}-1H-indazol-1-yl)-N-(1,1-dioxidotetrahydrothiophen-3-yl)benzami-
de,
3-(5-{[(1R,2S)-2-[(2,2-difluoropropanoyl)amino]-1-(6-methoxypyridin-3--
yl)propyl]oxy}-1H-indazol-1-yl)-N-(tetrahydrofuran-3-yl)benzamide,
3-(5-{[(1R,2S)-2-[(2,2-difluoropropanoyl)amino]-1-(6-methoxypyridin-3-yl)-
propyl]oxy}-1H-indazol-1-yl)-N-(2-hydroxybutyl)benzamide,
N-cyclopentyl-3-(5-{[(1R,2S)-2-[(2,2-difluoropropanoyl)amino]-3-hydroxy-1-
-(6-methoxypyridin-3-yl)propyl]oxy}-1H-indazol-1-yl)benzamide, and
3-(5-{[(1R,2S)-2-[(2,2-difluoropropanoyl)amino]-1-(6-methoxypyridin-3-yl)-
propyl]oxy}-1H-indazol-1-yl)-N-(pyridin-3-ylmethyl)benzamide, or a
pharmaceutically acceptable salt thereof.
7. A pharmaceutical composition comprising a compound according to
any one of claims 1 to 6, together with a pharmaceutically
acceptable adjuvant, diluent or carrier.
8. A compound according to any one of claims 1 to 6 for use in
therapy.
9. The use of a compound according to any one of claims 1 to 6, or
a pharmaceutical composition according to claim 7, in the
manufacture of a medicament for use in the treatment of a
glucocorticoid receptor mediated disease state.
10. The use of a compound according to any one of claims 1 to 6, or
a pharmaceutical composition according to claim 7, in the
manufacture of a medicament for use in the treatment of
inflammatory conditions or respiratory disorder.
11. The use of a compound according to any one of claims 1 to 6, or
a pharmaceutical composition according to claim 7, in the
manufacture of a medicament for use in the treatment of asthma.
12. The use of a compound according to any one of claims 1 to 6, or
a pharmaceutical composition according to claim 7, in the
manufacture of a medicament for use in the is treatment of
COPD.
13. A method of treating a glucocorticoid receptor mediated disease
state, inflammatory condition, respiratory disorder, asthma and/or
COPD in a mammal, which comprises administering to a mammal in need
of such treatment an effective amount of a compound according to
any one of claims 1 to 6, or a pharmaceutical composition according
to claim 7.
14. A combination of a compound according to any one of claims 1 to
6, and one or more agents selected from the list comprising: a PDE4
inhibitor; a selective .beta..sub2. adrenoceptor agonist; a
muscarinic receptor antagonist; a modulator of chemokine receptor
function; an inhibitor of p38 kinase function; an inhibitor of
matrix metalloproteases, for example targeting MMP-2, -9 or MMP-12;
or an inhibitor of neutrophil serine proteases, for example
neutrophil elastase or proteinase 3.
15. A process for the preparation of compounds of formula Ia
according to claim 1, by coupling a compound of formula (II):
##STR00064## with acylation reagents of formula (IIIa), (IIIb) or
(IIIc) ##STR00065## wherein R.sup.1, R.sup.3, A, X and Y are
defined above, W is as defined above and L.sup.1 is a leaving group
or, when L.sup.1.dbd.OH, a leaving group generated by reaction of a
coupling reagent.
Description
[0001] The present invention relates to novel indazolyl
derivatives, to pharmaceutical compositions comprising such
derivatives, to processes for preparing such novel derivatives and
to the use of such derivatives as medicaments (for example in the
treatment of an inflammatory disease state).
[0002] Sulphonamide derivatives are disclosed as
anti-inflammatories in WO 2004/019935 and WO 2004/050631.
Pharmaceutically active sulphonamides are also disclosed in Arch.
Pharm. (1980) 313 166-173, J. Med. Chem. (2003) 46 64-73, J. Med.
Chem. (1997) 40 996-1004, EP 0031954, EP 1190710 (WO 200124786),
U.S. Pat. No. 5,861,401, U.S. Pat. No. 4,948,809, U.S. Pat. No.
3,992,441 and WO 99/33786.
[0003] It is known that certain non-steroidal compounds interact
with the glucocorticoid receptor (GR) and, as a result of this
interaction, produce a suppression of inflammation (see, for
example, U.S. Pat. No. 6,323,199). Such compounds can show a clear
dissociation between anti-inflammatory and metabolic actions making
them superior to earlier reported steroidal and non-steroidal
glucocorticoids. The present invention provides further
non-steroidal compounds as modulators (for example agonists,
antagonists, partial agonists or partial antagonists) of the
glucocorticoid receptor. {Modulators of the glucocorticoid receptor
are disclosed in WO 2007/122165, WO 2008/076048 and WO
2008/043788.} These new compounds are contemplated to have improved
properties such as selectivity or efficacy over the known
compounds.
[0004] These new compounds are also contemplated to have an
improved low Log D and thus an improved distribution volume in
vivo. The systemic exposure of the compounds is also expected to be
improved. Further the compounds are contemplated to have a lower
melting point and improved crystallinity compared to the known
compounds.
[0005] The present invention provides a compound of formula Ia:
##STR00002##
wherein: A is C.sub.1-6alkyl, C.sub.1-6alkoxy, C.sub.3-7cycloalkyl,
C.sub.1-6haloalkyl, C.sub.1-6alkylthio, C.sub.1-6alkylC(O)--,
C.sub.1-6alkyloxyC(O)--, NR.sup.5R.sup.6, NR.sup.5R.sup.6C(O)-- or
C.sub.5-10heteroaryl, all optionally substituted by one or more
substituents independently selected from halo, cyano, hydroxyl,
C.sub.1-4alkyl, C.sub.1-4alkoxy and C.sub.1-4haloalkyl; R.sup.5 and
R.sup.6 are independently selected from hydrogen, C.sub.1-6alkyl,
C.sub.3-7cycloalkyl, C.sub.1-6alkylC(O)-- and
C.sub.3-7cycloalkylC(O)--, or R.sup.5 and R.sup.6 might form a ring
with the nitrogen to which they are attached; R.sup.1 is hydrogen,
C.sub.1-4alkyl, C.sub.1-4hydroxyalkyl-,
C.sub.1-4alkylthioC.sub.1-4alkyl- or C.sub.1-4haloalkyl; R.sup.3 is
C.sub.5-10aryl, C.sub.5-10arylC.sub.1-4alkyl-, C.sub.5-10arylO-,
C.sub.5-10aryloxyC.sub.1-4alkyl-, C.sub.5-10heteroaryl-,
C.sub.5-10heteroarylC.sub.1-4alkyl-,
C.sub.5-10heteroarylC.sub.1-4alkoxy- or
C.sub.5-10heteroaryoxyC.sub.1-4alkyl-, all of which are
unsubstituted or optionally substituted by one or more substituents
independently selected from B; B is hydroxyl, halo, cyano,
C.sub.1-4alkyl, C.sub.1-4alkoxy, C.sub.1-3hydroxyalkyl-,
C.sub.1-4alkoxyC.sub.1-4alkyl-,
C.sub.3-6cycloalkyloxyC.sub.1-4alkyl-, C.sub.3-6cycloalkylO-,
C.sub.3-6cycloalkylthioC.sub.1-4alkyl-, C.sub.3-6cycloalkylthio,
C.sub.1-3alkylS(O).sub.kC.sub.1-4alkyl-,
C.sub.1-3alkylS(O).sub.k--, C.sub.1-4haloalkyl or
C.sub.1-4haloalkoxy-, or B is one of the following groups which are
linked to adjacent carbons on an aryl or heteroaryl ring
(CH.sub.2).sub.tOC.sub.1-4alkylenylO(CH.sub.2).sub.v-- or
(CH.sub.2).sub.tO(CH.sub.2).sub.v--; k is 0, 1; t and v are,
independently, 0, 1, 2 or 3, and t and v are not both 0;
X is O or NH;
[0006] W is phenyl substituted by one or more substituents
independently selected from --(CH.sub.2).sub.nC(O)NR.sup.7R.sup.8,
--(CH.sub.2).sub.nNR.sup.9C(O)R.sup.8 or
--(CH.sub.2).sub.nC(O)NR.sup.9(CR.sup.14R.sup.15)C(O)NR.sup.7R.sup.8;
and W is optionally further substituted by halogen or
C.sub.1-4alkyl; R.sup.7 is hydrogen or C.sub.1-4 alkyl; R.sup.8 and
R.sup.9 are, independently, hydrogen, C.sub.1-4 alkyl (optionally
substituted by one or two groups selected from hydroxyl, C.sub.1-4
alkoxy, NH.sub.2, oxo, --C(O)NR.sup.10R.sup.11,
--NR.sup.10C.sub.1-4alkyl, --C(O)NR.sup.10C.sub.1-4 alkyl,
--NR.sup.10C.sub.1-4alkyl, C.sub.1-4 alkylthio,
C.sub.5-10heterocyclyl, C.sub.5-10aryl or C.sub.5-10heteroaryl),
C.sub.3-7 cycloalkyl (optionally substituted by --C(O)NH.sub.2),
C.sub.5-10heterocyclyl, C.sub.5-10aryl, C.sub.5-10heteroaryl or
--C(O)NR.sup.10R.sup.11; whereby C.sub.5-10aryl or
C.sub.5-10heteroaryl are optionally substituted by halogen,
C.sub.1-4 alkyl, C.sub.1-4alkoxy, CF.sub.3, --OCF.sub.3, hydroxy or
cyano; and whereby any heterocyclyl is optionally substituted by
C.sub.1-4 alkyl, --C.sub.1-4 alkoxy(C.sub.1-4 alkyl), oxo or
hydroxyl; or R.sup.7 and R.sup.8, together with the nitrogen to
which the are attached, form a 5- or 6-membered ring optionally
comprising a second ring-nitrogen atom, the ring being optionally
substituted by one or two groups selected from oxo, hydroxyl,
C.sub.1-4hydroxyalkyl-, C.sub.1-4 alkyl, --C.sub.1-4
alkoxy(C.sub.1-4 alkyl) or --(CH.sub.2).sub.pC(O)NR.sup.12R.sup.13;
R.sup.10, R.sup.11, R.sup.12, and R.sup.13 are, independently,
hydrogen or C.sub.1-4 alkyl; n and p are, independently, 0, 1, 2, 3
or 4; and Y is hydrogen, halo, C.sub.1-4alkyl or
C.sub.1-4haloalkyl; or a pharmaceutically acceptable salt
thereof.
[0007] One embodiment relates to compounds of formula Ib
##STR00003##
and A, R.sup.3, R.sup.7 and R.sup.8 are defined as in compounds of
formula Ia, or a pharmaceutically acceptable salt thereof.
[0008] One embodiment relates to compounds of formula Ia or Ib,
wherein:
A is C.sub.3-7cycloalkyl, C.sub.1-6haloalkyl optionally substituted
by cyano; R.sup.1 is C.sub.1-4alkyl or C.sub.1-4hydroxyalkyl;
R.sup.3 is C.sub.5-10aryl or C.sub.5-10heteroaryl optionally
substituted by C.sub.1-4alkoxy;
X is O;
[0009] W is phenyl substituted by --C(O)NR.sup.7R.sup.8; R.sup.7 is
hydrogen; R.sup.8 is C.sub.1-4 alkyl (optionally substituted by one
or two groups selected from hydroxyl, --C(O)NH.sub.2,
--NHC(O)C.sub.1-4 alkyl, C.sub.5-10heterocyclyl, C.sub.5-10aryl or
C.sub.5-10heteroaryl), C.sub.3-7 cycloalkyl, C.sub.5-10heterocyclyl
or C.sub.5-40heteroaryl, whereby any heterocyclyl is optionally
substituted by C.sub.1-4 alkyl or oxo; or R.sup.7 and R.sup.8,
together with the nitrogen to which the are attached, form a 5- or
6-membered ring optionally comprising a second ring-nitrogen atom,
the ring being optionally substituted by one or two groups selected
from oxo, hydroxyl, C.sub.1-4hydroxyalkyl or --C(O)NH.sub.2; and Y
is hydrogen; or a pharmaceutically acceptable salt thereof.
[0010] Another embodiment of the present invention provides a
compound of formula Ia or Ib wherein A is C.sub.1-6haloalkyl. In a
further embodiment A is C.sub.1-4haloalkyl. In a further embodiment
the present invention provides a compound of formula Ia or Ib
wherein A is fluoromethyl, difluoromethyl, trifluoromethyl,
fluoroethyl, difluoroethyl, trifluoroethyl, fluoropropyl,
difluoropropyl or trifluoropropyl. In one embodiment A is
difluoroethyl. In a further embodiment A is C.sub.3-5cycloalkyl
substituted with cyano, hydroxyl or methoxy. In yet a further
embodiment A cyclopropyl, cyclobutyl or cyclopentyl, optionally
substituted with cyano. In another embodiment A is cyclopropyl
substituted with cyano.
[0011] One embodiment of the present invention provides a compound
of formula Ia wherein R.sup.1 hydrogen, C.sub.1-3alkyl or
C.sub.1-3hydroxyalkyl;
[0012] In another embodiment R.sup.1 is methyl, ethyl or n-propyl,
iso-propyl, n-butyl or iso-butyl. In a further embodiment R.sup.1
is methyl.
[0013] In another embodiment R.sup.1 is hydroxymethyl, hydroxyethyl
or hydroxypropyl or hydroxybutyl. In a further embodiment R.sup.1
is hydroxymethyl.
[0014] One embodiment of the present invention provides a compound
of formula Ia or Ib wherein R.sup.3 is phenyl optionally
substituted as recited above (for example optionally substituted by
halogen, C.sub.1-3alkyl, C.sub.1-3alkoxy, CF.sub.3, OCF.sub.3,
hydroxyl or cyano).
[0015] In one embodiment R.sup.3 is phenyl.
[0016] One embodiment of the present invention provides a compound
of formula Ia or Ib wherein R.sup.3 is pyridyl optionally
substituted as recited above (for example optionally substituted by
halogen, C.sub.1-3alkyl, C.sub.1-3alkoxy, CF.sub.3, OCF.sub.3,
hydroxyl or cyano). In a further embodiment R.sup.3 is pyridyl. In
yet a further embodiment R.sup.3 is pyridyl substituted with
methoxy. In another embodiment R.sup.3 is methoxypyridin-3-yl.
[0017] One embodiment of the present invention provides a compound
of formula Ia wherein X is O.
[0018] One embodiment of the present invention provides a compound
of formula Ia or Ib wherein R.sup.7 is hydrogen, methyl or ethyl.
In another embodiment R.sup.7 is hydrogen.
[0019] In a further embodiment R.sup.7 is methyl.
[0020] One embodiment of the present invention provides a compound
of formula Ia or Ib wherein W is phenyl substituted by
--C(O)NR.sup.7R.sup.8;
R.sup.7 is hydrogen; and R.sup.8 is hydroxymethyl, hydroxyethyl,
hydroxypropyl, hydroxybutyl, aminooxomethyl, aminooxoethyl,
aminooxopropyl, aminomethyloxomethyl, aminomethyloxoethyl,
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
acetylaminomethyl, acetylaminoethyl, oxoimidazolidinylmethyl,
oxoimidazolidinylethyl, oxopyrrolidinylmethyl,
oxopyrrolidinylethyl, oxidotetrahydrothiophenyl,
dioxidotetrahydrothiophenyl, oxotertahydrofuranyl,
tertahydrofuranyl, methyldioxooxazolidinylmethyl,
dimethyldioxooxazolidinylmethyl, methyl dioxooxazolidinylethyl,
dimethyldioxooxazolidinylethyl, indazolylmethyl, indazolylethyl,
aminooxophenylmethyl, aminooxophenylethyl, pyridinyl, pyrimidyl,
pyrazinyl, pyridazinyl, pyridinylmethyl, pyridinylethyl,
indazolylmethyl or indazolylethyl.
[0021] In another embodiment R.sup.8 is hydroxyethyl, hydroxybutyl,
aminooxoethyl, aminomethyloxoethyl, aminooxopropyl, cyclopentyl,
acetylaminoethyl, oxoimidazolidinylethyl, tetrahydrothiophenyl,
oxopyrrolidinylethyl, dioxidotetrahydrothiophenyl,
oxotertahydrofuranyl, tertahydrofuranyl,
dimethyldioxooxazolidinylethyl, indazolylmethyl,
aminooxophenylethyl, pyridinyl or pyridinylmethyl.
[0022] One embodiment of the present invention provides a compound
of formula Ia or Ib wherein A is difluoroethyl or cyclopropyl
substituted with cyano; R.sup.1 is methyl or hydroxymethyl; R.sup.3
is phenyl or pyridyl substituted with methoxy; X is O; Y is
hydrogen;
W is phenyl substituted by --C(O)NR.sup.7R.sup.8; R.sup.7 is
hydrogen; and R.sup.8 is hydroxymethyl, hydroxyethyl,
hydroxypropyl, hydroxybutyl, aminooxomethyl, aminooxoethyl,
aminooxopropyl, aminomethyloxomethyl, aminomethyloxoethyl,
acetylaminomethyl, acetylaminoethyl, oxoimidazolidinylmethyl,
oxoimidazolidinylethyl, to oxopyrrolidinylmethyl,
oxopyrrolidinylethyl, methyldioxooxazolidinylmethyl,
dimethyldioxooxazolidinylmethyl, methyldioxooxazolidinylethyl,
dimethyldioxooxazolidinylethyl, indazolylmethyl, indazolylethyl,
aminooxophenylmethyl, aminooxophenylethyl, pyridinylmethyl,
pyridinylethyl, indazolylmethyl or indazolylethyl.
[0023] In another embodiment R.sup.8 is hydroxyethyl, hydroxybutyl,
aminooxoethyl, is aminomethyloxoethyl, aminooxopropyl,
acetylaminoethyl, oxoimidazolidinylethyl, oxopyrrolidinylethyl,
dimethyldioxooxazolidinylethyl, indazolylmethyl,
aminooxophenylethyl or pyridinylmethyl.
[0024] A further embodiment of the present invention provides a
compound of formula Ia or Ib wherein A is difluoroethyl or
cyclopropyl substituted with cyano; R.sup.1 is methyl or
hydroxymethyl; R.sup.3 is phenyl or pyridyl substituted with
methoxy; X is O; Y is hydrogen;
W is phenyl substituted by --C(O)NR.sup.7R.sup.8; R.sup.7 is
hydrogen; and R.sup.8 is C.sub.5-6cycloalkyl. In one embodiment
R.sup.8 is cyclopentyl.
[0025] A further embodiment of the present invention provides a
compound of formula Ia or Ib wherein A is difluoroethyl or
cyclopropyl substituted with cyano; R.sup.1 is methyl or
hydroxymethyl; R.sup.3 is phenyl or pyridyl substituted with
methoxy; X is O; Y is hydrogen;
W is phenyl substituted by --C(O)NR.sup.7R.sup.8; R.sup.7 is
hydrogen; and R.sup.8 is C.sub.5-6heterocyclyl, optionally
substituted by methyl, ethyl or oxo.
[0026] In one embodiment R.sup.8 is oxidotetrahydrothiophenyl,
dioxidotetrahydrothiophenyl, tetrahydrothiophenyl,
oxotertahydrofuranyl or tertahydrofuranyl.
[0027] In another embodiment R.sup.8 is
dioxidotetrahydrothiophenyl, oxotertahydrofuranyl or
tertahydrofuranyl.
[0028] A further embodiment of the present invention provides a
compound of formula Ia or Ib wherein A is difluoroethyl or
cyclopropyl substituted with cyano; R.sup.1 is methyl or
hydroxymethyl; R.sup.3 is phenyl or pyridyl substituted with
methoxy; X is O; Y is hydrogen;
W is phenyl substituted by --C(O)NR.sup.7R.sup.8; R.sup.7 is
hydrogen; and R.sup.8 is C.sub.5-6heteroaryl. In one embodiment
R.sup.8 is pyridyl.
[0029] When R.sup.7 and R.sup.8, together with the nitrogen to
which they are attached, form a 5- or 6-membered ring which
optionally comprises a second ring-nitrogen atom, said ring is, for
example, pyrrolidinyl, piperidinyl or piperazinyl.
[0030] One embodiment of the present invention provides a compound
of formula Ia or Ib is wherein W is phenyl substituted by
--C(O)NR.sup.7R.sup.8; and
R.sup.7 and R.sup.8, together form pyrrolidinyl, oxopyrrolidinyl,
carbamoylpyrrolidinyl, hydroxymethylpyrrolidinyl,
hydroxypyrrolidinyl, prolinamide, hydroxyprolinamide, piperidinyl,
hydroxypiperidinyl, oxopiperidinyl, imidazolidinyl,
oxoimidazolidinyl, hydroxyimidazolidinyl, piperazinyl,
hydroxypiperazinyl or oxopiperazinyl.
[0031] In one embodiment R.sup.7 and R.sup.8, together form
carbamoylpyrrolidinyl, hydroxymethylpyrrolidinyl,
hydroxypyrrolidinyl, prolinamide, hydroxyprolinamide or
oxopiperazinyl.
[0032] Another embodiment of the present invention provides a
compound of formula Ia or Ib wherein A is difluoroethyl, amide or
cyclopropyl substituted with cyano; R.sup.1 is methyl or
hydroxymethyl; R.sup.3 is phenyl or pyridyl substituted with
methoxy; X is O; Y is hydrogen; W is phenyl substituted by
--C(O)NR.sup.7R.sup.8;
R.sup.7 and R.sup.8, together with the nitrogen to which the are
attached, form a 5- or 6-membered ring optionally comprising a
second ring-nitrogen atom (for example the ring is pyrrolidinyl,
piperidinyl or piperazinyl), the ring being optionally substituted
by one or two groups selected from oxo, hydroxyl,
C.sub.1-4hydroxyalkyl or --C(O)NH.sub.2.
[0033] In one embodiment R.sup.7 and R.sup.8, together form
pyrrolidinyl, oxopyrrolidinyl, carbamoylpyrrolidinyl,
hydroxymethylpyrrolidinyl, hydroxypyrrolidinyl, prolinamide,
hydroxyprolinamide, piperidinyl, hydroxypiperidinyl,
oxopiperidinyl, imidazolidinyl, piperazinyl, hydroxypiperazinyl,
oxopiperazinyl, tetrahydrothiophenyl, oxidotetrahydrothiophenyl,
dioxidotetrahydrothiophenyl, oxotertahydrofuranyl or
tertahydrofuranyl.
[0034] In one embodiment R.sup.7 and R.sup.8, together form
carbamoylpyrrolidinyl, hydroxymethylpyrrolidinyl,
hydroxypyrrolidinyl, prolinamide, hydroxyprolinamide or
oxopiperazinyl.
[0035] One embodiment of the present invention provides a compound
of formula Ia wherein Y is hydrogen.
[0036] One embodiment of the present invention provides a compound
of formula Ia wherein:
A is C.sub.1-6alkyl, C.sub.1-6alkoxy, C.sub.3-7cycloalkyl,
C.sub.1-6alkylC(O), C.sub.1-6alkyloxyC(O), NR.sup.5R.sup.6,
NR.sup.5R.sup.6C(O) or C.sub.5-10heteroaryl, all optionally
substituted by one or more substituents independently selected from
halo, cyano, hydroxyl, C.sub.1-4alkyl, C.sub.1-4alkoxy and
C.sub.1-4haloalkyl; R.sup.5 and R.sup.6 are independently selected
from hydrogen, C.sub.1-6alkyl, C.sub.3-7cycloalkyl,
C.sub.1-6alkylC(O) and C.sub.3-7cycloalkylC(O), or R.sup.5 and
R.sup.6 might form a ring with the nitrogen to which they are
attached; R.sup.1 is hydrogen, C.sub.1-4alkyl,
C.sub.1-4hydroxyalkyl, C.sub.1-4alkylthioC.sub.1-4alkyl or
C.sub.1-4haloalkyl; R.sup.3 is C.sub.5-10aryl, C.sub.5-10arylO,
C.sub.1-4alkyl, C.sub.5-10arylO, C.sub.5-10arylC.sub.1-4alkoxy,
C.sub.5-10aryloxyC.sub.1-4alkyl, C.sub.5-10heteroaryl,
C.sub.5-10heteroarylC.sub.1-4alkyl,
C.sub.5-10heteroarylC.sub.1Alkoxy or
C.sub.5-10heteroaryoxyC.sub.1-4alkyl, all of which are
unsubstituted or optionally substituted by one or more substituents
independently selected from B; B is hydroxyl, halo, cyano,
C.sub.1-4alkyl, C.sub.1-4alkoxy, C.sub.1-3hydroxyalkyl,
C.sub.1-4alkoxyC.sub.1-4alkyl,
C.sub.3-6cycloalkyloxyC.sub.1-4alkyl, C.sub.3-6cycloalkyloxy,
C.sub.3-6cycloalkylthioC.sub.1-4alkyl, C.sub.3-6cycloalkylthio,
C.sub.1-3alkylS(O).sub.kC.sub.1-4alkyl, C.sub.1-3alkylS(O).sub.k,
C.sub.1-4haloalkyl or C.sub.1-4haloalkoxy, or B is one of the
following groups which are linked to adjacent carbons on an aryl or
heteroaryl ring
(CH.sub.2).sub.tOC.sub.1-4alkylenylO(CH.sub.2).sub.c or
(CH.sub.2).sub.tO(CH.sub.2).sub.v; k is 0, 1; t and v are,
independently, 0, 1, 2 or 3, and t and v are not both 0;
X is O or NH;
[0037] W is phenyl substituted by one or more substituents
independently selected from (CH.sub.2).sub.nC(O)NR.sup.7R.sup.8,
(CH.sub.2).sub.nNR.sup.9C(O)R.sup.8 or
(CH.sub.2).sub.nC(O)NR.sup.9(CR.sup.14R.sup.15)C(O)NR.sup.7R.sup.8;
and W is optionally further substituted by halogen or
C.sub.1-4alkyl; R.sup.7 is hydrogen or C.sub.1-4 alkyl; R.sup.8 and
R.sup.9 are, independently, hydrogen, C.sub.1-4 alkyl (optionally
substituted by one or two groups selected from hydroxyl, C.sub.1-4
alkoxy, NH.sub.2, oxo,
C(O)NR.sup.10R.sup.11NR.sup.10C.sub.1-4alkyl,
C(O)NR.sup.10C.sub.1-4 alkyl, NR.sup.10C(O)C.sub.1-4 alkyl,
C.sub.1-4 alkylthio, C.sub.5-10heterocyclyl, C.sub.5-10aryl or
C.sub.5-10heteroaryl), C.sub.3-7 cycloalkyl (optionally substituted
by C(O)NH.sub.2), C.sub.5-10heterocyclyl, C.sub.5-10aryl,
C.sub.5-10heteroaryl or C(O)NR.sup.10R.sup.11; C.sub.5-10aryl or
C.sub.5-10heteroaryl are optionally substituted by halogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, CF.sub.3, OCF.sub.3, hydroxy or
cyano; heterocyclyl is optionally substituted by C.sub.1-4 alkyl,
C.sub.1-4 alkoxy(C.sub.1-4 alkyl), oxo or hydroxyl; or R.sup.7 and
R.sup.8, together with the nitrogen to which the are attached, form
a 5- or 6-membered ring optionally comprising a second
ring-nitrogen atom, the ring being optionally substituted by oxo,
hydroxyl, C.sub.1-4hydroxyalkyl, C.sub.1-4 alkyl, C.sub.1-4
alkoxy(C.sub.1-4 alkyl) or (CH.sub.2).sub.pC(O)NR.sup.12R.sup.13,
R.sup.14 and R.sup.15 are, independently, hydrogen, C.sub.1-4 alkyl
or C.sub.1-4 hydroxyalkyl; or R.sup.14 and R.sup.15 join to form a
C.sub.3-6 cycloalkyl ring; R.sup.10, R.sup.11, R.sup.12 and
R.sup.13 are, independently, hydrogen or C.sub.1-4 alkyl; n and p
are, independently, 0, 1, 2, 3 or 4; Y is hydrogen, halo,
C.sub.1-4alkyl or C.sub.1-4haloalkyl; or a pharmaceutically
acceptable salt thereof.
[0038] For the avoidance of doubt, the present invention relates to
any compound falling within the scope of compounds of formula Ia or
Ib and any one specific compound mentioned below.
[0039] In another aspect the present invention provides compounds
selected from: [0040]
1-({3-[5-({(1R,2S)-2-[(2,2-difluoropropanoyl)amino]-1-phenylpropyl}oxy)-1-
H-indazol-1-yl]phenyl}carbonyl)-D-prolinamide, [0041]
N-[(1S,2R)-2-{[1-(3-{[(2R)-2-carbamoyl
pyrrolidin-1-yl]carbonyl}-phenyl)-1H-indazol-5-yl]oxy}-1-methyl-2-phenyl
ethyl]ethanediamide, [0042]
3-[5-({(1R,2S)-2-[(2,2-difluoropropanoyl)amino]-1-phenylpropyl}oxy)-1H-in-
dazol-1-yl]-N-(2-hydroxyethyl)benzamide, [0043]
N-(2-amino-2-oxoethyl)-3-[5-({(1R,2S)-2-[(2,2-difluoropropanoyl)amino]-1--
phenylpropyl}oxy)-1H-indazol-1-yl]benzamide, [0044]
N-[(1S)-2-amino-1-methyl-2-oxoethyl]-3-[5-({(1R,2S)-2-[(2,2-difluoropropa-
noyl)amino]-1-phenylpropyl}oxy)-1H-indazol-1-yl]benzamide, [0045]
N-[2-(acetylamino)ethyl]-3-[5-({(1R,2S)-2-[(2,2-difluoropropanoyl)amino]--
1-phenylpropyl}oxy)-1H-indazol-1-yl]benzamide, [0046]
3-[5-({(1R,2S)-2-[(2,2-difluoropropanoyl)amino]-1-phenylpropyl}oxy)-1H-in-
dazol-1-yl]-N-[2-(2-oxoimidazolidin-1-yl)ethyl]benzamide, [0047]
2,2-difluoro-N-[(1S,2R)-2-{[1-(3-{[(2R)-2-(hydroxymethyl)pyrrolidin-1-yl]-
carbonyl}-phenyl)-1H-indazol-5-yl]oxy}-1-methyl-2-phenylethyl]propanamide,
[0048]
2,2-difluoro-N-[(1S,2R)-2-{[1-(3-{[(3R)-3-hydroxypyrrolidin-1-yl]c-
arbonyl}phenyl)-1H-indazol-5-yl]oxy}-1-methyl-2-phenylethyl]propanamide,
[0049]
3-[5-({(1R,2S)-2-[(2,2-difluoropropanoyl)amino]-1-phenylpropyl}oxy-
)-1H-indazol-1-yl]-N-[(3R)-2-oxotetrahydrofuran-3-yl]benzamide,
[0050]
1-({3-[5-({(1R,2S)-2-[(2,2-difluoropropanoyl)amino]-1-phenylpropyl}oxy)-1-
H-indazol-1-yl]phenyl}carbonyl)-L-prolinamide, [0051]
2,2-difluoro-N-{[(1S,2R)-1-methyl-2-[(1-{3-[(3-oxopiperazin-1-yl)carbonyl-
]phenyl}-1H-indazol-5-yl]oxy}-2-phenylethyl}propanamide, [0052]
3-[5-({(1R,2S)-2-[(2,2-difluoropropanoyl)amino]-1-phenylpropyl}oxy)-1H-in-
dazol-1-yl]-N-[2-(2-oxopyrrolidin-1-yl)ethyl]benzamide, [0053]
3-[5-({(1R,2S)-2-[(2,2-difluoropropanoyl)amino]-1-phenylpropyl}oxy)-1H-in-
dazol-1-yl]-N-[2-(5,5-dimethyl-2,4-dioxo-1,3-oxazolidin-3-yl)ethyl]benzami-
de, [0054]
3-[5-({(1R,2S)-2-[(2,2-difluoropropanoyl)amino]-1-phenylpropyl}-
oxy)-1H-indazol-1-yl]-N-(1,1-dioxidotetrahydrothiophen-3-yl)benzamide,
[0055]
3-[5-({(1R,2S)-2-[(2,2-difluoropropanoyl)amino]-1-phenylpropyl}oxy-
)-1H-indazol-1-yl]-N-(1H-indazol-3-ylmethyl)benzamide, [0056]
N-[(1R)-2-amino-2-oxo-1-phenylethyl]-3-[5-({(1R,2S)-2-[(2,2-difluoropropa-
noyl)amino]-1-phenylpropyl}oxy)-1H-indazol-1-yl]benzamide, [0057]
N-(2-amino-2-oxoethyl)-3-[5-({(1R,2S)-2-[(2,2-difluoropropanoyl)amino]-1--
phenylpropyl}oxy)-1H-indazol-1-yl]-N-methylbenzamide, [0058]
N-(3-amino-3-oxopropyl)-3-[5-({(1R,2S)-2-[(2,2-difluoropropanoyl)amino]-1-
-phenylpropyl}oxy)-1H-indazol-1-yl]benzamide, [0059]
(4R)-1-({3-[5-({(1R,2S)-2-[(2,2-difluoropropanoyl)amino]-1-phenylpropyl}o-
xy)-1H-indazol-1-yl]phenyl}carbonyl)-4-hydroxy-L-prolinamide,
[0060]
1-{[3-(5-{[(1R,2S)-2-{[1-cyanocyclopropyl)carbonyl]amino}-1-phenylpropyl]-
oxy}-1H-indazol-1-yl)phenyl]carbonyl}-D-prolinamide, or a
pharmaceutically acceptable salt thereof.
[0061] In a further aspect the present invention provides compounds
selected from: [0062]
N-cyclopentyl-3-(5-{[(1R,2S)-2-[(2,2-difluoropropanoyl)amino]-1-(6-methox-
ypyridin-3-yl)propyl]oxy}-1H-indazol-1-yl)benzamide, [0063]
3-(5-{[(1R,2S)-2-[(2,2-difluoropropanoyl)amino]-1-(6-methoxypyridin-3-yl)-
propyl]oxy}1-1H-indazol-1-yl)-N-pyridin-3-yl)benzamide, [0064]
3-(5-({(1R,2S)-2-[(2,2-difluoropropanoyl)amino]-1-(6-methoxypyridin-3-yl)-
propyl]oxy}-1H-indazol-1-yl)-N-(1,1-dioxidotetrahydrothiophen-3-yl)benzami-
de, [0065]
3-(5-{[(1R,2S)-2-[(2,2-difluoropropanoyl)amino]-1-(6-methoxypyr-
idin-3-yl)propyl]oxy}-1H-indazol-1-yl)-N-(tetrahydrofuran-3-yl)benzamide,
[0066]
3-(5-{[(1R,2S)-2-[(2,2-difluoropropanoyl)amino]-1-(6-methoxypyridi-
n-3-yl)propyl]oxy}-1H-indazol-1-yl)-N-(2-hydroxybutyl)benzamide,
[0067]
N-cyclopentyl-3-(5-{[(1R,2S)-2-[(2,2-difluoropropanoyl)amino]-3-hydroxy-1-
-(6-methoxypyridin-3-yl)propyl]oxy}-1H-indazol-1-yl)benzamide, and
[0068]
3-(5-{[(1R,2S)-2-[(2,2-difluoropropanoyl)amino]-1-(6-methoxypyridin-3-yl)-
propyl]oxy}-1H-indazol-1-yl)-N-(pyridin-3-ylmethyl)benzamide, or a
pharmaceutically acceptable salt thereof.
[0069] For the avoidance of doubt it is to be understood that where
in this specification a group is qualified by `hereinbefore
defined`, `defined hereinbefore` or `defined above` the said group
encompasses the first occurring and broadest definition as well as
each and all of the other definitions for that group.
[0070] For the avoidance of doubt it is to be understood that in
this specification `C.sub.1-6` means a carbon group having 1, 2, 3,
4, 5 or 6 carbon atoms.
[0071] In this specification, unless stated otherwise, the term
"alkyl" includes both straight and branched chain alkyl groups and
may be, but are not limited to methyl, ethyl, n-propyl, propyl,
n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, neo-pentyl,
n-hexyl or i-hexyl. The term C.sub.1-4 alkyl having 1 to 4 carbon
atoms and may be but are not limited to methyl, ethyl, n-propyl,
i-propyl or t-butyl. The term "C.sub.0" in C.sub.0-4 alkyl refers
to a situation where no carbon atom is present.
[0072] The term alkylenyl refers to a straight or branched chain
alkyl group linking two other atoms. It is, for example, CH.sub.2
or CH.sub.2CH.sub.2.
[0073] The term "alkoxy", unless stated otherwise, refers to
radicals of the general formula O--R, wherein R is selected from a
hydrocarbon radical. The term "alkoxy" may include, but is not
limited to methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy,
iso-butoxy, cyclopropylmethoxy, allyloxy or propargyloxy.
[0074] In this specification, unless stated otherwise, the term
"cycloalkyl" refers to an optionally substituted, partially or
completely saturated monocyclic, bicyclic or bridged hydrocarbon
ring system. The term "C.sub.1-6cycloalkyl" may be, but is not
limited to cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
[0075] In this specification, unless stated otherwise, the term
"heterocycloalkyl" or "heterocyclyl" refers to an optionally
substituted, partially or completely saturated monocyclic, bicyclic
or bridged hydrocarbon ring system having one or more heteroatoms
independently selected from O, N or S. The term
"C.sub.1-6heterocycloalkyl" may be, but is not limited to
pyrrolidinyl, piperidinyl, piperazinyl, imidazolidinyl,
tetrahydrothiophenyl oxidotetrahydrothiophenyl,
dioxidotetrahydrothiophenyl, oxotertahydrofuranyl or
tertahydrofuranyl.
[0076] In this specification, unless stated otherwise, the term "a
5- or 6-membered ring optionally comprising a second ring-nitrogen
atom" refers to heterocycloalkyl as defined above and may be, but
is not limited to pyrrolidinyl, prolinamide or piperazinyl.
[0077] In this specification, unless stated otherwise, the terms
"halo" and "halogen" may be fluorine (fluoro), iodine (iodo),
chlorine (chloro) or bromine (bromo).
[0078] In this specification, unless stated otherwise, the term
"haloalkyl" means an alkyl group as defined above, which is
substituted with halo as defined above. The term
"C.sub.1-6haloalkyl" may include, but is not limited to
fluoromethyl, difluoromethyl, difluoroethyl, trifluoromethyl,
chloromethyl, dichloromethyl, trichloromethyl or
fluorochloromethyl.
[0079] The term "C.sub.1-3haloalkylO" or "C.sub.1-3haloalkoxy" may
include, but is not limited to fluoromethoxy, difluoromethoxy,
trifluoromethoxy, fluoroethoxy or difluoroethoxy.
[0080] In this specification, unless stated otherwise, the term
"thioalkyl" means an alkyl group as defined above, which is
substituted with sulphur atom. The term "C.sub.1-6thioalkyl" may
include, but is not limited to methylsulfanyl, ethylsulfanyl or
propylsulfanyl.
[0081] The term "cycloalkylthio" means a sulphur atom substituted
with a cycloalkyl as defined above such as for instance
cyclopropylsulfanyl.
[0082] The term "C.sub.1-4alkylthioalkyl" means a alkyl group with
a sulphur atom between the carbon atoms. The term
"C.sub.1-4alkylthioC.sub.1-4alkyl" may include, but is not limited
to ethylsulfanylmethyl.
[0083] In this specification, unless stated otherwise, the term
"C.sub.5-10aryl" or aryl refers to an aromatic or partial aromatic
group having 5 to 10 carbon atoms such as for example, phenyl or
naphthyl. The term "C.sub.5-10aryloxy" or "C.sub.5-10arylO" refers
to for example phenoxy.
[0084] In this specification, unless stated otherwise, the term
"C.sub.5-10heteroaryl" or heteroaryl refers to a mono- or bicyclic
aromatic or partially aromatic ring with 5 to 10 atoms and
containing one or more heteroatoms independently selected from
nitrogen, oxygen or sulphur. Heteroaryl is, for example, oxazolyl,
isoxazolyl, 1,2,4-oxadiazolyl, furyl, thienyl, thiophenyl,
pyrrolyl, pyrazolyl, imidazolyl, 1,2,4-triazolyl, pyridinyl,
pyrimidinyl, indolyl, indazolyl, benzofuryl, benzothienyl,
dioxabicyclodecatrienyl, quinolinyl or isoquinolinyl.
[0085] When aryl (for example phenyl) or heteroaryl is substituted
by (CH.sub.2).sub.tOC.sub.1-4alkylenylO(CH.sub.2).sub.v or
(CH.sub.2).sub.tO(CH.sub.2).sub.v; wherein t and v are,
independently, 0, 1, 2 or 3, but t and v are not both 0; these
substituents can be, for example, CH.sub.2OCH.sub.2O, OCH.sub.2O,
OCH.sub.2CH.sub.2O or OCH.sub.2CH.sub.2 linking adjacent carbons on
the aryl or heteroaryl ring.
[0086] For the avoidance of doubt a group R.sup.3 defined as
C.sub.5-10aryl e.g. phenyl, substituted with a group
C.sub.1-2alkylS(O).sub.k includes a phenyl substituted with
methylsulphonyl group.
[0087] It will be appreciated that throughout the specification,
the number and nature of substituents on rings in the compounds of
the invention will be selected so as to avoid sterically
undesirable combinations.
[0088] Compounds of the present invention have been named with the
aid of computer software (ACDLabs 10.06/Name(IUPAC)).
[0089] Compounds of the invention may include an asymmetric centre
and be chiral in nature. Where the compound is chiral, it may be in
the form of a single stereoisomer, such as a enantiomer, or it may
be in the form of mixtures of these stereoisomers in any
proportions, including racemic mixtures. Therefore, all
enantiomers, diastereomers, racemates and mixtures thereof are
included within the scope of the invention. The various optical
isomers may be isolated by separation of a racemic mixture of the
compounds using conventional techniques, for example, fractional
crystallisation, or HPLC. Alternatively the optical isomers may be
obtained by asymmetric synthesis, or by synthesis from optically
active starting materials.
[0090] Compounds of the invention may be converted to a
pharmaceutically acceptable salt thereof, such as an acid addition
salt such as a hydrochloride, hydrobromide, phosphate, sulphate,
acetate, ascorbate, benzoate, fumarate, hemifumarate, furoate,
succinate, maleate, tartrate, citrate, oxalate, xinafoate,
methanesulphonate, p-toluenesulphonate, benzenesulphonate,
ethanesulphonate, 2-naphthalenesulfonate, mesytilenesulfonate,
nitric acid, 1,5-naphthalene-disulphonate, p-xylenesulphonate,
aspartate or glutamate. They may also include basic addition salts
such as an alkali metal salt for example sodium or potassium salts,
an alkaline earth metal salt for example calcium or magnesium
salts, a transition metal salt such as a zinc salt, an organic
amine salt for example a salt of triethylamine, diethylamine,
morpholine, N-methylpiperidine, N-ethylpiperidine, piperazine,
procaine, dibenzylamine, N,N-dibenzylethylamine, choline or
2-aminoethanol or amino acids for example lysine or arginine.
[0091] The compounds of the invention, or a pharmaceutically
acceptable salt thereof, may exist is in solvated, for example
hydrated, as well as unsolvated forms, or as cocrystals and the
present invention encompasses all such forms.
Process
[0092] The compounds of the invention can be prepared using or
adapting methods disclosed in the art, or by using or adapting the
method disclosed in the Example below. Starting materials for the
preparative methods are either commercially available or can be
prepared by using or adapting literature methods.
[0093] A process for the synthesis of a compound of formula Ia or
Ib can comprise using an acid/amine coupling reaction disclosed in
WO 2007/122165, WO 2008/043788 or WO 2008/076048. For example using
as an intermediate a compound of formula (Ic) or (Id):
##STR00004##
wherein R.sup.1, R.sup.3, X and Y are defined as above, and Z is
A-C(O) or A-S(O).sub.2. A compound of the invention can be prepared
if an acid of formula (Ic) is reacted with an amine of formula
HNR.sup.7R.sup.8 or
HNR.sup.9(CR.sup.14R.sup.15)C(O)NR.sup.7R.sup.8. Alternatively, a
compound of the invention can be prepared by reaction of an amine
of formula (Id) with an acid as defined by HOC(O)R.sup.8. The
compounds of formula (Ic) and (Id) can be synthesised from
protected precursors such as alkylesters for the synthesis of (Ic),
or from an N-protected precursor of NR.sup.9H such as NR.sup.9BOC
or N.sub.3 for the preparation of (Id).
[0094] One embodiment relates to a process for the preparation of
compounds of formula Ia or Ib by coupling a compound of formula
(II):
##STR00005##
with acylation reagents of formula (IIIa), (IIIb) or (IIIc)
##STR00006##
wherein R.sup.1, R.sup.3, A, X and Y are defined above, W is as
defined above or can be a group that can be converted into W as
defined above, and L.sup.1 is a leaving group {such as halogen (for
example chloro) or, when L.sup.1.dbd.OH, a leaving group generated
by reaction of a coupling reagent (such as HART with a carboxylic
acid)}. The reaction may be performed in a suitable solvent (such
as pyridine, THF or DMF), in the presence of a suitable base (such
as a tri(C.sub.1-6 alkyl)amine, for example diisopropylethylamine,
or pyridine) and at a suitable temperature (such as -10.degree. to
50.degree. C.).
[0095] A compound of formula (II) can be prepared according to step
a, b or c.
a) A compound of formula (II) can be prepared by coupling a
compound of formula (IV)
##STR00007##
wherein W and Y are as defined above and L.sup.2 is a leaving group
(such as halogen or triflate) with a compound of formula (V)
##STR00008##
wherein R.sup.1 and X are defined above and G corresponds to
R.sup.3 or a protected precursor to R.sup.3. The reaction can be
performed in a suitable solvent (such as an aromatic solvent, for
example toluene) or a polar, aprotic solvent, such as DMF or
butyronitril, in the presence of a suitable base (such as a alkali
metal alkoxide (for example sodium tert-butoxide) or, cesium
carbonate, such as mediated by a suitable metal catalyst such as
Copper(I) iodide at a suitable temperature (for example in the
range 80.degree. to 120.degree. C.).
Or,
[0096] b) A compound of formula (II) can be prepared by reacting a
compound of formula (VII)
##STR00009##
with a compound of formula (VIII)
##STR00010##
wherein R.sup.1, X, W and Y are defined above, G corresponds to
R.sup.3 or a protected precursor to R.sup.3, and L.sup.3 is a
leaving group (such as halogen, mesylate or tosylate). The reaction
can be performed in a suitable solvent (such as DCM, DMF or
acetonitrile), in the presence of a suitable base (such as an
alkali metal carbonate, for example cesium carbonate or potassium
carbonate) at a suitable temperature (for example in the range -10
to 50.degree. C.), followed by a subsequent reductive amination
step using or adopting literature methods.
Or,
[0097] c) a compound of formula (II) may be prepared by reacting a
compound of formula (VIII) with a compound of formula (IX)
##STR00011##
wherein R.sup.1 and R.sup.3 are as defined above, and PG is a
suitable protecting group such as BOC, mesyl or tosyl or related
carbonyl- or sulfonyl residues. The reaction can be performed in a
suitable solvent such as DCM or toluene in the presence of a
suitable base such as NaH or KOtBu, followed by a deprotection step
using or adopting literature methods.
[0098] As a specific case of a compound of formula (V), a compound
of formula (X) might be used to prepare a compound of formula
(II)
##STR00012##
wherein R.sup.1 and G are defined as in compounds of formula
(V).
[0099] Compounds of formula (X) may be prepared by reacting a
nucleophile G-M with a carbonyl compound of formula (XI) followed
reduction and subsequent deprotection of the intermediate of
formula (XII)
##STR00013##
wherein R.sup.1, R.sup.3, G and PG are as defined above, and L is a
leaving group (such as alkoxy, methoxy(methyl)amino), M is a metal
such as Li or Mg-halide. The addition of the nucleophile may be
performed in a suitable aprotic solvent such as THF at moderate
temperature between -10 and 50.degree. C. The following reduction
and deprotection steps might be carried out by using or adopting
literature methods.
[0100] Alternatively, compounds of formula (X) may be prepared by a
reaction of a nucleophile G-M with an aldehyde of formula (XIII)
and a subsequent deprotection.
##STR00014##
wherein R.sup.1, R.sup.3, G and PG are as defined above, and M is a
metal such as an alkali metal (e.g. Li) or Mg-halide. The reaction
may be performed by following disclosed protocols for addition of
carbanions to aldehydes.
[0101] Another way to prepare a compound of formula (X) is the
reaction of a nitroalkyle of formula (XIV) with an aldehyde of
formula (XV), followed by reduction of the nitro function
##STR00015##
wherein R.sup.1, R.sup.3 and G are as defined above. Both steps may
be carried out by following or adopting literature methods.
Medical Use
[0102] Because of their ability to bind to the glucocorticoid
receptor the compounds of the invention are useful as
anti-inflammatory agents, and can also display antiallergic,
immunosuppressive and anti-proliferative actions. Thus, a compound
of formula Ia, or a pharmaceutically acceptable salt thereof can be
used as a medicament for the treatment or prophylaxis of one or
more of the following pathologic conditions (disease states) in a
mammal (such as a human):
(i) Lung diseases, which coincide with inflammatory, allergic
and/or proliferative processes: chronically obstructive lung
diseases of any origin, mainly bronchial asthma, chronic
obstructive pulmonary disease bronchitis of different origins Adult
respiratory distress syndrome (ARDS), acute respiratory distress
syndrome Bronchiectases all forms of restructive lung diseases,
mainly allergic alveolitis all forms of pulmonary edema, mainly
toxic pulmonary edema sarcoidoses and granulomatoses, such as
Boeck's disease (ii) Rheumatic diseases/auto-immune
diseases/degenerative joint diseases, which coincide with
inflammatory, allergic and/or proliferative processes: all forms of
rheumatic diseases, for example rheumatoid arthritis, acute
rheumatic fever, polymyalgia rheumatica, collagenoses, Behcet's
disease reactive arthritis inflammatory soft-tissue diseases of
other origins arthritic symptoms in degenerative joint diseases
(arthroses) traumatic arthritides collagen diseases of other
origins, for example systemic lupus erythematodes, discoid lupus
erythematosus, sclerodermia, polymyositis, dermatomyositis,
polyarteritis nodosa, temporal arteritis Sjogren's syndrome, Still
syndrome, Felty's syndrome
Vitiligo
[0103] Soft-tissue rheumatism (iii) Allergies, which coincide with
inflammatory, allergic and/or proliferative processes: All forms of
allergic reactions, for example Quincke's edema, insect bites,
allergic reactions to pharmaceutical agents, blood derivatives,
contrast media, etc., anaphylactic shock, urticaria, contact
dermatitis (e.g. allergic and irritative), allergic vascular
diseases Allergic vasculitis inflammatory vasculitis (iv) Vascular
inflammations (vasculitides) Panarteritis nodosa, temporal
arteritis, erythema nodosum Polyarteris nodosa Wegner's
granulomatosis Giant-cell arteritis (v) Dermatological diseases,
which coincide with inflammatory, allergic and/or proliferative
processes: atopic dermatitis (mainly in children) exfoliative
dermatitis, psoriasis erythematous diseases, triggered by different
noxae, for example radiation, chemicals, burns, etc. acid burns
bullous dermatoses, such as, for example, autoimmune pemphigus
vulgaris, bullous pemphigoid diseases of the lichenoid group
itching (for example of allergic origins) all forms of eczema, such
as, for example, atopic eczema or seborrheal eczema rosacea
pemphigus vulgaris erythema exudativum multiforme erythema nodosum
balanitis Pruritis, such as, for example, allergic origin)
Manifestation of vascular diseases vulvitis inflammatory hair loss,
such as alopecia greata cutaneous T-cell lymphoma Rashes of any
origin or dermatoses Psoriasis and parapsoriasis groups Pityriasis
rubra pilaris (vi) Nephropathies, which coincide with inflammatory,
allergic and/or proliferative processes: nephrotic syndrome all
nephritides, such as, for example, glomerulonephritis (vii) Liver
diseases, which coincide with inflammatory, allergic and/or
proliferative processes: acute liver cell decomposition acute
hepatitis of different origins, for example virally-, toxically- or
pharmaceutical agent-induced chronically aggressive and/or
chronically intermittent hepatitis (viii) Gastrointestinal
diseases, which coincide with inflammatory, allergic and/or
proliferative processes: regional enteritis (Crohn's disease)
Gastritis
[0104] Reflux esophagitis ulcerative colitis gastroenteritis of
other origins, for example native sprue (ix) Proctological
diseases, which coincide with inflammatory, allergic and/or
proliferative processes: anal eczema fissures haemorrhoids
idiopathic proctitis (x) Eye diseases, which coincide with
inflammatory, allergic and/or proliferative processes: allergic
keratitis, uvenitis iritis conjunctivitis blepharitis optic
neuritis chorioiditis sympathetic ophthalmia (xi) Diseases of the
ear-nose-throat area, which coincide with inflammatory, allergic
and/or proliferative processes: allergic rhinitis, hay fever otitis
externa, for example caused by contact dermatitis, infection, etc.
otitis media (xii) Neurological diseases, which coincide with
inflammatory, allergic and/or proliferative processes: cerebral
edema, mainly tumor-induced cerebral edema multiple sclerosis acute
encephalomyelitis different forms of convulsions, for example
infantile nodding spasms
Meningitis
[0105] spinal cord injury
Stroke
[0106] (xiii) Blood diseases, which coincide with inflammatory,
allergic and/or proliferative processes: acquired haemolytic anemia
thrombocytopenia such as for example idiopathic thrombocytopenia M.
Hodgkins or Non-Hodgkins lymphomas, thrombocythemias,
erythrocytoses (xiv) Tumor diseases, which coincide with
inflammatory, allergic and/or proliferative processes: acute
lymphatic leukaemia malignant lymphoma lymphogranulomatoses
lymphosarcoma extensive metastases, mainly in breast and prostate
cancers (xv) Endocrine diseases, which coincide with inflammatory,
allergic and/or proliferative processes: endocrine orbitopathy
thyrotoxic crisis de Quervain's thyroiditis Hashimoto's
thyroiditis
Hyperthyroidism
[0107] Basedow's disease Granulomatous thyroiditis Lymphadenoid
goiter (xvi) Transplants, which coincide with inflammatory,
allergic and/or proliferative processes; (xvii) Severe shock
conditions, which coincide with inflammatory, allergic and/or
proliferative processes, for example anaphylactic shock (xviii)
Substitution therapy, which coincides with inflammatory, allergic
and/or proliferative processes, with: innate primary suprarenal
insufficiency, for example congenital adrenogenital syndrome
acquired primary suprarenal insufficiency, for example Addison's
disease, autoimmune adrenalitis, meta-infective, tumors,
metastases, etc. innate secondary suprarenal insufficiency, for
example congenital hypopituitarism acquired secondary suprarenal
insufficiency, for example meta-infective, tumors, etc. (xix)
Emesis, which coincides with inflammatory, allergic and/or
proliferative processes: for example in combination with a
5-HT.sub.3-antagonist in cytostatic-agent-induced vomiting. (xx)
Pains of inflammatory origins, e.g., lumbago
[0108] Without prejudice to the foregoing, the compounds of the
invention can also be used to treat disorders such as: diabetes
type I (insulin-dependent diabetes), Guillain-Barre syndrome,
restenoses after percutaneous transluminal angioplasty, Alzheimer's
disease, acute and chronic pain, arteriosclerosis, reperfusion
injury, thermal injury, multiple organ injury secondary to trauma,
acute purulent meningitis, necrotizing enterocolitis and syndromes
associated with hemodialysis, leukopheresis, granulocyte
transfusion, Conies Syndrome, primary and secondary
hyperaldosteronism, increased sodium retention, increased magnesium
and potassium excretion (diuresis), increased water retention,
hypertension (isolated systolic and combined systolic/diastolic),
arrhythmias, myocardial fibrosis, myocardial infarction, Butter's
Syndrome, disorders associated with excess catecholamine levels,
diastolic and systolic congestive heart failure (CHF), peripheral
vascular disease, diabetic nephropathy, cirrhosis with edema and
ascites, oesophageal varicies, muscle weakness, increased melanin
pigmentation of the skin, weight loss, hypotension, hypoglycemia,
Cushing's Syndrome, obesity, glucose intolerance, hyperglycemia,
diabetes mellitus, osteoporosis, polyuria, polydipsia,
inflammation, autoimmune disorders, tissue rejection associated
with organ transplant, malignancies such as leukemias and
lymphomas, rheumatic fever, granulomatous polyarteritis, inhibition
of myeloid cell lines, immune proliferation/apoptosis, HPA axis
suppression and regulation, hypercortisolemia, modulation of the
Th1/Th2 cytokine balance, chronic kidney disease, hypercalcemia,
acute adrenal insufficiency, chronic primary adrenal insufficiency,
secondary adrenal insufficiency, congenital adrenal hyperplasia,
Little's syndrome, systemic inflammation, inflammatory bowel
disease, Wegener's granulomatosis, giant cell arthritis,
osteoarthritis, angioneurotic edema, tendonitis, bursitis,
autoimmune chronic active hepatitis, hepatitis, cinhosis,
panniculitis, inflamed cysts, pyoderma gangrenosum, eosinophilic
fasciitis, relapsing polychondritis, sarcoidosis Sweet's disease,
type 1 reactive leprosy, capillary hemangiomas, lichen planus,
erythema nodosum acne, hirsutism, toxic epidermal necrolysis,
erythema multiform, psychoses, cognitive disorders (such as memory
disturbances) mood disorders (such as depression and bipolar
disorder), anxiety disorders and personality disorders.
[0109] As used herein the term "congestive heart failure" (CHF) or
"congestive heart disease" refers to a disease state of the
cardiovascular system whereby the heart is unable to efficiently
pump an adequate volume of blood to meet the requirements of the
body's tissues and organ systems. Typically, CHF is characterized
by left ventricular failure (systolic dysfunction) and fluid
accumulation in the lungs, with the underlying cause being
attributed to one or more heart or cardiovascular disease states
including coronary artery disease, myocardial infarction,
hypertension, diabetes, valvular heart disease, and cardiomyopathy.
The term "diastolic congestive heart failure" refers to a state of
CHF characterized by impairment in the ability of the heart to
properly relax and fill with blood. Conversely, the term "systolic
congestive heart failure" refers to a state of CHF characterized by
impairment in the ability of the heart to properly contract and
eject blood.
[0110] As will be appreciated by one of skill in the art,
physiological disorders may present as a "chronic" condition, or an
"acute" episode. The term "chronic", as used herein, means a
condition of slow progress and long continuance. As such, a chronic
condition is treated when it is diagnosed and treatment continued
throughout the course of the disease. Conversely, the term "acute"
means an exacerbated event or attack, of short course, followed by
a period of remission. Thus, the treatment of physiological
disorders contemplates both acute events and chronic conditions. In
an acute event, compound is administered at the onset of symptoms
and discontinued when the symptoms disappear.
[0111] In another aspect the present invention provides a compound
of formula Ia or Ib, or a pharmaceutically acceptable salt thereof,
for use in therapy (such as a therapy described above).
[0112] In yet another aspect the present invention provides the use
of a compound of formula Ia or Ib, or a pharmaceutically acceptable
salt thereof, in the manufacture of a medicament for use in the
treatment of a glucocorticoid receptor mediated disease state (such
as a disease state described above).
[0113] In a further aspect the invention provides the use of a
compound of formula Ia or Ib, or a pharmaceutically acceptable salt
thereof, in the manufacture of a medicament for use in the
treatment of an inflammatory condition (such as an arthritic). In
one aspect the invention provides the use of a compound of formula
Ia or Ib, or a pharmaceutically acceptable salt thereof, in the
manufacture of a medicament for use in the treatment of a
respiratory disorder.
[0114] In a still further aspect the invention provides the use of
a compound of formula Ia or Ib, or a pharmaceutically acceptable
salt thereof, in the manufacture of a medicament for use in the
treatment of asthma.
[0115] In another aspect the invention provides the use of a
compound of formula Ia or Ib, or a pharmaceutically acceptable salt
thereof, in the manufacture of a medicament for use in the
treatment of COPD.
[0116] In another aspect the present invention provides a compound
of formula Ia or Ib, or a pharmaceutically acceptable salt thereof,
for use in treating an inflammatory condition, respiratory
disorder, asthma and/or COPD.
[0117] The present invention further provides a method of treating
a glucocorticoid receptor is mediated disease state (such as a
disease state described above), an inflammatory condition, asthma
and/or COPD, in a mammal (such as man), which comprises
administering to a mammal in need of such treatment an effective
amount of a compound of formula Ia, or a pharmaceutically
acceptable salt thereof.
[0118] In the context of the present specification, the term
"therapy" and "treatment" also includes prophylaxis and prevention
unless there are specific indications to the contrary. The terms
"therapeutic" and "therapeutically" should be construed
accordingly. In this specification, unless stated otherwise, the
terms "inhibitor" and "antagonist" mean a compound that by any
means, partly or completely, blocks the transduction pathway
leading to the production of a response by the agonist. An agonist
may be a full or partial agonist. The term "disorder", unless
stated otherwise, means any condition and disease associated with
glucocorticoid receptor activity.
Pharmaceutical Composition
[0119] In order to use a compound of formula Ia, or a
pharmaceutically acceptable salt thereof, for the therapeutic
treatment of a mammal, said active ingredient is normally
formulated in accordance with standard pharmaceutical practice as a
pharmaceutical composition.
[0120] Therefore another aspect the present invention provides a
pharmaceutical composition comprising a compound of formula Ia or
Ib, or a pharmaceutically acceptable salt thereof, (active
ingredient) and a pharmaceutically acceptable adjuvant, diluent or
carrier. One embodiment relates to the use of a pharmaceutical
composition comprising a compound of formula Ia, or a
pharmaceutically acceptable salt thereof, for treating a
glucocorticoid receptor mediated disease state (such as a disease
state described above), an inflammatory condition, respiratory
disorder, asthma and/or COPD.
[0121] A further aspect the present invention provides a process
for the preparation of said composition comprising mixing the
active ingredient with a pharmaceutically to acceptable adjuvant,
diluent or carrier. Depending on the mode of administration, the
pharmaceutical composition can comprise from 0.05 to 99% w (percent
by weight), for example from 0.05 to 80% w, such as from 0.10 to
70% w (for example from 0.10 to 50% w), of active ingredient, all
percentages by weight being based on total composition.
[0122] A pharmaceutical composition of the present invention can be
administered in a is standard manner for the disease condition that
it is desired to treat, for example by topical (such as to the lung
and/or airways or to the skin), oral, rectal or parenteral
administration. Thus, a compound of formula Ia, or a
pharmaceutically acceptable salt thereof, may be formulated into
the form of, for example, an aerosol, a powder (for example dry or
dispersible), a tablet, a capsule, a syrup, a granule, an aqueous
or oily solution or suspension, an (lipid) emulsion, a suppository,
an ointment, a cream, drops, or a sterile injectable aqueous or
oily solution or suspension.
[0123] A suitable pharmaceutical composition of this invention is
one suitable for oral administration in unit dosage form, for
example a tablet or capsule containing between 0.1 mg and 10 g of
active ingredient.
[0124] In another aspect a pharmaceutical composition of the
invention is one suitable for intravenous, subcutaneous,
intraarticular or intramuscular injection.
[0125] In one embodiment a compound of formula Ia or Ib, or a
pharmaceutically acceptable salt thereof, is administered
orally.
[0126] In another embodiment a compound of formula Ia or Ib, or a
pharmaceutically acceptable salt thereof, is administered by
inhalation.
[0127] Buffers, pharmaceutically-acceptable cosolvents such as
polyethylene glycol, polypropylene glycol, glycerol or ethanol or
complexing agents such as hydroxy-propyl .beta.-cyclodextrin may be
used to aid formulation.
[0128] The above formulations may be obtained by conventional
procedures well known in the pharmaceutical art. Tablets may be
enteric coated by conventional means, for example to provide a
coating of cellulose acetate phthalate.
[0129] The invention further relates to a combination therapy or
composition wherein a compound of formula Ia, or a pharmaceutically
acceptable salt thereof, or a pharmaceutical composition comprising
a compound of formula Ia or Ib, or a pharmaceutically acceptable
salt thereof, is administered concurrently (possibly in the same
composition) or sequentially with one or more agents for the
treatment of any of the above disease states.
[0130] For example, for the treatment of rheumatoid arthritis,
osteoarthritis, COPD, asthma or allergic rhinitis a compound of
formula Ia or Ib, or a pharmaceutically is acceptable salt thereof,
can be combined with one or more agents for the treatment of such a
condition. Where such a combination is to be administered by
inhalation, then the one or more agents is selected from the list
comprising: [0131] a PDE4 inhibitor including an inhibitor of the
isoform PDE4D; [0132] a selective .beta..sub2. adrenoceptor agonist
such as metaproterenol, isoproterenol, isoprenaline, albuterol,
salbutamol, formoterol, salmeterol, terbutaline, orciprenaline,
bitolterol mesylate, pirbuterol or indacaterol; [0133] a muscarinic
receptor antagonist (for example a M1, M2 or M3 antagonist, such as
a selective M3 antagonist) such as ipratropium bromide, tiotropium
bromide, oxitropium bromide, pirenzepine or telenzepine; [0134] a
modulator of chemokine receptor function (such as a CCR1 receptor
antagonist); [0135] an inhibitor of p38 kinase function; [0136] an
inhibitor of matrix metalloproteases, such as targeting MMP-2, -9
or MMP-12; or, [0137] an inhibitor of neutrophil serine proteases,
such as neutrophil elastase or proteinase 3.
[0138] In another embodiment of the invention where such a
combination is for the treatment of COPD, asthma or allergic
rhinitis, a compound of formula Ia or Ib, or a pharmaceutically
acceptable salt thereof, can be administered by inhalation or by
the oral route and the other agent, e.g. xanthine (such as
aminophylline or theophylline) can be administered by inhalation or
by the oral route. A compound of formula Ia or Ib, or a
pharmaceutically acceptable salt thereof, and the other agent, e.g
xanthine may be administered together. They may be administered
sequentially. Or they may be administered separately.
[0139] The following Examples illustrate the invention. The
following abbreviations are used in the Examples:
[0140] The following Examples illustrate the invention: [0141] TFA
Trifluoroacetic acid; [0142] THF Tetrahydrofuran [0143] DCM
Dichloromethane [0144] HPLC High Performance Liquid Chromatography;
[0145] LC/MS Liquid Column Chromatography/Mass Spectroscopy; [0146]
GC Gas Chromatography [0147] DMSO Dimethylsulfoxide; [0148] APCI-MS
Atmospheric Pressure Chemical Ionisation Mass Spectroscopy; [0149]
NMP 1-methyl-2-pyrrolidinone [0150] DIEA N,N-diisopropylethylamine
[0151] HATU O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate [0152] HBTU
2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium
hexafluorophosphate(V) [0153] r.t. Room temperature, which is a
temperature in the range from of 16.degree. C. to 25.degree. C.
General Methods
[0154] NMR spectra were recorded on a Varian Mercury-VX 300 MHz
instrument or a Varian Inova 400 MHz instrument. The central peaks
of chloroform-d (H 7.27 ppm), acetone (H 2.05 ppm),
dichloromethane-d2 (H 5.32 ppm) or DMSO-d.sub.6 (H 2.50 ppm) were
used as internal references. Alternatively, NMR. spectra were
recorded on a Varian Inova Unity 500 MHz instrument. Proton-NMR
experiments were acquired using dual suppression of residual
solvent peak and H.sub.2O.
[0155] The following methods was used for chiral SFC analysis:
[0156] Using an Analytical Method Development System from Thar
Technologies, Inc. Using CO.sub.2 as mobile phase with MeOH as
modifier and pressure at 150 bar. Columns used was kept at
+37.degree. C. by using an column oven. Detection was carried out
on 254 nm.
[0157] Chiral SFC (method A) Chiralpak.RTM. AS, 0.46.times.25 cm
column, 30% MeOH, 3 mL/min.
[0158] Chiral SFC (method B) Chiralpak.RTM. IB, 0.46.times.25 cm
column, 35% MeOH, 2 mL/min.
[0159] The following method was used for LC/MS analysis:
[0160] Instrument Agilent 1100; Column Waters Symmetry 2.1.times.30
mm; Mass APCI; Flow rate 0.7 mL/min; Wavelength 254 nm; Solvent A:
water+0.1% TFA; Solvent B: acetonitrile+0.1% TFA; Gradient 15-95%/B
2.7 min, 95% B 0.3 min.
[0161] The following method was used for GC-MS analysis:
[0162] Low resolution mass spectra and accurate mass determination
were recorded on a Hewlett-Packard GC. MS system equipped with EI
ionisation chamber, 70 eV.
[0163] The following method was used for HPLC analysis:
[0164] LC Method A: HPLC method A was performed with Agilent 1100
series machines on Kromassil.COPYRGT. C18 5 .mu.m 3.0.times.100 mm
colum. Aqueous phase was water/TFA (99.8/0.1) and organic phase was
acetonitrile/TFA (99.92/0.08). Flow was 1 ml/min and gradient was
set from 10 to 100% of organic phase during 20 minutes. Detection
was carried out on 220, 254 and 280 nm.
[0165] LC Method B: HPLC method B was performed with Agilent 1100
series machines on XTerra.RTM. RP.sub.8 5 .mu.m 3.0.times.100 mm
colum. Aqueous phase was 15 nM NH3 in water and organic phase was
acetonitrile. Flow was 1 ml/min or 0.6 ml/min when indicated and
gradient was set from 10 to 100% of organic phase during 20
minutes. Detection was carried out on 220, 254 and 280 nm.
[0166] Unless stated otherwise, starting materials were
commercially available. All solvents and commercial reagents were
of laboratory grade and were used as received.
[0167] Preparative HPLC system A:
[0168] Column: XBridge C18, dimension (150.times.30 mm, 5 .mu.m
packing), 20 ml/min solvent speed and gradient 20% to 90% MeCN (0.1
TFA) in Water (0.1% TFA) over 20 min)
EXAMPLE 1
1-({3-[5-({(1R,2S)-2-[(2,2-difluoropropanoyl)amino]-1-phenylpropyl}oxy)-1H-
-indazol-1-yl]phenyl}carbonyl)-D-prolinamide
##STR00016##
[0170] In a 10 mL round-bottomed flask, 2,2-difluoropropanoic acid
(25.04 mg, 0.23 mmol), and
2-(3H[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium
hexafluorophosphate(V) (90 mg, 0.24 mmol) were dissolved in DMF
(1.5 mL). At room temperature N-ethyl-N-isopropylpropan-2-amine
(0.051 mL, 0.31 mmol) was slowly added via a syringe. After 10 min
continued stirring
(R)-1-(3-(5-((1R,2S)-2-amino-1-phenylpropoxy)-1H-indazol-1-yl)benzoyl)pyr-
rolidine-2-carboxamide (1a, 100 mg, 0.21 mmol) in THF (0.5 mL) was
added and stirring was continued over night. The mixture was
diluted with ethyl acetate and washed with sat. aq. sodium
bicarbonate and brine. After drying over sodium sulfate and removal
of the volatiles the crude was dissolved in acetonitril/water (1:1)
and subjected to HPLC-purification [Kromasil 100 C18,
acetonitril/water 35:65 to 65:35]. After freeze drying 34 mg (29%)
of a colourless powder were obtained.
[0171] APCI-MS: m/z 576.2 [MH.sup.+]
[0172] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.71 (1H, d),
8.21 (0.7H, s), 8.19 (0.3H, s), 7.89 (0.6H, s), 7.82 (0.6H, m),
7.78-7.72 (1.3H, m), 7.63 (1H, t), 7.56 (1H, t), 7.45-7.39 (2.7H,
m), 7.38-7.20 (5.3H, m), 7.13 (1H, m), 6.96 (0.7H, s), 6.91 (0.3H,
s), 5.28 (1H, d), 4.37 (0.7H, m), 4.23 (1.3H, m), 3.65-3.56 (1.3H,
m), 3.51-3.34 (0.7H, m; partially covered by water signal), 2.19
(1H, m), 1.93-1.73 (3H, m), 1.49 (3H, t), 1.32 (3H, d).
[0173] LC (method A) rt=9.40 min
[0174] LC (method B) rt=8.43 min
1-{[3-(5-{[(1R,2S)-2-amino-1-phenylpropyl]oxy}-1H-indazol-1-yl)phenyl]carb-
onyl}-D-prolinamide (1a)
##STR00017##
[0176] In a 100 mL round-bottomed flask, tert-butyl
(1R,2S)-1-(1-(3-((R)-2-carbamoylpyrrolidine-1-carbonyl)phenyl)-1H-indazol-
-5-yloxy)-1-phenylpropan-2-ylcarbamate (1b, 472 mg, 0.81 mmol) was
dissolved in ethyl acetate (12 mL). At room temperature hydrogen
chloride (3 mL, 6N in iso-propanol) was added and stirring was
continued for 20 h. Thereafter temperature was raised to 50.degree.
C. and stirring was continued for an additional hour. The mixture
was transferred to a separation funnel and extracted with water and
0.5M aq. hydrogen chloride. The aquous phases were combined and
basified with sodium carbonate. Ethyl acetate was added to the
mixture and the phases it) were separated. The organic phase was
extracted once more with ethyl acetate and the combined organic
phases were washed with brine and dried over sodium sulfate. After
removal of the volatiles the residue was taken up in dioxane/water
(1:2) and freeze dried to obtain a yield 284 mg of colourless
powder (73%).
[0177] APCI-MS: m/z 484.1 [MH.sup.+]
[0178] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.19 (1H, s),
8.17 (1H, s), 7.89 (1H, s), 7.82 (1H, d), 7.78-7.70 (2H, m), 7.62
(1H, t), 7.55 (1H, t), 7.42 (2H, m), 7.38-7.21 (6H, m), 7.15 (1H,
m), 6.98-6.89 (1H, m), 5.11 (1H, d), 4.37 (1H, dd), 4.21 (OH, m),
3.61 (2H, m), 3.47 (1H, m), 3.18 (1H, quintet), 2.18 (1H, m),
1.93-1.74 (3H, m), 1.07 (3H, d).
Tert-butyl[(1S,2R)-2-{[1-(3-{[(2R)-2-carbamoylpyrrolidin-1-yl]carbonyl}phe-
nyl)-1H-indazol-5-yl]oxy}-1-methyl-2-phenylethyl]carbamate (1b)
##STR00018##
[0180] To a solution of
3-(5-((1R,2S)-2-(tert-butoxycarbonylamino)-1-phenylpropoxy)-1H-indazol-1--
yl)benzoic acid (1c, 461 mg, 0.95 mmol) and
2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium
hexafluorophosphate(V) (378 mg, 0.99 mmol) in DMF (3 mL)
N-ethyl-N-isopropylpropan-2-amine (0.313 mL, 1.89 mmol) was added
dropwise at room temperature and a slight exothermic reaction was
observed. After stirring at room temperature for 1 hour the mixture
was diluted with ethyl acetate and washed with brine, 0.5M
hydrochloric acid, brine, aqu. sat. sodium bicarbonate and again
brine. Drying over sodium sulfate and evaporation of the solvent
the residue was dissolved in a dioxane-water mixture (1:2) and
freezedried to give 477 mg (86%) of a colourless solid.
[0181] APCI-MS: m/z 528.1 [MH.sup.+--C4H9], 584.1 [MH.sup.+]
[0182] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.20 (0.7H, s),
8.18 (0.3H, s), 7.90 (0.7H, s), 7.82 (0.7H, d), 7.78-7.72 (1.4H,
m), 7.63 (1H, t), 7.56 (1H, t), 7.46-7.28 (5.3H, m), 7.28-7.19 (2H,
m), 7.09 (1H, m), 7.00 (1H, d), 6.98-6.90 (1H, m), 5.25 (1H, d),
4.37 (0.7H, dd), 4.21 (0.3H, dm), 3.84 (1H, dd), 3.60 (1.3H, m),
3.47 (0.7H, m), 2.19 (1H, m), 1.94-1.74 (3H, m), 1.28 (9H, s), 1.17
(3H, d).
3-[5-({(1R,2S)-2-[(tert-butoxycarbonyl)amino]-1-phenylpropyl}oxy)-1H-indaz-
ol-1-yl]benzoic acid (1c)
##STR00019##
[0184] In a 50 mL round-bottomed flask was dissolved isobutyl
3-(5-((1R,2S)-2-(tert-butoxycarbonylamino)-1-phenylpropoxy)-1H-indazol-1--
yl)benzoate (1d, 1.23 g, 2.26 mmol) in 1,4-dioxane (10 mL) and
water (2 mL) to give a colorless solution. Aquous sodium hydroxide
(2M, 3.3 mL) was added and the solution was heated to 80.degree. C.
for 1 h. The mixture was concentrated in vacuo, diluted with water
to approx. 100 mL and washed with MTBE. The organic phase was
extracted with 0.5M aq. sodium hydroxide. The aquous phases were
combined, acidified with 2M hydrochloric acid and extracted with
ethyl acetate. After evaporation of the organic phase the product
was obtained as a yellow oil. Dissolving in acetonitril/water (1:1)
and freezedrying yielded 980 mg (89%) of a colourless solid.
[0185] APCI-MS: m/z 488.2 [MH.sup.+]
[0186] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.43 (1H, t), 8.06
(2H, d), 8.02 (2H, s), 7.97 (2H, d), 7.70-7.59 (2H, m), 7.47-7.33
(7H, m), 7.33-7.21 ('7H, m), 6.98 (1H, m), 5.51-5.37 (1H, m), 4.09
(1H, m), 1.46 (9H, s), 1.18 (3H, d).
2-Methylpropyl
3-[5-({(1R,2S)-2-[(tert-butoxycarbonyl)amino]-1-phenylpropyl}oxy)-1H-inda-
zol-1-yl]benzoate (1d)
##STR00020##
[0188] In a 25 mL round-bottomed flask was isobutyl
3-(5-((1R,2S)-2-amino-1-phenylpropoxy)-1H-indazol-1-yl)benzoate
(1e, 1.10 g, 2.48 mmol) and di-tert-butyl dicarbonate (0.627 mL,
2.73 mmol) dissolved in THF (5 mL). At 0.degree. C. triethylamine
(0.516 mL, 3.72 mmol) was added dropwise. The ice bath was removed
and stirring was continued over night. The mixture was diluted with
ethyl acetate (80 mL) and washed with sat. aq. ammonium acetate and
with brine. After drying over sodium sulfate and removal of the
solvents the crude was obtained as an pale yellow oil and subjected
to flashchromatography on silica gel (heptane/MTBE=5:4). 1.23 g
(91%) of the product were obtained as a colourless foam.
[0189] APCI-MS: m/z 544.3 [MH.sup.+]
Isobutyl
3-(5-((1R,2S)-2-amino-1-phenylpropoxy)-1H-indazol-1-yl)benzoate
(1e)
##STR00021##
[0191] A 15 mL vial was charged with cesium carbonate (1.043 g,
3.20 mmol), (1R,2S)-2-amino-1-phenylpropan-1-ol (0.181 g, 1.20
mmol), 2-(dimethylamino)acetic acid (0.052 g, 0.50 mmol), copper(I)
iodide (0.048 g, 0.25 mmol) and butyronitrile (3.8 mL) and heated
at 85.degree. C. for 30 min.
[0192] A 3 mL vial was charged with isobutyl
3-(5-iodo-1H-indazol-1-yl)benzoate (1f, 0.420 g, 1 mmol) and
butyronitrile (0.8 mL) and heated to 60.degree. C. for 10 min. The
Iodoindazole solution was transferred to the catalyst mixture in
one portion. The vessel was rinsed with butyronitrile (0.4 mL) and
this solution was transferred to the catalyst mixture as well. The
reaction mixture was then stirred at 85.degree. C. overnight,
cooled and filtered through a plug of silica using ethyl
acetate/methanol (9/1) as eluent. The solvents were evaporated at
reduced pressure and the crude product was purified by flash
chromatography on silica, using a gradient of ethyl acetate in
heptane (both solvents containing 2% TEA) as eluent to give the
title compound (70 mg, 16%).
[0193] APCI-MS: m/z=444.2 [MH+]
[0194] .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.31 (1H, t), 8.06
(1H, s), 8.01 (1H, d), 7.96 (1H, d), 7.68 (2H, dd), 7.43 (2H, d),
7.37 (2H, t), 7.29 (2H, m), 7.11 (1H, d), 5.18 (1H, d), 4.16 (2H,
d),* (1H in solvent peak), 2.11 (1H, m), 1.2 (3H, d), 1.05 (6H,
d).
[0195] LC (method A) rt=10.9 min
Isobutyl 3-(5-iodo-1H-indazol-1-yl)benzoate (1f)
##STR00022##
[0197] A 50 mL.s flask was charged with sodium carbonate (0.700 g,
6.60 mmol), 3-(5-iodo-1H-indazol-1-yl)benzoic acid (2.185 g, 6
mmol) and NMP (15 mL) at 40.degree. C. with magnetic stirring.
After a couple of minutes 1-bromo-2-methylpropane (0.971 mL, 9.00
mmol) was added in one portion. After one hour at 40.degree. C.,
the temperature was raised to 55.degree. C. and another portion of
1-bromo-2-methylpropane (0.971 mL, 9.00 mmol) was added. The
stirring was continued overnight.
[0198] After cooling, the reaction mixture was partitioned between
water and ethyl acetate. The organic phase was washed twice with
water, dried over Na.sub.2SO.sub.4, filtered and evaporated to
dryness to afford the title compound as a syrup (2.5 g, 99%). The
product solidified to a beige material upon standing.
[0199] APCI-MS: m/z=421 [MH+]
[0200] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.38 (1H, t), 8.19
(1H, d), 8.16 (1H, d), 8.07 (1H, dt), 7.92 (1H, ddd), 7.70 (1H,
dd), 7.64 (1H, t), 7.56 (1H, d), 4.17 (2H, d), 2.12 (1H, m), 1.05
(6H, d).
[0201] LC (method A) rt=17.6 min
EXAMPLE 2
N-[(1S,2R)-2-{[1-(3-{[(2R)-2-carbamoylpyrrolidin-1-yl]carbonyl}phenyl)-1H--
indazol-5-yl]oxy}-1-methyl-2-phenylethyl]ethanediamide
##STR00023##
[0203] The title compound was prepared according to the protocol
described for example 2, starting from 2-amino-2-oxoacetic acid
(17.62 mg, 0.20 mmol) and
(R)-1-(3-(5-((1R,2S)-2-amino-1-phenylpropoxy)-1H-indazol-1-yl)b-
enzoyl)pyrrolidine-2-carboxamide (87 mg, 0.18 mmol). Yield after
freeze drying: 14 mg (14%) of a colourless powder.
[0204] APCI-MS: m/z 555.1 [MH.sup.+]
[0205] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.57 (1H, d),
8.22 (0.7H, s), 8.20 (0.3H, s), 7.93 (1H, s), 7.87 (0.7H, s), 7.82
(0.7H, d), 7.77-7.72 (2.3H, m), 7.63 (1H, m), 7.55 (1H, m),
7.44-7.39 (2.7H, m), 7.38-7.28 (2.7H, m), 7.27-7.20 (2H, m), 7.12
(1H, m), 6.96 (0.7H, m), 6.92 (0.3H, m), 5.40 (1H, d), 4.36 (0.7H,
m), 4.21 (1.3H, m), 3.60 (1.3H, m), 3.46 (0.7H, m), 2.19 (1H, m),
1.92-1.74 (3H, m), 1.28 (3H, d).
[0206] LC (method A) rt=7.58 min
[0207] LC (method B) rt=7.08 min
EXAMPLE 3
3-[5-({(1R,2S)-2-[(2,2-difluoropropanoyl)amino]-1-phenylpropyl}oxy)-1H-ind-
azol-1-yl]-N-(2-hydroxyethyl)benzamide
##STR00024##
[0209] A solution of
3-[5-({(1R,2S)-2-[(2,2-difluoropropanoyl)amino]-1-phenylpropyl}oxy)-1H-in-
dazol-1-yl]benzoic acid (3a) in DCM 3 mL and NMP 0.1 mL was added
to a mixture of HBTU (127 mg, 0.33 mmol) and 2-aminoethanol (30 mg,
0.50 mmol). TEA (0.140 mL, 1.00 mmol) was added to the mixtures and
the solution was stirred over weekend. The mixture was diluted with
15% NaHSO.sub.4 (2 ml), the organic layer was separated (phase
separator) and the water layer was back extracted with DCM 3 mL,
the combined organic layers were evaporated. The crude product was
dissolved in MeCN 3 mL and purified by mass directed
autopreparartion using Preparativ HPLC system A, the pure fractions
were combined and freeze dried to obtain the title compound (40 mg,
46%).
[0210] APCI-MS: m/z=523 [MH.sup.+]
[0211] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 8.72 (1H, d),
8.61 (1H, t), 8.22 (1H, d), 8.16 (1H, t), 7.89-7.82 (2H, m), 7.78
(1H, d), 7.64 (1H, t), 7.44-7.39 (2H, m), 7.37-7.31 (2H, m),
7.29-7.20 (2H, m), 7.13 (1H, d), 5.28 (1H, d), 4.74 (1H, t),
4.27-4.18 (1H, m), 3.52 (2H, q), 3.43-3.38 (2H, m), 1.49 (3H, t),
1.32 (3H, d).
[0212] LC (method A) rt=9.5 min
[0213] LC (method B) rt=8.9 min
3-[5-({1R,2S)-2-[(2,2-difluoropropanoyl)amino]-1-phenylpropyl}oxy)-1H-inda-
zol-1-yl]benzoic acid (3a)
##STR00025##
[0215] Isobutyl
3-[5-[(1R,2S)-2-(2,2-difluoropropanoylamino)-1-phenyl-propoxy]indazol-1-y-
l]benzoate (1e) (1.97 g, 3.68 mmol) was dissolved in MeOH (10 mL)
and THF (10.00 mL), lithium hydroxide (0.264 g, 11.03 mmol)
dissolved in water (10.00 mL) was added to the solution and stirred
over night at room temperature. The mixture was diluted with water
and washed with TBME, acidified (2M HCl) and extracted with
EtOAc.times.2, the organic phases were combined and dried with
Na.sub.2SO.sub.4, filtered, evaporated to obtain the title compound
(1.760 g, 100%) as dry film.
[0216] APCI-MS: m/z=480 [MH.sup.+]
[0217] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 13.22 (1H, s),
8.71 (1H, d), 8.25-8.20 (2H, m), 8.02-7.97 (1H, m), 7.92 (1H, d),
7.77 (1H, d), 7.69 (1H, t), 7.42 (2H, d), 7.34 (2H, t), 7.28-7.21
(2H, m), 7.14 (1H, d), 5.29 (1H, d), 4.27-4.18 (1H, m), 1.49 (3H,
t), 1.32 (3H, d).
EXAMPLE 4
N-(2-amino-2-oxoethyl)-3-[5-({(1R,2S)-2-[(2,2-difluoropropanoyl)amino]-1-p-
henylpropyl}oxy)-1H-indazol-1-yl]benzamide
##STR00026##
[0219] Prepared similarly to Example 3 from
3-[5-({(1R,2S)-2-[(2,2-difluoropropanoyl)amino]-1-phenylpropyl}oxy)-1H-in-
dazol-1-yl]benzamide (3a) and glycinamide hydrochloride.
[0220] APCI-MS: m/z=536 [MH.sup.+]
[0221] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 8.87 (1H, t),
8.72 (1H, d), 8.22 (1H, d), 8.19 (1H, t), 7.91-7.84 (2H, m), 7.81
(1H, d), 7.66 (1H, t), 7.44-7.38 (2H, m), 7.37-7.31 (2H, m),
7.29-7.20 (3H, m), 7.14 (1H, d), 7.05 (1H, s), 5.28 (1H, d),
4.29-4.17 (1H, m), 3.83 (2H, d), 1.49 (3H, t), 1.32 (3H, d).
[0222] LC (method A) rt=9.1 min
[0223] LC (method B) rt=8.6 min
EXAMPLE 5
N-[(1S)-2-amino-1-methyl-2-oxoethyl]-3-[5-({(1R,2S)-2-[(2,2-difluoropropan-
oyl)amino]-1-phenylpropyl}oxy)-1H-indazol-1-yl]benzamide
##STR00027##
[0225] Prepared similarly to Example 3 from
3-[5-({(1R,2S)-2-[(2,2-difluoropropanoyl)amino]-1-phenylpropyl}oxy)-1H-in-
dazol-1-yl]benzamide (3a) and L-alaninamide hydrochloride.
[0226] APCI-MS: m/z=550 [MH.sup.+]
[0227] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 8.71 (1H, d),
8.63 (1H, d), 8.22 (1H, d), 8.21 (1H, t), 7.91-7.85 (2H, m), 7.79
(1H, d), 7.64 (1H, t), 7.44-7.39 (2H, m), 7.37-7.31 (2H, m),
7.28-7.20 (3H, m), 7.13 (1H, d), 6.99 (1H, s), 5.28 (1H, d),
4.48-4.38 (1H, m), 4.28-4.17 (1H, m), 1.49 (3H, t), 1.36-1.30 (6H,
m).
[0228] LC (method A) rt=9.5 min
[0229] LC (method B) rt=8.9 min
EXAMPLE 6
N-[2-(acetylamino)ethyl]-3-[5-({(1R,2S)-2-[(2,2-difluoropropanoyl)amino]-1-
-phenylpropyl}oxy)-1H-indazol-1-yl]benzamide
##STR00028##
[0231] Prepared similarly to Example 3 from
3-[5-({(1R,2S)-2-[(2,2-difluoropropanoyl)amino]-1-phenylpropyl}oxy)-1H-in-
dazol-1-yl]benzamide (3a) and N-(2-aminoethyl)acetamide.
[0232] APCI-MS: m/z=564 [MH.sup.+]
[0233] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.73-8.64 (2H,
m), 8.22 (1H, s), 8.15 (1H, s), 7.97 (1H, t), 7.88-7.79 (3H, m),
7.64 (1H, t), 7.42 (2H, d), 7.34 (2H, t), 7.28-7.20 (2H, m), 7.14
(1H, d), 5.28 (1H, d), 4.23 (1H, q), 3.34-3.28 (2H, m), 3.21 (2H,
q), 1.80 (3H, s), 1.49 (3H, t), 1.32 (3H, d).
[0234] LC (method A) rt=9.4 min
[0235] LC (method B) rt=8.9 min
EXAMPLE 7
3-[5-({(1R,2S)-2-[(2,2-difluoropropanoyl)amino]-1-phenylpropyl}oxy)-1H-ind-
azol-1-yl]-N-[2-(2-oxoimidazolidin-1-yl)ethyl]benzamide
##STR00029##
[0237] Prepared similarly to Example 3 from
3-[5-({(1R,2S)-2-[(2,2-difluoropropanoyl)amino]-1-phenylpropyl}oxy)-1H-in-
dazol-1-yl]benzamide (3a) and
1-(2-aminoethyl)imidazolidin-2-one.
[0238] APCI-MS: m/z=591 [MH.sup.+]
[0239] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 8.75-8.66 (2H,
m), 8.22 (1H, d), 8.13 (1H, t), 7.89-7.84 (1H, m), 7.83-7.76 (2H,
m), 7.64 (1H, t), 7.44-7.39 (2H, m), 7.34 (2H, t), 7.29-7.20 (2H,
m), 7.13 (1H, d), 6.26 (1H, s), 5.28 (1H, d), 4.29-4.18 (1H, m),
3.45-3.34 (2H, m), 3.27-3.15 (6H, m), 1.49 (3H, t), 1.32 (3H,
d).
[0240] LC (method A) rt=9.4 min
[0241] LC (method B) rt=8.9 min
EXAMPLE 8
2,2-Difluoro-N-[(1S,2R)-2-{[1-(3-{[(2R)-2-(hydroxymethyl)pyrrolidin-1-yl]c-
arbonyl}phenyl)-1H-indazol-5-yl]oxy}-1-methyl-2-phenylethyl]propanamide
##STR00030##
[0243] Prepared similarly to Example 3 from
3-[5-({(1R,2S)-2-[(2,2-difluoropropanoyl)amino]-1-phenylpropyl}oxy)-1H-in-
dazol-1-yl]benzamide (3a) and (2R)-pyrrolidin-2-ylmethanol.
[0244] APCI-MS: m/z=563 [MH.sup.+]
[0245] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 8.71 (1H, d),
8.20 (1H, d), 7.82-7.72 (3H, m), 7.61 (1H, t), 7.50-7.38 (3H, m),
7.37-7.30 (2H, m), 7.28-7.19 (2H, m), 7.13 (1H, d), 5.28 (1H, d),
4.30-4.08 (2H, m), 3.61-3.57 (1H, m), 3.50-3.35 (4H, m), 2.01-1.80
(3H, m), 1.77-1.62 (1H, m), 1.49 (3H, t), 1.32 (3H, d).
[0246] LC (method A) rt=10.5 min
[0247] LC (method B) rt=9.6 min
EXAMPLE 9
2,2-Difluoro-N-[(1S,2R)-2-{[1-(3-{[(3R)-3-hydroxypyrrolidin-1-yl]carbonyl}-
phenyl)-1H-indazol-5-yl]oxy}-1-methyl-2-phenylethyl]propanamide
##STR00031##
[0249] Prepared similarly to Example 3 from
3-[5-({(1R,2S)-2-[(2,2-difluoropropanoyl)amino]-1-phenylpropyl}oxy)-1H-in-
dazol-1-yl]benzamide (3a) and (3R)-pyrrolidin-3-ol.
[0250] APCI-MS: m/z=549 [MH+]
[0251] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 8.71 (1H, d),
8.21 (1H, d), 7.84-7.73 (3H, m), 7.62 (1H, t), 7.51-7.46 (1H, m),
7.44-7.39 (2H, m), 7.37-7.30 (2H, m), 7.28-7.20 (2H, m), 7.13 (1H,
d), 5.28 (1H, d), 4.37-4.30 (1H, m), 4.28-4.16 (2H, m), 3.64-3.51
(2H, m), 3.46-3.43 (1H, m), 3.30-3.26 (1H, m), 2.01-1.74 (2H, m),
1.49 (3H, t), 1.32 (3H, d).
[0252] LC (method A) rt=9.4 min
[0253] LC (method B) rt=8.8 min
EXAMPLE 10
3-[5-({(1R,2S)-2-[(2,2-difluoropropanoyl)amino]-1-phenylpropyl}oxy)-1H-ind-
azol-1-yl]-N-[(3R)-2-oxotetrahydrofuran-3-yl]benzamide
##STR00032##
[0255] Prepared similarly to Example 3 from
3-[5-({(1R,2S)-2-[(2,2-difluoropropanoyl)amino]-1-phenylpropyl}oxy)-1H-in-
dazol-1-yl]benzamide (3a) and (3R)-3-aminodihydrofuran-2(3H)-one
hydrochloride.
[0256] APCI-MS: m/z=563 [MH.sup.+]
[0257] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 9.16 (1H, d),
8.71 (1H, d), 8.23 (1H, s), 8.18 (1H, s), 7.95-7.91 (1H, m), 7.85
(1H, d), 7.79 (1H, d), 7.69 (1H, t), 7.42 (2H, d), 7.34 (2H, t),
7.28-7.21 (2H, m), 7.14 (1H, d), 5.29 (1H, d), 4.85-4.77 (1H, m),
4.45-4.40 (1H, m), 4.32-4.20 (2H, m), 2.50-2.44 (1H, m), 2.40-2.30
(1H, m), 1.49 (3H, t), 1.32 (3H, d).
[0258] LC (method A) rt=10.7 min
[0259] LC (method B) rt=10.0 min
EXAMPLE 11
1-({3-[5-({(1R,2S)-2-[(2,2-difluoropropanoyl)amino]-1-phenylpropyl}oxy)-1H-
-indazol-1-yl]phenyl}carbonyl)-L-prolinamide
##STR00033##
[0261] Prepared similarly to Example 3 from
3-[5-({(1R,2S)-2-[(2,2-difluoropropanoyl)amino]-1-phenylpropyl}oxy)-1H-in-
dazol-1-yl]benzamide (3a) and L-prolinamide.
[0262] APCI-MS: m/z=576 [MH.sup.+]
[0263] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 8.71 (1H, d),
8.21 (1H, s), 7.90-7.79 (1H, m), 7.75 (1H, d), 7.66-7.52 (2H, m),
7.46-7.39 (2H, m), 7.37-7.30 (3H, m), 7.29-7.20 (3H, m), 7.13 (1H,
d), 6.98-6.90 (1H, m), 5.28 (1H, d), 4.40-433 (1H, m), 4.28-4.17
(1H, m), 3.66-3.41 (2H, m), 2.24-2.11 (1H, m), 1.94-1.71 (3H, m),
1.49 (3H, t), 1.37-1.27 (3H, m).
[0264] LC (method A) rt=9.4 min
[0265] LC (method B) rt=8.7 min
EXAMPLE 12
2,2-Difluoro-N-{(1S,2R)-1-methyl-2-[(1-{3-[(3-oxopiperazin-1-yl)carbonyl]p-
henyl}-1H-indazol-5-yl)oxy]-2-phenylethyl}propanamide
##STR00034##
[0267] Prepared similarly to Example 3 from
3-[5-({(1R,2S)-2-[(2,2-difluoropropanoyl)amino]-1-phenylpropyl}oxy)-1H-in-
dazol-1-yl]benzamide (3a) and piperazin-2-one.
[0268] APCI-MS: m/z=562 [MH.sup.+]
[0269] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.71 (1H, d),
8.21 (1H, d), 8.13 (1H, s), 7.86-7.82 (1H, m), 7.80-7.74 (2H, m),
7.64 (1H, t), 7.44-7.39 (3H, m), 7.34 (2H, t), 7.28-7.19 (2H, m),
7.13 (1H, d), 5.28 (1H, d), 4.27-4.18 (1H, m), 4.15-3.92 (2H, m),
3.39-3.34 (2H, m), 3.29-3.19 (2H, m), 1.49 (3H, t), 1.32 (3H,
d).
[0270] LC (method A) rt=9.1 min
[0271] LC (method B) rt=8.6 min
EXAMPLE 13
3-[5-({(1R,2S)-2-[(2,2-difluoropropanoyl)amino]-1-phenylpropyl}oxy)-1H-ind-
azol-1-yl]-N-[2-(2-oxopyrrolidin-1-yl)ethyl]benzamide
##STR00035##
[0273] Prepared similarly to Example 3 from
3-[5-({(1R,2S)-2-[(2,2-difluoropropanoyl)amino]-1-phenylpropyl}oxy)-1H-in-
dazol-1-yl]benzamide (3a) and 1-(2-aminoethyl)pyrrolidin-2-one
hydrochloride.
[0274] APCI-MS: m/z=590 [MH.sup.30]
[0275] .sup.1H NMR. (300 MHz, DMSO-d.sub.6) .delta. 8.74-8.66 (2H,
m), 8.22 (1H, d), 8.10 (1H, t), 7.89-7.75 (2H, m), 7.64 (1H, t),
7.44-7.39 (2H, m), 7.37-7.30 (2H, m), 7.29-7.19 (3H, m), 7.14 (1H,
d), 5.28 (1H, d), 4.28-4.18 (1H, m), 3.44-3.27 (6H, m), 2.16 (2H,
t), 1.95-1.84 (2H, m), 1.49 (3H, t), 1.32 (3H, d).
[0276] LC (method A) rt=9.9 min
[0277] LC (method B) rt=9.2 min
EXAMPLE 14
3-[5-({(1R,2S)-2-[(2,2-difluoropropanoyl)amino]-1-phenylpropyl}oxy)-1H-ind-
azol-1-yl]-N-[2-(5,5-dimethyl-2,4-dioxo-1,3-oxazolidin-3-yl)ethyl]benzamid-
e
##STR00036##
[0279] Prepared similarly to Example 3 from
3-[5-({(1R,2S)-2-[(2,2-difluoropropanoyl)amino]-1-phenylpropyl}oxy)-1H-in-
dazol-1-yl]benzamide (3a) and
3-(2-aminoethyl)-5,5-dimethyl-1,3-oxazolidine-2,4-dione
hydrochloride.
[0280] APCI-MS: m/z=634 [MH.sup.+]
[0281] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 8.83 (1H, t),
8.72 (1H, d), 8.22 (1H, d), 8.04 (1H, t), 7.89-7.84 (1H, m),
7.80-7.71 (2H, m), 7.64 (1H, t), 7.44-7.40 (2H, m), 7.37-7.31 (2H,
m), 7.29-7.19 (2H, m), 7.14 (1H, d), 5.28 (1H, d), 4.28-4.18 (1H,
m), 3.64-3.58 (2H, m), 3.55-3.48 (2H, m), 1.49 (3H, t), 1.45 (6H,
s), 1.32 (3H, d).
[0282] LC (method A) rt=11.7 min
[0283] LC (method B) rt=10.8 min
EXAMPLE 15
3-[5-({(1R,2S)-2-[(2,2-difluoropropanoyl)amino]-1-phenylpropyl}oxy)-1H-ind-
azol-1-yl]-N-(1,1-dioxidotetrahydrothiophen-3-yl)benzamide
##STR00037##
[0285] Prepared similarly to Example 3 from
3-[5-({(1R,2S)-2-[(2,2-difluoropropanoyl)amino]-1-phenylpropyl}oxy)-1H-in-
dazol-1-yl]benzamide (3a) and tetrahydrothiophene-3-amine
1,1-dioxide.
[0286] APCI-MS: m/z=597 [MH.sup.+]
[0287] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.90 (1H, d),
8.71 (1H, d), 8.23 (1H, s), 8.19-8.16 (1H, m), 7.92-7.89 (1H, m),
7.85 (1H, d), 7.77 (1H, d), 7.67 (1H, t), 7.44-7.40 (2H, m),
7.36-7.31 (2H, m), 7.28-7.21 (2H, m), 7.14 (1H, d), 5.28 (1H, d),
4.78-4.66 (1H, m), 4.29-4.17 (1H, m), 3.52 (1H, dd), 3.39-3.33 (1H,
m), 3.25-3.15 (1H, m), 3.10 (1H, dd), 2.49-2.40 (1H, m), 2.29-2.16
(1H, m), 1.49 (3H, t), 1.32 (3H, d)
[0288] LC (method A) rt=10.6 min
[0289] LC (method B) rt=10.0 min
EXAMPLE 16
3-[5-({(1R,2S)-2-[(2,2-difluoropropanoyl)amino]-1-phenylpropyl}oxy)-1H-ind-
azol-1-yl]-N-(1H-indazol-3-ylmethyl)benzamide
##STR00038##
[0291] Prepared similarly to Example 3 from
3-[5-({(1R,2S)-2-[(2,2-difluoropropanoyl)amino]-1-phenylpropyl}oxy)-1H-in-
dazol-1-yl]benzamide (3a) and 1-(1H-indazol-3-yl)methanamine.
APCI-MS: m/z=609 [MH+]
[0292] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 9.27 (1H, t),
8.71 (1H, d), 8.21-8.18 (2H, m), 7.90-7.80 (2H, m), 7.77 (2H, d),
7.64 (1H, t), 7.51-7.46 (1H, m), 7.44-7.39 (2H, m), 7.37-7.29 (3H,
m), 7.28-7.18 (2H, m), 7.13 (1H, d), 7.10-7.03 (2H, m), 5.27 (1H,
d), 4.85 (2H, d), 4.28-4.17 (1H, m), 1.49 (3H, t), 1.31 (3H,
d).
[0293] LC (method A) rt=11.6 min
[0294] LC (method B) rt=11.2 min
EXAMPLE 17
N-[(1R)-2-amino-2-oxo-1-phenylethyl]-3-[5-({(1R,2S)-2-[(2,2-difluoropropan-
oyl)amino]-1phenylpropyl}oxy)-1H-indazol-1-yl]benzamide
##STR00039##
[0296] Prepared similarly to Example 3 from
3-[5-({(1R,2S)-2-[(2,2-difluoropropanoyl)amino]-1-phenylpropyl}oxy)-1H-in-
dazol-1-yl]benzamide (3a) and (2R)-2-amino-2-phenylethanamide
hydrochloride.
[0297] APCI-MS: m/z=612 [MH.sup.+]
[0298] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.98 (1H, d),
8.72 (1H, d), 8.22 (2H, d), 7.94-7.86 (2H, m), 7.78 (1H, d), 7.72
(1H, s), 7.64 (1H, t), 7.53 (2H, d), 7.42 (2H, d), 7.38-7.20 (8H,
m), 7.14 (1H, d), 5.65 (1H, d), 5.29 (1H, d), 4.24 (1H, dd), 1.50
(3H, t), 1.32 (3H, d).
[0299] LC (method A) rt=11.1 min
[0300] LC (method B) rt=10.5 min
EXAMPLE 18
N-(2-amino-2-oxoethyl)-3-[5-{(1R,2S)-2-[(2,2-difluoropropanoyl)amino]-1-ph-
enylpropyl}oxy)-1H-indazol-1-yl]-N-methylbenzamide
##STR00040##
[0302] Prepared similarly to Example 3 from
3-[5-({(1R,2S)-2-[(2,2-difluoropropanoyl)amino]-1-phenylpropyl}oxy)-1H-in-
dazol-1-yl]benzamide (3a) and N-methylglycinamide
hydrochloride.
[0303] APCI-MS: m/z=550 [MH.sup.+]
[0304] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 8.71 (1H, d),
8.20 (1H, s), 7.84-7.56 (4H, m), 7.51-7.29 (6H, m), 7.28-7.20 (2H,
m), 7.19-7.10 (2H, m), 5.28 (1H, d), 4.27-4.17 (1H, m), 4.04 (1H,
s), 3.83 (1H, s), 2.96 (3H, s), 1.49 (3H, t), 1.32 (3H, d).
[0305] LC (method A) rt=9.0 min
[0306] LC (method B) rt=8.4 min
EXAMPLE 19
N-(3-amino-3-oxopropyl)-3-[5-({(1R,2S)-2-[(2,2-difluoropropanoyl)amino]-1--
phenylpropyl}oxy)-1H-indazol-1-yl]benzamide
##STR00041##
[0308] Prepared similarly to Example 3 from
3-[5-({(1R,2S)-2-[(2,2-difluoropropanoyl)amino]-1-phenylpropyl}oxy)-1H-in-
dazol-1-yl]benzamide (3a) and beta-alaninamide hydrochloride.
[0309] APCI-MS: m/z=550 [MH.sup.+]
[0310] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 8.74-8.66 (2H,
m), 8.22 (1H, d), 8.14 (1H, t), 7.89-7.74 (3H, m), 7.64 (1H, t),
7.45-7.30 (5H, m), 7.29-7.20 (2H, m), 7.13 (1H, d), 6.83 (1H, s),
5.28 (1H, d), 4.27-4.18 (1H, m), 3.46 (2H, dd), 2.37 (2H, t), 1.49
(3H, t), 1.32 (3H, d).
[0311] LC (method A) rt=9.1 min
[0312] LC (method B) rt=8.6 min
EXAMPLE 20
(4R)-1-({3-[5-({(1R,2S)-2-[(2,2-difluoropropanoyl)amino]-1-phenylpropyl}ox-
y)-1H-indazol-1-yl]phenyl}carbonyl)-4-hydroxy-L-prolinamide
##STR00042##
[0314] Prepared similarly to Example 3 from
3-[5-({(1R,2S)-2-[(2,2-difluoropropanoyl)amino]-1-phenylpropyl}oxy)-1H-in-
dazol-1-yl]benzamide (3a) and (4R)-4-hydroxy-L-prolinamide.
[0315] APCI-MS: m/z=592 [MH.sup.+]
[0316] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 8.71 (1H, d),
8.22 (1H, d), 7.91-7.89 (1H, m), 7.86-7.81 (1H, m), 7.74 (1H, d),
7.64 (1H, t), 7.58-7.53 (1H, m), 7.50-7.47 (1H, m), 7.44-7.39 (2H,
m), 7.37-7.30 (2H, m), 7.28-7.20 (2H, m), 7.14 (1H, d), 6.96 (1H,
s), 5.28 (1H, d), 4.46 (1H, t), 4.27-4.18 (2H, m), 3.81-3.73 (1H,
m), 3.36-3.33 (2H, m), 2.21-2.10 (1H, m), 1.95-1.84 (1H, m), 1.49
(3H, t), 1.32 (3H, d).
[0317] LC (method A) rt=8.3 min
[0318] LC (method B) rt=7.8 min
EXAMPLE 21
1-{[3-(5-{[(1R,2S)-2-{-[1(1-cyanocyclopropyl)carbonyl]amino}-1-phenylpropy-
l]oxy}-1H-indazol-1-yl)phenyl]carbonyl}-D-prolinamide
##STR00043##
[0320] The title compound was prepared according to the protocol
described for Example 1, starting from
1-cyanocyclopropanecarboxylic acid (23.76 mg, 0.21 mmol) and
(R)-1-(3-(5-((1R,2S)-2-amino-1-phenylpropoxy)-1H-indazol-1-yl)benzoyl)pyr-
rolidine-2-carboxamide (94 mg, 0.19 mmol). Yield after freeze
drying: 53 mg (47%) of a colourless powder.
[0321] APCI-MS: m/z 577.1 [MH.sup.+]
[0322] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.22 (0.7H, s),
8.20 (0.3H, s), 8.04 (1.3H, d), 7.90 (0.7H, s), 7.82 (0.7H, d),
7.75 (1.3H, d), 7.63 (1.3H, t), 7.55 (1H, t), 7.42 (3H, d),
7.36-7.29 (3.3H, m), 7.24 (3H, m), 7.13 (1.3H, m), 6.98 (0.7H, s),
6.93 (0.3H, s), 5.34 (1H, d), 4.37 (0.7H, m), 4.22 (1.3H, m),
3.65-3.57 (1.3H, m), 3.47 (0.7H, m), 2.19 (1H, m), 1.93-1.73 (3H,
m), 1.45 (2H, m), 1.29 (3H, d), 1.20 (1H, m).
[0323] LC (method A) rt=9.36 min
[0324] LC (method B) rt=8.31 min
EXAMPLE 22
N-cyclopentyl-3-(5-{[(1R,2S)-2-[(2,2-difluoropropanoyl)amino]-1-(6-methoxy-
pyridin-3-yl)propyl]oxy}-1H-indazol-1-yl)benzamide
##STR00044##
[0326] To
N-[(1R,2S)-1-{[1-(3-bromophenyl)-1H-indazol-5-yl]oxy}-1-(6-metho-
xypyridin-3-yl)propan-2-yl]-2,2-difluoropropanamide (20 mg, 37
.mu.mol), cyclopentylamine (4.4 mg, 51 .mu.mol),
Tri-t-butylphosphoniumtetrafluoroborat (2.1 mg, 7 .mu.mol) and
trans-bis(acetato)bis[o-(di-o-tolylphosphino)-benzyl]dipalladium(II)
(5.6 mg, 7 .mu.mol) in 1 ml THF was added molybdenum hexacarbonyl
(4.6 mg, 18 .mu.mol). The microwave vessel was closed and radiated
in microwave reactor (CEM discover) at 150 W and 125.degree. C. for
6 minutes (5 minutes ramp time). Then the solvent was removed
i.vac., and the product purified by preparative thin layer
chromatography on silica gel (ethyl acetate 100%) to yield 6.7 mg
(32%) of
N-cyclopentyl-3-(5-{[(1R,2S)-2-[(2,2-difluoropropanoyl)amino]-1-(6-methox-
ypyridin-3-yl)propyl]oxy}-1H-indazol-1-yl)benzamide
[0327] ES+MS: m/z 578 [MH.sup.+]
[0328] .sup.1H-NMR (300 MHz, CDCl.sub.3); .delta.=8.20 (d, 1H),
8.05 (dd, 1H), 8.01 (s, 1H), 7.81 (m, 1H), 7.72 (d, 1H), 7.66 (d,
1H), 7.60 (dd, 1H), 7.57 (t, 1H), 7.15 (dd, 1H), 6.98 (d, 1H), 6.75
(d, 1H), 6.67 (br, 1H), 6.15 (br, 1H), 5.36 (d, 1H), 4.41 (m, 1H),
4.38 (m, 1H), 3.92 (s, 3H), 2.10 (m, 2H), 1.77 (t, 3H), 1.64-1.74
(m., 4H), 1.52 (m, 2H), 1.29 (d, 3H).
[(1S)-2-(methoxymethylamino)-1-methyl-2-oxoethyl]carbamic acid
t-butyl ester
##STR00045##
[0330] Boc-Ala-OH (200 g, 1057 mmol) in 3400 ml dichloromethane
were cooled to 0.degree. C. 1,1'-Carbonyldiimidazol (205.7 g, 1268
mmol) was added in multiple portions over 30 min and stirring was
continued for 30 minutes at 0.degree. C. Triethylamine (175.8 ml,
1268 mmol) was added over 20 min at 2.degree. C. followed by
N,O-dimethyl hydroxylamine mono hydrochloride (123.7 g, 1268 mmol)
in multiple portions and stirring was continued for 30 minutes at
0.degree. C. After stirring for 14 hours at room temperature the
mixture was diluted with 4 L t-butyl methyl ether and washed with
1M HCl solution (2 times 800 ml, 15 min stirring, then phase
separation), saturated NaHCO.sub.3 solution (1.3 L) and brine (1.3
L). After drying over Na.sub.2SO.sub.4 the solvent was removed
i.vac., and the white crystalline product purified by
recrystallization in 500 ml t-butyl methyl ether to yield 217.8 g
(89%) of [(1S)-2-(methoxymethylamino)-1-methyl-2-oxoethyl]-carbamic
acid t-butyl ester.
[0331] .sup.1H-NMR (300 MHz, CDCl.sub.3); .delta.=5.25 (br, 1H),
4.67 (dq, 1H), 3.76 (s, 3H), 3.20 (s, 3H), 1.43 (s, 9H), 1.30 (d,
3H).
[(1S)-2-(6-methoxy-3-pyridinyl)-1-methyl-2-oxoethyl]carbamic acid
t-butyl ester
##STR00046##
[0333] To 248 ml Isopropylmagnesium chloride (2M in THY, 496 mmol)
were added 20.97 g (495 mmol) lithium chloride and the resulting
suspension was stirred for 60 min at room temperature. At 0.degree.
to 10.degree. C. 93 g (495 mmol) 5-Brom-2-methoxypyridin were added
over 30 min and stirred for 60 min at room temperature. In parallel
91.91 g (396 mmol)
[(1S)-2-(methoxymethylamino)-1-methyl-2-oxoethyl]carbamic acid
t-butyl ester were suspended in 425 ml THF and over 40 min at
20.degree. bis 25.degree. C. 198 ml isopropylmagnesium chlorid (2M
in THF, 396 mmol) were added and stirred for additional 15 minutes
at room temperature. The clear LiCl/5-Brom-2-methoxypyridin/iPrMgBr
solution was slowly added to the Weinreb amid suspension at
20.degree. to 25.degree. C. and stirred over night. The reaction
mixture was cooled to 2.degree. C. and added slowly to a mixture of
70 ml conc. HCl and 210 ml water at 2.degree. C. While the addition
an external cooling bath at -15.degree. C. was used to keep the
internal temperature in the range of 0.degree. to 5.degree. C. The
pH was adjusted to 5 and 210 ml tert.-butyl methyl ether were added
and the mixture stirred for 15 min at room temperature, phases were
separated and the organic phase was washed with water (210 ml) and
brine (210 ml). The solvent was evaporated and the residue resolved
in 130 ml THF. 1050 ml n-heptane were added and the mixture was
heated to 60.degree. C. to form a single phase. The volume was
reduced to 675 ml and the mixture cooled to room temperature over 1
h and cooled to 2.degree. C. over 30 min. After 60 min at 2.degree.
C. the product is filtered of and dried in vacuum to yield 87.45 g
[(1S)-2-(6-methoxy-3-pyridinyl)-1-methyl-2-oxoethyl]-carbamic acid
t-butyl ester.
[0334] .sup.1H-NMR (300 MHz, CDCl.sub.3); .delta.=8.81 (d, 1H),
8.14 (dd, 1H), 6.81 (d, 1H), 5.52 (br, 1H), 5.18 (dq, 1H), 4.01 (s,
3H), 1.44 (s, 9H), 1.40 (d, 3H).
[(1S,2R)-2-Hydroxy-2-(6-methoxy-3-pyridinyl)-1-methylethyl]-carbamic
acid t-butyl ester
##STR00047##
[0336] To
[(1S)-2-(6-methoxy-3-pyridinyl)-1-methyl-2-oxoethyl]-carbamic acid
t-butyl ester. (102 g, 364 mmol) in 2-propanol (310 mL) and toluene
(475 mL) was added aluminum tri iso-propylate (44.6 g, 218 mmol).
The reaction mixture was stirred at 50.degree. C. for 72 hours and
water (220 ml) ethyl acetate (550 ml) were added. The mixtures pH
is adjusted to 4 (10 ml 6M HCl) and extracted with ethyl acetate
(first phase sep. was decanted). The organic phase is washed with
brine (220 ml), dried over MgSO.sub.4, the solvent is removed
i.vac., and the product purified by chromatography on silica gel
(3000 g, ethyl acetate in hexane 0% to 50%. Yield 100.7 g (98%)
[1S,2R)-2-Hydroxy-2-(6-methoxy-3-pyridinyl)-1-methylethyl]-carbamic
acid t-butyl ester.
[0337] .sup.1H-NMR (300 MHz, CDCl.sub.3); .delta.=8.07 (d, 1H),
7.56 (dd, 1H), 6.72 (d, 1H), 4.75 (m, 1H), 4.57 (d, 1H), 3.98 (m,
1H) 3.92 (s, 3H), 3.81 (br, 1H), 1.44 (s, 9H), 1.00 (d, 3H).
(1R,2S)-2-Amino-1-[6-methoxypyridin-3-yl]propan-1-ol
##STR00048##
[0339] To
[1S,2R)-2-Hydroxy-2-(6-methoxy-3-pyridinyl)-1-methylethyl]-carba-
mic acid t-butyl ester (33 g, 117 mmol) in 290 mL 1,4-dioxane was
added 292 ml HCl in 1,4-dioxane (4 M, 1168 mmol) and the mixture
was stirred for two hours at room temperature. The solvent is
removed i.vac., and the residual HCl salt tree times coevaporated
with 100 mL toluene. The residue (32.53 g) was suspended in 325 mL
acetonitrile and 176.2 g K.sub.2CO.sub.3 was added and the mixture
was stirred over night at 60.degree. C. After cooling to room
temperature the suspension was filtered through a path of cellites
and the solid residues were washed with additional 500 ml
acetonitrile. Acetonitile filtrates were combined and the solvent
was removed i.vac to yield 8.35 g (39.2%)
(1R,2S)-2-Amino-1-[6-methoxypyridin-3-yl]propan-1-ol as free base.
The cellites with the residue were suspended in additional 750 mL
acetonitrile and additional 100 g K.sub.2CO.sub.3 were added.
Stirring at 60.degree. C. was repeated over night. After cooling to
room temperature the suspension was filtered through an additional
path of cellites and the solid residues were washed with additional
500 ml acetonitrile. Combination of filtrates yields 8.45 g (39.6%)
(1R,2S)-2-amino-1-[6-methoxypyridin-3-yl]propan-1-ol as free base,
16.8 g overall.
[0340] .sup.1H-NMR (300 MHz, CDCl.sub.3); .delta.=8.05 (d, 1H),
7.57 (dd, 1H), 6.71 (d, 1H), 4.47 (d, 1H), 3.91 (s, 3H), 3.13 (dq,
1H), 0.94 (d, 3H).
(1R,2S)-1-{[1-(3-Bromophenyl)-1H-indazol-5-yl]oxy}-1-(6-methoxypyridin-3-y-
l)propan-2-amine
##STR00049##
[0342] (1R,2S)-2-Amino-1-[6-methoxypyridin-3-yl]propan-1-ol (200
mg, 0.79 mmol), copper(I)iodide (30 mg, 0.16 mmol),
N,N-dimethylglycin (32 mg, 0.31 mmol) and caesium carbonate (512
mg, 1.57 mmole) were suspended in butyronitrile (1.6 mL). The
reaction vessel was capped and the mixture was stirred at
110.degree. C. for 2 hours. Then 1-(3-bromophenyl)-5-iodoindazole
(266 mg, 0.79 mmole) was added and heating to 130.degree. C. was
continued for 20 hours. The solvent was removed i.vac., and the
product purified by chromatography on silica gel. (ethyl acetate in
hexane 0 to 100%, then methanol in ethyl acetate 10%) to yield 307
mg (86%)
(1R,2S)-1-{[1-(3-Bromophenyl)-1H-indazol-5-yl]oxy}-1-(6-methoxypyridin-3--
yl)propan-2-amine.
[0343] .sup.1H-NMR (300 MHz, CDCl.sub.3); .delta.=8.21 (d, 1H),
7.98 (d, 1H), 7.83 (t, 1H), 7.60 (m, 3H), 7.44 (ddd, 1H), 7.35 (t,
1H), 7.19 (dd, 1H), 7.02 (d, 1H), 6.72 (d, 1H), 5.23 (d, 1H), 3.89
(s, 3H), 3.54 (dq, 1H), 1.27 (d, 3H)
N-[(1R,2S)-1-{[1-(3-bromophenyl)-1H-indazol-5-yl]oxy}-1-(6-methoxypyridin--
3-yl)propan-2-yl]]-2,2-difluoropropanamide
##STR00050##
[0345] 1,1'-Carbonyldiimidazol (217 mg, 1.34 mmol) was added to
2,2-difluorpropionic acid (111 mg, 1.0 mmol) in 4 mL THF and
stirred for 7 hours.
(1R,2S)-1-{[1-(3-bromophenyl)-1H-indazol-5-yl]oxy}-1-(6-methoxyp-
yridin-3-yl)propan-2-amine (304 mg, 0.67 mmol) in THF (2 mL) was
added and stirring was continued for 64 hours at room temperature.
The solvent was removed i.vac., and the product purified by
chromatography on silica gel. (ethyl acetate in hexane 0 to 40%) to
yield 205 mg (56%)
N-[(1R,2S)-1-{[1-(3-bromophenyl)-1H-indazol-5-yl]oxy}-1-(6-methoxypyridin-
-3-yl)propan-2-yl]-2,2-difluoropropanamide.
[0346] .sup.1H-NMR (300 MHz, CDCl.sub.3); .delta.=8.19 (d, 1H),
8.00 (d, 1H), 7.86 (t, 1H), 7.64 (d, 1H), 7.63 (m, 1H), 7.60 (dd,
1H), 7.46 (ddd, 1H), 7.37 (t, 1H), 7.16 (dd, 1H), 6.97 (d, 1H),
6.76 (d, 1H), 6.67 (br, 1H), 5.36 (d, 1H), 4.39 (dq, 1H), 3.92 (s,
3H), 1.77 (t, 3H), 1.28 (d, 3H).
EXAMPLE 23
3-(5-{[(1R,2S)-2-[(2,2-difluoropropanoyl)amino]-1-(6-methoxypyridin-3-yl)p-
ropyl]oxy}-1H-indazol-1-yl)-N-(pyridin-3-yl)benzamide
##STR00051##
[0348] To
N-[(1R,2S)-1-{[1-(3-bromophenyl)-1H-indazol-5-yl]oxy}-1-(6-metho-
xypyridin-3-yl)propan-2-yl]-2,2-difluoropropanamide (37 mg, 68
.mu.mol), 3-aminopyridine (19.2 mg, 204 .mu.mol),
tri-t-butylphosphoniumtetrafluoroborat (8.9 mg, 31 .mu.mol) and
trans-bis(acetato)bis[o-(di-o-tolylphosphino)benzyl]dipalladium(II)
(10.3 mg, 14 .mu.mol) in 1.9 ml THF was added molybdenum
hexacarbonyl (12.5 mg, .mu.mol). The microwave vessel was closed
and radiated in a microwave reactor (CEM discover) at 150 W and
125.degree. C. for 6 minutes (5 minutes ramp time). Then the
solvent was removed i.vac., and the product purified by preparative
thin layer chromatography on silica gel (ethyl acetate 100%) to
yield 22 mg (55%)
3-(5-{[(1R,25)-2-[(2,2-difluoropropanoyl)amino]-1-(6-methoxypyridin-3-yl)-
propyl]oxy}-1H-indazol-1-yl)-N-(pyridin-3-yl)benzamide.
[0349] ES+MS: m/z 587 [MH.sup.+]
[0350] .sup.1H-NMR (300 MHz, CDCl.sub.3); .delta.=8.74 (d, 1H),
8.41 (d, 1H), 8.31 (m, 2H), 8.20 (m, 2H), 7.89 (d, 1H), 7.86 (d,
1H), 7.68 (d, 1H), 7.64 (t, 1H), 7.61 (dd, 1H), 7.33 (dd, 1H), 7.17
(dd, 1H), 6.99 (d, 1H), 6.75 (d, 1H), 6.68 (d, 1H), 5.37 (d, 1H),
4.40 (dq, 1H), 3.92 (s, 3H), 1.77 (t., 3H), 1.25 (d, 3H).
EXAMPLE 24
3-(5-{[(1R,2S)-2-[(2,2-difluoropropanoyl)amino]-1-(6-methoxypyridin-3-yl)p-
ropyl]oxy}-1H-indazol-1-yl)-N-(1,1-dioxidotetrahydrothiophen-3-yl)benzamid-
e
##STR00052##
[0352] To
N-[(1R,2S)-1-{[1-(3-bromophenyl)-1H-indazol-5-yl]oxy}-1-(6-metho-
xypyridin-3-yl)propan-2-yl]-2,2-difluoropropanamide (40 mg, 73
.mu.mol), tetrahydrothiophene-3-amine 1,1-dioxide (13 mg, 135
.mu.mol), tri-t-butylphosphoniumtetrafluoroborat (2.6 mg, 9
.mu.mol) and
trans-bis(acetato)bis[o-(di-o-tolylphosphino)benzyl]dipalladium(II)
(2.8 mg, 14 .mu.mol) in 2 mL THF was added molybdenum hexacarbonyl
(9.3 mg, 35 .mu.mol). The microwave vessel was closed and radiated
in a microwave reactor (CEM discover) at 150 W and 125.degree. C.
for 6 minutes (5 minutes ramp time). Additional
tetrahydrothiophen-3-amine 1,1-dioxide (13 mg, 135 .mu.mol),
tri-t-butylphosphoniumtetrafluoroborat (1.3 mg, 4 .mu.mol) and
trans-bis(acetato)bis[o-(di-o-tolylphosphino)benzyl]dipalladium(H)
(1.4 mg, 2 .mu.mol) were added and microwave radiation was
continued for 8 minutes. Then the solvent was removed i.vac., and
the product purified by chromatography on silica gel (ethyl acetate
in hexane 0% to 30% then additional 5% methanol) to yield 6.5 mg
(14%)
3-(5-{[(1R,2S)-2-[(2,2-difluoropropanoyl)amino]-1-(6-methoxypyridin-3-yl)-
propyl]oxy}-1H-indazol-1-yl)-N-(1,1-dioxidotetrahydrothiophen-3-yl)benzami-
de.
[0353] ES+MS: m/z 628 [MH.sup.+]
[0354] .sup.1H-NMR (300 MHz, CDCl.sub.3); .delta.=8.20 (d, 1H),
8.11 (d, 1H), 8.01 (s, 1H), 7.85 (m, 1H), 7.71 (d, 1H), 7.63 (t,
1H), 7.60 (dd, 1H), 7.16 (dd, 1H), 7.08 (m, 1H), 6.99 (d, 1H), 6.76
(d, 1H), 6.67 (d, 1H), 5.36 (d, 1H), 5.00 (m, 1H), 4.39 (dq, 1H),
3.92 (s, 3H), 3.47 (m, 1H), 3.29 (m, 1H), 3.16 (m, 2H), 2.63 (m,
1H), 2.44 (m 1H), 1.77 (t., 3H), 1.29 (d, 3H).
EXAMPLE 25
3-(5-{[(1R,2S)-2-[(2,2-difluoropropanoyl)amino]-1-(6-methoxypyridin-3-yl)p-
ropyl]oxy}-1H-indazol-1-yl)-N-(tetrahydrofuran-3-yl)benzamide
##STR00053##
[0356] To
N-[(1R,2S)-1-{[1-(3-bromophenyl)-1H-indazol-5-yl]oxy}-1-(6-metho-
xypyridin-3-yl)propan-2-yl]-2,2-difluoropropanamide (37 mg, 68
.mu.mol), 3-aminotetrahydrofuran (18 mg, 204 .mu.mol),
tri-t-butylphosphoniumtetrafluoroborat (8.8 mg, 31 .mu.mol) and
trans-bis(acetato)bis[o-(di-o-tolylphosphino)-benzyl]dipalladium(II)
(10.3 mg, 14 .mu.mol) in 1.5 mL THF was added molybdaenhexacarbonyl
(12.5 mg, 47 .mu.mol). The microwave vessel was closed and radiated
in a microwave reactor (CEM discover) at 150 W and 125.degree. C.
for 10 minutes (5 minutes ramp time. Then the solvent was removed
i.vac., and the product purified by preparative thin layer
chromatography on silica gel (ethyl acetate 100%) to yield 11 mg
(30%)
3-(5-{[(1R,2S)-2-[(2,2-difluoropropanoyl)amino]-1-(6-methoxypyridin-3-yl)-
propyl]oxy}-1H-indazol-1-yl)-N-(tetrahydrofuran-3-yl)benzamide.
[0357] ES+MS: m/z 580 [MH.sup.+]
[0358] .sup.1H-NMR (300 MHz, CDCl.sub.3); .delta.=8.20 (d, 1H),
8.08 (dd, 1H), 8.02 (s, 1H), 7.83 (m, 1H), 7.71 (m, 1H), 7.67 (d,
1H), 7.60 (dd, 1H), 7.58 (t, 1H), 7.16 (dd, 1H), 6.99 (d, 1H), 6.76
(d, 1H), 6.66 (br, 1H), 6.43 (br, 1H), 5.36 (d, 1H), 4.75 (m, 1H),
4.40 (dq, 1H), 4.01 (m, 1H), 3.92 (s, 3H), 3.91 (m, 1H), 3.83 (m,
2H), 2.38 (m, 1H), 1.95 (m, 1H), 1.77 (t, 3H), 1.29 (d, 3H).
EXAMPLE 26
3-(5-{[(1R,2S)-2-[(2,2-difluoropropanoyl)amino]-1-(6-methoxypyridin-3-yl)p-
ropyl]oxy}-1H-indazol-1-yl)-N-(2-hydroxybutyl)benzamide
##STR00054##
[0360] To
N-[(1R,2S)-1-{[1-(3-bromophenyl)-1H-indazol-5-yl]oxy}-1-(6-metho-
xypyridin-3-yl)propan-2-yl]-2,2-difluoropropanamide (50 mg, 92
.mu.mol), 1-amino-2-butanole (25 mg, 275 .mu.mol),
tri-t-butylphosphoniumtetrafluoroborat (12 mg, 41 .mu.mol) and
trans-bis(acetato)bis[o-(di-o-tolylphosphino)-benzyl]dipalladium(II)
(mg, 7 .mu.mol) in 2 mL THF was added molybdenum hexacarbonyl (17
mg, 64 .mu.mol). The microwave vessel was closed and radiated in a
microwave reactor (CEM discover) at 150 W and 125.degree. C. for 10
minutes (5 minutes ramp time). Then the solvent was removed i.vac.,
and the product purified by chromatography on silica gel (ethyl
acetate in hexane 0% to 100%) to yield 35 mg (66%)
3-(5-{[(1R,2S)-2-[(2,2-difluoropropanoyl)amino]-1-(6-methoxypyridin-3-yl)-
propyl]oxy}-1H-indazol-1-yl)-N-(2-hydroxybutyl)benzamide.
[0361] ES+MS: m/z 582 [MH.sup.+]
[0362] .sup.1-NMR (300 MHz, CDCl.sub.3); .delta.=8.20 (d, 1H), 8.11
(s, 1H), 8.01 (s, 1H), 7.82 (m, 1H), 7.73 (d, 1H), 7.66 (d, 1H),
7.60 (dd, 1H), 7.57 (t, 1H), 7.16 (dd, 1H), 6.98 (d, 1H), 6.75 (d,
1H), 6.74 (br, 1H), 6.66 (br, 1H), 5.36 (d, 1H), 4.40 (dq, 1H),
3.92 (s, 3H), 3.76 (m, 1H), 3.74 (dddd, 1H), 3.34 (dddd, 1H), 1.77
(t, 3H), 1.57 (m, 2H), 1.29 (d, 3H), 1.00 (t, 3H).
EXAMPLE 27
N-cyclopentyl-3-(5-{[1R,
2S)-2-[(2,2-difluoropropanoyl)amino]-3-hydroxy-1-(6-methoxypyridin-3-yl)p-
ropyl]oxy}-1H-indazol-1-yl)benzamide
##STR00055##
[0364] To
N-[(1R,2S)-1-{[1-(3-bromophenyl)-1H-indazol-5-yl]oxy}-3-tert-but-
oxy-1-(6-methoxypyridin-3-yl)propan-2-yl]-2,2-difluoropropanamide
(37 mg, 60 .mu.mol), cyclopentylamine (7.1 mg, 84 .mu.mol),
Tri-t-butylphosphoniumtetrafluoroborat (3.5 mg, 12 .mu.mol) and
trans-bis(acetato)bis[o-(di-o-tolylphosphino)-benzyl]dipalladium(II)
(9.1 mg, 12 .mu.mol) in 1.6 ml THF was added molybdenum
hexacarbonyl (7.6 mg, 29 .mu.mol). The microwave vessel was closed
and radiated in microwave reactor (CEM discover) at 150 W and
125.degree. C. for 6 minutes (5 minutes ramp time). Then the
solvent was removed i.vac., and the product purified by preparative
thin layer chromatography on silica gel (ethyl acetate in hexane
50%) to yield 15 mg of
3-(5-{[1R,2S)-3-tert-butoxy-2-[(2,2-difluoropropanoyl)amino]-1-(6-methoxy-
pyridin-3-yl)propyl]oxy}-1H-indazol-1-yl)-N-cyclopentylbenzamide,
which were treated with 178 .mu.l trifluoroacetic acid in 0.6 ml
dichloromethane over 18 hours at room temperature. Saturated sodium
hydrogen carbonate solution was added, the mixture was stirred
vigorously and extracted with ethyl acetate after 30 minutes. Then
the solvent was removed i.vac., and the product purified by
preparative thin layer chromatography on silica gel (ethyl acetate
100%) to yield 15 mg of
N-cyclopentyl-3-(5-{[(1R,2S)-2-[(2,2-difluoropropanoyl)amino]-3-hydroxy-1-
-(6-methoxypyridin-3-yl)propyl]oxy}-1H-indazol-1-yl)benzamide.
[0365] ES+MS: m/z 594 [MH.sup.+]
[0366] .sup.1H-NMR (400 MHz, CDCl.sub.3); .delta.=8.17 (d, 1H),
8.02 (s, 1H), 7.97 (s, 1H), 7.77 (d, 1H), 7.69 (d, 1H), 7.66 (dd,
1H), 7.61 (d, 1H), 7.56 (t, 1H), 7.08 (dd, 1H), 6.98 (d, 1H), 6.74
(d, 1H), 6.24 (d, 1H), 5.42 (d, 1H), 4.42 (ddd, 1H), 4.35 (m, 1H),
4.20 (d, 1H), 3.90 (s, 3H), 3.78 (m, 1H), 2.76 (br, 1H), 2.11 (m,
2H), 1.66 (t, 3H), 1.64-1.74 (m., 4H), 1.52 (m, 2H).
carbamic acid,
[(1S)-1-[(1,1-dimethylethoxy)methyl]-2-(methoxymethylamino)-2-oxoethyl]-9-
H-fluoren-9-ylmethyl ester
##STR00056##
[0368] FMOC-SER(TBU)-OH (50 g, 130 mmol) in 320 ml dichloromethane
were cooled to 0.degree. C. 1,1'-Carbonyldiimidazol (28.3 g, 175
mmol) were added in multiple portions and stirring was continued
for 30 minutes at 0.degree. C. Triethylamine (24.2 ml, 175 mmol)
was added followed by N,O-dimethyl hydroxylamine mono hydrochloride
(17 g, 175 mmol) in multiple portions and stirring was continued
for 30 minutes at 0.degree. C. After stirring for 14 hours at room
temperature the mixture was diluted with 400 ml t-butyl methylether
and washed with 1M HCL solution (2 times 100 ml), saturated
NaHCO.sub.3 solution and brine. After drying over Na.sub.2SO.sub.4
the solvent was removed i.vac., and the product purified by
chromatography on silica gel (ethyl acetate in hexane, 0% to 70%)
to yield 39.2 g of carbamic acid,
[(1S)-1-[(1,1-dimethylethoxy)methyl]-2-(methoxymethylamino)-2-oxoethyl]-,
9H-fluoren-9-ylmethyl ester (92%).
[0369] .sup.1H-NMR (300 MHz, CDCl.sub.3); .delta.=7.76 (d, 2H),
7.61 (m, 2H), 7.40 (dd, 2H), 7.31 (dd, 2H), 5.68 (d, 1H), 4.87 (br,
1H), 4.36 (d, 2H), 4.24 (t, 1H), 3.78 (s, 3H), 3.62 (m, 2H), 3.25
(s, 3H), 1.16 (s, 9H).
9H-fluoren-9-ylmethyl[(2S)-3-tent-butoxy-1-(6-methoxypyridin-3-yl)-1-oxopr-
opan-2-yl]carbamate
##STR00057##
[0371] 64 ml Isopropylmagnesium chloride (2M in THF, 128 mmol) were
added to 5-Brom-2-methoxypyridin (10 g, 53 mmol) and carbamic acid,
[(1S)-1-[(1,1-dimethylethoxy)methyl]-2-(methoxymethylamino)-2-oxoethyl]-,
9H-fluoren-9-ylmethyl ester (18.1 g, 43 mmol) in 55 ml THF at
-15.degree. C. and stirred over night while the mixture was warmed
to room temperature. The reaction mixture was cooled to 2.degree.
C. and added slowly to a 2M HCl-ice mixture and stirred vigorously.
The pH was adjusted to 5 and the aqueous phase extracted with ethyl
acetate. After drying over Na.sub.2SO.sub.4 the solvent was removed
i.vac., and the product purified by chromatography on silica gel
(ethyl acetate in hexane, 0 to 100%) to yield 3.28 g (13%)
9H-fluoren-9-ylmethyl[(2S)-3-tert-butoxy-1-(6-methoxypyridin-3-yl)-1-oxop-
ropan-2-yl]carbamate.
[0372] .sup.1H-NMR (300 MHz, CDCl.sub.3); .delta.=8.82 (d, 1H),
8.16 (dd, 1H), 7.77 (d, 2H), 7.63 (m, 2H), 7.41 (dd, 2H), 7.32 (dd,
2H), 6.81 (d, 1H), 5.95 (d, 1H), 5.29 (m, 1H), 4.40 (d, 2H), 4.25
(t, 1H), 4.02 (s, 3H), 3.76 (dd, 1H), 3.66 (dd, 1H), 1.02 (s,
9H).
9H-fluoren-9-ylmethyl[(1R,2S)-3-tert-butoxy-1-hydroxy-1-(6-methoxypyridin--
3-yl)propan-2-yl]carbamate
##STR00058##
[0374]
9H-fluoren-9-ylmethyl[(2S)-3-tert-butoxy-1-(6-methoxypyridin-3-yl)--
1-oxopropan-2-yl]carbamate (2.26 g, 4.76 mmol) in 2-propanol (4.4
mL) and toluene (6 mL) was added aluminum tri iso-propylate (300
mg, 1.4 mmol) The reaction mixture was stirred at 65.degree. C. for
72 hours, additional aluminum tri iso-propylate (300 mg, 1.4 mmol)
was added and stirring was continued for 24 hours. Water was added,
the mixture was stirring for 15 minutes and extracted with ethyl
acetate. The organic phase was dried over Na.sub.2SO.sub.4, the
solvent is removed i.vac., and the product purified by
chromatography on silica gel (ethyl acetate in hexane 0% to 100%)
to yield 1.46 g (65%) 9H-fluoren-9-ylmethyl
[(1R,2R)-3-tert-butoxy-1-hydroxy-1-(6-methoxypyridin-3-yl)propan-2-yl]car-
bamate.
[0375] .sup.1H-NMR (300 MHz, CDCl.sub.3); .delta.=8.18 (s, 1H),
7.78 (d, 2H), 7.66 (m, 3H), 7.41 (dd, 2H), 7.32 (dd, 2H), 6.75 (d,
1H), 5.64 (d, 1H), 4.91 (m, 1H), 4.41 (m, 2H), 4.23 (m, 2H), 3.93
(s, 3H), 3.50 (dd, 2H), 1.18 (s, 9H).
(1R,2S)-2-amino-3-tert-butoxy-1-(6-methoxypyridin-3-yl)propan-1-ol
##STR00059##
[0377] To
9H-fluoren-9-ylmethyl[(1R,2S)-3-tert-butoxy-1-hydroxy-1-(6-metho-
xypyridin-3-yl)propan-2-yl]carbamate (2.38 g, 5.0 mmol) in 19 mL
N,N-dimethylformamide was added piperidine (4.9 mL, 50 mmol) at
room temperature. The reaction mixture was stirred 20 hours at room
temperature. The reaction mixture was added to ice-water and the
precipitate removed by filtration through cellites followed by
careful washing of the solids with water. The aqueous filtrate was
extracted with 10% methanol in dichloromethane and the organic
phase was dried over Na.sub.2SO.sub.4. The solvent was removed
i.vac., and the product purified by chromatography on silica gel.
(methanol in dichloromethane 0% to 10%) to yield 426 mg (34%)
(1R,2S)-2-amino-3-tert-butoxy-1-(6-methoxypyridin-3-yl)propan-1-ol.
[0378] .sup.1H-NMR (400 MHz, CDCl.sub.3); .delta.=8.13 (d, 1H),
7.63 (dd, 1H), 6.76 (d, 1H), 4.62 (d, 1H), 3.94 (s, 3H), 3.47 (dd,
1H), 3.35 (dd, 1H), 3.09 (m, 1H), 1.20 (s, 9H).
(1R,2S)-1-{[1-(3-bromophenyl)-1H-indazol-5-yl]oxy}-3-tert-butoxy-1-(6-meth-
oxypyridin-3-yl)propan-2-amine
##STR00060##
[0380]
(1R,2S)-2-Amino-3-tert-butoxy-1-(6-methoxypyridin-3-yl)propan-1-ol
(350 mg, 1.38 mmol), copper(I)iodide (52 mg, 0.28 mmol),
N,N-dimethylglycine (57 mg, 0.55 mmol) and caesium carbonate (896
mg, 2.75 mmole) were suspended in butyronitrile (2.9 mL). The
reaction vessel was capped and the mixture was stirred at
110.degree. C. for 2 hours. Then 1-(3-bromophenyl)-5-iodoindazole
(465 mg, 1.38 mmole) was added and heating to 130.degree. C. was
continued for 20 hours. The mixture was filtered through cellites
followed by careful washing of the solids with 10% triethylamine in
methanol. The solvent was removed i.vac., and the product purified
by chromatography on silica gel. (ethyl acetate in dichloromethane
0 to 100%, then methanol in ethyl acetate 10%+1% triethylamine) to
yield 122 mg (17%)
(1R,2S)-1-{[1-(3-bromophenyl)-1H-indazol-5-yl]oxy}-3-tert-butoxy-1-(6-met-
hoxypyridin-3-yl)propan-2-amine.
[0381] .sup.1H-NMR (300 MHz, CDCl.sub.3); .delta.=8.22 (d, 1H),
8.01 (d, 1H), 7.86 (t, 1H), 7.67 (dd, 1H), 7.62 (ddd, 1H), 7.60 (d,
1H), 7.45 (ddd, 1H), 7.36 (t, 1H), 7.13 (dd, 1H), 7.04 (d, 1H),
6.75 (d, 1H), 5.18 (d, 1H), 3.91 (s, 3H), 3.58 (dd, 1H), 3.50 (dd,
1H), 3.37 (m, 1H), 1.20 (s, 1H)
N-[(1R,2S)-1-{[1-(3-bromophenyl)-1H-indazol-5-yl]oxy}-3-tert-butoxy-1-(6-m-
ethoxypyridin-3-yl)propan-2-yl]-2,2-difluoropropanamide
##STR00061##
[0383] 1,1'-Carbonyldiimidazol (74 mg, 0.46 mmol) was added to
2,2-difluorpropionic acid (50 mg, 0.46 mmol) in 1.2 mL THF and
stirred for 3 hours.
(1R,2S)-1-{[1-(3-bromophenyl)-1H-indazol-5-yl]oxy}-3-tert-butoxy-1-(6-met-
hoxypyridin-3-yl)propan-2-amine (120 mg, 0.23 mmol) in THF (1.2 ml)
was added and stirring was continued for 20 hours at room
temperature. Water and ethyl acetate were added, the mixture was
stirred vigorously, extracted with ethyl acetate after 30 minutes
and washed with brine. The solvent was removed i.vac., and the
product purified by chromatography on silica gel. (ethyl acetate in
hexane 0 to 50%) to yield 52 mg (37%)
N-[(1R,2S)-1-{[1-(3-bromophenyl)-1H-indazol-5-yl]oxy}-3-tert-butoxy-1-(6--
methoxypyridin-3-yl)propan-2-yl]-2,2-difluoropropanamide.
[0384] .sup.1H-NMR. (300 MHz, CDCl.sub.3); .delta.=8.13 (d, 1H),
8.02 (d, 1H), 7.86 (t, 1H), 7.71 (dd, 1H), 7.63 (ddd, 1H), 7.61 (d,
1H), 7.45 (ddd, 1H), 7.37 (t, 1H), 7.13 (dd, 1H), 7.06 (d, 1H),
6.76 (br, 1H), 6.72 (d, 1H), 5.27 (d, 1H), 4.51 (m, 1H), 4.01 (dd,
1H), 3.89 (s, 3H), 3.49 (dd, 1H), 1.57 (t, 3H), 1.18 (s, 9H).
EXAMPLE 28
3-(5-{[(1R,2S)-2-[(2,2-difluoropropanoyl)amino]-1-(6-methoxypyridin-3-yl)p-
ropyl]oxy}-1H-indazol-1-yl)-N-(pyridin-3-ylmethyl)benzamide
##STR00062##
[0386] To
N-[1R,2S)-1-{[1-(3-bromophenyl)-1H-indazol-5-yl]oxy}-1-(6-methox-
ypyridin-3-yl)propan-2-yl]-2,2-difluoropropanamide (50 mg, 92
.mu.mol), 3-aminomethylpyridine (30 mg, 275 .mu.mol),
tri-t-butylphosphoniumtetrafluoroborat (12 mg, 41 .mu.mol) and
trans-bis(acetato)bis[o-(di-o-tolylphosphino)benzyl]dipalladium(II)
(13.9 mg, 18 .mu.mol) in 2 ml THF was added molybdenum hexacarbonyl
(17 mg, 64 .mu.mol). The microwave vessel was closed and radiated
in a microwave reactor (CEM discover) at 150 W and 125.degree. C.
for 10 minutes (5 minutes ramp time). Then the solvent was removed
i.vac., and the product purified chromatography on silica gel
(hexane/ethyl acetate 0 to 100%) to yield 19 mg (35%)
3-(5-{[(1R,2S)-2-[(2,2-difluoropropanoyl)amino]-1-(6-methoxypyridin-3-yl)-
propyl]oxy}-1H-indazol-1-yl)-N-(pyridin-3-ylmethyl)benzamide.
[0387] ES+MS: m/z 601[MH.sup.+]
[0388] .sup.1H-NMR (300 MHz, CDCl.sub.3); .delta.=8.62 (br, 1H),
8.55 (br, 1H), 8.19 (d, 1H), 8.12 (m, 1H), 8.00 (s, 1H), 7.84 (d,
1H), 7.74 (m, 2H), 7.67 (d, 1H), 7.58 (m, 2H), 7.29 (dd, 1H), 7.15
(dd, 1H), 6.98 (d, 1H), 6.75 (d, 1H), 6.69 (m, 2H), 5.35 (d, 1H),
4.68 (d, 2H), 4.39 (dq, 1H), 3.92 (s, 3H), 1.76 (t., 3H), 1.28 (d,
3H).
Assay
Human Glucocorticoid Receptor (GR) Assay
[0389] The radioligand GR binding assay is based on a competition
assay using .sup.3H-labeled Dexamethasone. Dexamethasone is known
to bind in the ligand binding domain of GR and compete for binding
with endogenous ligands like e.g. cortisol (Necela, 2003). In the
GR radioligand binding assay, test compounds were serially diluted
in semi-log steps (10 concentrations) with a final concentration of
10 .mu.M. Test compounds (1 .mu.L) and controls (1 .mu.L) in 100%
DMSO were added to 96 Greiner V-bottom polypropylene plates. 0%
control was 6.7% DMSO (final concentration in assay) and 100%
control was 6.7 .mu.M Dexamethasone.
[0390] The full length GR was diluted to a final concentration of
3.3% (0.495 mg/ml) in assay buffer (20 mM Tris-HCl, 1 mM EDTA, 10%
(w/v) Glycerol, 20 mM Sodium molybdate, pH 7.4). 45 .mu.L of GR was
added to each well and the plates were incubated for 15 min at room
temperature.
[0391] .sup.3H-dexamethasone solution was diluted to a
concentration of 70 nM in assay buffer (7 nM final assay
concentration) and 5 .mu.L was added to each well. The samples were
mixed for 5 min using a plate shaker at 700 rpm, before incubation
for 2 h at room temperature.
[0392] 50 .mu.L ice-cold charcoal solution (pH 7.4:2% Charcoal,
0.2% Dextran T70 in 20 mM Tris-HCl, 1 mM EDTA and 20 mM Sodium
molybdate) was added to each well and the samples were mixed on
plate shaker for 5 minutes.
[0393] The plate was then centrifuged for 1.5 min at 1500 rpm, the
samples (80 .mu.L) were is transferred from each well to a filter
plate (Millipore, 0.45 .mu.m, MHVBN45) on a vacuum manifold and
then collected into new plates (Greiner, 96 well white/transparent,
655095). The filter plate was washed once with 20 .mu.l of water
and then 100 .mu.L of scintillation liquid was added to each well
and mixed by incubation on plate shaker for 5 min. Radioactivity
was measured in a 1450 Microbeta Trilux Reader (Wallac) counting
cpm for 2 minutes per well. The data obtained from each replicate
experiment were analysed using the software ActivityBase, version
5.4.3 (ID Business Solutions Ltd) and IC.sub.50 values were
calculated. Ref: Necela, B M, Cidlowski, J A, Trends Pharmacol Sci,
24: 58, 2003
TABLE-US-00001 Example GR Binding IC50 Nr [nM] 1 2.81 2 19.9 3 1.69
4 1.61 5 1.93 6 5.06 7 16.9 8 6.88 9 5.65 10 1.73 11 6.77 12 2.54
13 38.4 14 40.2 15 1.72 16 42.4 17 3.55 18 4.22 19 2.29 20 75.9 21
2.91 22 1.37 23 0.86 24 4.46 25 2.99 26 4.13 27 13.6 28 1.39
* * * * *