U.S. patent application number 11/931313 was filed with the patent office on 2011-07-14 for condensed n-heterocyclic compounds and their use as crf receptor antagonists.
This patent application is currently assigned to SB Pharmco Puerto Rico Inc. Invention is credited to Daniele Andreotti, Giovanni Bernasconi, Emiliano Castiglioni, Stefania Anne Contini, Romano Di Fabio, Elettra Fazzolari, Aldo Feriani, Gabriella Gentile, Mario Mattioli, Anna Mingardi, Fabio Maria Sabbatini, Yves St-Denis.
Application Number | 20110172255 11/931313 |
Document ID | / |
Family ID | 33312357 |
Filed Date | 2011-07-14 |
United States Patent
Application |
20110172255 |
Kind Code |
A1 |
Andreotti; Daniele ; et
al. |
July 14, 2011 |
Condensed N-Heterocyclic Compounds and their Use as CRF Receptor
Antagonists
Abstract
The present invention provides compounds of formula (I),
processes for their preparation, pharmaceutical compositions
containing them and their use in the treatment of conditions
mediated by corticotropin-releasing factor (CRF). ##STR00001##
Inventors: |
Andreotti; Daniele; (Verona,
IT) ; Bernasconi; Giovanni; (Verona, IT) ;
Castiglioni; Emiliano; (Verona, IT) ; Contini;
Stefania Anne; (Verona, IT) ; Fabio; Romano Di;
(Verona, IT) ; Fazzolari; Elettra; (Verona,
IT) ; Feriani; Aldo; (Verona, IT) ; Gentile;
Gabriella; (Verona, IT) ; Mattioli; Mario;
(Verona, IT) ; Mingardi; Anna; (Verona, IT)
; Sabbatini; Fabio Maria; (Verona, IT) ; St-Denis;
Yves; (Verona, IT) |
Assignee: |
SB Pharmco Puerto Rico Inc
Neurocrine Bioscienses, Inc.
|
Family ID: |
33312357 |
Appl. No.: |
11/931313 |
Filed: |
October 31, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10552493 |
Sep 21, 2006 |
7427630 |
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11931313 |
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Current U.S.
Class: |
514/265.1 ;
514/303; 544/280; 546/113 |
Current CPC
Class: |
A61P 1/04 20180101; A61P
19/08 20180101; A61P 27/02 20180101; C07D 471/04 20130101; A61P
25/34 20180101; A61P 11/16 20180101; A61P 15/08 20180101; A61P
25/00 20180101; A61P 25/18 20180101; A61P 37/08 20180101; A61P
19/02 20180101; A61P 25/02 20180101; A61P 43/00 20180101; A61P
25/32 20180101; A61P 1/02 20180101; A61P 11/04 20180101; A61P 17/04
20180101; A61P 25/04 20180101; A61P 1/08 20180101; A61P 25/24
20180101; A61P 5/00 20180101; A61P 25/06 20180101; A61P 31/22
20180101; A61P 11/06 20180101; A61P 25/28 20180101; A61P 37/02
20180101; A61P 17/00 20180101; A61P 35/00 20180101; A61P 5/38
20180101; A61P 17/02 20180101; A61P 1/14 20180101; A61P 3/08
20180101; A61P 19/06 20180101; A61P 27/16 20180101; A61P 3/10
20180101; A61P 11/02 20180101; A61P 25/22 20180101; A61P 15/00
20180101; A61P 25/30 20180101; A61P 29/00 20180101; A61P 31/04
20180101; A61P 31/16 20180101; A61P 13/02 20180101; A61P 25/20
20180101; A61P 3/04 20180101; A61P 13/10 20180101; C07D 487/04
20130101; A61P 9/10 20180101; A61P 17/06 20180101; A61P 25/36
20180101 |
Class at
Publication: |
514/265.1 ;
544/280; 546/113; 514/303 |
International
Class: |
A61K 31/519 20060101
A61K031/519; C07D 487/04 20060101 C07D487/04; C07D 471/04 20060101
C07D471/04; A61K 31/437 20060101 A61K031/437; A61P 25/24 20060101
A61P025/24; A61P 25/22 20060101 A61P025/22 |
Foreign Application Data
Date |
Code |
Application Number |
Apr 9, 2003 |
GB |
0308208.8 |
Claims
1. A compound according to formula (IV) ##STR00101## wherein: R is
aryl or heteroaryl, each of which may be substituted by 1 to 4
groups J selected from: halogen, C1-C6 alkyl, C1-C6 alkoxy, halo
C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo C1-C6 alkoxy,
--C(O)R2, nitro, hydroxy, --NR.sub.3R.sub.4, cyano and a group Z;
R.sub.1 is hydrogen or C1-C6 alkyl; R.sub.2 is C1-C4 alkyl; R.sub.3
is hydrogen or C1-C6 alkyl; R.sub.4 is hydrogen or C1-C6 alkyl;
R.sub.5 is a C1-C6 alkyl, halo C1-C6 alkyl, C1-C6 alkoxy, halo
C1-C6 alkoxy, C3-C7 cycloalkyl, hydroxy, halogen, nitro, cyano,
--NR.sub.3R.sub.4, or --C(O)R.sub.2; R.sub.6 is C1-C6 alkyl, halo
C1-C6 alkyl, C1-C6 alkoxy, halo C1-C6 alkoxy, C3-C7 cycloalkyl,
hydroxy, halogen, nitro, cyano, --NR.sub.3R.sub.4, or
--C(O)R.sub.2; R.sub.7 is hydrogen; R.sub.8 is hydrogen; R.sub.9 is
hydrogen; R.sub.10 is hydrogen; R.sub.11 is hydrogen; R.sub.12 is
R.sub.3 or --C(O)R.sub.2; D is CR.sub.8R.sub.9; G is
CR.sub.10R.sub.11; Z is a 5-6 membered heterocycle, which may be
substituted by 1 to 8 R.sub.5 groups or a phenyl ring, which may be
substituted by 1 to 4 R.sub.5 groups; m is an integer from 0 to 2;
and q is an integer from 0 to 2; or a pharmaceutically acceptable
salt thereof.
2. A compound according to claim 1 wherein: R is aryl or
heteroaryl, each of which may be substituted by 1 to 4 groups J
selected from: halogen, C1-C6 alkyl, C1-C6 alkoxy, halo C1-C6
alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo C1-C6 alkoxy,
--C(O)R.sub.2, nitro, hydroxy, --NR.sub.3R.sub.4, cyano or a group
Z; R.sub.1 is hydrogen, C1-C6 alkyl; R.sub.2 is a C1-C4 alkyl;
R.sub.3 is hydrogen or C1-C6 alkyl; R.sub.4 is hydrogen or C1-C6
alkyl; R.sub.5 is a C1-C6 alkyl, halo C1-C6 alkyl, C1-C6 alkoxy,
halo C1-C6 alkoxy, C3-C7 cycloalkyl, hydroxy, halogen, nitro,
cyano, --NR.sub.3R.sub.4, or --C(O)R.sub.2; R.sub.6 is a C1-C6
alkyl, halo C1-C6 alkyl, C1-C6 alkoxy, halo C1-C6 alkoxy, C3-C7
cycloalkyl, hydroxy, halogen, nitro, cyano, --NR.sub.3R.sub.4 or
--C(O)R.sub.2; R.sub.7 is hydrogen; R.sub.8 is hydrogen; R.sub.9 is
hydrogen; R.sub.10 is hydrogen; R.sub.11 is hydrogen; R.sub.12 is
hydrogen; D is CR.sub.8R.sub.9; G is CR.sub.10R.sub.11; Z is a 5-6
membered heterocycle, which may be substituted by 1 to 8 R.sub.5
groups or a phenyl ring, which may be substituted by 1 to 4 R.sub.5
groups; m is an integer from 0 to 2; and q is 0; or a
pharmaceutically acceptable salt thereof.
3. A compound according to claim 2 wherein Z is selected from the
group consisting of pyrimidinyl, pyridinyl, thiazolyl, pyrazolyl,
triazolyl and phenyl; or a pharmaceutically acceptable salt
thereof.
4. A compound according to claim 2 wherein R is an aryl group
selected from: 2,4-dichlorophenyl, 2-chloro-4-methylphenyl,
2-chloro-4-trifluoromethylphenyl, 2-chloro-4-methoxyphenyl,
2,4,5-trimethylphenyl, 2,4-dimethylphenyl,
2-methyl-4-methoxyphenyl, 2-methyl-4-ethoxyphenyl,
2-methyl-4-isopropoxyphenyl, 2-methyl-4-hydroxyphenyl,
2-methyl-4-chlorophenyl, 2-methyl-4-trifluoromethylphenyl,
2,4-dimethoxyphenyl, 2-methoxy-4-trifluoromethylphenyl,
2-methoxy-4-chlorophenyl, 3-methoxy-4-chlorophenyl,
2,5-dimethoxy-4-chlorophenyl, 2-methoxy-4-isopropylphenyl,
2-methoxy-4-trifluoromethylphenyl, 2-methoxy-4-isopropylphenyl,
2-methoxy-4-methylphenyl, 2-trifluoromethyl-4-chlorophenyl,
2,4-bis-trifluoromethylphenyl, 2-trifluoromethyl-4-methylphenyl,
2-trifluoromethyl-4-methoxyphenyl,
2-difluoromethyl-4-methoxyphenyl, 2-bromo-4-isopropylphenyl,
2-methyl-4-cyanophenyl, 2-chloro-4-cyanophenyl,
2-trifluoromethyl-4-cyanophenyl, 2-trifluoromethoxy-4-cyanophenyl,
2-ethyl-4-cyanophenyl, 2-methyl-4-trifluoromethoxyphenyl,
4-methyl-6-dimethylaminopyridin-3-yl, 2,6-bismethoxy-pyridin-3-yl,
2-methyl-6-methoxy-pyridin-3-yl,
2-trifluoromethyl-6-methoxy-pyridin-3-yl
3-chloro-5-trichloromethyl-pyridin-2-yl,
2-methyl-4-(pyrazol-1-yl)-phenyl,
2-methoxy-4-(pyrazol-1-yl)-phenyl, 2,4,6-trimethoxyphenyl,
2-methyl-4,5-benzodioxolyl, and 2-methyl-3,4-benzodioxolyl; or a
pharmaceutically acceptable salt thereof.
5. A compound according to claim 1 selected from:
1-{1-[1-(4-Methoxy-2-methylphenyl)-6-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]-
pyridin-4-yl]-1H-pyrazol-3-yl}-3-methylimidazolidin-2-one;
1-{1-[1-(2,4-Dichlorophenyl)-6-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridi-
n-4-yl]-1H-pyrazol-3-yl}imidazolidin-2-one;
1-(1-{1-[2,4-Bis(trifluoromethyl)phenyl]-6-methyl-2,3-dihydro-1H-pyrrolo[-
2,3-b]pyridin-4-yl}-1H-pyrazol-3-yl)-2-imidazolidinone;
1-{1-[1-(4-Hydroxy-2-methylphenyl)-6-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]-
pyridin-4-yl]-1H-pyrazol-3-yl}-2-imidazolidinone;
1-(1-{1-[4-(Ethyloxy)-2-methylphenyl]-6-methyl-2,3-dihydro-1H-pyrrolo[2,3-
-b]pyridin-4-yl}-1H-pyrazol-3-yl)-2-imidazolidinone;
1-[1-(6-Methyl-1-{2-methyl-4-[(1-methylethyl)oxy]phenyl}-2,3-dihydro-1H-p-
yrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-3-yl]-2-imidazolidinone;
1-[1-(6-Methyl-1-{2-methyl-4-[(trifluoromethyl)oxy]phenyl}-2,3-dihydro-1H-
-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-3-yl]-2-imidazolidinone;
3-Methyl-4-{6-methyl-4-[3-(2-oxo-1-imidazolidinyl)-1H-pyrazol-1-yl]-2,3-d-
ihydro-1H-pyrrolo[2,3-b]pyridin-1-yl}benzonitrile;
1-(1-{6-Methyl-1-[2-methyl-4-(1H-pyrazol-1-yl)phenyl]-2,3-dihydro-1H-pyrr-
olo[2,3-b]pyridin-4-yl}-1H-pyrazol-3-yl)-2-imidazolidinone;
4-{6-Methyl-4-[3-(2-oxo-1-imidazolidinyl)-1H-pyrazol-1-yl]-2,3-dihydro-1H-
-pyrrolo[2,3-b]pyridin-1-yl}-3-(trifluoromethyl)benzonitrile;
1-(1-{1-[2-(Difluoromethyl)-4-(methyloxy)phenyl]-6-methyl-2,3-dihydro-1H--
pyrrolo[2,3-b]pyridin-4-yl}-1H-pyrazol-3-yl)-2-imidazolidinone;
4-{6-Methyl-4-[3-(2-oxo-1-imidazolidinyl)-1H-pyrazol-1-yl]-2,3-dihydro-1H-
-pyrrolo[2,3-b]pyridin-1-yl}-3-[(trifluoromethyl)oxy]benzonitrile;
3-Ethyl-4-{6-methyl-4-[3-(2-oxo-1-imidazolidinyl)-1H-pyrazol-1-yl]-2,3-di-
hydro-1H-pyrrolo[2,3-b]pyridin-1-yl}benzonitrile;
1-(1-{6-Methyl-1-[2-(methyloxy)-4-(1H-pyrazol-1-yl)phenyl]-2,3-dihydro-1H-
-pyrrolo[2,3-b]pyridin-4-yl}-1H-pyrazol-3-yl)-2-imidazolidinone;
1-{1-[6-Methyl-1-(6-methyl-1,3-benzodioxol-5-yl)-2,3-dihydro-1H-pyrrolo[2-
,3-b]pyridin-4-yl]-1H-pyrazol-3-yl}-2-imidazolidinone;
1-(1-{6-Methyl-1-[2,4,6-tris(methyloxy)phenyl]-2,3-dihydro-1H-pyrrolo[2,3-
-b]pyridin-4-yl}-1H-pyrazol-3-yl)-2-imidazolidinone;
1-{1-[6-Methyl-1-(6-methyl-1,3-benzodioxol-5-yl)-2,3-dihydro-1H-pyrrolo[2-
,3-b]pyridin-4-yl]-1H-pyrazol-3-yl}-2-imidazolidinone;
1-(1-{2,6-Dimethyl-1-[2-methyl-4-(methyloxy)phenyl]-2,3-dihydro-1H-pyrrol-
o[2,3-b]pyridin-4-yl}-1H-pyrazol-3-yl)-2-imidazolidinone;
1-(5-Methyl-1-{6-methyl-1-[2-methyl-4-(methyloxy)phenyl]-2,3-dihydro-1H-p-
yrrolo[2,3-b]pyridin-4-yl}-1H-pyrazol-3-yl)-2-imidazolidinone; and
1-[1-(1-{4-[(difluoromethyl)oxy]-2-methylphenyl}-6-methyl-2,3-dihydro-1H--
pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-3-yl]-2-imidazolidinone; or
a pharmaceutically acceptable salt thereof.
6. A pharmaceutical composition comprising a compound according to
claim 1, or a pharmaceutically acceptable salt thereof, in
admixture with one or more physiologically acceptable carriers or
excipients.
7. A method for the treatment of a condition mediated by CRF
(corticotropin-releasing factor), comprising administration of an
effective amount of a compound according claim 1, or a
pharmaceutically acceptable salt thereof, to a mammal in need of
treatment thereof.
8. A method, according to claim 7, for the treatment of depression
or anxiety, comprising administration of an effective amount of a
compound according to claim 1, or a pharmaceutically acceptable
salt thereof.
9. A method, according to claim 7, for the treatment of IBS
(irritable bowel disease) or IBD (inflammatory bowel disease),
comprising administration of an effective amount of a compound
according to claim 1, or a pharmaceutically acceptable salt
thereof.
10. A process for the preparation of the compound according to
claim 1, corresponding to a compound of formula (IIr) in which: R
is 4-methoxy-2-methyl-phenyl; X.sub.1 is oxygen; Y is CH--; Lg is
triflate and Z--W is: ##STR00102## starting from the corresponding
compound of formula (XXIII), comprising the following steps as in
Scheme 2: ##STR00103## in which: step a' stands for the formation
of the pyrrolidinone moiety of compounds (XXIV), which will form
the cycle B present in the final compounds (IIr), by reacting the
compounds (XXIII) with a reactive derivative of the butyric acid,
such as 4-chlorobutyryl chloride; followed by a cyclisation
reaction in basic conditions; step b' stands for amidine formation
by reacting the compounds (XXIV) with a 3-aminocrotonate derivative
and POCl.sub.3 when X.sub.1 is oxygen; or stands for alkylation of
the amidine formation by reacting the compound (XXIV) with a
butynoate derivative, when X.sub.1 is NH; step c' stands for the
cyclisation of the compounds (XXV) or (XXVa) in basic conditions to
give the hydroxy pyridine precursor of cycle A in the final
compounds (IIr); step d' stands for the formation of a reactive
derivative of the hydroxy pyridine of compounds (XXVI) by reaction
with, triflic anhydride; step e' stands for nucleophilic
displacement of the leaving group of compounds (XXVII) to give the
halogenated compounds (XXVIII); step f' stands for the arylation
reaction with the suitable --Z--W derivative by a metal catalysed
coupling reaction procedure to give the final compounds (IIr); such
--Z--W derivative may be suitably protected with a P group, as
defined in Scheme 1, step g' stands for activation of carbon 3 by
the addition of an electron-withdrawing group; step h' corresponds
to step b)' when X1 is oxygen. step i' stands for a metal-halogen
exchange reaction followed by a trans-metalation reaction with a
suitable metalating agent; step j' stands for the cyclisation of
the p-amidoester of formula (XXIVb) with a salt of a substituted
amidine in order to form the pyrimidine cycle A, when Y is N; step
m' stands for conversion of the hydroxy group into an halogen by
the halogenation reaction carried out using treatment with
PO(Hal).sub.3.
11. An intermediate compound which is
1-(4-Methoxy-2-methylphenyl)pyrrolidin-2-one.
12. An intermediate compound which is ethyl
3-{[1-(4-methoxy-2-methylphenyl)pyrrolidin-2-ylidene]amino}but-2-enoate.
13. An intermediate compound which is
1-(4-Methoxy-2-methylphenyl)-6-methyl-1,2,3,7-tetrahydro-4H-pyrrolo[2,3-b-
]pyridin-4-one.
14. An intermediate compound which is
1-(4-Methoxy-2-methylphenyl)-6-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridi-
n-4-yl trifluoromethanesulfonate.
15. An intermediate compound which is
4-Iodo-6-methyl-1-[2-methyl-4-(methyloxy)phenyl]-2,3-dihydro-1H-pyrrolo[2-
,3-b]pyridine.
16. An intermediate compound which is
1-[2-Methyl-4-(methyloxy)phenyl]-2-pyrrolidinimine.
17. An intermediate compound which is
4-{[2-Methyl-4-(methyloxy)phenyl]amino}butanenitrile.
18. An intermediate compound which is
N-(2-Chloroethyl)-3-({[(2-chloroethyl)amino]carbonyl}amino)-1H-pyrazole-1-
-carboxamide.
19. An intermediate compound which is
N-(2-Chloroethyl)-3-(2-oxoimidazolidin-1-yl)-1H-pyrazole-1-carboxamide.
20. An intermediate compound which is
1-(1H-Pyrazol-3-yl)imidazolidin-2-one.
21. An intermediate compound which is
4-{[2-Methyl-4-(methyloxy)phenyl]amino}butanenitrile.
22. An intermediate compound which is
1-[2-Methyl-4-(methyloxy)phenyl]-2-pyrrolidinimine.
23. A method for the treatment of a condition mediated by CRF
(corticotropin-releasing factor), comprising administration of an
effective amount of the compound
1-{1-[1-(4-Methoxy-2-methylphenyl)-6-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]-
pyridin-4-yl]-1H-pyrazol-3-yl}imidazolidin-2-one, or a
pharmaceutically acceptable salt thereof, to a mammal in need of
treatment thereof.
24. A method, according to claim 23, for the treatment of
depression or anxiety, comprising administration of an effective
amount of a compound according to claim 1, or a pharmaceutically
acceptable salt thereof.
25. A method, according to claim 23, for the treatment of IBS
(irritable bowel disease) or IBD (inflammatory bowel disease),
comprising administration of an effective amount of a compound
according to claim 1, or a pharmaceutically acceptable salt
thereof.
Description
[0001] The present invention relates to bicyclic derivatives, to
processes for their preparation, to pharmaceutical compositions
containing them and to their use in therapy.
[0002] The first corticotropin-releasing factor (CRF) was isolated
from ovine hypothalami and identified as a 41-amino acid peptide
(Vale et al., Science 213: 1394-1397, 1981). CRF has been found to
produce profound alterations in endocrine, nervous and immune
system function. CRF is believed to be the major physiological
regulator of the basal and stress-release of adrenocorticotropic
hormone ("ACTH"), Bendorphin and other propiomelanocortin
("POMC")-derived peptides from the anterior pituitary (Vale et al.,
Science 213: 1394-1397, 1981).
[0003] In addition to its role in stimulating the production of
ACTH and POMC, CRF appears to be one of the pivotal central nervous
system neurotransmitters and plays a crucial role in integrating
the body's overall response to stress.
[0004] Administration of CRF directly to the brain elicits
behavioral, physiological and endocrine responses identical to
those observed for an animal exposed to a stressful environment.
Accordingly, clinical data suggests that CRF receptor antagonists
may represent novel antidepressant and/or anxiolytic drugs that may
be useful in the treatment of the neuropsychiatric disorders
manifesting hypersecretion of CRF.
[0005] The first CRF receptor antagonists were peptides (see, e.g.,
Rivier et al., U.S. Pat. No. 4,605,642; Rivier et al., Science 224:
889, 1984). While these peptides established that CRF receptor
antagonists can attenuate the pharmacological responses to CRF,
peptide CRF receptor antagonists suffer from the usual drawbacks of
peptide therapeutics including lack of stability and limited oral
activity. More recently, small molecule CRF receptor antagonists
have been reported.
[0006] WO 95/10506 describes inter alia compounds of general
formula (A) with general CRF antagonist activity
##STR00002##
wherein Y may be CR29; V may be nitrogen, Z may be carbon or
nitrogen, R3 may correspond to an amine derivative and R4 may be
taken together with R29 to form a 5-membered ring and is --CH(R28)
when R29 is --CH(R30).
[0007] WO 95/33750 also describes compounds of general formula (B)
having CRF antagonistic activity,
##STR00003##
in which A and Y may be nitrogen and carbon and B may correspond to
an amine derivative.
[0008] Recently a patent application has been published as WO
02/08895 in which the following compounds, CRF antagonists, are
objects of the patent application:
##STR00004##
[0009] In particular, R.sub.2 and R.sub.3 with N may form a
saturated or unsaturated heterocycle, which may be substituted by a
5-6 membered heterocycle, which may be substituted by 1 to 3 groups
selected among: C1-C6 alkyl, halo C1-C2 alkyl, C1-C6 alkoxy,
halogen, nitro or cyano.
[0010] Another recent patent application has been published as WO
03/008412 in which the following compounds, CRF antagonists, are
objects of the patent application:
##STR00005##
[0011] In particular, R.sub.2 and R.sub.3 with N may form a 5-14
membered heterocycle, which may be substituted by a 5-6 membered
heterocycle, which may be saturated or may contain one to three
double bonds, and which may be substituted by 1 or more groups such
as C3-C7 cycloalkyl, C1-C6 alkyl, C1-C6 alkoxy, halo C1-C6 alkyl,
C2-C6 alkenyl, C2-C6 alkynyl, halo C1-C6 alkoxy, hydroxy, halogen,
nitro, cyano, or C(O)NR.sub.6R.sub.7
[0012] None of the above references disclosed compounds falling
into the scope of the present invention.
[0013] Due to the physiological significance of CRF, the
development of biologically-active small molecules having
significant CRF receptor binding activity and which are capable of
antagonizing the CRF receptor remains a desirable goal. Such CRF
receptor antagonists would be useful in the treatment of endocrine,
psychiatric and neurologic conditions or illnesses, including
stress-related disorders in general.
[0014] While significant strides have been made toward achieving
CRF regulation through administration of CRF receptor antagonists,
there remains a need in the art for effective small molecule CRF
receptor antagonists. There is also a need for pharmaceutical
compositions containing such CRF receptor antagonists, as well as
methods relating to the use thereof to treat, for example,
stress-related disorders. The present invention fulfills these
needs, and provides other related advantages.
[0015] In particular the invention relates to novel compounds which
are potent and specific antagonists of corticotropin-releasing
factor (CRF) receptors.
[0016] The present invention provides compounds of formula (I)
including stereoisomers, prodrugs and pharmaceutically acceptable
salts or solvates thereof
##STR00006##
[0017] wherein
[0018] the dashed line may represent a double bond; [0019] R is
aryl or heteroaryl, each of which may be substituted by 1 to 4
groups J selected from: [0020] halogen, C1-C6 alkyl, C1-C6 alkoxy,
halo C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo C1-C6 alkoxy,
--C(O)R.sub.2, nitro, hydroxy, --NR.sub.3R.sub.4, cyano or a group
Z; [0021] R.sub.1 is hydrogen, C3-C7 cycloalkyl, C1-C6 alkyl, C1-C6
alkoxy, C1-C6 thioalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo C1-C6
alkyl, halo C1-C6 alkoxy, halogen, NR.sub.3R.sub.4 or cyano; [0022]
R.sub.2 is a C1-C4 alkyl, --OR.sub.3 or --NR.sub.3R.sub.4; [0023]
R.sub.3 is hydrogen or C1-C6 alkyl; [0024] R.sub.4 is hydrogen or
C1-C6 alkyl; [0025] R.sub.5 is a C1-C6 alkyl, halo C1-C6 alkyl,
C1-C6 alkoxy, halo C1-C6 alkoxy, C3-C7 cycloalkyl, hydroxy,
halogen, nitro, cyano, --NR.sub.3R.sub.4; --C(O)R.sub.2; [0026]
R.sub.6 is a C1-C6 alkyl, halo C1-C6 alkyl, C1-C6 alkoxy, halo
C1-C6 alkoxy, C3-C7 cycloalkyl, hydroxy, halogen, nitro, cyano,
--NR.sub.3R.sub.4; --C(O)R.sub.2; [0027] R.sub.7 is hydrogen, C1-C6
alkyl, halogen or halo C1-C6 alkyl; [0028] R.sub.5 is hydrogen,
C3-C7 cycloalkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl,
NR.sub.3R.sub.4 or cyano; [0029] R.sub.9 is hydrogen, C3-C7
cycloalkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl,
NR.sub.3R.sub.4 or cyano; [0030] R.sub.10 is hydrogen, C3-C7
cycloalkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl,
NR.sub.3R.sub.4 or cyano; [0031] R.sub.11 is hydrogen, C3-C7
cycloalkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl,
NR.sub.3R.sub.4 or cyano; [0032] R.sub.12 is R.sub.3 or
--C(O)R.sub.2; [0033] D is CR.sub.8R.sub.9 or is CR.sub.8 when
double bonded with G; [0034] G is CR.sub.10R.sub.11 or is CR.sub.10
when double bonded with D or is CR.sub.10 when double bonded with X
when X is carbon; [0035] X is carbon or nitrogen; [0036] Y is
nitrogen or --CR.sub.7; [0037] W is a 4-8 membered ring, which may
be saturated or may contain one to three double bonds, and [0038]
in which: [0039] one carbon atom is replaced by a carbonyl or
S(O).sub.m; and [0040] one to four carbon atoms may optionally be
replaced by oxygen, nitrogen or NR.sub.12, S(O).sub.m, carbonyl,
and such ring may be further substituted by 1 to 8 R.sub.6 groups;
[0041] Z is a 5-6 membered heterocycle, which may be substituted by
1 to 8 R.sub.5 groups or a phenyl ring, which may be substituted by
1 to 4 R.sub.5 groups; [0042] m is an integer from 0 to 2.
[0043] The compounds of the present invention may be in the form of
and/or may be administered as a pharmaceutically acceptable salt.
For a review on suitable salts see Berge et al, J. Pharm. Sci.,
1977, 66, 1-19.
[0044] Typically, a pharmaceutical acceptable salt may be readily
prepared by using a desired acid or base as appropriate. The salt
may precipitate from solution and be collected by filtration or may
be recovered by evaporation of the solvent.
[0045] Suitable addition salts are formed from acids which form
non-toxic salts and examples are hydrochloride, hydrobromide,
hydroiodide, sulphate, bisulphate, nitrate, phosphate, hydrogen
phosphate, acetate, maleate, malate, fumarate, lactate, tartrate,
citrate, formate, gluconate, succinate, piruvate, oxalate,
oxaloacetate, trifluoroacetate, saccharate, benzoate,
methansulphonate, ethanesulphonate, benzenesulphonate,
p-toluensulphonate, methanesulphonic, ethanesulphonic,
p-toluenesulphonic, and isethionate.
[0046] Pharmaceutically acceptable base salts include ammonium
salts, alkali metal salts such as those of sodium and potassium,
alkaline earth metal salts such as those of calcium and magnesium
and salts with organic bases, including salts of primary, secondary
and tertiary amines, such as isopropylamine, diethylamine,
ethanolamine, trimethylamine, dicyclohexyl amine and
N-methyl-D-glucamine.
[0047] Those skilled in the art of organic chemistry will
appreciate that many organic compounds can form complexes with
solvents in which they are reacted or from which they are
precipitated or crystallized. These complexes are known as
"solvates". For example, a complex with water is known as a
"hydrate". Solvates of the compound of the invention are within the
scope of the invention.
[0048] In addition, prodrugs are also included within the context
of this invention.
[0049] As used herein, the term "prodrug" means a compound which is
converted within the body, e.g. by hydrolysis in the blood, into
its active form that has medical effects. Pharmaceutically
acceptable prodrugs are described in T. Higuchi and V. Stella,
Prodrugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium
Series, Edward B. Roche, ed., Bioreversible Carriers in Drug
Design, American Pharmaceutical Association and Pergamon Press,
1987, and in D. Fleisher, S. Ramon and H. Barbra "Improved oral
drug delivery: solubility limitations overcome by the use of
prodrugs", Advanced Drug Delivery Reviews (1996) 19(2) 115-130,
each of which are incorporated herein by reference.
[0050] Prodrugs are any covalently bonded carriers that release a
compound of structure (I) in vivo when such prodrug is administered
to a patient. Prodrugs are generally prepared by modifying
functional groups in a way such that the modification is cleaved,
either by routine manipulation or in vivo, yielding the parent
compound. Prodrugs include, for example, compounds of this
invention wherein hydroxy, amine or sulfhydryl groups are bonded to
any group that, when administered to a patient, cleaves to form the
hydroxy, amine or sulfhydryl groups. Thus, representative examples
of prodrugs include (but are not limited to) acetate, formate and
benzoate derivatives of alcohol, sulfhydryl and amine functional
groups of the compounds of structure (I). Further, in the case of a
carboxylic acid (--COOH), esters may be employed, such as methyl
esters, ethyl esters, and the like. Esters may be active in their
own right and/or be hydrolysable under in vivo conditions in the
human body. Suitable pharmaceutically acceptable in vivo
hydrolysable ester groups include those which break down readily in
the human body to leave the parent acid or its salt.
[0051] With regard to stereoisomers, the compounds of structure (I)
may have one or more asymmetric carbon atom and may occur as
recemates, racemic mixtures and as individual enantiomers or
diastereomers. All such isomeric forms are included within the
present invention, including mixtures thereof.
[0052] Where a compound of the invention contains an alkenyl or
alkenylene group, cis (E) and trans (Z) isomerism may also occur.
The present invention includes the individual stereoisomers of the
compound of the invention and, where appropriate, the individual
tautomeric forms thereof, together with mixtures thereof.
[0053] Separation of diastereoisomers or cis and trans isomers may
be achieved by conventional techniques, e.g. by fractional
crystallisation, chromatography or H.P.L.C. of a stereoisomeric
mixture of the agent may also be prepared from a corresponding
optically pure intermediate or by resolution, such as H.P.L.C. of
the corresponding racemate using a suitable chiral support or by
fractional crystallisation of the diastereoisomeric salts formed by
reaction of the corresponding racemate with a suitable optically
active acid or base, as appropriate.
[0054] Those skilled in the art of organic chemistry will
appreciate that many organic compounds can form complexes with
solvents in which they are reacted or from which they are
precipitated or crystallized. These complexes are known as
"solvates". For example, a complex with water is known as a
"hydrate". Solvates of the compounds of the invention are within
the scope of the invention.
[0055] Furthermore, some of the crystalline forms of the compounds
of structure (I) may exist as polymorphs, which are included in the
present invention.
[0056] The term C1-C6 alkyl as used herein as a group or a part of
the group refers to a linear or branched alkyl group containing
from 1 to 6 carbon atoms; examples of such groups include methyl,
ethyl, propyl, isopropyl, n-butyl, isobutyl, tert butyl, pentyl or
hexyl.
[0057] The term C3-C7 cycloalkyl group means a non aromatic
monocyclic hydrocarbon ring of 3 to 7 carbon atom such as, for
example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or
cycloheptyl; while unsaturated cycloalkyls include cyclopentenyl
and cyclohexenyl, and the like.
[0058] The term halogen refers to a fluorine, chlorine, bromine or
iodine atom.
[0059] The term halo C1-C6 alkyl, or halo C1-C2 alkyl means an
alkyl group having one or more carbon atoms and wherein at least
one hydrogen atom is replaced with halogen such as for example a
trifluoromethyl group and the like.
[0060] The term C1-C6 thioalkyl may be a linear or a branched chain
thioalkyl group, for example thiomethyl, thioethyl, thiopropyl,
thioisopropyl, thiobutyl, thiosec-butyl, thiotert-butyl and the
like.
[0061] The term C2-C6 alkenyl defines straight or branched chain
hydrocarbon radicals containing one or more double bond and having
from 2 to 6 carbon atoms such as, for example, ethenyl, 2-propenyl,
3-butenyl, 2-butenyl, 2-pentenyl, 3-pentenyl, 3-methyl-2-butenyl or
3-hexenyl and the like.
[0062] The term C1-C6 alkoxy group may be a linear or a branched
chain alkoxy group, for example methoxy, ethoxy, propoxy,
prop-2-oxy, butoxy, but-2-oxy or methylprop-2-oxy and the like.
[0063] The term halo C1-C6 alkoxy group may be a C1-C6 alkoxy group
as defined before substituted with at least one halogen, preferably
fluorine, such as OCHF.sub.2, or OCF.sub.3.
[0064] The term C2-C6 alkynyl defines straight or branched chain
hydrocarbon radicals containing one or more triple bond and having
from 2 to 6 carbon atoms including acetylenyl, propynyl, 1-butynyl,
1-pentynyl, 3-methyl-1-butynyl and the like.
[0065] The term aryl means an aromatic carbocyclic moiety such as
phenyl, biphenyl or naphthyl.
[0066] The term heteroaryl means an aromatic heterocycle ring of 5
to 10 members and having at least one heteroatom selected from
nitrogen, oxygen and sulfur, and containing at least 1 carbon atom,
including both mono- and bicyclic ring systems.
[0067] Representative heteroaryls include (but are not limited to)
furyl, benzofuranyl, thiophenyl, benzothiophenyl, pyrrolyl,
indolyl, isoindolyl, azaindolyl, pyridyl, quinolinyl,
isoquinolinyl, oxazolyl, isooxazolyl, benzoxazolyl, pyrazolyl,
imidazolyl, benzimidazolyl, thiazolyl, benzothiazolyl,
isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl,
cinnolinyl, phthalazinyl, triazolyl, tetrazolyl, quinazolinyl, and
benzodioxolyl.
[0068] The term 5-6 membered heterocycle means, according to the
above definition, a 5-6 monocyclic heterocyclic ring which is
either saturated, unsaturated or aromatic, and which contains from
1 to 4 heteroatoms independently selected from nitrogen, oxygen and
sulfur, and wherein the nitrogen and sulfur heteroatoms may be
optionally oxidized, and the nitrogen heteroatom may be optionally
quaternized. Heterocycles include heteroaryls as defined above. The
heterocycle may be attached via any heteroatom or carbon atom.
Thus, the term include (but are not limited to) morpholinyl,
pyridinyl, pyrazinyl, pyrazolyl, thiazolyl, triazolyl, imidazolyl,
oxadiazolyl, oxazolyl, isoxazolyl, pyrrolidinonyl, pyrrolidinyl,
piperidinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl,
tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl,
tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl,
and the like.
[0069] The term W defines a 4-8 membered ring, which may be
saturated or may contain from one to three double bonds, and in
which: [0070] one carbon atom is replaced by a carbonyl or
S(O).sub.m; and [0071] one to four carbon atoms may optionally be
replaced by oxygen, nitrogen or NR.sub.12, S(O).sub.m, carbonyl,
and such ring may be further substituted by 1 to 8 R.sub.6
groups;
[0072] The 4-8 membered ring means a 4-8 monocyclic carbocyclic
ring which is either saturated, or unsaturated o aromatic and one
to four carbon atoms may be replaced by an heteroatom as defined
above. The carbocycle may be attached via any heteroatom or carbon
atom. Thus, the term include (but are not limited to): cyclobutane,
cyclopentane, cyclohexane, cycloheptane, cyclooctane, azirydinyl,
azetidinyl, pyrrolidinyl, piperidinyl, imidazolidinyl, morpholinyl,
piperazinyl, hydantoinyl, valerolactamyl, oxetanyl,
tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl,
tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl,
1,3-dihydro-2H-imidazol-2-one, imidazolidin-2-one,
tetrahydropyrimidin-2(1H)-one, 2,5-dihydro-1,2,5-thiadiazole
1-oxide, 1,2,5-thiadiazolidine 1-oxide,
2,5-dihydro-1,2,5-thiadiazole 1,1-dioxide, 1,2,6-thiadiazinane
1-oxide, pyrrolidin-2-one, 2,5-dihydro-1,2,5-thiadiazolidine
1,1-dioxide, 1,3-oxazolidin-2-one derivative, isothiazolidine
1,1-dioxide, 2(1H)-pyridinone, 3(2H)-pyridazinone,
2,3-piperazinedione and the like.
[0073] Representative ring of the W definition include, but are not
limited to, the following structure and derivatives:
##STR00007## ##STR00008##
in which: [0074] W1 represents a 1,3-dihydro-2H-imidazol-2-one
derivative; [0075] W2 represents a imidazolidin-2-one derivative;
[0076] W3 represents a tetrahydropyrimidin-2(1H)-one derivative;
[0077] W4 represents a 2,5-dihydro-1,2,5-thiadiazole 1-oxide
derivative; [0078] W5 represents a 1,2,5-thiadiazolidine 1-oxide
derivative; [0079] W6 represents a 2,5-dihydro-1,2,5-thiadiazole
1,1-dioxide derivative; [0080] W7 represents a 1,2,6-thiadiazinane
1-oxide derivative; [0081] W8 represents a 1,2,6-thiadiazinane
1,1-dioxide derivative; [0082] W9 represents a pyrrolidin-2-one
derivative; [0083] W10 represents a
2,5-dihydro-1,2,5-thiadiazolidine 1,1-dioxide derivative; [0084]
W11 represents a 1,3-oxazolidin-2-one derivative; [0085] W12
represents a isothiazolidine 1,1-dioxide derivative; [0086] W13
represents a 2(1H)-pyridinone derivative; [0087] W14 represents a
3(2H)-pyridazinone; [0088] W15 represents a 2,3-piperazinedione
derivative; and q is an integer from 0 to 4, n is an integer from 0
to 6, p is an integer from 0 to 3 and m, R6 and R12 are defined as
above.
[0089] The compounds of formula (II) and (IIa) are representatives
of the present invention.
##STR00009##
[0090] In particular they correspond to compounds (I) in which X is
nitrogen or carbon and R, R1, Y, Z, W, D, and G have the meanings
as previously defined.
[0091] The compounds of formula (II) are specific representatives
of the present invention. Particularly preferred are the compounds
of formula (II), in which W is selected in the group consisting
from: W1, W2, W3, W9, W10, W11, W12, W13, and W14.
[0092] Equally preferred are the compounds of formula (II), in
which Z is selected in a group consisting from: pyrimidine,
pyridine, thiazol, pyrazol, triazol and phenyl.
[0093] Equally preferred are the compounds of formula (II), in
which W is selected in the group consisting from: W1, W2, W3, W9,
W10, W11, W12, W13, and W14 and in which Z is selected in a group
consisting from: pyrimidine, pyridine, thiazol, pyrazol, triazol
and phenyl.
[0094] Examples of compounds of formula (II) are reported in the
Experimental Part.
[0095] The compounds of formula (IIb), (IIc), (IId), (IIe), (IIf),
(IIg), (IIh), (IIi), (IIl), (IIm), (IIn), (IIo), (IIp) and (IIq)
are illustratives of the compounds of formula (II).
##STR00010## ##STR00011##
[0096] They correspond to the compounds of formula (II), depending
on the meaning of X and Y, and where R, R1, R7, Z, W, D, and G have
the meanings as previously defined.
[0097] Particularly preferred are the compounds of formula (IIb),
(IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIl), (IIm),
(IIn), (IIo), (IIp) and (IIq) in which W is selected in the group
consisting from: W1, W2, W3, W9, W10, W11, W12, W13, and W14.
[0098] Equally preferred are the compounds of formula (IIb), (IIc),
(IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIl), (IIm), (IIn),
(IIo), (IIp) and (IIq) in which Z is selected in a group consisting
from: pyrimidine, pyridine, thiazol, pyrazol, triazol and
phenyl.
[0099] Equally preferred are the compounds of formula (IIb), (IIc),
(IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIl), (IIm), (IIn),
(IIo), (IIp) and (IIq) in which W is selected in the group
consisting from: W1, W2, W3, W9, W10, W11, W12, W13, and W14 and in
which Z is selected in a group consisting from: pyrimidine,
pyridine, thiazol, pyrazol, triazol and phenyl.
[0100] The compounds of formula (IIr), (IIs) and (IIt), which
correspond to the compounds of formula (II) in which D and G are
--CH.sub.2 are preferred.
##STR00012##
[0101] Particularly preferred are the compounds of formula (IIr),
(IIs) and (IIt), in which W is selected in the group consisting
from: W1, W2, W3, W9, W10, W11, W12, W13, and W14. Equally
preferred are the compounds of formula (IIr), in which Z is
selected in a group consisting from: pyrimidine, pyridine, thiazol,
pyrazol, triazol and phenyl.
[0102] Equally preferred are the compounds of formula (IIr), (IIs)
and (IIt), in which W is selected in the group consisting from: W1,
W2, W3, W9, W10, W11, W12, W13, and W14 and in which Z is selected
in a group consisting from: pyrimidine, pyridine, thiazol, pyrazol,
triazol and phenyl.
[0103] In particular, the compounds of formula (III) are
representatives of the compounds of formula (II).
##STR00013##
[0104] They correspond to the compounds of formula (II), in which Z
is a pyrazolyl derivative and R, R.sub.1, R.sub.5, Y, W, D, m and G
have the meanings as previously defined and the dashed line may
represent a double bond.
[0105] The compounds of formula (IIIa), (IIIb), (IIIc) and (IIId)
are specific representatives of the compounds of formula (III).
##STR00014##
[0106] They correspond to the compounds of formula (III) depending
on the meaning of Y, in which R, R.sub.1, R.sub.5, R.sub.7,
R.sub.8, R.sub.9, R.sub.10, R.sub.11, W, D, m and G have the
meanings as previously defined.
[0107] Particularly preferred are the compounds of formula (IIIa),
(IIIb), (IIIc) and (IIId), in which W is selected in the group
consisting from: W1, W2, W3, W9, W10, W11, W12, W13, and W14 and R,
R.sub.1, R.sub.5, R.sub.7, R.sub.8, R.sub.9, R.sub.10, R.sub.11, m,
have the meanings as previously defined.
[0108] In particular, the compounds of formula (IV) are
representatives of the compounds of formula (III).
##STR00015##
[0109] They correspond to compounds of formula (III), in which W
corresponds to a W2 derivative and R, R.sub.1, R.sub.5, R.sub.6,
R.sub.7, R.sub.12, m, q, D and G have the meanings as previously
defined and the dashed line may represent a double bond.
[0110] The compounds of formula (IVa), (IVb) and (IVc) are specific
representatives of the compound of formula (IV)
##STR00016##
[0111] They correspond to the compounds of formula (IV), in which
R.sub.7 is hydrogen and R, R.sub.1, R.sub.5, R.sub.6, R.sub.7,
R.sub.12, m, q, D and G have the meanings as previously defined and
the dashed line may represent a double bond.
[0112] The compounds of formula (V) are equally representatives of
the compounds of formula (II).
##STR00017##
[0113] They correspond to the compounds of formula (II), in which W
is a W2 derivative and Z, R, R.sub.1, R.sub.6, q, Y, W, D and G
have the meanings as previously defined and the dashed line may
represent a double bond.
[0114] The compounds of formula (VI) are specific representatives
of the compounds of formula (V), in which Y is --CR.sub.7 and Z, R,
R.sub.1, R.sub.6, R.sub.7, q, Y, W, D and G have the meanings as
previously and the dashed line may represent a double bond.
##STR00018##
[0115] The compounds of formula (VIa), (VIb) and (VIc) are specific
representatives of the compound of formula (VI)
##STR00019##
[0116] They correspond to the compounds of formula (VI) in which
R.sub.7 is hydrogen and R, R.sub.1, R.sub.6, R.sub.8, R.sub.9,
R.sub.10, R.sub.11, R.sub.12, q, D and G have the meanings as
previously defined and the dashed line may represent a double
bond.
[0117] Particularly preferred are the compounds of formula (VIa),
(VIb) and (VIc), in which Z is selected in a group consisting from:
pyrimidine, pyridine, thiazol, pyrazol, triazol and phenyl and R,
R.sub.1, R.sub.6, R.sub.8, R.sub.9, R.sub.10, R.sub.11, R.sub.12,
q, D and G have the meanings as previously defined.
[0118] Even more preferred embodiments of the invention include,
but are not limited to, compounds of the formula (I), (IIb), (IIc),
(IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIl), (IIm), (IIn),
(IIo), (IIp), (IIq), (IIl), (IIIa), (IIIb), (IIIc), (IIId), (IV),
(IVa), (IVb), (IVc), (V), (VI), (Via), (VIb), (VIc) wherein:
[0119] R.sub.1 is C1-C3 alkyl group or halo C1-C3 alkyl group,
preferably methyl or trifluoromethyl;
[0120] R.sub.7 is hydrogen;
[0121] R.sub.8, (R.sub.9), R.sub.10 (R.sub.11) are hydrogen;
[0122] R is an aryl group selected from: 2,4-dichlorophenyl,
2-chloro-4-methylphenyl, 2-chloro-4-trifluoromethylphenyl,
2-chloro-4-methoxyphenyl, 2,4,5-trimethylphenyl,
2,4-dimethylphenyl, 2-methyl-4-methoxyphenyl,
2-methyl-4-ethoxyphenyl, 2-methyl-4-isopropoxyphenyl,
2-methyl-4-hydroxyphenyl, 2-methyl-4-chlorophenyl,
2-methyl-4-trifluoromethylphenyl, 2,4-dimethoxyphenyl,
2-methoxy-4-trifluoromethylphenyl, 2-methoxy-4-chlorophenyl,
3-methoxy-4-chlorophenyl, 2,5-dimethoxy-4-chlorophenyl,
2-methoxy-4-isopropylphenyl, 2-methoxy-4-trifluoromethylphenyl,
2-methoxy-4-isopropylphenyl, 2-methoxy-4-methylphenyl,
2-trifluoromethyl-4-chlorophenyl, 2,4-bis-trifluoromethylphenyl,
2-trifluoromethyl-4-methylphenyl,
2-trifluoromethyl-4-methoxyphenyl,
2-difluoromethyl-4-methoxyphenyl, 2-bromo-4-isopropylphenyl,
2-methyl-4-cyanophenyl, 2-chloro-4-cyanophenyl,
2-trifluoromethyl-4-cyanophenyl, 2-trifluoromethoxy-4-cyanophenyl,
2-ethyl-4-cyanophenyl, 2-methyl-4-trifluoromethoxy-phenyl,
4-methyl-6-dimethylaminopyridin-3-yl, 2,6-bismethoxy-pyridin-3-yl,
2-methyl-6-methoxy-pyridin-3-yl,
2-trifluoromethyl-6-methoxy-pyridin-3-yl
3-chloro-5-trichloromethyl-pyridin-2-yl,
2-methyl-4-(pyrazol-1-yl)-phenyl,
2-methoxy-4-(pyrazol-1-yl)-phenyl, 2,4,6-trimethoxyphenyl,
2-methyl-4,5-benzodioxolyl, 2-methyl-3,4-benzodioxolyl.
[0123] Preferred compounds according to the invention are: [0124]
1-{1-[1-(4-Methoxy-2-methylphenyl)-6-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]-
pyridin-4-yl]-1H-pyrazol-3-yl}imidazolidin-2-one (compound 1-1);
[0125]
1-{1-[1-(4-Methoxy-2-methylphenyl)-6-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]-
pyridin-4-yl]-1H-pyrazol-3-yl}-3-methylimidazolidin-2-one (compound
1-2); [0126]
1-{1-[1-(2,4-Dichlorophenyl)-6-methyl-2,3-dihydro-1H-pyrrolo[2,3-b-
]pyridin-4-yl]-1H-pyrazol-3-yl}imidazolidin-2-one (compound 1-3);
[0127]
1-(1-{1-[2,4-Bis(trifluoromethyl)phenyl]-6-methyl-2,3-dihydro-1H-pyrrolo[-
2,3-b]pyridin-4-yl}-1H-pyrazol-3-yl)-2-imidazolidinone (compound
1-4); [0128]
1-{1-[1-(4-Hydroxy-2-methylphenyl)-6-methyl-2,3-dihydro-1H-pyrrolo-
[2,3-b]pyridin-4-yl}-1H-pyrazol-3-yl]-2-imidazolidinone (compound
1-5); [0129]
1-Acetyl-3-(1-{6-methyl-1-[2-methyl-4-(methyloxy)phenyl]-2,3-dihyd-
ro-1H-pyrrolo[2,3-b]pyridin-4-yl}-1H-pyrazol-3-yl)-2-imidazolidinone
(compound 1-5); [0130]
1-Acetyl-3-(1-{6-methyl-1-[2-methyl-4-(methyloxy)phenyl]-2,3-dihydro-1H-p-
yrrolo[2,3-b]pyridin-4-yl}-1H-pyrazol-3-yl)-2-imidazolidinone
(compound 1-6); [0131]
1-(1-{1-[4-(Ethyloxy)-2-methylphenyl]-6-methyl-2,3-dihydro-1H-pyrrolo[2,3-
-b]pyridin-4-yl}-1H-pyrazol-3-yl)-2-imidazolidinone (compound 1-7);
[0132]
1-[1-(6-Methyl-1-{2-methyl-4-[(1-methylethyl)oxy]phenyl}-2,3-dihydro-1H-p-
yrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-3-yl]-2-imidazolidinone
(compound 1-8); [0133]
1-[1-(6-Methyl-1-{2-methyl-4-[(trifluoromethyl)oxy]phenyl}-2,3-dihydro-1H-
-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-3-yl]-2-imidazolidinone
(compound 1-9); [0134]
3-Methyl-4-{6-methyl-4-[3-(2-oxo-1-imidazolidinyl)-1H-pyrazol-1-yl]-2,3-d-
ihydro-1H-pyrrolo[2,3-b]pyridin-1-yl}benzonitrile (compound 1-10);
[0135]
1-(1-{6-Methyl-1-[2-methyl-4-(1H-pyrazol-1-yl)phenyl]-2,3-dihydro-1H-pyrr-
olo[2,3-b]pyridin-4-yl}-1H-pyrazol-3-yl)-2-imidazolidinone
(compound 1-11); [0136]
4-{6-Methyl-4-[3-(2-oxo-1-imidazolidinyl)-1H-pyrazol-1-yl]-2,3-dihydro-1H-
-pyrrolo[2,3-b]pyridin-1-yl}-3-(trifluoromethyl)benzonitrile
(compound 1-12); [0137]
1-(1-{1-[2-(Difluoromethyl)-4-(methyloxy)phenyl]-6-methyl-2,3-dihydro-1H--
pyrrolo[2,3-b]pyridin-4-yl}-1H-pyrazol-3-yl)-2-imidazolidinone
(compound 1-13); [0138]
4-{6-Methyl-4-[3-(2-oxo-1-imidazolidinyl)-1H-pyrazol-1-yl]-2,3-dihydro-1H-
-pyrrolo[2,3-b]pyridin-1-yl}-3-[(trifluoromethyl)oxy]benzonitrile
(compound 1-14); [0139]
3-Ethyl-4-{6-methyl-4-[3-(2-oxo-1-imidazolidinyl)-1H-pyrazol-1-yl]-2,3-di-
hydro-1H-pyrrolo[2,3-b]pyridin-1-yl}benzonitrile (compound 1-15);
[0140]
1-(1-{6-Methyl-1-[2-(methyloxy)-4-(1H-pyrazol-1-yl)phenyl]-2,3-dihydro-1H-
-pyrrolo[2,3-b]pyridin-4-yl}-1H-pyrazol-3-yl)-2-imidazolidinone
(compound 1-16); [0141]
1-{1-[6-Methyl-1-(6-methyl-1,3-benzodioxol-5-yl)-2,3-dihydro-1H-pyrrolo[2-
,3-b]pyridin-4-yl]-1H-pyrazol-3-yl}-2-imidazolidinone (compound
1-17); [0142]
1-(1-{6-Methyl-1-[2,4,6-tris(methyloxy)phenyl]-2,3-dihydro-1H-pyrr-
olo[2,3-b]pyridin-4-yl}-1H-pyrazol-3-yl)-2-imidazolidinone
(compound 1-18); [0143]
1-{1-[6-Methyl-1-(6-methyl-1,3-benzodioxol-5-yl)-2,3-dihydro-1H-pyrrolo[2-
,3-b]pyridin-4-yl]-1H-pyrazol-3-yl}-2-imidazolidinone (compound
1-19); [0144]
1-(6-{6-Methyl-1-[2-methyl-4-(methyloxy)phenyl]-2,3-dihydro-1H-pyr-
rolo[2,3-b]pyridin-4-yl}-2-pyridinyl)-2-imidazolidinone (compound
1-20); [0145]
(4-{6-Methyl-1-[2-methyl-4-(methyloxy)phenyl]-2,3-dihydro-1H-pyrro-
lo[2,3-b]pyridin-4-yl}-2-pyrimidinyl)-2-imidazolidinone (compound
1-21); [0146]
1-(2-{6-Methyl-1-[2-methyl-4-(methyloxy)phenyl]-2,3-dihydro-1H-pyr-
rolo[2,3-b]pyridin-4-yl}-4-pyrimidinyl)-2-imidazolidinone (compound
1-22); [0147]
1-(1-{6-Methyl-1-[2-methyl-4-(methyloxy)phenyl]-2,3-dihydro-1H-pyr-
rolo[2,3-b]pyridin-4-yl}-1H-pyrazol-3-yl)-2-imidazolidinone
(compound 1-23); [0148]
1-(1-{2,6-Dimethyl-1-[2-methyl-4-(methyloxy)phenyl]-2,3-dihydro-1H-pyrrol-
o[2,3-b]pyridin-4-yl}-1H-pyrazol-3-yl)-2-imidazolidinone (compound
1-24); [0149]
1-(3-{6-Methyl-1-[2-methyl-4-(methyloxy)phenyl]-2,3-dihydro-1H-pyr-
rolo[2,3-b]pyridin-4-yl}phenyl)-2-imidazolidinone (compound 1-25);
[0150]
1-(5-Methyl-1-{6-methyl-1-[2-methyl-4-(methyloxy)phenyl]-2,3-dihydro-1H-p-
yrrolo[2,3-b]pyridin-4-yl}-1H-pyrazol-3-yl)-2-imidazolidinone
(compound 1-26); [0151]
1-[1-(1-{4-[(difluoromethyl)oxy]-2-methylphenyl]-6-methyl-2,3-dihydro-1H--
pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-3-yl}-2-imidazolidinone
(compound 1-27); [0152]
1-{1-[1-(4-Methoxy-2-methylphenyl)-6-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]-
pyridin-4-yl]-1H-pyrazol-3-yl}pyrrolidin-2-one (compound 2-1);
[0153]
1-{1-[1-(4-Methoxy-2-methylphenyl)-6-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]-
pyridin-4-yl]-1H-pyrazol-3-yl}tetrahydropyrimidin-2(1H)-one
(compound 3-1); [0154]
3-(1-{6-Methyl-1-[2-methyl-4-(methyloxy)phenyl]-2,3-dihydro-1H-pyrrolo[2,-
3-b]pyridin-4-yl}-1H-pyrazol-3-yl)-1,3-oxazolidin-2-one (compound
4-1); [0155] Methyl
5-(1-{6-methyl-1-[2-methyl-4-(methyloxy)phenyl]-2,3-dihydro-1H-pyrrolo[2,-
3-b]-pyridin-4-yl}-1H-pyrazol-3-yl)-1,2,5-thiadiazolidine-2-carboxylate
1,1-dioxide) (compound 5-1); [0156]
4-[3-(1,1-Dioxido-1,2,5-thiadiazolidin-2-yl)-1H-pyrazol-1-yl]-6-methyl-1--
[2-methyl-4-(methyloxy)phenyl]-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine
(compound 5-2). [0157]
4-[3-(1,1-Dioxido-2-isothiazolidinyl)-1H-pyrazol-1-yl]-6-methyl-1-[2-meth-
yl-4-(methyloxy)phenyl]-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine
(compound 6-1); [0158]
3-Methyl-1-(1-{6-methyl-1-[2-methyl-4-(methyloxy)phenyl]-2,3-dihydro-1H-p-
yrrolo[2,3-b]pyridin-4-yl}-1H-pyrazol-3-yl)-2(1H)-pyridinone
(compound 7-1); [0159]
2-(1-{6-Methyl-1-[2-methyl-4-(methyloxy)phenyl]-2,3-dihydro-1H-pyrrolo[2,-
3-b]pyridin-4-yl}-1H-pyrazol-3-yl)-3(2H)-pyridazinone (compound
8-1); [0160]
1-(1-{6-Methyl-1-[2-methyl-4-(methyloxy)phenyl]-2,3-dihydro-1H-pyr-
rolo[2,3-b]pyridin-4-yl}-1H-pyrazol-3-yl)-1,3-dihydro-2H-imidazol-2-one
(compound 9-1); [0161]
1-(1-{6-Methyl-1-[2-methyl-4-(methyloxy)phenyl]-1H-pyrrolo[2,3-b]pyridin--
4-yl}-1H-pyrazol-3-yl)-2-imidazolidinone (compound 10-1); [0162]
1-(6-{6-Methyl-1-[2-methyl-4-(methyloxy)phenyl]-2,3-dihydro-1H-pyrrolo[2,-
3-b]pyridin-4-yl}-3-pyridinyl)-2-imidazolidinone (compound 11-1);
[0163]
1-{1-[7-(2,4-Dichlorophenyl)-2-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimi-
din-4-yl}-1H-pyrazol-3-yl]-2-pyrrolidinone (compound 11-2).
[0164] In general, the compounds of structure (I) may be made
according to the organic synthesis techniques known to those
skilled in this field, as well as by the representative methods set
forth in the Examples.
[0165] Compounds of formula (I), and salts and solvates thereof,
may be prepared by the general methods outlined hereinafter. In the
following description, the groups R, R.sub.1, R.sub.2, R.sub.3,
R.sub.4, R.sub.5, R.sub.6, R.sub.7, R.sub.8, R.sub.9, R.sub.10,
R.sub.11, R.sub.12, m, n, q, D, G, Z, W, X, Y have the meanings as
previously defined for compounds of formula (I) unless otherwise
stated.
[0166] Compounds of formula (II) may be conveniently prepared,
starting from compounds of formula (VII), according to the
following Scheme 1:
##STR00020##
[0167] in which [0168] step a stands for conversion of the leaving
group L, selected in a group consisting from: halogen or reactive
residue of sulphonic acid (e.g. mesylate, tosylate), preferably
chloride, in the compounds (VIII), by reaction with the suitable
Z--W derivative; [0169] step b stands for reduction of the ester
group (E) with a suitable reducing agent (such as DIBAI-H) to
hydroxy group of compounds (IX); [0170] step c stands for suitable
protection of an NH group eventually present in W group with a P
group, such as a p-methoxybenzyl group; [0171] step d stands for
oxidation of the hydroxy group with a suitable oxidizing agent
(such as Dess-Martin periodinane) to the aldehyde group of
compounds (XI); [0172] steps e+f stands for formation of the
aldehyde group of compounds (XIII) by Wittig reaction in the usual
conditions, through formation of enol ether followed by acid
hydrolysis (step f); [0173] step g stands for the optional
alkylation of the .alpha. position of the aldehyde by deprotonation
with a suitable base (such as LiN(SiMe3)2), followed by the
addition of a suitable alkylating agent (such as MeI) to form the
alkylated aldehyde of compounds (XIV), (XV); [0174] step h stands
for the conversion of the aldehyde group by a Grignard reagent
(such as MeMgBr) into an alcohol group of compounds (XVI) and
(XVIII); [0175] step i stands for oxidation of the hydroxy group
with a suitable oxidizing agent (such as Dess-Martin periodinane)
to the ketone group of compounds (XVII); [0176] step j stands for
conversion of the hydroxy group in the suitable protecting group of
compounds (XIX) (such as TBS: tert-butyldimethylsilyl); [0177] step
k stands for a Buchwald coupling reaction with the suitable amine
RNH2 to give the compounds of formula (XX); [0178] step l stands
for the deprotection reaction to give the hydroxy group of
compounds (XXI); [0179] step m stands for intramolecular
cyclisation after conversion of the hydroxy group of compounds
(XXI) in a suitable leaving group (such as bromide, by reaction
with CBr4 and PPh3) to give the cyclized compounds (XXII); [0180]
step n stands for the deprotection reaction of the protected NH
group eventually present in W group, to give final compounds (II);
[0181] step o stands for oxidation by a suitable oxidating agent
(such as DDQ) in order to give formation of the double bond of
compounds (II), when D is CHR8 and G is CHR10.
[0182] Compounds of formula (VII) are known compounds or may be
prepared according to known method in the literature.
[0183] Alternatively, compounds of formula (IIr) may be
conveniently prepared, starting from compounds of formula (XXIII),
in which R, R.sub.1 Z and W are defined as above, according to the
following Scheme 2:
##STR00021##
in which: [0184] step a' stands for the formation of the
pyrrolidinone moiety of compounds (XXIV), which will form the cycle
B present in the final compounds (IIr), by reacting the compounds
(XXIII) with a reactive derivative of the butyric acid, such as
4-chlorobutyryl chloride; followed by a cyclisation reaction in
basic conditions (e.g. KOtBu); [0185] step b' stands for amidine
formation by reacting the compounds (XXIV) with a 3-aminocrotonate
derivative and POCl.sub.3 when X.sub.1 is oxygen; or stands for
alkylation of the amidine formation by reacting the compound (XXIV)
with a butynoate derivative, when X.sub.1 is NH; [0186] step c'
stands for the cyclisation of the compounds (XXV) or (XXVa) in
basic conditions (e.g. tBuOK) to give the hydroxy pyridine
precursor of cycle A in the final compounds (IIr); [0187] step d'
stands for the formation of a reactive derivative (i.e. a leaving
group, Lg) of the hydroxy pyridine (for example selected in a group
consisting of triflate, halogen, and mesylate) of compounds (XXVI)
by reaction with, for example, triflic anhydride; [0188] step e'
stands for nucleophilic displacement of the leaving group of
compounds (XXVII) to give the halogenated compounds (XXVIII),
preferably iodinated or brominated compounds; [0189] step f' stands
for the arylation reaction with the suitable --Z--W derivative by a
metal catalysed coupling reaction (for example a Buchwald reaction
or a Suzuki coupling) procedure to give the final compounds (IIr);
such --Z--W derivative may be suitably protected with a P group, as
defined in Scheme 1, [0190] step g' stands for activation of carbon
3 by the addition of an electron-withdrawing group (e.g. acylation
to give an ester group such as acylation with diethyl carbonate to
give the ethyl ester derivative, E); [0191] step h' corresponds to
step b)' when X1 is oxygen. [0192] step i' stands for a
metal-halogen exchange reaction (with a suitable base, such as
n-BuLi) followed by a trans-metalation reaction with a suitable
metalating agent (such as a trialkylborate or a trialkylstannyl
chloride); [0193] step j' stands for the cyclisation of the
.beta.-amidoester of formula (XXIVb) with a salt (e.g.
hydrochloride) of a substituted amidine (such as acetamidine
hydrochloride) in order to form the pyrimidine cycle A, when Y is
N; [0194] step m' stands for conversion of the hydroxy group into
an halogen by the halogenation reaction carried out using, for
example, treatment with PO(Hal).sub.3, wherein Hal is preferably
chlorine.
[0195] In general, the starting compounds of formula (XXIII) are
known compounds or may be prepared according to known methods in
the literature.
[0196] The process of Scheme 2 is particularly convenient for the
preparation of compounds of general formula (IV), (V), (VI).
[0197] The compounds of general formula (XXIV), (XXIVb), (XXVI),
(XXVII), (XXVIII), (XXIX) are novel intermediates useful for the
preparation of the CRF antagonists object of the present invention
or other CRF antagonists, which may be conveniently prepared using
such intermediates. Representative CRF antagonists which may be
prepared using the above intermediates include, but are not limited
to, those disclosed in the above cited patent applications: WO
95/10506, WO 95/33750, WO 02/08895 and WO 03/008412. The above
cited publications, including but not limited to patents and patent
applications, are herein incorporated by reference as if each
individual publication were specifically and individually indicated
to be incorporated by reference herein as though fully set
forth.
[0198] In particular, the compounds of formula (XXVIA),
corresponding to the compounds of formula (XXVI) when Y corresponds
to a carbon atom, may exist in the tautomeric form (XXVIB).
##STR00022##
[0199] The compounds of general formula (IIt) may be prepared in an
alternative way according to the method described in the
International Patent Application WO 02/088095, as illustrated in
the following Scheme 3.
##STR00023##
in which [0200] step a'' stands for reduction of the ester with a
suitable reducing agent (such as DIBAI-H) to give compounds (XXXI);
[0201] step b'' stands for conversion of the hydroxy group in the
suitable protecting group of compounds (XXXII) (such as TBS:
tert-butyldimethylsilyl); [0202] step c'' stands for a nucleophilic
displacement reaction with the suitable amine RNH.sub.2 to give the
compounds of formula (XXXIII); [0203] step d'' stands for the
deprotection reaction to give the hydroxy group of compounds
(XXXIV); [0204] step e'' stands for intramolecular cyclisation
after conversion of the hydroxy group of compounds (XXXIV) in a
suitable leaving group (such as mesylate, by reaction with
Et.sub.3N and CH.sub.3SO.sub.2Cl) to give the cyclized compounds
(XXXV); [0205] step f'' stands for a metal mediated coupling
reaction with a suitable Z--W derivative to give compounds
[0206] The starting material is already known in literature, as
acid derivative (see Snider, Barry B.; Ahn, Yong; Foxman, Bruce M.
Synthesis of the tricyclic triamine core of martinelline and
martinellic acid. Tetrahedron Letters (1999), 40(17),
3339-3342).
[0207] When the --Z--W moiety of compounds of formula (I) is not a
known compound already described in the literature, it may be
prepared in analogy to the following Schemes.
[0208] The Schemes represent the preparation of specific
derivatives of --Z--W moieties, sometimes without the presence of
further substituents as defined above, in order to simplify the
understanding of the chemical processes.
[0209] This does not limit at all the availability of such
processes for the preparations of derivatives containing more
substituents or linked to different moieties.
[0210] Examples of the following preparations can be found in the
Experimental section.
[0211] Scheme for the synthesis of a derivative suitable for the
preparation of the compounds of formula (II) in which Z corresponds
to a pyrazolyl derivative and W is a W2 derivative, for example
1-(1H-pyrazol-3-yl)imidazolidin-2-one (intermediate 8):
##STR00024##
in which [0212] step a''' stands for the reaction of
3-aminopyrazole with chloroethyl isocyanate in DMF at 0.degree. C.;
[0213] step b''' stands for cyclisation reaction with KOt-Bu in THF
at r.t.; [0214] step c''' stands for deprotection reaction by LiOH
in MeOH/H.sub.2O at 80.degree. C.
[0215] Scheme for the synthesis of a derivative suitable for the
preparation of the compounds of formula (II) in which Z corresponds
to a pyrazolyl derivative and W is a W9 derivative, for example of
1-(1H-pyrazol-3-yl)pyrrolidin-2-one (intermediate 10):
##STR00025##
in which [0216] step a.sup.iv stands for reaction of
3-aminopyrazole with 4-chloro butyryl chloride in presence of
K.sub.2HPO.sub.4, and in CH.sub.2Cl.sub.2; [0217] step b.sup.iv
stands for cyclisation reaction with NaH, in DMF, at r.t.; [0218]
step c.sup.iv stands for deprotection reaction by MeONa/MeOH, at
r.t.
[0219] Scheme for the synthesis of a derivative suitable for the
preparation of the compounds of formula (II), in which Z
corresponds to a pyrazolyl derivative and W is a W3 derivative, for
example of 1-(1H-pyrazol-3-yl)tetrahydropyrimidin-2(1H)-one
(intermediate 13)
##STR00026##
in which [0220] step a.sup.v stands for the reaction of
3-aminopyrazole with chloropropyl isocyanate, in DMF, at 0.degree.
C.; [0221] step b.sup.v stands for cyclisation reaction with
KOt-Bu, in THF, at r.t.; [0222] step c.sup.v stands deprotection
reaction by LiOH, in MeOH/H.sub.2O, at 80.degree. C.
[0223] Scheme for the synthesis of a derivative suitable for the
preparation of the compounds of formula (II), in which Z
corresponds to a pyridyl derivative and W is a W2 derivative, for
example, protected 1-(6-bromo-2-pyridinyl)-2-imidazolidinone
(intermediate 96).
##STR00027##
in which [0224] step a.sup.vi stands for the condensation of
1-chloro-2-isocyanatoethane with 6-bromo-2-pyridinamine to give the
urea; [0225] step b.sup.vi stands for the cyclisation reaction in
basic conditions (t-BuOK in THF); [0226] step c.sup.vi stands for
protection of the urea NH group with a suitable protecting group
(such as a para-methoxybenzyl group).
[0227] Scheme for the synthesis of derivatives suitable for the
preparation of the compounds of formula (II), in which Z
corresponds to a pyrimidinyl derivative and W is a W2 derivative,
for example, protected 1-(4-bromo-2-pyrimidinyl)-2-imidazolidinone
(intermediate 102) and protected
1-(2-bromo-4-pyrimidinyl)-2-imidazolidinone (intermediate 104).
##STR00028##
in which [0228] step a.sup.vii stands for the condensation of
1-chloro-2-isocyanatoethane with 4-methoxybenzyl amine to give the
urea derivative; [0229] step b.sup.vii stands for the cyclisation
reaction in basic conditions (t-BuOK in THF); [0230] step c.sup.vii
stands for the nucleophilic substitution of the cyclic urea on
2,4-dichloropyrimidine in basic conditions (such as NaH in DMF);
[0231] step d.sup.vii stands for exchange of the chloride group
into a bromide group by reaction with TMSBr (trimethylsilyl
bromide).
[0232] Scheme for the synthesis of the compounds of formula (II),
in which Z is a triazolyl or pyrazolyl derivative. In particular
the synthesis of the compounds (IIr) in which Z is triazolyl or
pyrazolyl derivative and W is a W2 derivative,
1-(1H-1,2,4-triazol-3-yl)-2-imidazolidinone substituent
(R.sub.5.dbd.H, X.dbd.N) and
1-(5-methyl-1H-pyrazol-3-yl)-2-imidazolidinone substituent
(R.sub.5=Me, X.dbd.C)
##STR00029##
in which [0233] step a.sup.viii stands for the arylation reaction
with a 3-aminoheterocycle by a metal catalysed coupling reaction
(for example a Buchwald reaction) procedure; [0234] step b.sup.viii
stands for the condensation of 1-chloro-2-isocyanatoethane with the
amino heterocycle to give the urea; [0235] step c.sup.viii stands
for the cyclisation reaction in basic conditions (t-BuOK in
THF).
[0236] Scheme for the synthesis of a derivative suitable for the
preparation of the compounds of formula (II), in which Z
corresponds to a phenyl derivative and W is a W2 derivative, for
example, 1-phenyl-2-imidazolidinone substituent.
##STR00030##
in which [0237] step a.sup.ix stands for step f)' as defined in
Scheme 2 (Suzuki coupling with the boronic acid derivative); [0238]
step b.sup.ix stands for the condensation of
1-chloro-2-isocyanatoethane with 6-bromo-2-pyridinamine to give the
urea; [0239] step c.sup.ix stands for the cyclisation reaction in
basic conditions (t-BuOK in THF).
[0240] Scheme for the synthesis of a derivative suitable for the
preparation of the compounds of formula (II), in which Z
corresponds to a pyrazolyl derivative and W is a W11, W13, or a W14
derivative, for example, 3-(1H-pyrazol-3-yl)-1,3-oxazolidin-2-one
(intermediate 16), 3-methyl-1-(1H-pyrazol-3-yl)-2(1H)-pyridinone
(intermediate 26) and 2-(1H-pyrazol-3-yl)-3(2H)-pyridazinone
(intermediate 28).
##STR00031##
In which [0241] step a.sup.x stands for the protection of
3-bromopyrazole with a suitable protecting group (such as a trityl
group); [0242] step b.sup.x stands for the copper catalysed
coupling reaction between the protected bromopyrazole and
1,3-oxazolidin-2-one, 3-methyl-2(1H)-pyridinone and
3(2H)-pyridazinone, respectively; [0243] step c.sup.x stands for
the deprotection reaction to give the desired bicyclic
derivative.
[0244] Scheme for the synthesis of a derivative suitable for the
preparation of the compounds of formula (IIr), in which Z
corresponds to a pyrazolyl derivative and W is a W10 derivative,
for example, 2-(1H-pyrazol-3-yl)-1,2,5-thiadiazolidine 1,1-dioxide
substituent.
##STR00032##
in which [0245] step a.sup.xi stands for alkylation of the amino
group using ethyl 2-bromoacetate as an alkylating agent; [0246]
step b.sup.xi stands for reduction of the ester group into the
alcohol, using a suitable reducing agent (such as LiAlH.sub.4);
[0247] step c.sup.xi stands for cyclisation of the amino alcohol
using Burgess' reagent ((methoxycarbonylsulfamoyl)triethylammonium
hydroxide inner salt) to give the cyclic sulfonylurea; [0248] step
d.sup.xi stands for the deprotection of the sulfonylurea using
basic conditions (such as NaOH in a CH.sub.2Cl.sub.2/MeOH
mixture).
[0249] Scheme for the synthesis of a derivative suitable for the
preparation of the compounds of formula (II), in which Z
corresponds to a pyrazolyl derivative and W is a W12 derivative,
for example, 2-(1H-pyrazol-3-yl)isothiazolidine 1,1-dioxide
substituent.
##STR00033##
in which [0250] step a.sup.xii stands for alkylation of the amino
group using 1,2-oxathiolane 2,2-dioxide as an alkylating agent;
[0251] step b.sup.xii stands for the cyclisation step mediated by
the addition of POCl.sub.3.
[0252] Scheme for the synthesis of a derivative suitable for the
preparation of the compounds of formula (IIr), in which Z
corresponds to a pyrazolyl derivative and W is a W1 derivative, for
example, 1-(1H-pyrazol-3-yl)-1,3-dihydro-2H-imidazol-2-one
substituent.
##STR00034##
in which [0253] step a.sup.xiii stands for the preparation of the
phenyl carbamate using phenyl chloroformate; [0254] step b.sup.xiii
stands for the addition of aminoacetaldehyde dimethyl acetal to the
activated carbamate group; [0255] step c.sup.xiii stands for the
cyclisation reaction in the presence of an acid (such as HCl) to
give the 2H-imidazol-2-one substituent.
[0256] The R group present in compounds of formula (I) is generally
a known compound. When such R group is not a compound already
described in the literature, it may be prepared in analogy to the
following Schemes.
[0257] The Schemes represent the preparation of specific
derivatives of R groups, sometimes without the presence of further
substituents J as defined above, in order to simplify the
understanding of the chemical processes.
[0258] This does not limit at all the availability of such
processes for the preparations of R groups containing more J
substituents.
[0259] Examples of the following preparations can be found in the
Experimental section. Scheme for the synthesis of
2-(difluoromethyl)-4-(methyloxy)aniline.
##STR00035##
in which [0260] step a.sup.xiv stands for reduction of the acid
group with a suitable reducing agent (such as cyanuric
chloride/NMM/NaBH.sub.4); [0261] step b.sup.xiv stands for
oxidation of the alcohol to the aldehyde with a suitable oxidizing
agent (such as Dess-Martin periodinane); [0262] step c.sup.xiv
stands for difluorination of the aldehyde using a suitable
fluorinating agent (such as DAST: (diethylamino)sulfur
trifluoride); [0263] step d.sup.xiv stands for the reduction of the
nitro group with a suitable reducing agent (such as H.sub.2,
catalysed with palladium on activated charcoal).
[0264] Scheme for the preparation of
2-(Methyloxy)-4-(1H-pyrazol-1-yl)aniline (intermediate 88).
##STR00036##
In which [0265] step a.sup.xv stands for the copper catalysed
coupling reaction between 4-bromo-2-(methyloxy)aniline and
pyrazole.
[0266] Compounds of formula (IIn) may be conveniently prepared
according to the following Scheme 4 and where the starting material
was prepared according to WO 02/088095 A1
##STR00037##
in which [0267] step a.sup.xvi stands for the cyclisation of the
p-ketoester of formula (XXIVb) with a salt (e.g. hydrochloride) of
a substituted amidine (such as acetamidine hydrochloride); [0268]
step b.sup.xvi stands for the transformation of the hydroxy group
of formula (XXVIb) into a suitable leaving group, selected in a
group consisting from: halogen or reactive residue of sulphonic
acid (e.g. mesylate, tosylate), preferably chloride; [0269] step
c.sup.xvi stands for conversion of the leaving group L in the
compounds (XXVIIIb), by reaction with the suitable --Z--W
derivative; [0270] step d.sup.xvi corresponds to previous step o in
Scheme 1.
[0271] In particular, when J is a group --OCHF.sub.2, this can be
introduced directly in the R group by methods already known in the
literature or, eventually, the group --OCH.sub.3 may be deprotected
using one of the methods listed in the Greene's reference cited
below. Then, the hydroxyl group may be alkylated by using a
suitable fluoroalkylating agent, such as CF.sub.2Br.sub.2, as
exemplified for Intermediate 125.
[0272] Those skilled in the art will appreciate that in the
preparation of the compound of the invention or a solvate thereof
it may be necessary and/or desirable to protect one or more
sensitive groups in the molecule to prevent undesirable side
reactions. Suitable protecting groups for use according to the
present invention are well known to those skilled in the art and
may be used in a conventional manner. See, for example, "Protective
groups in organic synthesis" by T. W. Greene and P. G. M. Wuts
(John Wiley & sons 1991) or "Protecting Groups" by P. J.
Kocienski (Georg Thieme Verlag 1994). Examples of suitable amino
protecting groups include acyl type protecting groups (e.g. formyl,
trifluoroacetyl, acetyl), aromatic urethane type protecting groups
(e.g. benzyloxycarbonyl (Cbz) and substituted Cbz), aliphatic
urethane protecting groups (e.g. 9-fluorenylmethoxycarbonyl (Fmoc),
t-butyloxycarbonyl (Boc), isopropyloxycarbonyl,
cyclohexyloxycarbonyl) and alkyl type protecting groups (e.g.
benzyl, trityl, chlorotrityl). Examples of suitable oxygen
protecting groups may include for example alky silyl groups, such
as trimethylsilyl or tert-butyldimethylsilyl; alkyl ethers such as
tetrahydropyranyl or tert-butyl; or esters such as acetate
[0273] Pharmaceutical acceptable salts may also be prepared from
other salts, including other pharmaceutically acceptable salts, of
the compound of formula (I) using conventional methods.
[0274] The compounds of formula (I) may readily be isolated in
association with solvent molecules by crystallisation or
evaporation of an appropriate solvent to give the corresponding
solvates.
[0275] When a specific enantiomer of a compound of general formula
(I) is required, this may be obtained for example by resolution of
a corresponding enantiomeric mixture of a compound of formula (I)
using conventional methods. Thus the required enantiomer may be
obtained from the racemic compound of formula (I) by use of chiral
HPLC procedure.
[0276] The subject invention also includes isotopically-labelled
compounds, which are identical to those recited in formula (I) and
following, but for the fact that one or more atoms are replaced by
an atom having an atomic mass or mass number different from the
atomic mass or mass number usually found in nature. Examples of
isotopes that can be incorporated into compounds of the invention
and pharmaceutically acceptable salts thereof include isotopes of
hydrogen, carbon, nitrogen, oxygen, phosphorous, sulphur, fluorine,
iodine, and chlorine, such as .sup.2H, .sup.3H, .sup.11C, .sup.13C,
.sup.14C, .sup.15N, .sup.17O, .sup.18O, .sup.31P, .sup.32P,
.sup.35S, .sup.18F, .sup.36Cl, .sup.123I and .sup.125I.
[0277] Compounds of the present invention and pharmaceutically
acceptable salts of said compounds that contain the aforementioned
isotopes and/or other isotopes of other atoms are within the scope
of the present invention. Isotopically-labelled compounds of the
present invention, for example those into which radioactive
isotopes such as 3H, 14C are incorporated, are useful in drug
and/or substrate tissue distribution assays. Tritiated, i.e.,
.sup.3H, and carbon-14, i.e., .sup.14C, isotopes are particularly
preferred for their ease of preparation and detectability. .sup.11C
and .sup.18F isotopes are particularly useful in PET (positron
emission tomography), and .sup.125I isotopes are particularly
useful in SPECT (single photon emission computerized tomography),
all useful in brain imaging. Further, substitution with heavier
isotopes such as deuterium, i.e., .sup.2H, can afford certain
therapeutic advantages resulting from greater metabolic stability,
for example increased in vivo half-life or reduced dosage
requirements and, hence, may be preferred in some circumstances.
Isotopically labelled compounds of formula I and following of this
invention can generally be prepared by carrying out the procedures
disclosed in the Schemes and/or in the Examples below, by
substituting a readily available isotopically labelled reagent for
a non-isotopically labelled reagent.
[0278] The CRF receptor antagonists of the present invention
demonstrate activity at the CRF receptor site and may be used in
the treatment of conditions mediated by CRF or CRF receptors.
[0279] The effectiveness of a compound as a CRF receptor antagonist
may be determined by various assay methods. Suitable CRF
antagonists of this invention are capable of inhibiting the
specific binding of CRF to its receptor and antagonizing activities
associated with CRF. A compound of structure (I) may be assessed
for activity as a CRF antagonist by one or more generally accepted
assays for this purpose, including (but not limited to) the assays
disclosed by DeSouza et al. (J. Neuroscience 7: 88, 1987) and
Battaglia et al. (Synapse 1: 572, 1987).
[0280] The CRF receptors-binding assay was performed by using the
homogeneous technique of scintillation proximity (SPA). The ligand
binds to recombinant membrane preparation expressing the CRF
receptors which in turn bind to wheatgerm agglutinin coated SPA
beads. In the Experimental Part will be disclosed the details of
the experiments.
[0281] With reference to CRF receptor binding affinities, CRF
receptor antagonists of this invention have a Ki less than 10
.mu.m.
[0282] Compounds of the invention are useful in the treatment of
central nervous system disorders where CRF receptors are involved.
In particular in the treatment or prevention of major depressive
disorders including bipolar depression, unipolar depression, single
or recurrent major depressive episodes with or without psychotic
features, catatonic features, melancholic features, atypical
features or postpartum onset, the treatment of anxiety and the
treatment of panic disorders. Other mood disorders encompassed
within the term major depressive disorders include dysthymic
disorder with early or late onset and with or without atypical
features, neurotic depression, post traumatic stress disorders,
post operative stress and social phobia; dementia of the
Alzheimer's type, with early or late onset, with depressed mood;
vascular dementia with depressed mood; mood disorders induced by
alcohol, amphetamines, cocaine, hallucinogens, inhalants, opioids,
phencyclidine, sedatives, hypnotics, anxiolytics and other
substances; schizoaffective disorder of the depressed type; and
adjustment disorder with depressed mood. Major depressive disorders
may also result from a general medical condition including, but not
limited to, myocardial infarction, diabetes, miscarriage or
abortion, etc.
[0283] Compounds of the invention are also useful in the treatment
or prevention of schizophrenic disorders including paranoid
schizophrenia, disorganised schizophrenia, catatonic schizophrenia,
undifferentiated schizophrenia, residual schizophrenia.
[0284] Compounds of the invention are useful as analgesics. In
particular they are useful in the treatment of traumatic pain such
as postoperative pain; traumatic avulsion pain such as brachial
plexus; chronic pain such as arthritic pain such as occurring in
osteo-, rheumatoid or psoriatic arthritis; neuropathic pain such as
post-herpetic neuralgia, trigeminal neuralgia, segmental or
intercostal neuralgia, fibromyalgia, causalgia, peripheral
neuropathy, diabetic neuropathy, chemotherapy-induced neuropathy,
AIDS related neuropathy, occipital neuralgia, geniculate neuralgia,
glossopharyngeal neuralgia, reflex sympathetic dystrophy, phantom
limb pain; various forms of headache such as migraine, acute or
chronic tension headache, temporomandibular pain, maxillary sinus
pain, cluster headache; odontalgia; cancer pain; pain of visceral
origin; gastrointestinal pain; nerve entrapment pain; sports injury
pain; dysmennorrhoea; menstrual pain; meningitis; arachnoiditis;
musculoskeletal pain; low back pain e.g. spinal stenosis; prolapsed
disc; sciatica; angina; ankylosing spondyolitis; gout; burns; scar
pain; itch; and thalamic pain such as post stroke thalamic
pain.
[0285] Compounds of the invention are also useful for the treatment
of dysfunction of appetite and food intake and in circumstances
such as anorexia, anorexia nervosa and bulimia.
[0286] Compounds of the invention are also useful in the treatment
of sleep disorders including dysomnia, insomnia, sleep apnea,
narcolepsy, and circadian rhythmic disorders.
[0287] Compounds of the invention are also useful in the treatment
or prevention of cognitive disorders. Cognitive disorders include
dementia, amnestic disorders and cognitive disorders not otherwise
specified.
[0288] Furthermore compounds of the invention are also useful as
memory and/or cognition enhancers in healthy humans with no
cognitive and/or memory deficit.
[0289] Compounds of the invention are also useful in the treatment
of tolerance to and dependence on a number of substances. For
example, they are useful in the treatment of dependence on
nicotine, alcohol, caffeine, phencyclidine (phencyclidine like
compounds), or in the treatment of tolerance to and dependence on
opiates (e.g. cannabis, heroin, morphine) or benzodiazepines; in
the treatment of cocaine, sedative ipnotic, amphetamine or
amphetamine-related drugs (e.g. dextroamphetamine,
methylamphetamine) addiction or a combination thereof.
[0290] Compounds of the invention are also useful as
anti-inflammatory agents. In particular they are useful in the
treatment of inflammation in asthma, influenza, chronic bronchitis
and rheumatoid arthritis; in the treatment of inflammatory diseases
of the gastrointestinal tract such as Crohn's disease, ulcerative
colitis, postoperative gastric ileus (POI), inflammatory bowel
disease (IBD) and non-steroidal anti-inflammatory drug induced
damage; inflammatory diseases of the skin such as herpes and
eczema; inflammatory diseases of the bladder such as cystitis and
urge incontinence; and eye and dental inflammation.
[0291] Compounds of the invention are also useful in the treatment
of allergic disorders, in particular allergic disorders of the skin
such as urticaria, and allergic disorders of the airways such as
rhinitis.
[0292] Compounds of the invention are also useful in the treatment
of emesis, i.e. nausea, retching and vomiting. Emesis includes
acute emesis, delayed emesis and anticipatory emesis. The compounds
of the invention are useful in the treatment of emesis however
induced. For example, emesis may be induced by drugs such as cancer
chemotherapeutic agents such as alkylating agents, e.g.
cyclophosphamide, carmustine, lomustine and chlorambucil; cytotoxic
antibiotics, e.g. dactinomycin, doxorubicin, mitomycin-C and
bleomycin; anti-metabolites, e.g. cytarabine, methotrexate and
5-fluorouracil; vinca alkaloids, e.g. etoposide, vinblastine and
vincristine; and others such as cisplatin, dacarbazine,
procarbazine and hydroxyurea; and combinations thereof; radiation
sickness; radiation therapy, e.g. irradiation of the thorax or
abdomen, such as in the treatment of cancer; poisons; toxins such
as toxins caused by metabolic disorders or by infection, e.g.
gastritis, or released during bacterial or viral gastrointestinal
infection; pregnancy; vestibular disorders, such as motion
sickness, vertigo, dizziness and Meniere's disease; post-operative
sickness; gastrointestinal obstruction; reduced gastrointestinal
motility; visceral pain, e.g. myocardial infarction or peritonitis;
migraine; increased intercranial pressure; decreased intercranial
pressure (e.g. altitude sickness); opioid analgesics, such as
morphine; and gastro-oesophageal reflux disease, acid indigestion,
over-indulgence of food or drink, acid stomach, sour stomach,
waterbrash/regurgitation, heartburn, such as episodic heartburn,
nocturnal heartburn, and meal-induced heartburn and dyspepsia.
[0293] Compounds of the invention are of particular use in the
treatment of gastrointestinal disorders such as irritable bowel
syndrome (IBS); skin disorders such as psoriasis, pruritis and
sunburn; vasospastic diseases such as angina, vascular headache and
Reynaud's disease; cerebral ischeamia such as cerebral vasospasm
following subarachnoid haemorrhage; fibrosing and collagen diseases
such as scleroderma and eosinophilic fascioliasis; disorders
related to immune enhancement or suppression such as systemic lupus
erythematosus and rheumatic diseases such as fibrositis; and
cough.
[0294] Compounds of the invention are useful for the treatment of
neurotoxic injury which follows cerebral stroke, thromboembolic
stroke, hemorrhagic stroke, cerebral ischemia, cerebral vasospam,
hypoglycemia, hypoxia, anoxia, perinatal asphyxia cardiac
arrest.
[0295] The invention therefore provides a compound of formula (I)
or a pharmaceutically acceptable salt or solvate thereof for use in
therapy, in particular in human medicine.
[0296] There is also provided as a further aspect of the invention
the use of a compound of formula (I) or a pharmaceutically
acceptable salt or solvate thereof in the preparation of a
medicament for use in the treatment of conditions mediated by
CRF.
[0297] In an alternative or further aspect there is provided a
method for the treatment of a mammal, including man, in particular
in the treatment of condition mediated by CRF, comprising
administration of an effective amount of a compound of formula (I)
or a pharmaceutically acceptable salt or a solvate thereof.
[0298] While it is possible that, for use in therapy, a compound of
the present invention may be administered as the raw chemical, it
is preferable to present the active ingredient as a pharmaceutical
formulation e.g. when the agent is in admixture with a suitable
pharmaceutical excipient, diluent or carrier selected with regard
to the intended route of administration and standard pharmaceutical
practice.
[0299] In a further aspect, the invention provides a pharmaceutical
composition comprising at least one compound of the invention or a
pharmaceutically acceptable derivative thereof in association with
a pharmaceutically acceptable carrier and/or excipient. The carrier
and/or excipient must be "acceptable" in the sense of being
compatible with the other ingredients of the formulation and not
deletrious to the recipient thereof.
[0300] Accordingly, the present invention further provides a
pharmaceutical formulation comprising at least one compound of the
invention or a pharmaceutically acceptable derivative thereof, in
association with a pharmaceutically acceptable carrier and/or
excipient. The carrier and/or excipient must be "acceptable" in the
sense of being compatible with the other ingredients of the
formulation and not deletrious to the recipient thereof.
[0301] There is further provided by the present invention a process
of preparing a pharmaceutical composition, which process comprises
mixing at least one compound of the invention or a pharmaceutically
acceptable derivative thereof, together with a pharmaceutically
acceptable carrier and/or excipient.
[0302] The pharmaceutical compositions may be for human or animal
usage in human and veterinary medicine and will typically comprise
any one or more of a pharmaceutically acceptable diluent, carrier
or excipient. Acceptable carriers or diluents for therapeutic use
are well known in the pharmaceutical art, and are described, for
example, in Remington's Pharmaceutical Sciences, Mack Publishing
Co. (A. R. Gennaro edit. 1985). The choice of pharmaceutical
carrier, excipient or diluent can be selected with regard to the
intended route of administration and standard pharmaceutical
practice. The pharmaceutical compositions may comprise as--or in
addition to--the carrier, excipient or diluent any suitable
binder(s), lubricant(s), suspending agent(s), coating agent(s),
solubilising agent(s).
[0303] Preservatives, stabilisers, dyes and even flavouring agents
may be provided in the pharmaceutical composition. Examples of
preservatives include sodium benzoate, sorbic acid and esters of
p-hydroxybenzoic acid. Antioxidants and suspending agents may be
also used.
[0304] There may be different composition/formulation requirements
dependent on the different delivery systems. By way of example, the
pharmaceutical composition of the present invention may be
formulated to be delivered using a mini-pump or by a mucosal route,
for example, as a nasal spray or aerosol for inhalation or
ingestible solution, or parenterally in which the composition is
formulated by an injectable form, for delivery, by, for example, an
intravenous, intramuscular or subcutaneous route. Alternatively,
the formulation may be designed to be delivered by both routes.
[0305] Where the agent is to be delivered mucosally through the
gastrointestinal mucosa, it should be able to remain stable during
transit though the gastrointestinal tract; for example, it should
be resistant to proteolytic degradation, stable at acid pH and
resistant to the detergent effects of bile.
[0306] Where appropriate, the pharmaceutical compositions can be
administered by inhalation, in the form of a suppository or
pessary, topically in the form of a lotion, solution, cream,
ointment or dusting powder, by use of a skin patch, orally in the
form of tablets containing excipients such as starch or lactose, or
in capsules or ovules either alone or in admixture with excipients,
or in the form of elixirs, solutions or suspensions containing
flavouring or colouring agents, or they can be injected
parenterally, for example intravenously, intramuscularly or
subcutaneously. For parenteral administration, the compositions may
be best used in the form of a sterile aqueous solution which may
contain other substances, for example enough salts or
monosaccharides to make the solution isotonic with blood. For
buccal or sublingual administration the compositions may be
administered in the form of tablets or lozenges which can be
formulated in a conventional manner.
[0307] For some embodiments, the agents of the present invention
may also be used in combination with a cyclodextrin. Cyclodextrins
are known to form inclusion and non-inclusion complexes with drug
molecules. Formation of a drug-cyclodextrin complex may modify the
solubility, dissolution rate, bioavailability and/or stability
property of a drug molecule. Drug-cyclodextrin complexes are
generally useful for most dosage forms and administration routes.
As an alternative to direct complexation with the drug the
cyclodextrin may be used as an auxiliary additive, e.g. as a
carrier, diluent or solubiliser. Alpha-, beta and
gamma-cyclodextrins are most commonly used and suitable examples
are described in WO-A-91/11172, WO-A-94/02518 and
WO-A-98/55148.
[0308] In a preferred embodiment, the agents of the present
invention are delivered systemically (such as orally, buccally,
sublingually), more preferably orally.
[0309] Hence, preferably the agent is in a form that is suitable
for oral delivery.
[0310] It is to be understood that not all of the compounds need be
administered by the same route. Likewise, if the composition
comprises more than one active component, then those components may
be administered by different routes.
[0311] The compounds of the invention may be milled using known
milling procedures such as wet milling to obtain a particle size
appropriate for tablet formation and for other formulation types.
Finely divided (nanoparticulate) preparations of the compounds of
the invention may be prepared by processes known in the art, for
example see International Patent Application No. WO 02/00196
(SmithKline Beecham).
[0312] For oral administration, the pharmaceutical compositions may
take the form of, for example, tablets or capsules prepared by
conventional means with pharmaceutically acceptable excipients such
as binding agents (e.g. pregelatinised maize starch,
polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers
(e.g. lactose, microcrystalline cellulose or calcium hydrogen
phosphate); lubricants (e.g. magnesium stearate, talc or silica);
disintegrants (e.g. potato starch or sodium starch glycollate); or
wetting agents (e.g. sodium lauryl sulphate). The tablets may be
coated by methods well known in the art. Liquid preparations for
oral administration may take the form of, for example, solutions,
syrups or suspensions, or they may be presented as a dry product
for constitution with water or other suitable vehicle before use.
Such liquid preparations may be prepared by conventional means with
pharmaceutically acceptable additives such as suspending agents
(e.g. sorbitol syrup, cellulose derivatives or hydrogenated edible
fats); emulsifying agents (e.g. lecithin or acacia); non-aqueous
vehicles (e.g. almond oil, oily esters, ethyl alcohol or
fractionated vegetable oils); and preservatives (e.g. methyl or
propyl-p-hydroxybenzoates or sorbic acid). The preparations may
also contain buffer salts, flavouring, colouring and sweetening
agents as appropriate.
[0313] Preparations for oral administration may be suitably
formulated to give controlled release of the active compound.
[0314] For buccal administration the composition may take the form
of tablets or formulated in conventional manner.
[0315] The compounds of the invention may be formulated for
parenteral administration by bolus injection or continuous
infusion. Formulations for injection may be presented in unit
dosage form e.g. in ampoules or in multi-dose containers, with an
added preservative. The compositions may take such forms as
suspensions, solutions or emulsions in oily or aqueous vehicles,
and may contain formulatory agents such as suspending, stabilising
and/or dispersing agents. Alternatively, the active ingredient may
be in powder form for constitution with a suitable vehicle, e.g.
sterile pyrogen-free water, before use.
[0316] The compounds of the invention may be formulated for topical
administration in the form of ointments, creams, gels, lotions,
pessaries, aerosols or drops (e.g. eye, ear or nose drops).
Ointments and creams may, for example, be formulated with an
aqueous or oily base with the addition of suitable thickening
and/or gelling agents. Ointments for administration to the eye may
be manufactured in a sterile manner using sterilised
components.
[0317] Lotions may be formulated with an aqueous or oily base and
will in general also contain one or more emulsifying agents,
stabilising agents, dispersing agents, suspending agents,
thickening agents, or colouring agents. Drops may be formulated
with an aqueous or non-aqueous base also comprising one or more
dispersing agents, stabilising agents, solubilising agents or
suspending agents. They may also contain a preservative.
[0318] The compounds of the invention may also be formulated in
rectal compositions such as suppositories or retention enemas, e.g.
containing conventional suppository bases such as cocoa butter or
other glycerides.
[0319] The compounds of the invention may also be formulated as
depot preparations. Such long acting formulations may be
administered by implantation (for example subcutaneously or
intramuscularly) or by intramuscular injection. Thus, for example,
the compounds of the invention may be formulated with suitable
polymeric or hydrophobic materials (for example as an emulsion in
an acceptable oil) or ion exchange resins, or as sparingly soluble
derivatives, for example, as a sparingly soluble salt.
[0320] For intranasal administration, the compounds of the
invention may be formulated as solutions for administration via a
suitable metered or unitary dose device or alternatively as a
powder mix with a suitable carrier for administration using a
suitable delivery device.
[0321] A proposed dose of the compounds of the invention is 1 to
about 1000 mg per day. It will be appreciated that it may be
necessary to make routine variations to the dosage, depending on
the age and condition of the patient and the precise dosage will be
ultimately at the discretion of the attendant physician or
veterinarian. The dosage will also depend on the route of
administration and the particular compound selected.
[0322] Thus for parenteral administration a daily dose will
typically be in the range of 1 to about 100 mg, preferably 1 to 80
mg per day. For oral administration a daily dose will typically be
within the range 1 to 300 mg e.g. 1 to 100 mg.
EXAMPLES
[0323] In the Intermediates and Examples unless otherwise
stated:
[0324] All temperatures refer to .degree. C. Infrared spectra were
measured on a FT-IR instrument. Compounds were analysed by direct
infusion of the sample dissolved in acetonitrile into a mass
spectra operated in positive electro spray (ES.sup.+) ionisation
mode. Proton Magnetic Resonance (.sup.1H-NMR) spectra were recorded
at 400 MHz, chemical shifts are reported in ppm downfield (d) from
Me.sub.4Si, used as internal standard, and are assigned as singlets
(s), broad singlets (bs), doublets (d), doublets of doublets (dd),
triplets (t), quartets (q) or multiplets (m). A strategy comprising
of NOE (Nuclear Overhauser Effect) correlation and/or 1H,15N long
range scalar correlations measurements has been implemented in
order to allow elucidation of possible regio-isomers structure of
compounds of the present invention. Proposed structures were
verified by measurement of the vicinity in the space of key
hydrogens, thus 1D Nuclear Overhauser difference spectra were used
to measure 1H,1H-dipole-dipole correlations.
[0325] In cases where NOE measurements were not conclusive, 1H,15N
long range scalar correlations were measured via 1H,15N-HMBC
experiments. A delay corresponding to an average long range scalar
coupling 2,3J(1H,15N) of 6 Hz was set for optimal result. Column
chromathography was carried out over silica gel (Merck AG
Darmstaadt, Germany). The following abbreviations are used in the
text: EtOAc=ethyl acetate, cHex=cyclohexane,
CH.sub.2Cl.sub.2=dichloromethane, Et.sub.2O=dietyl ether,
DMF=N,N'-dimethylformamide, DIPEA=N,N-diisopropylethylamine,
DME=ethylene glycol dimethyl ether, MeOH=methanol,
Et.sub.3N=triethylamine, TFA=trifluoroacetic acid,
THF=tetrahydrofuran, DIBAI-H=diisobutylaluminium hydride,
DMAP=dimethylaminopyridine, LHMDS=lithiumhexamethyldisilazane,
KOtBu=potassium tert-butoxide, NMP=M-methyl-2-pyrrolidinone,
MTBE=methyl-tert-butyl ether, IPA=isopropanol,
DAST=(diethylamino)sulfur trifluoride, TMSBr=trimethylsilyl
bromide, DDQ=2,3-dichloro-5,6-dicyano-1,4-benzoquinone, SCX=strong
cation exchanger, Tlc refers to thin layer chromatography on silica
plates, and dried refers to a solution dried over anhydrous sodium
sulphate, r.t. (RT) refers to room temperature.
Intermediate 1
1-(4-Methoxy-2-methylphenyl)pyrrolidin-2-one
[0326] To a solution of Et.sub.3N (156 mL, 1 eq) and
4-methoxy-2-methylaniline (150 g, 1.09 mole) in anh. THF (2.4 L),
in a 10 L reaction vessel, at 0.degree. C., under N.sub.2, was
added dropwise a solution of 4-chlorobutyryl chloride (126 mL, 1
eq) in anh. THF (480 mL). The internal temperature was maintained
at circa 10.degree. C. and the reaction mixture was stirred for 1.5
hr. It was cooled down to 0.degree. C. and KOt-Bu 1M/THF (2.64 L,
2.4 eq) was added dropwise over a period of 1.5 hr, keeping the
internal temperature <10.degree. C. The reaction mixture was
stirred at that temperature for 30 min. Water (1.5 L) was then
added slowly (20 min) and the phases were separated. The organic
layer was treated with conc. HCl (250 mL) and water (1.26 L) and
the phases were separated. The combined aqueous layers were
extracted with EtOAc (2.6 L) and the combined organic layers were
washed with brine (2 L). The solvent was evaporated and the residue
purified by flash chromatography (Biotage 150, EtOAc/cHex 8:2) to
give the title compound as a pale brown solid (206 g, 92%).
[0327] NMR (.sup.1H, CDCl.sub.3): .delta. 7.05 (d, 1H), 6.79-6.72
(m, 2H), 3.75 (s, 3H), 3.64 (t, 2H), 2.18 (s, 6H).
[0328] MS (m/z): 206 [MH].sup.+.
Intermediate 2
Ethyl
3-{[1-(4-methoxy-2-methylphenyl)pyrrolidin-2-ylidene]amino}but-2-eno-
ate
[0329] To a solution of intermediate 1 (8.3 g, 40.49 mmol) in anh.
1,2-dichloroethane (100 mL), at r.t., under N.sub.2, was added
POCl.sub.3 (7.5 mL, 2 eq) dropwise followed by ethyl
3-aminocrotonate (5.17 mL, 1 eq). The reaction mixture was heated
at 60.degree. C. for 3.5 hr. It was then cooled down to r.t. and
neutralized to pH 7 by the careful addition of sat.aq. NaHCO.sub.3.
The neutralized solution was extracted with CH.sub.2Cl.sub.2
(3.times.50 mL). The combined organic extracts were washed with
sat.aq. NaCl and dried over anh. Na.sub.2SO.sub.4. The solids were
filtered and the solvent evaporated. The crude product was used as
such in the next step (17.8 g).
[0330] Alternatively, to a solution of intermediate 91 (3 g, 14.7
mmol) in anh. THF (18 mL), at r.t., under N.sub.2, was added
ethyl-2-butynoate (2.23 mL, 1.3 eq). The reaction mixture was
heated to reflux for 14 hr and was then cooled down to r.t. The
reaction mixture was evaporated to dryness. The crude oil was used
as such in the next step (5.05 g).
[0331] MS (m/z): 317 [MH].sup.+.
Intermediate 3
1-(4-Methoxy-2-methylphenyl)-6-methyl-1,2,3,7-tetrahydro-4H-pyrrolo[2,3-b]-
pyridin-4-one
[0332] A solution of intermediate 2 (17.8 g, 55 mmol) in anh. DMF
(50 mL) was added dropwise to a suspension of NaH 60%/oil (4.5 g, 2
eq) in anh. DMF. The reaction mixture was heated at 100.degree. C.
for 8 hr. More NaH 60%/oil (2.25 g, 1 eq) was added and the
reaction mixture was heated for an additional 4 hr. It was cooled
down to r.t. and carefully poured in sat.aq. NH.sub.4Cl. The
aqueous solution was extracted with CH.sub.2Cl.sub.2 (5.times.50
mL) and the combined organic extracts were dried over anh.
Na.sub.2SO.sub.4. The solids were filtered and the solvent was
evaporated. The crude compound was purified by flash chromatography
(Biotage 75, CH.sub.2Cl.sub.2/MeOH 95:5->80:20). The title
compound was obtained as a brown oil (952 mg, 9%, two steps)
[0333] Alternatively, to a solution of intermediate 2 (2.46 g, 7.77
mmol) in anh. THF (10 mL), at r.t., under N.sub.2, was added 1M
t-BuOK/THF (15.6 mL, 2 eq). The reaction mixture was heated to
reflux and stirred for 6 hr. The solution was allowed to cool down
to r.t., evaporated to circa 10 mL and diluted with MTBE (10 mL).
The organic layer was extracted with water (10 mL), the organic
phase discarded while the aqueous one was diluted with sat.aq.
NH.sub.4Cl (10 mL). The aqueous layer was extracted with
CH.sub.2Cl.sub.2 (10 mL). The combined organic extracts were
evaporated to dryness and the crude product thus obtained was used
as such in the next step (1.32 g).
[0334] NMR (.sup.1H, DMSO-d.sub.6): .delta. 9.8 (b, 1H), 7.08 (d,
1H), 6.80 (d, 1H), 6.75 (dd, 1H), 5.92 (s, 1H), 3.72 (s, 3H), 3.68
(t, 2H), 2.89 (t, 2H), 2.12 (s, 3H), 2.02 (s, 3H).
[0335] MS (m/z): 271 [MH].sup.+.
Intermediate 4
1-(4-Methoxy-2-methylphenyl)-6-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-
-4-yl trifluoromethanesulfonate
[0336] To a solution of intermediate 3 (9.0 g, 33.3 mmol) in anh.
CH.sub.2Cl.sub.2 (64 mL), at r.t., under N.sub.2, was added
pyridine (5.08 mL, 1.8 eq). The solution was cooled down to
-20.degree. C. and triflic anhydride (5.9 mL, 1.1 eq) was added
dropwise over 50 min. The temperature never exceeded -10.degree. C.
The reaction mixture was allowed to warm up to ambient and stirred
for 30 min. Sat.aq NaHCO.sub.3 (31.2 mL) was added and the phases
separated. The organic layer was further washed with water (31.2
mL) and concentrated to an oil, which was passed through a pad of
silica gel (12.7 g, EtOAc/cHex 1/9). The crude product thus
obtained was diluted with MTBE (38.1 mL) and washed twice with 10%
HCl (63.5 mL). The combined aqueous layers were treated with conc.
NH.sub.4OH (38.1 mL) and extracted with CH.sub.2Cl.sub.2 (25.4 mL).
The organic layer was further washed with 10% NaCl (12.7 mL) and
evaporated to an oil. The oil was dissolved with IPA (38.1 mL) and
seeded with authentic intermediate 4 (0.02 g). The suspension was
stirred for 30 min. Water (38 mL) was added over 30 min and the
mixture left standing for 1.5 hr. The suspension was filtered, the
cake washed with a 1:1 mixture of IPA/water (12.7 mL), collected
and dried in the oven at 40.degree. C. under high vacuum for 14 hr.
The title compound was obtained as a pale yellow solid (3.8 g,
42%).
[0337] NMR (.sup.1H, DMSO-d.sub.6): .delta. 7.17 (d, 1H), 6.85 (d,
1H), 6.77 (dd, 1H), 6.40 (s, 1H), 3.89 (t, 2H), 3.73 (s, 3H), 3.16
(t, 2H), 2.17-2.11 (2s, 6H)
[0338] M/S (m/z): 403 [MH].sup.+
Intermediate 5
4-Iodo-6-methyl-1-[2-methyl-4-(methyloxy)phenyl]-2,3-dihydro-1H-pyrrolo[2,-
3-b]pyridine
[0339] To a solution of intermediate 4 (913 mg, 2.27 mmol) in anh.
NMP (7 mL) was added KI (1.13 g, 3 eq) and the reaction mixture was
stirred at 150.degree. C. for 18 hr. It was then cooled down to
r.t. and diluted in water/sat.aq. NaCl. The aqueous phase was
extracted with EtOAc (3.times.30 mL) and the combined organic
extracts were dried over anh. Na.sub.2SO.sub.4. The solids were
filtered and the solvent evaporated. The crude product was purified
by flash chromatography (silica gel, cHex/EtOAc 9:1) to give the
title compound as a clear oil, which solidified upon standing (681
mg, 79%).
[0340] NMR (.sup.1H, CDCl.sub.3): .delta. 7.14 (d, 1H), 6.81-6.74
(m, 2H), 6.70 (s, 1H), 3.84 (t, 2H), 3.81 (s, 3H), 3.03 (t, 2H),
2.22 (s, 6H).
[0341] MS (m/z): 381 [MH].sup.+.
Intermediate 6
N-(2-Chloroethyl)-3-({[(2-chloroethyl)amino]carbonyl}amino)-1H-pyrazole-1--
carboxamide
[0342] To a solution of 3-aminopyrazole (500 mg, 6 mmol) in anh.
DMF (3 mL), at 0.degree. C., under N.sub.2, was added 3-chloroethyl
isocyanate (1.53 mL, 3 eq) and the reaction mixture was stirred at
r.t. for 2 hr, after which the solvent was evaporated. The crude
product was purified by flash chromatography (silica gel,
cHex/EtOAc 1:1) to give the title compound (1.593 g, 89%).
[0343] NMR (.sup.1H, DMSO): .delta. 9.20 (s, 1H), 8.26 (m, 1H),
8.10 (d, 1H), 7.25 (bs, 1H), 6.37 (d, 1H), 3.74 (m, 2H), 3.66 (m,
2H), 3.58 (m, 2H), 3.46 (m, 2H).
[0344] MS (m/z): 296 [MH].sup.+.
Intermediate 7
N-(2-Chloroethyl)-3-(2-oxoimidazolidin-1-yl)-1H-pyrazole-1-carboxamide
[0345] To a solution of intermediate 6 (100 mg, 0.34 mmol) in anh.
THF (4 mL), at r.t., under N.sub.2, was added KOt-Bu (42 mg, 1.1
eq) and the reaction mixture was stirred for 2 hr. Water (0.5 mL)
was added and the solvent was evaporated. The aqueous phase was
diluted with H.sub.2O and extracted with EtOAc (3.times.20 mL). The
combined organic extracts were dried over anh. Na.sub.2SO.sub.4.
The solids were filtered and the solvent evaporated. The crude
product was purified by flash chromatography (silica gel,
EtOAc/cHex 8:2, then 9:1) to give the title compound as a white
solid (39 mg, 44%)
[0346] NMR (.sup.1H, DMSO): .delta. 8.18 (bt, 1H), 8.11 (d, 1H),
7.14 (bs, 1H), 6.75 (d, 1H), 3.89 (m, 2H), 3.73 (m, 2H), 3.56 (m,
2H), 3.40 (m, 2H).
[0347] MS (m/z): 258 [MH].sup.+.
Intermediate 8
1-(1H-Pyrazol-3-yl)imidazolidin-2-one
[0348] To a solution of intermediate 7 (190 mg, 0.74 mmol) in a 2:1
mixture of MeOH/H.sub.2O (15 mL), at r.t., under N.sub.2, was added
LiOH (177 mg, 10 eq) and the reaction mixture was heated at
80.degree. C. for 3 hr. It was cooled down to r.t. and neutralized
to pH 7 with 2M HCl. Silica gel was then added and the solvents
were evaporated. The adsorbed crude product was purified by flash
chromatography (silica gel, EtOAc/MeOH 9:1) to give the title
compound as a white solid (80 mg, 71%)
[0349] NMR (.sup.1H, DMSO): .delta. 12.10 (bs, 1H), 7.6 (s, 1H),
6.7 (s, 1H), 6.4 (s, 1H), 3.8 (t, 2H), 3.4 (t, 2H).
[0350] MS (m/z): 152 [MH].sup.+.
Intermediate 9
4-Chloro-N-[1-(4-chlorobutanoyl)-1H-pyrazol-3-yl]butanamide
[0351] To a solution of 3-aminopyrazole (300 mg, 3.61 mmol) in anh.
CH.sub.2Cl.sub.2 (6 mL), at r.t., under N.sub.2, was added
K.sub.2HPO.sub.4 (1.26 g, 2 eq) and the reaction mixture was
stirred at r.t. for 15 min. 4-Chloro-butyryl chloride (406 .mu.L,
3.6 mmol) was then added and the reaction mixture was stirred for
24 hr. It was then poured into water and the phases were separated.
The aqueous layer was extracted with EtOAc (2.times.20 mL) and the
combined organic extracts were dried over anh. Na.sub.2SO.sub.4.
The solids were filtered and the solvent evaporated. The crude
product was purified by flash chromatography (silica gel,
cHex/EtOAc 7:3) to give the title compound as a white solid (354
mg, 34%)
[0352] NMR (.sup.1H, CDCl.sub.3): .delta. 8.09 (d, 1H), 7.83 (bs,
1H), 6.98 (s, 1H), 3.64 (m, 2H), 3.17 (m, 1H), 2.57 (m, 1H), 2.21
(m, 2H).
[0353] MS (m/z): 292 [M].sup.+.
Intermediate 10
1-(1H-Pyrazol-3-yl)pyrrolidin-2-one
[0354] To a suspension of NaH 80%/oil (31 mg, 1.1 eq) in anh. DMF
(1.5 mL), at r.t., under N.sub.2, was added a solution of
intermediate 9 (340 mg, 1.16 mmol) in anh. DMF (1 mL). The reaction
mixture was stirred at r.t. for 1 hr, after which it was quenched
carefully with water. The aqueous phase was extracted with EtOAc
(3.times.20 mL) and the combined organic extracts were washed with
sat.aq. NaCl and dried over anh. Na.sub.2SO.sub.4. The solids were
filtered and the solvent evaporated. The crude product (70 mg, 0.27
mmol) was dissolved in anh. MeOH (3 mL), at r.t., under N.sub.2,
and 1M MeONa/MeOH was added until pH 9 was reached. The reaction
mixture was stirred at r.t. for 30 min and water was added. The
aqueous phase was extracted with EtOAc (3.times.20 mL) and the
combined organic extracts were washed with sat.aq. NaCl and dried
over anh. Na.sub.2SO.sub.4. The solids were filtered and the
solvent evaporated. The crude product was purified by flash
chromatography (silica gel, cHex/EtOAc 7:3) to give the title
compound as a white solid (35 mg, 20%).
[0355] NMR (.sup.1H, CDCl.sub.3): .delta. 7.46 (s, 1H), 6.55 (s,
1H), 3.90 (t, 2H), 2.59 (t, 2H), 2.18 (m, 2H).
[0356] MS (m/z): 152 [M].sup.+.
Intermediate 11
N-(3-Chloropropyl)-3-({[(3-chloropropyl)amino]carbonyl}amino)-1H-pyrazole--
1-carboxamide
[0357] To a solution of 3-aminopyrazole (500 mg, 6 mmol), in anh.
DMF (10 mL), at r.t., under N.sub.2, was added 3-chloropropyl
isocyanate (1.2 mL, 2 eq) and the reaction was stirred for 24 hr.
The reaction was not complete and more isocyanate (1.2 mL, 2 eq)
was added. The reaction mixture was stirred for an additional 48
hr. It was then poured into CH.sub.2Cl.sub.2/sat.aq. NaCl and the
phases were separated. The aqueous layer was extracted with
CH.sub.2Cl.sub.2 (2.times.20 mL) and the combined organic extracts
were dried over anh. Na.sub.2SO.sub.4. The solids were filtered and
the solvent evaporated. The crude product was purified by flash
chromatography (Biotage 40, cHex/EtOAc 7:3) to give the title
compound as a white solid (620 mg, 32%).
[0358] NMR (.sup.1H, DMSO): .delta. 9.05 (s, 1H), 8.25 (t, 1H),
8.08 (d, 1H), 7.17 (t, 1H), 6.30 (d, 1H), 4.7-4.6 (m, 4H), 3.37 (q,
2H), 3.26 (q, 2H), 2.05-1.87 (m, 4H).
[0359] MS (m/z): 322 [MH].sup.+.
Intermediate 12
N-(3-Chloropropyl)-3-(2-oxotetrahydropyrimidin-1(2H)-yl)-1H-pyrazole-1-car-
boxamide
[0360] To a solution of intermediate 11 (620 mg, 1.93 mmol) in anh.
THF (20 mL), at r.t., under N.sub.2, was added KOt-Bu (237 mg, 1.1
eq). The reaction mixture was stirred at r.t. for 2 hr. Water was
then added and the solvent was evaporated. The aqueous phase was
extracted with EtOAc (3.times.20 mL) and the combined organic
extracts were dried over anh. Na.sub.2SO.sub.4. The solids were
filtered and the solvent evaporated. The crude product was purified
by flash chromatography (Flash Master, 10 g SiO.sub.2, cHex/EtOAc
7:3, then 100% EtOAc) to give the title compound as a white solid
(200 mg, 37%)
[0361] NMR (.sup.1H, DMSO): .delta. 8.23 (t, 1H), 8.06 (d, 1H),
6.93 (bs, 1H), 6.82 (d, 1H), 3.86 (t, 2H), 3.57 (t, 2H), 3.34 (m,
2H), 3.19 (m, 2H), 1.98 (m, 2H), 1.91 (m, 2H).
[0362] MS (m/z): 286 [MH].sup.+.
Intermediate 13
1-(1H-Pyrazol-3-yl)tetrahydropyrimidin-2(1H)-one
[0363] A solution of intermediate 12 (180 mg, 0.63 mmol) and LiOH
(265 mg, 10 eq) in a 2:1 mixture of MeOH/H.sub.2O (7.5 mL), in a
sealed vial, was subjected to microwave irradiation (80.degree. C.)
for 10 min. The reaction mixture was then cooled down to r.t., and
the solvent was evaporated to dryness. The residue was purified on
an SCX cartridge (EtOAc/MeOH 8:2, then 100% MeOH) to give the title
compound as a white solid (102 mg, 98%)
[0364] NMR (.sup.1H, DMSO): .delta. 12.13 (bs, 1H), 7.50 (s, 1H),
6.60 (bs, 1H), 6.46 (s, 1H), 3.73 (m, 2H), 3.15 (m, 2H), 1.88 (m,
2H).
[0365] MS (m/z): 167 [MH].sup.+.
Intermediate 14
3-Bromo-1-(triphenylmethyl)-1H-pyrazole
[0366] To a solution of 3-bromo-pyrazole (2.0 g, 13.6 mmol) in anh.
CH.sub.2Cl.sub.2 (40 mL), at r.t., under N.sub.2, were added
triphenylmethyl chloride (4.17 g, 1.1 eq) and Et.sub.3N (2.1 mL,
1.1 eq). The reaction mixture was stirred at r.t. for 4 hr. It was
poured into water/CH.sub.2Cl.sub.2. The phases were separated and
the aqueous layer was further extracted with CH.sub.2Cl.sub.2
(2.times.30 mL). The combined organic extracts were dried over anh.
Na.sub.2SO.sub.4, the solids were filtered and the solvent
evaporated. The residue was purified by flash chromatography
(silica gel, 100% CH.sub.2Cl.sub.2) to give the title compound as a
white solid (3.39 g, 64%).
[0367] NMR (.sup.1H, DMSO-d.sub.6): .delta. 7.34 (m, 10H), 7.01 (m,
6H), 6.45 (d, 1H).
[0368] MS (m/z): 412 [M+Na].sup.+.
Intermediate 15
3-[1-(Triphenylmethyl)-1H-pyrazol-3-yl]-1,3-oxazolidin-2-one
[0369] A mixture of intermediate 14 (389 mg, 1 mmol),
1,3-oxazolidin-2-one (87 mg, 1 mmol), CuI (20 mg, 10 mol %),
(1R,2R)-diaminomethylcyclohexane (43 mg, 30 mol %) and
K.sub.2CO.sub.3 (414 mg, 3 mmol) in anh. NMP (2 mL) in a seaded
vial was stirred at 130.degree. C. for 4 hr. It was poured into
water/EtOAc. The phases were separated and the aqueous layer was
further extracted with EtOAc (2.times.10 mL). The combined organic
extracts were dried over anh. Na.sub.2SO.sub.4, the solids were
filtered and the solvent evaporated. The residue was purified by
flash chromatography (silica gel, EtOAc/cHex 2:8) to give the title
compound as a white solid (210 mg, 53%).
[0370] NMR (.sup.1H, CDCl.sub.3): .delta. 7.28 (m, 9H), 7.21 (d,
1H), 7.13 (m, 6H), 6.64 (d, 1H), 4.40 (t, 2H), 3.98 (t, 2H).
[0371] MS (m/z): 418 [M+Na].sup.+.
Intermediate 16
3-(1H-Pyrazol-3-yl)-1,3-oxazolidin-2-one
[0372] To a solution of intermediate 15 (210 mg, 0.53 mmol) in anh.
MeOH (4 mL), under N.sub.2, was added trifluoroacetic acid (0.2 mL,
2.66 mmol). The reaction mixture was subjected to microwave
irradiation (100.degree. C.) for 15 min. The solvent was evaporated
and the residue was purified on an SCX cartridge (100%
CH.sub.2Cl.sub.2, then 0.5M NH.sub.3/MeOH) to give the title
compound as a white solid (30 mg, 37%).
[0373] NMR (.sup.1H, DMSO-d.sub.6): .delta. 7.64 (d, 1H), 6.40 (d,
1H), 4.41 (t, 2H), 3.97 (t, 2H).
[0374] MS (m/z): 155 [MH].sup.+.
Intermediate 17
N-1H-Pyrazol-3-ylacetamide
[0375] To a solution of 3-aminopyrazole (20 g, 0.24 mol) in
H.sub.2O (36 mL), at 5-10.degree. C., was slowly added NaHCO.sub.3
(9.1 g, mol, 3 eq) and then Ac.sub.2O (6.79 ml, 2 eq). The reaction
mixture was refluxed for 8 hr. It was cooled down to r.t. and was
left standing at this temperature for 12 hr to allow
crystallization. The white solid was filtered (12.9 g) and the
mother liquor volume was reduced. A second batch of white solid
(3.4 g) was obtained after crystallization. The two batches were
combined to give the title compound (16.3 g, 54%).
[0376] NMR (.sup.1H, DMSO-d.sub.6): .delta. 12.22 (bs, 1H), 10.28
(bs, 1H), 7.53 (bs, 1H), 6.43 (bs, 1H), 1.96 (s, 1H).
[0377] MS (m/z): 126 [MH].sup.+, 148 [M+Na].sup.+.
Intermediate 18
N-(1-{6-Methyl-1-[2-methyl-4-(methyloxy)phenyl]-2,3-dihydro-1H-pyrrolo[2,3-
-b]pyridin-4-yl}-1H-pyrazol-3-yl)acetamide
[0378] A mixture of intermediate 5 (500 mg, 1.32 mmol),
intermediate 17 (329 mg, 2 eq.), CuI (50 mg, 0.2 eq.),
K.sub.2CO.sub.3 (382 mg, 2.1 eq.), dodecane (60 .mu.L, 0.2 eq.) and
(+/-)-trans-1,2-diaminocyclohexane (45 .mu.L, 0.3 eq.) in anh. NMP
(5 mL), in a sealed vial, was heated at 150.degree. C. for 4 hr. It
was cooled down to r.t. and poured into sat.aq. NH.sub.4Cl. EtOAc
was added and the phases were separated. The aqueous layer was
further extracted with EtOAc (2.times.10 mL). The combined organic
extracts were dried over anh. Na.sub.2SO.sub.4, the solids were
filtered and the solvent evaporated. The residue was purified on an
SCX cartridge (silica gel, CH.sub.2Cl.sub.2, then MeOH, then conc.
NH.sub.4OH in MeOH, 25:75) and then by flash chromatography
(cHex/EtOAc 7:3) to give the title compound as a white solid (358
mg, 72%).
[0379] NMR (.sup.1H, DMSO-d.sub.6): .delta. 10.62 (bs, 1H), 8.24
(d, 1H), 7.15 (d, 1H), 6.84 (d, 1H), 6.78-6.73 (m, 3H), 3.83 (t,
2H), 3.74 (s, 3H), 3.4 (t, 2H), 2.16 (s, 3H), 2.14 (s, 3H), 2.04
(s, 3H).
[0380] MS (m/z): 378 [MH].sup.+.
Intermediate 19
1-{6-Methyl-1-[2-methyl-4-(methyloxy)phenyl]-2,3-dihydro-1H-pyrrolo[2,3-b]-
pyridin-4-yl}-1H-pyrazol-3-amine
[0381] To a dispersion of intermediate 18 (358 mg, 0.95 mmol) in
EtOH (7 mL), at r.t., was added 25% NaOH (2.5 mL) and the reaction
mixture was subjected to microwave irradiation (130.degree. C.) for
20 min. The EtOH was evaporated and the crude product was
partitioned between EtOAc and sat.aq. NaCl. The phases were
separated and the aqueous layer was further extracted with EtOAc
(2.times.10 mL). The combined organic extracts were dried over anh.
Na.sub.2SO.sub.4, the solids were filtered and the solvent
evaporated to give the title compound (282 mg, 89%) which was used
in the next step without any further purification.
[0382] NMR (.sup.1H, DMSO-d.sub.6): .delta. 7.98 (d, 1H), 7.12 (d,
1H), 6.83 (d, 1H), 6.75 (dd, 1H), 6.67 (s, 1H), 5.77 (d, 1H), 5.10
(bs, 2H), 3.78 (t, 2H), 3.74 (s, 3H), 3.35 (t, 2H), 2.13 (s, 3H),
2.12 (s, 3H).
[0383] MS (m/z): 336 [MH].sup.+.
Intermediate 20
Ethyl
N-(1-{6-methyl-1-[2-methyl-4-(methyloxy)phenyl]-2,3-dihydro-1H-pyrro-
lo[2,3-b]-pyridin-4-yl}-1H-pyrazol-3-yl)glycinate
[0384] To a solution of intermediate 19 (200 mg, 0.6 mmol) in anh.
DMF (5 mL), at r.t., under N.sub.2, was added NaH 60%/oil (26 mg,
1.1 eq). The reaction mixture was stirred at r.t. for 20 min, ethyl
2-bromoacetate (73 .mu.L, 1.1 eq) was then added dropwise and the
reaction mixture was heated at 80.degree. C. Continuous additions
of the alkyl bromide were done at 80.degree. C. over a period of
7.2 h (5.times.36 .mu.L, 5.times.0.55 eq). The reaction mixture was
cooled down to r.t. and poured into H.sub.2O. EtOAc was added and
the phases were separated. The aqueous layer was further extracted
with EtOAc (2.times.10 mL). The combined organic extracts were
dried over anh. Na.sub.2SO.sub.4, the solids were filtered and the
solvent evaporated. The residue was purified by flash
chromatography (silica gel, cHex/EtOAc 7:3) to give the title
compound as a yellow oil (155 mg, 62%).
[0385] NMR (.sup.1H, DMSO-d.sub.6): .delta. 8.09 (d, 1H), 7.13 (d,
1H), 6.83 (d, 1H), 6.76 (dd, 1H), 6.37 (s, 1H), 6.17 (t, 1H), 5.86
(d, 1H), 5.73 (s, 1H), 4.09 (q, 2H), 3.89 (d, 2H), 3.77 (t, 2H),
3.74 (s, 3H), 3.36 (t, 2H), 2.13 (bs, 6H), 1.17 (t, 3H).
[0386] MS (m/z): 422 [MH].sup.+.
Intermediate 21
2-[(1-{6-Methyl-1-[2-methyl-4-(methyloxy)phenyl]-2,3-dihydro-1H-pyrrolo[2,-
3-b]pyridin-4-yl}-1H-pyrazol-3-yl)amino]ethanol
[0387] To a cold (-78.degree. C.) solution of 1N LiAlH.sub.4/THF
(0.5 mL, 2.7 eq), under N.sub.2, was added dropwise a solution of
intermediate 20 (77.5 mg, 0.184 mmol) in anh. THF (5 mL). The
reaction mixture was stirred at -78.degree. C. for 20 min.
Continuous additions of 1N LiAlH.sub.4/THF were done at this
temperature over a period of 40 min (3.times.200 .mu.L,
3.times.1.09 eq). To the reaction mixture was added water (42
.mu.L), 1N NaOH (42 .mu.L) and water (125 .mu.L) and a precipitate
was formed. The solid was filtered and washed with EtOAc (2.times.)
and CH.sub.2Cl.sub.2 (2.times.). The combined organic extracts were
concentrated and the residue was purified by flash chromatography
(silica gel, cHex/EtOAc 7:3) to give the title compound as a yellow
solid (25 mg, 36%).
[0388] NMR (.sup.1H, DMSO-d.sub.6): .delta. 8.04 (d, 1H), 7.13 (d,
1H), 6.83 (d, 1H), 6.76 (dd, 1H), 6.66 (s, 1H), 5.82 (d, 1H), 5.58
(t, 1H), 4.59 (t, 1H), 3.78 (t, 2H), 3.74 (s, 3H), 3.55 (q, 2H),
3.40 (t, 2H), 3.20 (q, 2H), 2.13 (bs, 6H).
[0389] MS (m/z): 380 [MH].sup.+.
Intermediate 22
3-[(1-{6-Methyl-1-[2-methyl-4-(methyloxy)phenyl]-2,3-dihydro-1H-pyrrolo[2,-
3-b]pyridin-4-yl}-1H-pyrazol-3-yl)amino]-1-propanesulfonic acid
[0390] To a suspension of intermediate 19 (25 mg, 0.0746 mmol) in
n-BuOH (1 mL), at r.t., under N.sub.2, was added 1,2-oxathiolane
2,2-dioxide (30 .mu.L, 3 eq). The reaction mixture was subjected to
microwave irradiation (20+60+60 min, T=150/180.degree. C.). The
solvent was evaporated and the residue was purified by
flash-chromatography (silica gel, 100% EtOAc.fwdarw.7:3 EtOAc/sol.
NH.sub.3 in MeOH (0.5 M)) and SCX cartridge (Eluents: MeOH and a
sol. of NH.sub.3 in MeOH (0.5 M)) to give the title compound as a
yellow oil (10 mg, 30%).
[0391] NMR (.sup.1H, CDCl.sub.3): .delta. 7.54 (bs, 1H), 7.05 (d,
1H), 6.72 (m, 1H), 6.66 (m, 1H), 6.48 (bs, 1H), 5.78 (bs, 1H), 3.72
(m, 5H), 3.3 (m, 4H), 2.97 (m, 2H), 2.03-2.2 (m, 8H).
[0392] MS (m/z): 458 [MH].sup.+.
Intermediate 23
Phenyl
(1-{6-methyl-1-[2-methyl-4-(methyloxy)phenyl]-2,3-dihydro-1H-pyrrol-
o[2,3-b]pyridin-4-yl}-1H-pyrazol-3-yl)carbamate
[0393] To a suspension of intermediate 19 (391 mg, 1.17 mmol) in
anh. CH.sub.2Cl.sub.2 (8 mL), at 0.degree. C., under N.sub.2, were
added pyridine (103 .mu.L, 1.1 eq) and phenyl chloroformate (161
.mu.L, 1.1 eq). The reaction mixture was stirred at r.t. for 1 hr.
The solvent was evaporated in vacuo, sat.aq. NaCl (50 mL) was then
added and the solution extracted with EtOAc (3.times.15 mL). The
combined organic extracts were dried over anh. Na.sub.2SO.sub.4,
the solids were filtered and the solvents evaporated in vacuo. The
crude compound thus obtained was purified by flash chromatography
(silica gel, MeOH-Ammonia solution in MeOH 0.5 M) to give 284 mg
(53%) of the title compound as a white solid.
[0394] NMR (.sup.1H, CDCl.sub.3): .delta. 10.8 (bs, 1H) 8.28 (d,
1H), 7.39 (m, 2H), 7.18 (m, 4H), 6.73 (dd, 1H), 6.64 (s, 1H), 3.81
(t, 2H), 3.72 (s, 3H), 3.32 (t, 2H), 2.14 (s, 3H), 2.12 (s,
3H).
[0395] MS (m/z): 456 [MH].sup.+.
Intermediate 24
Phenyl
(1-{6-methyl-1-[2-methyl-4-(methyloxy)phenyl]-2,3-dihydro-1H-pyrrol-
o[2,3-b]pyridin-4-yl}-1H-pyrazol-3-yl)carbamate
[0396] A mixture of intermediate 23 (284 mg, 0.62 mmol), pyridine
(50 .mu.L, 1.2 eq) and 2,2-bis(ethyloxy)ethanamine (108 .mu.L, 1.2
eq) was heated for 3 hr at 60.degree. C. H.sub.2O (50 mL) was then
added and the solution extracted with CH.sub.2Cl.sub.2 (3.times.15
mL). The combined organic extracts were dried over anh.
Na.sub.2SO.sub.4, the solids were filtered and the solvent
evaporated in vacuo. The crude compound thus obtained was purified
by flash chromatography (silica gel, cHex/EtOAc 1:1) to give 214 mg
(84%) of the title compound as a white solid.
[0397] NMR (.sup.1H, CDCl.sub.3): .delta. 9.21 (s, 1H), 8.24 (d,
1H), 7.15 (d, 1H), 6.95 (bs, 1H), 6.95 (d, 1H), 6.78 (dd, 1H), 6.72
(s, 1H), 6.42 (s, 1H), 4.5 (m, 1H), 3.82 (t, 2H), 3.60 (m, 1H),
3.48 (m, 1H), 3.65 (s, 3H), 3.3 (s, 6H), 3.23 (t, 2H), 3.16 (s,
3H), 2.14 (s, 3H).
[0398] MS (m/z): 495 [MH].sup.+.
Intermediate 25
3-Methyl-1-[1-(triphenylmethyl)-1H-pyrazol-3-yl]-2(1H)-pyridinone
[0399] A solution of intermediate 14 (300 mg, 0.77 mmol),
3-methylpyridinone (168 mg, 1 eq), CuI (146 mg, 1 eq),
K.sub.2CO.sub.3 (223 mg, 2.1 eq), N--N'-dimethyl
trans-cyclohexanediamine (109 mg, 0.5 eq) in anh. NMP (4 mL) was
heated at 150.degree. C. for 24 hr. Sat.aq. NH.sub.4Cl (100 mL) was
then added and the mixture extracted with CH.sub.2Cl.sub.2 (250
mL). The organic layer was dried over anh. Na.sub.2SO.sub.4, the
solids were filtered and the solvent evaporated in vacuo. The crude
compound thus obtained was purified by flash chromatography (silica
gel, cHex/EtOAc 95:5) to give 80 mg (25%) of the title compound as
white solid.
[0400] NMR (.sup.1H, CDCl.sub.3): .delta. 7.76(d, 1H), 7.30 (m,
11H), 7.15 (m, 6H), 6.98 (d, 1H), 6.06 (t, 1H), 2.15 (s, 3H).
[0401] MS (m/z): 440 [M+Na].
Intermediate 26
3-Methyl-1-(1H-pyrazol-3-yl)-2(1H)-pyridinone
[0402] CF.sub.3COOH (3 mL) was added to a solution of intermediate
25 (80 mg, 0.19 mmol) in an anh. mixture of MeOH/CH.sub.2Cl.sub.2
2:1 (3 mL) at r.t., under N.sub.2. The solution was heated at
80.degree. C. for 18 hr. The solvents were evaporated in vacuo. The
crude compound thus obtained was purified on an SCX cartridge (1 g,
preconditioned with CH.sub.2Cl.sub.2) to give 13 mg (39%) of the
title compound as a white solid.
[0403] NMR (.sup.1H, CDCl.sub.3): .delta. 7.61(d, 1H), 7.55 (s,
1H), 7.24 (m, 1H), 7.1 (d, 1H), 6.76 (d, 1H), 6.16 (t, 1H), 2.15
(s, 3H).
[0404] MS (m/z): 176 [MH].sup.+.
Intermediate 27
2-[1-(Triphenylmethyl)-1H-pyrazol-3-yl]-3(2H)-pyridazinone
[0405] A solution of intermediate 14 (200 mg, 0.52 mmol),
pyridazinone (50 mg, 1 eq), CuI (100 mg, 1 eq), K.sub.2CO.sub.3
(148 mg, 2.eq) and N--N'-dimethyl trans-cyclohexanediamine (73 mg,
0.5 eq.) in anh. NMP (4 mL) was heated at 150.degree. C. for 8 hr.
Sat.aq. NH.sub.4Cl (100 mL) was then added and the solution
extracted with CH.sub.2Cl.sub.2 (250 mL). The organic layer was
dried over anh. Na.sub.2SO.sub.4, the solids were filtered and the
solvents evaporated in vacuo. The crude compound thus obtained was
purified by flash chromatography (silica gel, cHex/EtOAc 1:9) to
give a solution of the title compound in NMP, which was used in the
next step without further purification.
[0406] MS (m/z): 443 [M+K], 427 [M+Na].
Intermediate 28
2-(1H-Pyrazol-3-yl)-3(2H)-pyridazinone
[0407] The solution of intermediate 27 obtained above was dissolved
in a mixture of MeOH/CH.sub.2Cl.sub.2 2:1 (3 mL) and CF.sub.3COOH
(2.5 mL) was added, at r.t., under N.sub.2. The reaction mixture
was heated at 80.degree. C. for 4 hr. The solvents were evaporated
in vacuo. The crude compound thus obtained was purified on an SCX
cartridge (1 g, preconditioned with CH.sub.2Cl.sub.2) to give 20 mg
(24%, two steps) of the title compound as a white solid.
[0408] NMR (.sup.1H, CDCl.sub.3): .delta. 7.91(d, 1H), 7.59 (m,
1H), 7.24 (m, 1H), 7.07 (m, 1H), 6.76 (d, 1H).
[0409] MS (m/z): 163 [MH].sup.+.
Intermediate 29
1-Acetyl-3-{1-[1-(4-hydroxy-2-methylphenyl)-6-methyl-2,3-dihydro-1H-pyrrol-
o[2,3-b]pyridin-4-yl]-1H-pyrazol-3-yl}-2-imidazolidinone
[0410] To a solution of example 1-6 (80 mg, 0.179 mmol) in anh.
CH.sub.2Cl.sub.2 (1.8 mL), at r.t., under N.sub.2, was added
BBr.sub.3 1.0M/CH.sub.2Cl.sub.2 (0.72 mL, 5 eq) dropwise. The
reaction mixture was stirred at r.t. for 90 min. MeOH (1 mL) was
added and the solvent was evaporated. The residue was taken up in
EtOAc/sat.aq. NaHCO.sub.3 and the phases were separated. The
aqueous layer was extracted with CH.sub.2Cl.sub.2 (2.times.10 mL)
and the combined organic extracts were dried over anh.
Na.sub.2SO.sub.4. The solids were filtered and the solvent
evaporated. The crude compound was further purified by flash
chromatography (silica gel, 100% EtOAc.fwdarw.5% MeOH/EtOAc) to
give the title compound as a white solid (29 mg, 37%).
[0411] NMR (.sup.1H, DMSO-d.sub.6): .delta. 9.3 (s, 1H), 8.40 (d,
1H), 7.00 (d, 1H), 6.85 (d, 1H), 6.75 (s, 1H), 6.65 (d, 1H), 6.60
(dd, 1H), 4.00-3.70 (m, 6H), 3.40 (t, 2H), 2.45 (s, 3H), 2.15 (s,
3H), 2.05 (s, 3H).
[0412] MS (m/z): 433 [MH].sup.+.
Intermediate 30
1-Acetyl-3-(1-{1-[4-(ethyloxy)-2-methylphenyl]-6-methyl-2,3-dihydro-1H-pyr-
rolo[2,3-b]pyridin-4-yl}-1H-pyrazol-3-yl)-2-imidazolidinone
[0413] To a solution of intermediate 29 (13.6 mg, 0.0315 mmol) in
anh. DMF (1 mL), at r.t., under N.sub.2, was added NaH 60%/oil (2.5
mg, 2 eq) and the reaction mixture was stirred at r.t. for 20 min.
Iodoethane (10 .mu.L, 4 eq) was added and the reaction mixture was
stirred at r.t. for 1 hr. It was poured into EtOAc/sat.aq. NaCl and
the phases were separated. The organic layer was washed with
sat.aq. NaCl (2.times.10 mL) and dried over anh. Na.sub.2SO.sub.4.
The solids were filtered and the solvent was evaporated. The crude
compound was purified by flash chromatography (silica gel,
cHex/EtOAc 1:1). The mixed fraction were re-purified by flash
chromatography (silica gel, cHex/EtOAc 7:3). The title compound was
obtained as a white solid (5 mg, 34%)
[0414] NMR (.sup.1H,): .delta. 7.87 (d, 1H), 7.13 (d, 1H), 6.95 (d,
1H), 6.79 (d, 1H), 6.74 (d, 1H), 6.53 (s, 1H), 4.11-3.97 (m, 6H),
3.86 (t, 2H), 3.43 (t, 2H), 2.58 (s, 3H), 2.31 (s, 3H), 2.09 (s,
3H), 1.39 (t, 3H).
[0415] MS (m/z): 461 [MH].sup.+.
Intermediate 31
1-Acetyl-3-[1-(6-methyl-1-{2-methyl-4-[(1-methylethyl)oxy]phenyl}-2,3-dihy-
dro-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-3-yl]-2-imidazolidinone
[0416] To a solution of intermediate 29 (14 mg, 0.032 mmol) in anh.
DMF (1 mL), at r.t., under N.sub.2, was added NaH 60%/oil (3 mg, 2
eq) and the reaction mixture was stirred at r.t. for 20 min.
2-Iodopropane (13 .mu.L, 4 eq) was added and the reaction mixture
was stirred at r.t. for 1 hr. It was poured into EtOAc/sat.aq. NaCl
and the phases were separated. The organic layer was washed with
sat.aq. NaCl (2.times.10 mL) and dried over anh. Na.sub.2SO.sub.4.
The solids were filtered and the solvent was evaporated. The crude
compound was purified by flash chromatography (silica gel,
cHex/EtOAc 2:8). The title compound was obtained as a clear oil (11
mg, 79%) in an inseparable 2:1 mixture with
1-(1-methylethyl)-3-[1-(6-methyl-1-{2-methyl-4-[(1-methylethyl)oxy]phenyl-
}-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-3-yl]-2-imidazolid-
inone
[0417] MS (m/z): 475 [MH].sup.+.
Intermediate 32
1-(2,4-Dichlorophenyl)-2-pyrrolidinone
[0418] As in intermediate 1, except that 2,4-dichloroaniline was
used instead of 4-methoxy-2-methylaniline.
[0419] NMR (.sup.1H, CDCl.sub.3): .delta. 7.18-7.35 (m, 3H), 3.72
(t, 2H), 2.53 (t, 2H), 2.22 (t, 2H).
[0420] MS (m/z): 230 [MH].sup.+.
Intermediate 33
Ethyl 1-(2,4-dichlorophenyl)-2-oxo-3-pyrrolidinecarboxylate
[0421] To a solution of intermediate 32 (3.6 g, 15.65 mmol) in
(EtO).sub.2CO (25.2 mL, 13.2 eq), at r.t., under N.sub.2, was added
t-BuOK 1M/THF (47 mL, 3 eq) dropwise. The stirred reaction mixture
was heated at 80.degree. C. for 2 hr, then it was cooled to r.t.
and poured on ice. The mixture was then acidified with 6N HCl,
extracted with CH.sub.2Cl.sub.2 (300 mL), washed with sat.aq.
NaHCO.sub.3 (100 mL), sat.aq. NaCl (100 mL) and water (100 mL). The
organic layer was dried over anh. Na.sub.2SO.sub.4, the solids were
filtered and the solvent evaporated. The crude product was purified
by flash chromatography (silica gel, cHex/EtOAc 6:4) to give the
title compound as a yellow oil (3.2 g, 67%).
[0422] NMR (.sup.1H, DMSO-d.sub.6): .delta. 7.61 (s, 1H), 7.44 (m,
2H), 4.16 (q, 2H), 3.80 (m, 2H), 3.61 (t, 1H), 2.51 (m, 2H), 1.24
(t, 3H).
[0423] MS (m/z): 302 [MH].sup.+.
Intermediate 34
Ethyl
1-(2,4-dichlorophenyl)-2-{[3-(ethyloxy)-1-methyl-3-oxo-1-propen-1-yl-
]imino}-3-pyrrolidinecarboxylate
[0424] To a mixture of intermediate 33 (0.5 g, 1 eq) and ethyl
(2Z)-3-amino-2-butenoate (0.43 g, 2 eq), was added POCl.sub.3 (4
mL, 26 eq) and the resulting reaction mixture was stirred at
100.degree. C. for 4 hr. The reaction mixture was then cooled to
r.t., evaporated, poured on ice, neutralized with sat.aq.
NaHCO.sub.3 and extracted with EtOAc (200 mL). The organic layer
was dried over anh. Na.sub.2SO.sub.4, the solids were filtered and
the solvent evaporated. The crude product was used in the next step
without further purification.
[0425] MS (m/z): 413 [M].sup.+.
Intermediate 35
1-(2,4-Dichlorophenyl)-6-methyl-1,2,3,7-tetrahydro-4H-pyrrolo[2,3-b]pyridi-
n-4-one
[0426] A solution of crude intermediate 34 in anh. DMF (10 mL) was
added to a suspension of NaH 60%/oil (111 mg, 2 eq) in anh. DMF (10
mL), at r.t., under N.sub.2. The reaction mixture was heated at
100.degree. C. for 6 hr. The mixture was then cooled to r.t. and
the pH adjusted to 5 with sat.aq. NH.sub.4Cl. The reaction mixture
was then partitioned between EtOAc/sat.aq. NH.sub.4Cl (200 mL/100
mL). The phases were separated and the organic layer was dried over
anh. Na.sub.2SO.sub.4, the solids were filtered, the solvent
evaporated and the crude product was purified by flash
chromatography (silica gel, cHex/EtOAc 1:1.fwdarw.EtOAc/MeOH 1:1)
to give the title compound as a brown oil (0.038 g, 7%, two
steps).
[0427] NMR (.sup.1H, CDCl.sub.3): .delta. 7.33 (m, 2H), 7.17 (m,
1H), 6.00 (s, 1H), 2.88 (t, 2H), 2.98 (t, 2H), 2.22 (s, 3H).
[0428] MS (m/z): 295 [M].sup.+.
Intermediate 36
1-(2,4-Dichlorophenyl)-6-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl
trifluoromethanesulfonate
[0429] As in intermediate 4.
[0430] NMR (.sup.1H, CDCl.sub.3): .delta. 7.48 (s, 1H), 7.34 (d,
1H), 7.26 (d, 1H), 6.35 (s, 1H), 4.01 (t, 2H), 3.25 (t, 2H), 2.32
(s, 3H).
[0431] MS (m/z): 427 [M].sup.+.
Intermediate 37
1-(2,4-Dichlorophenyl)-4-iodo-6-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridi-
ne
[0432] As in intermediate 5.
[0433] NMR (.sup.1H, CDCl.sub.3): .delta. 7.42 (m, 3H), 6.81 (s,
1H), 3.96 (t, 2H), 3.04 (t, 2H), 2.24 (s, 3H).
[0434] MS (m/z): 405 [M].sup.+.
Intermediate 38
Ethyl
2-chloro-6-methyl-4-[3-(2-oxoimidazolidin-1-yl)-1H-pyrazol-1-yl]nico-
tinate
[0435] To a solution of intermediate 8 (9.73 g, 1.5 eq) in anh. DMF
(150 mL), at r.t., under N.sub.2, was added NaH 60%/oil (1.7 g, 1
eq) and the reaction mixture was stirred at r.t. for 20 min. A
solution of ethyl 2,4-dichloro-6-methyl-3-pyridinecarboxylate (10
g, 42.9 mmol) was then added dropwise and the reaction mixture was
stirred at 80.degree. C. for 4 hr. It was then cooled down to r.t.
and quenched with ice water. The addition of EtOAc caused a
precipitate to form. The white solid was collected by filtration,
washed with water and dried in vacuo (5.2 g). The filtrate was
transferred into a separatory funnel and the aqueous layer was
extracted with EtOAc (2.times.100 mL). The combined organic layers
were washed with sat.aq. NaCl, dried over anh. Na.sub.2SO.sub.4,
the solids were filtered and the solvent evaporated. The crude
product was treated with EtOAc and left at r.t. overnight. The
precipitate was filtrated, dried in vacuo and combined with the
previous batch to give the title compound as a white solid (7.2 g,
48%).
[0436] NMR (.sup.1H, DMSO-d.sub.6): .delta. 8.53 (d, 1H), 7.77 (s,
1H), 7.18 (bs, 1H), 6.89 (d, 1H), 4.32 (q, 2H), 3.75 (t, 2H), 3.42
(t, 2H), 3.31 (s, 3H), 1.26 (t, 3H).
[0437] MS (m/z): 350 [MH].sup.+.
Intermediate 39
1-{1-[2-Chloro-3-(hydroxymethyl)-6-methyl-4-pyridinyl]-1H-pyrazol-3-yl}-2--
imidazolidinone
[0438] To a suspension of intermediate 38 (7.2 g, 20.6 mmol) in
anh. CH.sub.2Cl.sub.2 (120 mL), at 0.degree. C., under N.sub.2, was
added dropwise DIBAI-H 1M/CH.sub.2Cl.sub.2, (41.2 mL, 2 eq). At the
end of the addition the resulting solution was allowed to warm to
r.t. and stirred for 2 hr. More DIBAI-H was added until the
reaction was complete (3.times.20.5 mL), each time cooling at
0.degree. C. and then stirring at r.t. for 1 hr. The reaction
mixture was then cooled to 0.degree. C., quenched by the slow
addition of a Rochelle salt solution (50 mL) and stirred at r.t.
overnight. The white lattice was treated with 4 L of Roschell's
salt solution and 3 L of CH.sub.2Cl.sub.2 and stirred at r.t. for
20 hr. The two phases were separated and the aqueous layer was
extracted with CH.sub.2Cl.sub.2 (5.times.500 mL). The combined
organic extracts were washed with sat.aq. NaCl, dried over anh.
Na.sub.2SO.sub.4, the solids were filtered and the solvent
evaporated to give the title compound as a white solid (4 g,
63%).
[0439] NMR (.sup.1H, DMSO-d.sub.6): .delta. 8.36 (d, 1H), 7.49 (s,
1H), 7.12 (bs, 1H), 6.86 (d, 1H), 5.47 (t, 1H), 4.61 (d, 2H), 3.88
(t, 2H), 3.44 (t, 2H), 3.30 (s, 3H).
[0440] MS (m/z): 308 [MH].sup.+.
Intermediate 40
1-{1-[2-Chloro-3-(hydroxymethyl)-6-methyl-4-pyridinyl]-1H-pyrazol-3-yl}-3--
{[4-(methyloxy)phenyl]methyl}-2-imidazolidinone
[0441] To a suspension of intermediate 39 (100 mg, 0.325 mmol) in
anh. DMF (6.5 mL), at r.t., under N.sub.2, was added NaH 60%/oil
(13 mg, 1 eq.). The reaction mixture was stirred at r.t. until a
pale yellow solution was obtained (circa 10 min). After cooling to
0.degree. C., 1-(chloromethyl)-4-(methyloxy)benzene (44 .mu.L, 1
eq) was added and the reaction mixture was stirred for 1.5 hr. It
was partitioned between EtOAc/sat.aq. NaCl, the phases were
separated and the organic layer was dried over anh.
Na.sub.2SO.sub.4. The solids were filtered and the solvent
evaporated. The crude product was purified by flash chromatography
(silica gel, EtOAc/cHex 6:4.fwdarw.7:3) to give the title compound
as a white solid (45.5 mg, 33%).
[0442] NMR (.sup.1H, CDCl.sub.3): .delta. 7.85 (d, 1H), 7.20 (dd,
2H), 7.15 (d, 1H), 7.10 (s, 1H), 6.89 (dd, 2H), 4.85 (s, 2H), 4.40
(s, 2H), 3.84 (t, 2H), 3.80 (s, 3H), 3.43 (t, 2H), 2.6 (s, 3H).
[0443] MS (m/z): 428 [MH].sup.+, 450 [M+23].sup.+
Intermediate 41
2-Chloro-6-methyl-4-[3-(3-{[4-(methyloxy)phenyl]methyl}-2-oxo-1-imidazolid-
inyl)-1H-pyrazol-1-yl]-3-pyridinecarbaldehyde
[0444] To a solution of intermediate 40 (925 mg, 2.16 mmol) in
CH.sub.2Cl.sub.2 (90 mL), was added Dess Martin periodinane (1.38
g, 1.5 eq) in three portions and the reaction mixture was stirred
at r.t. for 2 hr. More Dess Martin periodinane (750 mg, 0.2 eq) was
added and the reaction mixture was stirred for an additional 30
min. Na.sub.2S.sub.2O.sub.3 (5 eq) in a sat.aq. NaHCO.sub.3 (100
mL) was added and the phases were separated. The aqueous layer was
extracted with CH.sub.2Cl.sub.2 (3.times.50 mL) and the combined
organic extracts were dried over anh. Na.sub.2SO.sub.4, the solids
were filtered and the solvent evaporated. The crude product was
purified by flash chromatography (silica gel, EtOAc/cHex
6:4.fwdarw.7:3) to give the title compound as a white solid (520
mg, 57%).
[0445] NMR (.sup.1H, CDCl.sub.3): .delta. 10.26 (s, 1H), 7.85 (d,
1H), 7.23 (dd, 2H), 7.20 (s, 1H), 7.13 (d, 1H), 6.89 (dd, 2H), 4.41
(s, 2H), 3.84 (t, 2H), 3.80 (s, 3H), 3.39 (t, 2H), 2.6 (s, 3H).
[0446] MS (m/z): 426 [MH].sup.+.
Intermediate 42
1-(1-{2-Chloro-6-methyl-3-[(E)-2-(methyloxy)ethenyl]-4-pyridinyl}-1H-pyraz-
ol-3-yl)-3-{[4-(methyloxy)phenyl]methyl}-2-imidazolidinone
[0447] n-BuLi 1.6M/Hexane (0.44 mL, 3 eq) was added dropwise to a
suspension of (methoxymethyl)-triphenylphosphonium chloride (224
mg, 3 eq) in THF (5 mL) at 0.degree. C., under N.sub.2. At the end
of the addition the reaction mixture was allowed to warm to r.t.
and stirred for 20 min. A solution of intermediate 41 (100 mg,
0.235 mmol) in THF (8 mL) was added and the reaction mixture
stirred at r.t. for an additional 1.5 hr. The mixture was treated
with water, EtOAc was added and the phases were separated. The
organic layer was dried over anh. Na.sub.2SO.sub.4, the solids were
filtered and the solvent evaporated in vacuo to a residue which was
purified on an SCX cartridge (100% cHex.fwdarw.cHex/EtOAc 7:3) to
give the title compound as a white solid (68 mg, 63%) as a 7:3
mixture of trans:cis isomers.
[0448] NMR (.sup.1H, CDCl.sub.3): .delta. 7.36 (d, 1H), 7.24 (m,
3H), 6.99 (d, 1H), 6.87 (d, 2H), 6.58 (d, 2H), 5.59 (d, 2H), 4.40
(s, 2H), 3.89 (m, 2H), 3.78 (s, 3H), 3.64 (s, 3H), 3.37 (m, 2H),
2.50 (s, 3H).
[0449] MS (m/z): 454 [MH].sup.+.
Intermediate 43
{2-Chloro-6-methyl-4-[3-(3-{[4-(methyloxy)phenyl]methyl}-2-oxo-1-imidazoli-
dinyl)-1H-pyrazol-1-yl]-3-pyridinyl}acetaldehyde
[0450] To a solution of intermediate 42 (5.5 g, 12.5 mmol) in THF
(120 mL), at r.t., was added 6.0M HCl (60 mL, 28.4 eq.) and the
reaction mixture was stirred for 18 hr. The reaction mixture was
quenched with sat.aq. NaHCO.sub.3 until neutral pH, the solvent
partially removed and the crude mixture partitioned between
EtOAc/water. The phases were separated and the organic layer was
washed with sat.aq. NaCl (2.times.10 mL). It was dried over anh.
Na.sub.2SO.sub.4, the solids were filtered and the solvent
evaporated. The crude product was purified by flash chromatography
(silica gel, cHex/EtOAc 4:6) to give the title compound as a white
solid (4.6 g, 86%).
[0451] NMR (.sup.1H, CDCl.sub.3): .delta. 9.73 (s, 1H), 7.70 (d,
1H), 7.23 (d, 2H), 7.06 (m, 2H), 6.88 (d, 2H), 4.40 (s, 2H), 4.01
(s, 2H), 3.80 (s, 3H), 3.76 (t, 2H), 3.37 (t, 2H), 2.58 (s,
3H).
[0452] MS (m/z): 440 [MH].sup.+.
Intermediate 44
1-{1-[2-Chloro-3-(2-hydroxyethyl)-6-methyl-4-pyridinyl]-1H-pyrazol-3-yl}-3-
-{[4-(methyloxy)phenyl]methyl}-2-imidazolidinone
[0453] To a solution of intermediate 43 (4.4 g, 9.96 mmol) in anh.
MeOH (100 mL) at 0.degree. C., under N.sub.2, was added NaBH.sub.4
(397 mg, 1.0 eq) in small portions and the reaction mixture was
warmed up to r.t. and stirred for 30 min. The reaction mixture was
quenched with water, the solvent partially removed and partitioned
between EtOAc/water. The phases were separated and the organic
layer was washed with sat.aq. NaCl (2.times.10 mL). It was dried
over anh. Na.sub.2SO.sub.4, the solids were filtered and the
solvent evaporated. The crude product was purified by flash
chromatography (silica gel, cHex/EtOAc1:1) to give the title
compound as a white solid (4.26 g, 96%).
[0454] NMR (.sup.1H, CDCl.sub.3): .delta. 7.65 (d, 1H), 7.24 (d,
2H), 7.09 (d, 1H), 6.97 (s, 1H), 6.89 (d, 2H), 4.45 (s, 2H), 3.96
(m, 4H), 3.83 (s, 3H), 3.41 (t, 2H), 3.14 (t, 2H), 2.55 (s,
3H).
[0455] MS (m/z): 442 [MH].sup.+.
Intermediate 45
1-{1-[2-Chloro-3-(2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}ethyl)-6-meth-
yl-4-pyridinyl]-1H-pyrazol-3-yl}-3-{[4-(methyloxy)phenyl]methyl}-2-imidazo-
lidinone
[0456] To a solution of intermediate 44 (4.26 g, 7.66 mmol) in anh.
DMF (100 mL), at 0.degree. C., under N.sub.2, were added imidazole
(7.19 g, 11 eq), DMAP (122 mg, 0.1 eq), TBDMSCI (4.07 g, 2.8 eq)
and the reaction mixture was warmed up to r.t. and stirred for 1
hr. It was then partitioned between EtOAc/sat.aq. NH.sub.4Cl. The
phases were separated and the organic layer was washed with sat.aq.
NaCl (2.times.10 mL). It was dried over anh. Na.sub.2SO.sub.4, the
solids were filtered and the solvent evaporated. The crude product
was purified by flash chromatography (silica gel, cHex/EtOAc7:3) to
give the title compound as a yellow oil (4.92 g, 92%).
[0457] NMR (.sup.1H, CDCl.sub.3): .delta. 8.05 (d, 1H), 7.28 (d,
2H), 7.15 (s, 1H), 7.05 (d, 1H), 6.91 (d, 2H), 4.45 (s, 2H), 3.96
(m, 4H), 3.83 (s, 3H), 3.40 (t, 2H), 3.14 (t, 2H), 2.55 (s, 3H),
0.83 (s, 9H), 0.00 (s, 6H).
[0458] MS (m/z): 556 [MH].sup.+.
Intermediate 46
1-{1-[3-(2-{[(1,1-Dimethylethyl)(dimethyl)silyl]oxy}ethyl)-6-methyl-2-({2--
methyl-4-[(trifluoromethyl)oxy]phenyl}amino)-4-pyridinyl]-1H-pyrazol-3-yl}-
-3-{[4-(methyloxy)phenyl]methyl}-2-imidazolidinone
[0459] To a solution of intermediate 45 (500 mg, 0.703 mmol) in
anh. DME (10 mL), at r.t., under N.sub.2, were added
Pd.sub.2(dba).sub.3 (82 mg, 0.1 eq),
dicyclohexyl(2'-methyl-2-biphenylyl)phosphane (98 mg, 0.3 eq),
K.sub.3PO.sub.4 (573 mg, 3 eq) and
2-methyl-4-[(trifluoromethyl)oxy]aniline (258 mg, 1.5 eq) and the
reaction mixture was stirred and heated at reflux for 3 hr. It was
then partitioned between EtOAc/sat.aq. NH.sub.4Cl. The phases were
separated and the organic layer was washed with sat.aq. NaCl
(2.times.10 mL). It was dried over anh. Na.sub.2SO.sub.4, the
solids were filtered and the solvent evaporated. The crude product
was purified by flash chromatography (silica gel, cHex/EtOAc 7:3)
to give the title compound as a white solid (555 mg, 86%).
[0460] NMR (.sup.1H, CDCl.sub.3): .delta. 7.97 (m 1H), 7.63 (m,
2H), 7.44 (m, 1H), 7.28 (d, 2H), 7.01 (m, 2H), 6.91 (m, 2H), 6.62
(s, 1H), 4.45 (s, 2H), 4.18 (t, 2H), 3.88 (t, 2H), 3.83 (s, 3H),
3.41 (t, 2H), 2.87 (t, 2H), 2.47 (s, 3H), 2.31 (s, 3H), 0.84 (s,
9H), 0.00 (s, 6H).
[0461] MS (m/z): 711 [MH].sup.+.
Intermediate 47
1-{1-[3-(2-Hydroxyethyl)-6-methyl-2-({2-methyl-4-[(trifluoromethyl)oxy]phe-
nyl}amino)-4-pyridinyl]-1H-pyrazol-3-yl}-3-{[4-(methyloxy)phenyl]methyl}-2-
-imidazolidinone
[0462] To a solution of intermediate 46 (555 mg, 0.930 mmol) in
anh. THF (5 mL), at r.t., under N.sub.2, was added Et.sub.3N.3HF
(637 .mu.L, 5 eq) and the reaction mixture was stirred at r.t. for
18 hr. It was then partitioned between EtOAc/water. The phases were
separated and the organic layer was washed with sat.aq. NaCl
(2.times.10 mL). It was dried over anh. Na.sub.2SO.sub.4, the
solids were filtered and the solvent evaporated. The crude product
was purified by flash chromatography (silica gel, cHex/EtOAc 1:1)
to give the title compound as a white solid (281 mg, 60%).
[0463] NMR (.sup.1H, CDCl.sub.3): .delta. 7.92 (d, 1H), 7.61 (d,
1H), 7.35 (s, 1H), 7.25 (d, 2H), 7.01 (m, 2H), 6.89 (d, 2H), 6.58
(s, 1H), 4.41 (s, 2H), 4.14 (m, 2H), 3.86 (t, 2H), 3.80 (s, 3H),
3.38 (t, 2H), 2.88 (t, 2H), 2.44 (s, 3H), 2.28 (s, 3H).
[0464] MS (m/z): 597 [MH].sup.+.
Intermediate 48
1-[1-(6-Methyl-1-{2-methyl-4-[(trifluoromethyl)oxy]phenyl}-2,3-dihydro-1H--
pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-3-yl]-3-{[4-(methyloxy)phenyl]methy-
l}-2-imidazolidinone
[0465] To a solution of intermediate 47 (281 mg, 0.486 mmol) in
CH.sub.2Cl.sub.2 (10 mL), under N.sub.2, were added I.sub.2 (240
mg, 2 eq), PPh.sub.3 (247 mg, 2 eq) and Et.sub.3N (131 .mu.L, 2 eq)
and the reaction mixture was stirred at r.t. for 2 hr. The solvent
was then evaporated and the crude product was purified on an SCX
cartridge (100% CH.sub.2Cl.sub.2.fwdarw.2.0M Et.sub.3N in MeOH) and
flash chromatography (silica gel, cHex/EtOAc 1:1) to give the title
compound as a white solid (168 mg, 62%).
[0466] NMR (.sup.1H, CDCl.sub.3): .delta. 7.84 (d, 1H), 7.29 (d,
1H), 7.26 (d, 2H), 7.08 (m, 3H), 6.89 (d, 2H), 6.62 (s, 1H), 4.42
(s, 2H), 3.91 (m, 4H), 3.81 (s, 3H), 3.48 (t, 2H), 3.40 (t, 2H),
2.36 (s, 3H), 2.29 (s, 3H).
[0467] MS (m/z): 579 [MH].sup.+.
Intermediate 49
4-({3-(2-{[(1,1-Dimethylethyl)(dimethyl)silyl]oxy}ethyl)-6-methyl-4-[3-(3--
{[4-(methyloxy)phenyl]methyl}-2-oxo-1-imidazolidinyl)-1H-pyrazol-1-yl]-2-p-
yridinyl}amino)-3-methylbenzonitrile
[0468] As in intermediate 46, except that
4-amino-3-methylbenzonitrile was used instead of
2-methyl-4-[(trifluoromethyl)oxy]aniline.
[0469] NMR (.sup.1H, CDCl.sub.3): .delta. 8.21 (d, 1H), 7.89 (s,
1H), 7.6 (d, 1H), 7.42 (dd, 1H), 7.36 (bs, 1H), 7.23 (d, 2H), 6.99
(d, 1H), 6.87 (d, 2H), 6.71 (s, 1H), 4.41 (s, 2H), 4.19 (m, 2H),
4.04 (broad, 2H), 3.79 (s, 3H), 3.36 (t, 2H), 2.85 (t, 2H), 2.5 (s,
3H), 2.3 (s, 3H), 0.77 (s, 9H), -0.08 (s, 6H).
[0470] MS (m/z): 652 [MH].sup.+.
Intermediate 50
4-({3-(2-Hydroxyethyl)-6-methyl-4-[3-(3-{[4-(methyloxy)phenyl]methyl}-2-ox-
o-1-imidazolidinyl)-1H-pyrazol-1-yl]-2-pyridinyl}amino)-3-methylbenzonitri-
le
[0471] As in intermediate 47.
[0472] NMR (.sup.1H, CDCl.sub.3): .delta. 8.14 (d, 1H), 7.92 (s,
1H), 7.61 (d, 1H), 7.46 (dd, 1H), 7.4 (bs, 1H), 7.23 (d, 2H), 7.02
(d, 1H), 6.87 (d, 2H), 6.69 (s, 1H), 4.4 (s, 2H), 4.2 (m, 2H), 3.84
(t, 2H), 3.79 (s, 3H), 3.37 (t, 2H), 3.15 (bs, 1H), 2.86 (m, 2H),
2.48 (s, 3H), 2.28 (s, 3H).
[0473] MS (m/z): 538 [MH].sup.+.
Intermediate 51
3-Methyl-4-{6-methyl-4-[3-(3-{[4-(methyloxy)phenyl]methyl}-2-oxo-1-imidazo-
lidinyl)-1H-pyrazol-1-yl]-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl}benzon-
itrile
[0474] As in intermediate 48.
[0475] NMR (.sup.1H, CDCl.sub.3): .delta. 7.83 (d, 1H), 7.54 (bs,
1H), 7.48 (dd, 1H), 7.35 (d, 1H), 7.23 (d, 2H), 7.02 (d, 1H), 6.87
(d, 2H), 6.67 (s, 1H), 4.41 (s, 2H), 3.94 (m, 4H), 3.79 (s, 3H),
3.48 (t, 2H), 3.38 (t, 2H), 2.34 (s, 3H), 2.29 (s, 3H).
[0476] MS (m/z): 520 [MH].sup.+.
Intermediate 52
1-[1-(3-(2-{[(1,1-Dimethylethyl)(dimethyl)silyl]oxy}ethyl)-6-methyl-2-{[2--
methyl-4-(1
pyrazol-1-yl)phenyl]amino}-4-pyridinyl)-1H-pyrazol-3-yl]-3-{[4-(methyloxy-
)phenyl]methyl}-2-imidazolidinone
[0477] As in intermediate 46, except that intermediate 83
(2-methyl-4-(1H-pyrazol-1-yl)aniline) was used instead of
2-methyl-4-[(trifluoromethyl)oxy]aniline.
[0478] NMR (.sup.1H, CDCl.sub.3): .delta. 8.07 (d, 1H), 7.88 (d,
1H), 7.70 (s, 1H), 7.57 (m, 3H), 7.46 (dd, 1H), 7.25 (d, 2H), 7.03
(d, 1H), 6.91 (d, 2H), 6.60 (s, 1H), 6.45 (t, 1H), 4.44 (s, 2H),
4.18 (t, 2H), 3.92 (t, 2H), 3.88 (s, 3H), 3.40 (s, 2H), 2.87 (t,
2H), 2.46 (s, 3H), 2.36 (s, 3), 0.84 (s, 9H), 0.00 (s, 6H).
[0479] MS (m/z): 693 [MH].sup.+.
Intermediate 53
1-[1-(3-(2-Hydroxyethyl)-6-methyl-2-{[2-methyl-4-(1H-pyrazol-1-yl)phenyl]a-
mino}-4-pyridinyl)-1H-pyrazol-3-yl]-3-{[4-(methyloxy)phenyl]methyl}-2-imid-
azolidinone
[0480] As in intermediate 47.
[0481] NMR (.sup.1H, CDCl.sub.3): .delta. 7.94 (d, 1H), 7.81 (d,
1H), 7.65 (d, 1H), 7.57 (m, 2H), 7.48 (d, 1H), 7.38 (dd, 1H), 7.22
(d, 2H), 6.97 (d, 1H), 6.86 (d, 2H), 6.54 (s, 1H), 6.37 (t, 1H),
4.38 (t, 2H), 4.10 (m, 2H), 3.82 (t, 2H), 3.78 (s, 3H), 3.32 (t,
2H), 2.83 (t, 2H), 2.40 (s, 3H), 2.27 (s, 3H).
[0482] MS (m/z): 579 [MH].sup.+.
Intermediate 54
1-(1-{6-Methyl-1-[2-methyl-4-(1H-pyrazol-1-yl)phenyl]-2,3-dihydro-1H-pyrro-
lo[2,3-b]pyridin-4-yl}-1H-pyrazol-3-yl)-3-{[4-(methyloxy)phenyl]methyl}-2--
imidazolidinone
[0483] As in intermediate 48.
[0484] NMR (.sup.1H, CDCl.sub.3): .delta. 7.90 (d, 1H), 7.85 (d,
1H), 7.71 (m, 1H), 7.67 (m, 1H), 7.63 (m, 1H), 7.36 (d, 1H), 7.24
(d, 2H), 7.03 (d, 1H), 6.90 (d, 2H), 6.62 (s, 1H), 6.45 (t, 1H),
4.43 (s, 2H), 3.96 (m, 4H), 3.81 (s, 3H), 3.49 (t, 2H), 3.40 (t,
2H), 2.34 (s, 3H), 2.29 (s, 6H).
[0485] MS (m/z): 561 [MH].sup.+.
Intermediate 55
4-({3-(2-{[(1,1-Dimethylethyl)(dimethyl)silyl]oxy}ethyl)-6-methyl-4-[3-(3--
{[4-(methyloxy)phenyl]methyl}-2-oxo-1-imidazolidinyl)-1H-pyrazol-1-yl]-2-p-
yridinyl}amino)-3-(trifluoromethyl)benzonitrile
[0486] As in intermediate 46, except that
4-amino-3-(trifluoromethyl)benzonitrile was used instead of
2-methyl-4-[(trifluoromethyl)oxy]aniline.
[0487] NMR (.sup.1H, CDCl.sub.3): .delta. 8.41 (d, 1H), 8.32 (s,
1H), 7.92 (d, 1H), 7.74 (m, 2H), 7.35 (m, 3H), 7.12 (d, 1H), 6.96
(d, 2H), 4.52 (s, 2H), 4.18 (t, 2H), 4.00 (m, 2H), 3.90 (s, 3H),
3.48 (t, 2H), 3.21 (t, 2H), 2.63 (s, 3H), 0.91 (s, 9H), 0.07 (s,
6H).
[0488] MS (m/z): 706 [MH].sup.+.
Intermediate 56
4-({3-(2-Hydroxyethyl)-6-methyl-4-[3-(3-{[4-(methyloxy)phenyl]methyl}-2-ox-
o-1-imidazolidinyl)-1H-pyrazol-1-yl]-2-pyridinyl}amino)-3-(trifluoromethyl-
)benzonitrile
[0489] As in intermediate 47.
[0490] NMR (.sup.1H, CDCl.sub.3): .delta. 8.28 (d, 1H), 8.20 (s,
1H), 7.77 (d, 1H), 7.61 (dd, 1H), 7.56 (d, 1H), 7.16 (d, 2H), 6.98
(d, 1H), 6.81 (d, 2H), 6.72 (s, 1H), 6.14 (t, 1H), 4.35 (s, 2H),
4.06 (t, 2H), 3.78 (t, 2H), 3.73 (s, 3H), 3.32 (t, 2H), 2.84 (t,
2H), 2.43 (s, 3H).
[0491] MS (m/z): 592 [MH].sup.+.
Intermediate 57
4-{6-Methyl-4-[3-(3-{[4-(methyloxy)phenyl]methyl}-2-oxo-1-imidazolidinyl)--
1H-pyrazol-1-yl]-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl}-3-(trifluorome-
thyl)benzonitrile
[0492] As in intermediate 48.
[0493] NMR (.sup.1H, CDCl.sub.3): .delta. 8.00 (d, 1H), 7.85 (d,
1H), 7.81 (dd, 1H), 7.68 (d, 1H), 7.25 (d, 2H), 7.05 (d, 1H), 6.89
(d, 2H), 6.75 (s, 1H), 4.42 (s, 2H), 3.93 (m, 4H), 3.52 (t, 2H),
3.48 (s, 3H), 3.40 (t, 2H), 2.35 (s, 3H).
[0494] MS (m/z): 574 [MH].sup.+.
Intermediate 58
1-{1-[2-{[2-(Difluoromethyl)-4-(methyloxy)phenyl]amino}-3-(2-{[(1,1-dimeth-
ylethyl)(dimethyl)silyl]oxy}ethyl)-6-methyl-4-pyridinyl]-1H-pyrazol-3-yl}--
3-{[4-(methyloxy)phenyl]methyl}-2-imidazolidinone
[0495] As in intermediate 46, except that intermediate 87
(2-(difluoromethyl)-4-(methyloxy)aniline) was used instead of
2-methyl-4-[(trifluoromethyl)oxy]aniline.
[0496] NMR (.sup.1H, CDCl.sub.3): .delta. 7.62 (d, 1H), 7.56 (d,
1H), 7.50 (s, 1H), 7.26 (d, 2H), 7.13 (d, 1H), 7.01-6.98 (m, 2H),
6.87-6.92 (m, 2H), 6.73 (t, 1H, J.sub.(H-F)=56.1 Hz), 6.55 (s, 1H),
4.44 (s, 2H), 4.11 (t, 2H), 3.86 (t, 2H), 3.84 (s, 3H), 3.82 (s,
3H), 3.39 (t, 2H), 2.84 (t, 2H), 2.35 (s, 3H), 0.82 (s, 9H), 0.00
(s, 6H).
[0497] MS (m/z): 693 [MH].sup.+.
Intermediate 59
1-{1-[2-{[2-(Difluoromethyl)-4-(methyloxy)phenyl]amino}-3-(2-hydroxyethyl)-
-6-methyl-4-pyridinyl]-1H-pyrazol-3-yl}-3-{[4-(methyloxy)phenyl]methyl}-2--
imidazolidinone
[0498] As in intermediate 47.
[0499] NMR (.sup.1H, DMSO-d.sub.6): .delta. 8.32 (bs, 1H), 8.02 (d,
1H), 7.34-7.30 (m, 1H), 7.21 (d, 2H), 7.05-7.07 (m, 2H), 6.9 (d,
2H), 6.86 (t, 1H, J.sub.H-F=54.9 Hz), 6.76 (d, 1H), 6.63 (s, 1H),
5.29 (t, 1H), 4.31 (s, 2H), 3.73-3.84 (m, 10H), 3.34 (t, 2H), 2.77
(t, 2H), 2.19 (s, 3H).
[0500] MS (m/z): 579 [MH].sup.+.
Intermediate 60
1-(1-{1-[2-(Difluoromethyl)-4-(methyloxy)phenyl]-6-methyl-2,3-dihydro-1H-p-
yrrolo[2,3-b]pyridin-4-yl}-1H-pyrazol-3-yl)-3-{[4-(methyloxy)phenyl]methyl-
}-2-imidazolidinone
[0501] As in intermediate 48.
[0502] NMR (.sup.1H, CDCl.sub.3): .delta. 7.84 (d, 1H), 7.21-7.26
(m, 4H), 7.02-7.06 (m, 2H), 6.87-6.89 (m, 2H), 6.87 (t, 1H,
J.sub.(H-F)=55.5 Hz), 6.64 (s, 1H), 4.23 (s, 2H), 3.81-3.97 (m,
10H), 3.37-3.49 (m, 4H), 2.32 (s, 3H).
[0503] MS (m/z): 561 [MH].sup.+.
Intermediate 61
4-({3-(2-{[(1,1-Dimethylethyl)(dimethyl)silyl]oxy}ethyl)-6-methyl-4-[3-(3--
{[4-(methyloxy)phenyl]methyl}-2-oxo-1-imidazolidinyl)-1H-pyrazol-1-yl]-2-p-
yridinyl}amino)-3-[(trifluoromethyl)oxy]benzonitrile
[0504] As in intermediate 46, except that
4-amino-3-[(trifluoromethyl)oxy]benzonitrile was used instead of
2-methyl-4-[(trifluoromethyl)oxy]aniline.
[0505] MS (m/z): 722 [MH].sup.+.
Intermediate 62
4-({3-(2-Hydroxyethyl)-6-methyl-4-[3-(3-{[4-(methyloxy)phenyl]methyl}-2-ox-
o-1-imidazolidinyl)-1H-pyrazol-1-yl]-2-pyridinyl}amino)-3-[(trifluoromethy-
l)oxy]benzonitrile
[0506] As in intermediate 47.
[0507] NMR (.sup.1H, CDCl.sub.3): .delta. 8.84 (d, 1H), 8.56 (d,
1H), 7.61 (d, 1H), 7.5 (dd, 1H), 7.48 (bs, 1H), 7.23 (d, 2H), 7.02
(d, 1H), 6.87 (d, 2H), 6.87 (d, 2H), 6.74 (s, 1H), 4.4 (s, 2H), 4.2
(m, 2H), 3.84 (t, 2H), 3.79 (s, 3H), 3.37 (t, 2H), 3.1 (bs, 1H),
2.86 (m, 2H), 2.5 (s, 3H).
[0508] MS (m/z): 608 [MH].sup.+.
Intermediate 63
4-{6-Methyl-4-[3-(3-{[4-(methyloxy)phenyl]methyl}-2-oxo-1-imidazolidinyl)--
1H-pyrazol-1-yl]-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl}-3-[(trifluorom-
ethyl)oxy]benzonitrile
[0509] As in intermediate 48.
[0510] NMR (.sup.1H, CDCl.sub.3): .delta. 8.05 (d, 1H), 7.84 (m,
1H), 7.54 (bs, 1H), 7.5 (m, 1H), 7.23 (m, 1H), 7.03 (m, 1H), 6.87
(d, 2H), 6.78 (s, 1H), 4.41 (s, 2H), 4.11 (m, 2H), 3.91 (m, 2H),
3.79 (s, 3H), 3.5 (t, 2H), 3.38 (t, 2H), 2.41 (s, 3H).
[0511] MS (m/z): 590 [MH].sup.+.
Intermediate 64
4-({3-(2-{[(1,1-Dimethylethyl)(dimethyl)silyl]oxy}ethyl)-6-methyl-4-[3-(3--
{[4-(methyloxy)phenyl]methyl}-2-oxo-1-imidazolidinyl)-1H-pyrazol-1-yl]-2-p-
yridinyl}amino)-3-ethylbenzonitrile
[0512] As in intermediate 46, except that
4-amino-3-ethylbenzonitrile was used instead of
2-methyl-4-[(trifluoromethyl)oxy]aniline.
[0513] MS (m/z): 666 [MH].sup.+.
Intermediate 65
3-Ethyl-4-({3-(2-hydroxyethyl)-6-methyl-4-[3-(3-{[4-(methyloxy)phenyl]meth-
yl}-2-oxo-1-imidazolidinyl)-1H-pyrazol-1-yl]-2-pyridinyl}amino)benzonitril-
e
[0514] As in intermediate 47.
[0515] NMR (.sup.1H, CDCl.sub.3): .delta. 8.11 (d, 1H), 7.92 (s,
1H), 7.61 (d, 1H), 7.43 (dd, 1H), 7.42 (bs, 1H), 7.23 (d, 2H), 7.01
(d, 1H), 6.87 (d, 2H), 6.69 (s, 1H), 4.41 (s, 2H), 4.19 (m, 2H),
3.84 (t, 2H), 3.79 (s, 3H), 3.37 (t, 2H), 3.2 (bs, 1H), 2.86 (m,
2H), 2.64 (m, 2H), 2.47 (s, 3H), 1.27 (t, 3H).
[0516] MS (m/z): 552 [MH].sup.+.
Intermediate 66
3-Ethyl-4-{6-methyl-4-[3-(3-{[4-(methyloxy)phenyl]methyl}-2-oxo-1-imidazol-
idinyl)-1H-pyrazol-1-yl]-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl}benzoni-
trile
[0517] As in intermediate 48.
[0518] NMR (.sup.1H, CDCl.sub.3): .delta. 7.83 (d, 1H), 7.6 (bs,
1H), 7.48 (dd, 1H), 7.35 (d, 1H), 7.23 (d, 2H), 7.02 (d, 1H), 6.87
(d, 2H), 6.65 (s, 1H), 4.41 (s, 2H), 3.92 (m, 4H), 3.79 (s, 3H),
3.48 (t, 2H), 3.38 (t, 2H), 2.66 (q, 2H), 2.32 (s, 3H), 1.22 (t,
3H).
[0519] MS (m/z): 534 [MH].sup.+.
Intermediate 67
1-[1-(3-(2-{[(1,1-Dimethylethyl)(dimethyl)silyl]oxy}ethyl)-6-methyl-2-{[2--
(methyloxy)-4-(1H-pyrazol-1-yl)phenyl]amino}-4-pyridinyl)-1H-pyrazol-3-yl]-
-3-{[4-(methyloxy)phenyl]methyl}-2-imidazolidinone
[0520] As in intermediate 46, except that intermediate 88
(2-(methyloxy)-4-(1H-pyrazol-1-yl)aniline) was used instead of
2-methyl-4-[(trifluoromethyl)oxy]aniline.
[0521] NMR (.sup.1H, CDCl.sub.3): .delta. 7.88 (d, 1H), 7.76 (d,
1H), 7.65 (d, 1H), 7.5 (bs, 1H), 7.35 (d, 1H), 7.21 (m, 3H), 7.16
(dd, 1H), 7.02 (d, 1H), 6.88 (d, 2H), 6.69 (d, 1H), 6.54 (s, 1H),
6.44 (t, 1H), 4.41 (s, 2H), 4.11 (t, 2H), 3.95 (s, 3H), 3.86 (t,
2H), 3.79 (s, 3H), 3.36 (t, 2H), 2.85 (t, 2H), 2.51 (s, 3H), 0.79
(s, 9H), 0.07 (s, 6H).
[0522] MS (m/z): 709 [MH].sup.+
Intermediate 68
1-[1-(3-(2-Hydroxyethyl)-6-methyl-2-{[2-(methyloxy)-4-(1H-pyrazol-1-yl)phe-
nyl]amino}-4-pyridinyl)-1H-pyrazol-3-yl]-3-{[4-(methyloxy)phenyl]methyl}-2-
-imidazolidinone
[0523] As in intermediate 47.
[0524] NMR (.sup.1H, CDCl.sub.3): .delta. 8.66 (m, 1H), 7.88 (d,
1H), 7.69 (d, 1H), 7.62 (d, 1H), 7.5 (bs, 1H), 7.38 (d, 1H), 7.21
(m, 3H), 7.16 (dd, 1H), 7.02 (d, 1H), 6.88 (d, 2H), 6.54 (s, 1H),
6.44 (t, 1H), 4.41 (s, 2H), 4.11 (t, 2H), 3.98 (s, 3H), 3.9 (t,
2H), 3.79 (s, 3H), 3.40 (t, 2H), 2.9 (t, 2H), 2.49 (s, 3H).
[0525] MS (m/z): 595 [MH].sup.+.
Intermediate 69
1-(1-{6-Methyl-1-[2-(methyloxy)-4-(1H-pyrazol-1-yl)phenyl]-2,3-dihydro-1H--
pyrrolo[2,3-b]pyridin-4-yl}-1H-pyrazol-3-yl)-3-{[4-(methyloxy)phenyl]methy-
l}-2-imidazolidinone
[0526] As in intermediate 48.
[0527] NMR (.sup.1H, CDCl.sub.3): .delta. 7.88 (d, 1H), 7.83 (d,
1H), 7.70 (d, 1H), 7.59 (d, 1H), 7.42 (d, 1H), 7.22 (m, 3H), 7.00
(d, 1H), 6.88 (d, 2H), 6.63 (s, 1H), 6.43 (t, 1H), 4.41 (s, 2H),
3.98 (m, 4H), 3.90 (s, 3H), 3.78 (s, 3H), 3.40 (m, 4H), 2.34 (s,
3H).
Intermediate 70
1-(1-{3-(2-{[(1,1-Dimethylethyl)(dimethyl)silyl]oxy}ethyl)-6-methyl-2-[(6--
methyl-1,3-benzodioxol-5-yl)amino]-4-pyridinyl}-1H-pyrazol-3-yl)-3-{[4-(me-
thyloxy)phenyl]methyl}-2-imidazolidinone
[0528] As in intermediate 46, except that intermediate 89
(6-methyl-1,3-benzodioxol-5-amine) was used instead of
2-methyl-4-[(trifluoromethyl)oxy]aniline.
[0529] NMR (.sup.1H, CDCl.sub.3): .delta. 7.57 (d, 1H), 7.43 (bs,
1H), 7.25 (bs, 1H), 7.21 (d, 2H), 6.94 (d, 1H), 6.86 (d, 2H), 6.64
(d, 1H), 6.48 (bs, 1H), 5.88 (s, 2H), 4.40 (s, 2H), 4.08 (m, 2H),
3.83 (m, 2H), 3.79 (s, 3H), 3.35 (t, 2H), 2.78 (t, 2H), 2.38 (bs,
3H), 2.16 (s, 3H), 0.80 (s, 9H), -0.04 (s, 6H).
[0530] MS (m/z): 671 [MH].sup.+.
Intermediate 71
1-(1-{3-(2-Hydroxyethyl)-6-methyl-2-[(6-methyl-1,3-benzodioxol-5-yl)amino]-
-4-pyridinyl}-1H-pyrazol-3-yl)-3-{[4-(methyloxy)phenyl]methyl}-2-imidazoli-
dinone
[0531] As in intermediate 47.
[0532] NMR (.sup.1H, CDCl.sub.3): .delta. 7.59 (d, 1H), 7.39 (bs,
1H), 7.24 (m, 2H), 7.21, 6.99 (d, 1H), 6.87 (d, 2H), 6.70 (bs, 1H),
6.65 (s, 1H), 6.48 (s, 1H), 5.89 (s, 2H), 4.40 (s, 2H), 4.33 (t,
1H), 4.08 (m, 2H), 3.85 (t, 2H), 3.78 (s, 3H), 3.36 (t, 2H), 2.85
(t, 2H), 2.38 (s, 3H), 2.17 (s, 3H).
[0533] MS (m/z): 557 [MH].sup.+.
Intermediate 72
1-{1-[6-Methyl-1-(6-methyl-1,3-benzodioxol-5-yl)-2,3-dihydro-1H-pyrrolo[2,-
3-b]pyridin-4-yl]-1H-pyrazol-3-yl}-3-{[4-(methyloxy)phenyl]methyl}-2-imida-
zolidinone
[0534] As in intermediate 48.
[0535] NMR (.sup.1H, CDCl.sub.3): .delta. 7.81 (d, 1H), 7.23 (m,
2H), 6.99 (d, 1H), 6.87 (d, 2H), 6.73 (d, 2H), 6.56 (s, 1H), 5.90
(s, 2H), 4.40 (s, 2H), 3.92 (t, 2H), 3.78 (m, 5H), 3.39 (m, 4H),
2.31 (s, 3H), 2.15 (s, 3H).
[0536] MS (m/z): 539 [MH].sup.+.
Intermediate 73
1-[1-(3-(2-{[(1,1-Dimethylethyl)(dimethyl)silyl]oxy}ethyl)-6-methyl-2-{[2,-
4,6-tris(methyloxy)phenyl]amino}-4-pyridinyl)-1H-pyrazol-3-yl]-3-{[4-(meth-
yloxy)phenyl]methyl}-2-imidazolidinone
[0537] As in intermediate 46, except that
2,4,6-tris(methyloxy)aniline was used instead of
2-methyl-4-[(trifluoromethyl)oxy]aniline.
[0538] MS (m/z): 703 [MH].sup.+.
Intermediate 74
1-[1-(3-(2-Hydroxyethyl)-6-methyl-2-{[2,4,6-tris(methyloxy)phenyl]amino}-4-
-pyridinyl)-1H-pyrazol-3-yl]-3-{[4-(methyloxy)phenyl]methyl}-2-imidazolidi-
none
[0539] As in intermediate 47.
[0540] MS (m/z): 589 [MH].sup.+.
Intermediate 75
1-{[4-(Methyloxy)phenyl]methyl}-3-(1-{6-methyl-1-[2,4,6-tris(methyloxy)phe-
nyl]-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl}-1H-pyrazol-3-yl)-2-imidazo-
lidinone
[0541] As in intermediate 48.
[0542] NMR (.sup.1H, DMSO-d.sub.6): .delta. 8.84 (d, 1H), 7.24 (bs,
2H), 7.01 (bs, 1H), 6.88-6.83 (d-d, 2H), 6.54 (s, 1H), 6.20 (d,
1H), 6.18 (s, 1H), 4.44 (s, 2H), 3.92-3.84 (m, 2H), 3.81-3.72 (m,
14H), 3.48-3.36 (m, 4H), 2.40 (bs, 3H).
[0543] MS (m/z): 451 [MH].sup.+.
Intermediate 76
1-(1-{3-(2-{[(1,1-Dimethylethyl)(dimethyl)silyl]oxy}ethyl)-6-methyl-2-[(4--
methyl-1,3-benzodioxol-5-yl)amino]-4-pyridinyl}-1H-pyrazol-3-yl)-3-{[4-(me-
thyloxy)phenyl]methyl}-2-imidazolidinone
[0544] As in intermediate 46, except that
4-methyl-1,3-benzodioxol-5-amine (prepared as described in the U.S.
Pat. No. 5,965,595 A) was used instead of
2-methyl-4-[(trifluoromethyl)oxy]aniline.
[0545] NMR (.sup.1H, CDCl.sub.3): .delta. 7.57 (d, 1H), 7.41 (bs,
1H), 7.21 (m, 3H), 7.00 (d, 1H), 6.95 (d, 2H), 6.87 (d, 1H), 6.47
(s, 1H), 5.92 (s, 2H), 4.40 (s, 2H), 4.11 (m, 2H), 3.83 (s, 3H),
3.35 (t, 2H), 2.79 (t, 2H), 2.33 (s, 3H), 2.04 (s, 3H), 0.79 (s,
9H), -0.04 (s, 6H).
[0546] MS (m/z): 671 [MH].sup.+.
Intermediate 77
1-(1-{3-(2-Hydroxyethyl)-6-methyl-2-[(6-methyl-1,3-benzodioxol-5-yl)amino]-
-4-pyridinyl}-1H-pyrazol-3-yl)-3-{[4-(methyloxy)phenyl]methyl}-2-imidazoli-
dinone
[0547] As in intermediate 47.
[0548] NMR (.sup.1H, CDCl.sub.3): .delta. 7.59 (d, 1H), 7.20 (m,
3H), 7.10 (d, 1H), 6.99 (d, 1H), 6.87 (d, 2H), 6.70 (d, 1H), 6.47
(s, 1H), 5.93 (s, 2H), 4.40 (s, 2H), 4.08 (m, 2H), 3.85 (t, 2H),
3.78 (s, 3H), 3.36 (t, 2H), 2.85 (t, 2H), 2.35 (s, 3H), 2.09 (s,
3H).
[0549] MS (m/z): 557 [MH].sup.+.
Intermediate 78
1-{1-[6-Methyl-1-(6-methyl-1,3-benzodioxol-5-yl)-2,3-dihydro-1H-pyrrolo[2,-
3-b]pyridin-4-yl]-1H-pyrazol-3-yl}-3-{[4-(methyloxy)phenyl]methyl}-2-imida-
zolidinone
[0550] As in intermediate 48.
[0551] NMR (.sup.1H, CDCl.sub.3): .delta. 7.81 (d, 1H), 7.23 (m,
2H), 6.99 (d, 1H), 6.88 (d, 2H), 6.72 (dd, 2H), 6.56 (s, 1H), 5.95
(s, 2H), 4.40 (s, 2H), 3.92 (t, 2H), 3.81 (t, 2H), 3.78 (s, 3H),
3.39 (m, 4H), 2.31 (s, 3H), 2.08 (s, 3H).
[0552] MS (m/z): 539 [MH].sup.+
Intermediate 79
1-{1-[2-{[2,4-Bis(trifluoromethyl)phenyl]amino}-3-(2-{[(1,1-dimethylethyl)-
(dimethyl)silyl]oxy}ethyl)-6-methyl-4-pyridinyl]-1H-pyrazol-3-yl}-3-{[4-(m-
ethyloxy)phenyl]methyl}-2-imidazolidinone
[0553] As in intermediate 46, except that
2,4-bis(trifluoromethyl)aniline was used instead of
2-methyl-4-[(trifluoromethyl)oxy]aniline.
[0554] NMR (.sup.1H, CDCl.sub.3): .delta. 8.33 (d, 1H), 7.99 (bs,
1H), 7.78 (bs, 1H), 7.63 (m, 2H), 7.24 (m, 2H), 6.99 (m, 1H) 6.85
(d, 2H), 6.77 (bs, 1H), 4.40 (s, 2H), 4.05 (m, 2H), 3.83 (m, 2H),
3.78 (s, 3H), 3.36 (t, 2H), 2.90 (t, 2H), 2.49 (s, 3H), 0.73 (s,
9H), -0.11 (s, 6H).
[0555] MS (m/z): 749 [MH].sup.+.
Intermediate 80
1-{1-[2-{[2,4-Bis(trifluoromethyl)phenyl]amino}-3-(2-hydroxyethyl)-6-methy-
l-4-pyridinyl]-1H-pyrazol-3-yl}-3-{[4-(methyloxy)phenyl]methyl}-2-imidazol-
idinone
[0556] As in intermediate 47.
[0557] NMR (.sup.1H, CDCl.sub.3): .delta. 8.37 (d, 1H), 7.90 (bs,
1H), 7.79 (bs, 1H), 7.67 (m, 2H), 7.61 (d, 1H), 7.51 (m, 1H) 7.03
(bs, 1H), 6.88 (d, 2H), 6.72 (s, 1H), 4.40 (s, 2H), 4.20 (t, 2H),
4.05 (bs, 1H), 3.85 (t, 2H), 3.78 (s, 3H), 3.37 (t, 2H), 2.89 (t,
2H), 2.47 (s, 3H).
[0558] MS (m/z): 635 [MH].sup.+.
Intermediate 81
1-(1-{1-[2,4-Bis(trifluoromethyl)phenyl]-6-methyl-2,3-dihydro-1H-pyrrolo[2-
,3-b]pyridin-4-yl}-1H-pyrazol-3-yl)-3-{[4-(methyloxy)phenyl]methyl}-2-imid-
azolidinone
[0559] As in intermediate 48.
[0560] NMR (.sup.1H, CDCl.sub.3): .delta. 7.96 (s, 1H), 7.84 (d,
1H), 7.79 (bs, 1H), 7.58 (d, 1H), 7.22 (d, 2H), 7.02 (d, 1H), 6.88
(d, 2H) 6.70 (s, 1H), 4.41 (s, 2H), 3.92 (m, 4H), 3.79 (s, 3H),
3.49 (t, 2H), 3.37 (t, 2H), 2.31 (s, 3H).
[0561] MS (m/z): 617 [MH].sup.+.
Intermediate 82
1,1-Dimethylethyl (4-bromo-2-methylphenyl)carbamate
[0562] To a solution of 4-bromo-2-methylaniline (1 g, 5.37 mmol,)
in 1,4-dioxane (11 mL) and H.sub.2O (4 mL), at r.t., were added
Et.sub.3N (2.7 mL, 1.2 eq) and BOC.sub.2O (4.2 g, 1.2 eq). The
reaction mixture was stirred at r.t. for 96 hr. Sat.aq. NH.sub.4Cl
and EtOAc (20 mL) were added and the phases were separated. The
aqueous layer was further extracted with EtOAc (2.times.20 mL). The
combined organic extracts were dried over anh. Na.sub.2SO.sub.4,
the solids were filtered and the solvent evaporated. The residue
was purified on an SCX cartridge (CH.sub.2Cl.sub.2, MeOH and
NH.sub.3(0.5 M in MeOH)) to give the title compound as a white
solid (1.22 g, 79%).
[0563] NMR (.sup.1H, DMSO-d.sub.6): .delta. 8.55 (s, 1H), 7.35 (m,
1H), 7.28 (m, 2H), 2.17 (s, 3H), 1.44 (s, 9H).
[0564] MS (m/z): 230 [MH-tBu].sup.+, 186 [MH-BOC].sup.+.
Intermediate 83
2-Methyl-4-(1H-pyrazol-1-yl)aniline
[0565] A solution of intermediate 82 (200 mg, 0.7 mmol),
1H-pyrazole (95 mg, 2 eq), CuI (133 mg, 1 eq), K.sub.2CO.sub.3 (290
mg, 2.1 eq) and (1R,2R)-diaminomethylcyclohexane (100 mg, 1 eq) in
anh. NMP (1 mL), under N.sub.2, was heated at 150.degree. C. for 6
hr. It was cooled down to r.t. and poured into water. EtOAc was
added and the phases were separated. The aqueous layer was further
extracted with EtOAc (2.times.10 mL). The combined organic extracts
were dried over anh. Na.sub.2SO.sub.4, the solids were filtered and
the solvent evaporated. The residue was purified by
flash-chromatography (silica gel, cHex/EtOAc 8:2) to give the title
compound as a white solid (85.6 mg, 70%).
[0566] NMR (.sup.1H, CDCl.sub.3): .delta. 7.77 (dd, 1H), 7.66 (d,
1H), 7.39 (d, 1H), 7.29 (dd, 1H), 6.72 (d, 1H), 6.40 (t, 1H), 2.85
(bs, 1H).
[0567] MS (m/z): 174 [MH].sup.+.
Intermediate 84
(5-Methoxy-2-nitro-phenyl)-methanol
[0568] To a suspension of cyanuric chloride (1.84 g, 1 eq) in anh.
DME (60 mL) at r.t., under N.sub.2, was added NMM (1.1 mL, 1 eq).
The reaction mixture was stirred for 2 min and a precipitate was
formed. A solution of 5-(methyloxy)-2-nitrobenzoic acid (2.0 g, 10
mmol) in anh. DME (20 mL) was added and the reaction mixture was
stirred for 4 hr. The suspension was filtered and a solution of
NaBH.sub.4 (0.57 g, 1.5 eq) in water (30 mL) was added at 0.degree.
C. The reaction mixture was stirred for 20 min at 0.degree. C. It
was then diluted with Et.sub.2O (10 mL) and acidified to pH 5 by
addition of sat. aq. NH.sub.4Cl. The phases were separated and the
aqueous layer was extracted with Et.sub.2O (2.times.100 mL). The
combined organic extracts were washed with sat. aq.
Na.sub.2CO.sub.3 and dried over anh. Na.sub.2SO.sub.4. The solids
were filtered and the solvent evaporated to dryness. The crude
product was purified by flash chromatography (silica gel,
cHex/EtOAc 8:2) to give the title compound (958 mg, 53%).
[0569] NMR (.sup.1H, CDCl.sub.3): .delta. 8.15 (d, 1H), 7.19 (m,
1H), 6.85 (dd, 1H), 4.95 (d, 2H), 3.89 (s, 3H), 2.5 (t, 1H).
Intermediate 85
5-(Methyloxy)-2-nitrobenzaldehyde
[0570] To a solution of intermediate 84 (1.44 g, 7.9 mmol) in anh.
CH.sub.2Cl.sub.2 (40 mL) at r.t., under N.sub.2, was added
Dess-Martin periodinane (3.68 g, 1.1 eq). The reaction mixture was
stirred for 3 hr at r.t., then sat.aq. Na.sub.2S.sub.2O.sub.3 (5
mL) and sat.aq. NaHCO.sub.3 (20 mL) were added. The phases were
separated and the aqueous layer was extracted with EtOAc
(2.times.100 mL). The combined organic extracts were dried over
anh. Na.sub.2SO.sub.4, the solids were filtered and the solvent
evaporated to dryness to give 1.45 g (100%) of the title
compound.
[0571] NMR (.sup.1H, CDCl.sub.3): .delta. 10.47 (s, 1H), 8.14 (d,
1H), 7.31 (d, 1H), 7.13 (dd, 1H), 3.94 (s, 3H).
Intermediate 86
2-(Difluoromethyl)-4-(methyloxy)-1-nitrobenzene
[0572] To a solution of intermediate 85 (250 mg, 1.38 mmol) in anh.
CH.sub.2Cl.sub.2 (10 mL), at -78.degree. C., under N.sub.2, was
added slowly DAST (2.times.0.4 mL, 2.2 eq). The reaction mixture
was stirred at r.t. for 1.5 hr, after which was added sat.aq. NaCl.
The phases were separated and the aqueous layer was extracted with
EtOAc (3.times.20 mL). The combined organic extracts were dried
over anh. Na.sub.2SO.sub.4, the solids were filtered and the
solvent was evaporated to dryness. The crude product was purified
by flash chromatography (silica gel, cHex/EtOAc 8:2) to give the
title compound (176 mg, 63%) as a yellow oil.
[0573] NMR (.sup.1H, CDCl.sub.3): .delta. 8.21 (d, 1H), 7.43 (t,
1H, J.sub.(H-F)=54.9 Hz), 7.33 (d, 1H), 7.06 (dd, 1H), 3.95 (s,
3H).
Intermediate 87
2-(Difluoromethyl)-4-(methyloxy)aniline
[0574] To a solution of intermediate 86 (176 mg, 0.87 mmol) in anh.
MeOH (8.7 mL), at r.t., under N.sub.2, was added Pd/C 10% (88 mg,
5% wt). The reaction mixture was placed under an atmosphere of
H.sub.2 for 5 hr. The catalyst was filtered off and the solution
obtained was evaporated to dryness. The crude product was purified
by flash chromatography (silica gel, cHex/EtOAc 9:1) to give the
title compound (27 mg, 20%) as a yellow oil.
[0575] NMR (.sup.1H, CDCl.sub.3): .delta. 6.88-6.80 (m, 2H),
6.7-6.67 (m, 1H), 6.62 (t, 1H, J.sub.(H-F)=55.6 Hz), 3.8-3.5 (bs,
2H), 3.76 (s, 3H)
[0576] MS (m/z): 174 [MH].sup.+.
Intermediate 88
2-(Methyloxy)-4-(1H-pyrazol-1-yl)aniline
[0577] To a solution of 4-bromo-2-(methyloxy)aniline (400 mg, 1.979
mmol) in anh. NMP (4 mL), at r.t., under N.sub.2, were added
pyrazole (269 mg, 2 eq), K.sub.2CO.sub.3 (819 mg, 3 eq), CuI (377
mg, 1 eq) and (1R,2R)-diaminomethylcyclohexane (281 mg, 1 eq). The
reaction mixture was stirred at 150.degree. C. for 3 hr. It was
cooled down to r.t. and poured into EtOAc/sat.aq. NaCl. The phases
were separated and the organic layer was washed with sat.aq.
NH.sub.4Cl (20 mL) and sat.aq. NaCl (20 mL). The combined aqueous
layers were extracted back with EtOAc (20 mL) and the combined
organic extracts were dried over anh. Na.sub.2SO.sub.4. The solids
were filtered and the solvent evaporated. The crude product was
purified by flash chromatography (silica gel, cHex/EtOAc 7:3) to
give the title compound as a brown oil (336 mg, 90%)
[0578] NMR (.sup.1H, CDCl.sub.3): .delta. 7.78 (d, 1H), 7.65 (d,
1H), 7.21 (d, 1H), 6.97 (dd, 1H), 6.73 (d, 1H), 6.40 (m, 1H), 4.05
(bs, 2H), 3.87 (s, 3H).
[0579] MS (m/z): 190 [MH].sup.+.
Intermediate 89
6-Methyl-1,3-benzodioxol-5-amine
[0580] A mixture of 5-methyl-6-nitro-benzo(1,3)dioxole (50 mg, 0.28
mmol), Fe (54 mg, 3.5 eq) and ammonium chloride (51.2 mg, 3.5 eq)
in a 1:1 mixture of MeOH/H.sub.2O (2.8 mL) was subjected to
microwave irradiation (60 W, P=100 p.s.i.) at 80.degree. C. for
four 10 min periods. The brown solution was allowed to cool to r.t.
and more Fe (3.5 eq) and ammonium chloride (3.5 eq) were added. The
mixture was subjected to microwave irradiation (60 W, P=100 p.s.i.)
at 80.degree. C. for an additional 10 min. Fe was filtered off and
the solvent evaporated. The crude product was purified on an SCX
cartridge (cHex/EtOAc 9:1) to give the title compound as a brown
solid (40 mg, 93%).
[0581] NMR (.sup.1H, CDCl.sub.3): .delta. 6.54 (s, 1H), 6.27 (s,
1H), 5.80 (s, 2H), 2.27 (bs, 2H), 2.07 (s, 3H).
[0582] MS (m/z): 152 [MH].sup.+.
Intermediate 90
4-{[2-Methyl-4-(methyloxy)phenyl]amino}butanenitrile
[0583] A solution of DIPEA (39 mL, 1 eq) and
4-methoxy-2-methylaniline (30 g, 0.22 mol) in anh. DMF (90 mL),
under N.sub.2, was heated at 100.degree. C. 4-Bromobutanenitrile
(21 mL, 1 eq) was added dropwise. The internal temperature was
raised to 110.degree. C. and the reaction mixture was stirred for 2
hr. The mixture was cooled down to r.t. and diluted with MTBE (240
mL). Water (270 mL) was added and the phases were separated. The
organic layer was further washed with water (150 mL) and evaporated
to 150 mL. Fresh MTBE (150 mL) was added and the mixture again
evaporated to 150 mL. The mixture was treated with cHex (540 mL)
over 20 min and the resulting suspension left at room temperature
for 1.5 hr. The suspension was filtered and the cake washed with a
mixture MTBE (30 mL)/cHex (90 mL). The title compound was collected
as a violet solid (23.8 g, 53%).
[0584] NMR (.sup.1H, DMSO-d.sub.6): .delta. 6.65 (d, 1H), 6.63 (dd,
1H), 6.47 (d, 1H), 4.49 (bt, 1H), 3.64 (s, 3H), 3.10 (q, 2H), 2.59
(t, 2H), 2.09 (s, 3H), 1.86 (m, 2H).
[0585] MS (m/z): 205 [MH].sup.+.
Intermediate 91
1-[2-Methyl-4-(methyloxy)phenyl]-2-pyrrolidinimine
[0586] To a suspension of intermediate 90 (35.0 g, 0.173 mol) in
anh. IPA (280 mL), at r.t., under N.sub.2, was added 6N HCl/IPA
(51.45 mL, 1.5 eq). The mixture was heated to reflux for 4 hr,
allowed to cool down to r.t. and evaporated to 140 mL. Water (350
mL) was added, the clear solution evaporated again to 140 mL and
treated with 10% NaOH (140 mL). The mixture was extracted with
CH.sub.2Cl.sub.2 (350 mL) and the organic layer further washed with
10% NaCl (140 mL). The organic layer was evaporated to dryness. The
crude product was used as such in the next step (36.4 g, 100%)
[0587] NMR (.sup.1H, DMSO-d.sub.6): .delta. 7.09 (d, 1H), 6.87 (d,
1H), 6.80 (dd, 1H), 5.8-5.4 (b, 1H), 3.75 (s, 1H), 3.54 (t, 2H),
2.51 (t, 2H), 2.11 (s, 3H), 2.01 (m, 2H).
[0588] MS (m/z): 205 [MH].sup.+.
Intermediate 92
4-Bromo-6-methyl-1-[2-methyl-4-(methyloxy)phenyl]-2,3-dihydro-1H-pyrrolo[2-
,3-b]pyridine
[0589] To a solution of intermediate 4 (50.0 g, 0.15 mol) in anh.
DMF (175 mL), at r.t., under N.sub.2, was added CH.sub.3SO.sub.3H
(58.1 mL, 1.2 eq) followed by NaBr (19.18 g, 1.5 eq) and the
resulting mixture was heated at 85.degree. C. for 2 hr. It was then
diluted with MTBE (250 mL) and washed with 1N NaOH (250 mL). The
aqueous phase was extracted with MTBE (150 mL) and the combined
organic extracts washed twice with water (250 mL), then dried over
anh. Na.sub.2SO.sub.4. The solids were filtered and the solvent
evaporated to give the title compound (38.g, 76%) as a yellow
solid.
[0590] NMR (.sup.1H, DMSO-d.sub.6): .delta. 7.17 (d, 1H), 6.87 (d,
1H), 6.80 (dd, 1H), 6.56 (s, 1H), 3.86 (t, 2H), 3.76 (s, 3H), 3.06
(t, 2H), 2.15-2.14 (2s, 6H).
[0591] MS (m/z): 333/335 [MH].sup.+.
Intermediate 93
{6-Methyl-1-[2-methyl-4-(methyloxy)phenyl]-2,3-dihydro-1H-pyrrolo[2,3-b]py-
ridin-4-yl}boronic acid
[0592] To a mixture of triisopropyl borate (185 .mu.L, 3 eq) and
intermediate 5 (100 mg, 1 eq) in an anh. 1:4 mixture of THF/toluene
(0.5 mL), at -70.degree. C., under N2, was added n-BuLi (329 .mu.L,
2 eq) dropwise. The reaction mixture was stirred at -70.degree. C.
for 2.5 hr. It was warmed up to -20.degree. C. and quenched with 1M
HCl (0.5 mL, 2 eq). The mixture was warmed up to r.t. and
precipitation of the boronic acid was observed. The solid was
filtered and washed with CH.sub.3CN. The title compound was
obtained as a white solid (70 mg, 89%).
[0593] NMR (.sup.1H, CDCl.sub.3): .delta. 7.21 (d, 1H), 6.91 (d,
1H), 6.84 (dd, 1H), 6.61 (d, 1H), 4.02 (bt, 2H), 3.74 (s, 3H), 3.29
(bt, 2H), 2.21 (s, 3H), 2.15 (s, 3H).
[0594] MS (m/z): 299 [MH].sup.+.
Intermediate 94
N-(6-Bromo-2-pyridinyl)-N'-(2-chloroethyl)urea
[0595] To a solution of 6-bromo-2-pyridinamine (1 g, 5.78 mmol) in
anh. THF (25 mL), at r.t., under N.sub.2, was added
1-chloro-2-isocyanatoethane (1.2 mL, 2.5 eq) and the reaction
mixture was stirred at r.t. for 18 hr. The crude mixture was
partitioned between CH.sub.2Cl.sub.2 and water. The phases were
separated and the organic layer was dried over anh.
[0596] Na.sub.2SO.sub.4. The solids were filtered and the solvent
evaporated to give the title compound (1.06 g, 66%) which was used
in the next step without further purification.
[0597] NMR DMSO-d.sub.6): .delta. 9.56 (bs, 1H), 7.75 (m, 2H), 7.32
(t, 1H), 7.14 (t, 1H), 3.65 (t, 2H), 3.46 (m, 2H)
Intermediate 95
1-(6-Bromo-2-pyridinyl)-2-imidazolidinone
[0598] To a solution of intermediate 94 (1.06 g, 3.82 mmol) in anh.
THF (25 mL), at 0.degree. C., under N.sub.2, was added t-BuOK (644
mg, 1.5 eq) and the reaction mixture was allowed to warm up to r.t.
After 1 h at r.t. the reaction mixture was partitioned between
CH.sub.2Cl.sub.2 and water. The organic layer was dried over anh.
Na.sub.2SO.sub.4, the solids were filtered and the solvent
evaporated to give the title compound (0.988 g, quantitative) which
was used in the next step without further purification.
[0599] NMR DMSO-d.sub.6): .delta. 8.14 (d, 1H), 7.61 (t, 1H), 7.33
(bs, 1H), 7.19 (d, 1H), 3.95 (t, 2H), 3.40 (t, 2H)
Intermediate 96
1-(6-Bromo-2-pyridinyl)-3-{[4-(methyloxy)phenyl]methyl}-2-imidazolidinone
[0600] To a solution of intermediate 95 (0.5 g, 2.06 mmol) in anh.
DMF (25 mL), at r.t., under N.sub.2, was added NaH 60%/oil (82 mg,
1 eq) and p-methoxybenzyl chloride (280 .mu.L, 1 eq) and the
mixture was stirred at r.t. for 2 hr. It was then partitioned
between CH.sub.2Cl.sub.2 and water. The organic layer was dried
over anh. Na.sub.2SO.sub.4, the solids were filtered and the
solvent evaporated. The resulting crude product was purified by
flash chromatography (silica gel, CH.sub.2Cl.sub.2/MeOH 9:1) to
give the title compound (0.635 g, 85%).
[0601] NMR (.sup.1H, CDCl.sub.3): .delta. 8.33 (d, 1H), 7.71 (t,
1H), 7.29 (d, 2H), 7.10 (d, 1H), 6.85 (d, 2H), 4.43 (s, 2H), 4.00
(t, 2H), 3.83 (s, 3H), 3.55 (t, 2H)
Intermediate 97
1-(6-{6-Methyl-1-[2-methyl-4-(methyloxy)phenyl]-2,3-dihydro-1H-pyrrolo[2,3-
-b]pyridin-4-yl}-2-pyridinyl)-3-{[4-(methyloxy)phenyl]methyl}-2-imidazolid-
inone
[0602] To a solution of intermediate 93 (50 mg, 1 eq) and
intermediate 96 (121 mg, 2 eq) in a 1:1 mixture of toluene/EtOH (5
mL), at r.t., under N.sub.2, were added 2M Na.sub.2CO.sub.3 (168
.mu.L), Pd(PPh.sub.3).sub.4 (19 mg, 0.1 eq) and
tetra-n-butylammonium bromide (9 mg, 0.1 eq). The reaction mixture
was stirred at 90.degree. C. for 2 hr in a sealed vial. It was
partitioned between EtOAc and water. The phases were separated and
the organic layer was washed with sat.aq. NaCl. It was dried over
anh. Na.sub.2SO.sub.4, the solids were filtered and the solvent
evaporated. The crude product was purified by flash chromatography
(silica gel, cHex/EtOAc 8:2) to give the title compound as a white
solid (35 mg, 39%).
[0603] NMR (.sup.1H, CDCl.sub.3): .delta. 8.32 (d, 1H), 7.71 (d,
1H), 7.30-6.71 (m, 9H), 4.43 (s, 2H), 4.09 (t, 2H), 3.84-3.78 (m,
8H), 3.43-3.33 (m, 4H), 2.33 (s, 3H), 2.24 (s, 3H).
[0604] MS (m/z): 536 [MH].sup.+.
Intermediate 98
N-{[3,4-Bis(methyloxy)phenyl]methyl}-N'-(2-chloroethyl)urea
[0605] To a solution of 3,4-dimethoxybenzylamine (2 g, 12 mmol) in
anh. THF (25 mL), at r.t., under N.sub.2, was added 2-chloroethyl
isocyanate (1.02 mL, 1 eq). The reaction was complete after the
addition. It was concentrated and the residue was purified by flash
chromatography (silica gel, cHex/EtOAc 1:1.fwdarw.7:3
EtOAc/NH.sub.3 (0.5 in MeOH)) to give the title compound as a white
solid (2.9 g, 89%).
[0606] NMR (.sup.1H, DMSO-d.sub.6): .delta. 6.85 (d, 1H), 6.82 (d,
1H), 6.73 (dd, 1H), 6.41 (t, 1H), 6.16 (t, 1H), 4.10 (d, 2H), 3.70
(s, 3H), 3.69 (s, 3H), 3.56 (t, 2H), 3.31 (m, 2H).
[0607] MS (m/z): 273 [MH].sup.+.
Intermediate 99
1-{[3,4-Bis(methyloxy)phenyl]methyl}-2-imidazolidinone
[0608] To a suspension of intermediate 98 (1 g, 3.68 mmol) in anh.
THF (30 mL), at 0.degree. C., under N.sub.2, was added t-BuOK (500
mg, 1.2 eq). The ice bath was removed and the reaction mixture was
stirred at r.t. for 1 hr. Sat.aq. NH.sub.4Cl was added and the
solvents were evaporated to dryness. The residue was purified by
flash chromatography (silica gel, 100% EtOAc.fwdarw.EtOAc/MeOH 8:2)
to give the title compound as a white solid (555 mg, 64%).
[0609] NMR (' H, DMSO-d.sub.6): .delta. 6.88 (d, 1H), 6.79 (d, 1H),
6.73 (dd, 1H), 6.33 (s, 1H), 4.12 (s, 2H), 3.70 (s, 6H), 3.16 (m,
4H).
[0610] MS (m/z): 237 [MH].sup.+.
Intermediate 100
1-{[3,4-Bis(methyloxy)phenyl]methyl}-3-(4-chloro-2-pyrimidinyl)-2-imidazol-
idinone and intermediate 101
1-{[3,4-bis(methyloxy)phenyl]methyl}-3-(2-chloro-4-pyrimidinyl)-2-imidazol-
idinone
[0611] To a solution of 2,4-dichloropyrimidine (600 mg, 2.54 mmol,
1 eq) and intermediate 99 (100 mg, 0.42 mmol) in anh. DMF (27 mL),
at r.t., under N.sub.2, was added NaH 60%/oil (112 mg, 1.1 eq). The
reaction mixture was stirred at r.t. for 1 hr. Water and EtOAc were
added and the two phases were separated. The aqueous layer was
further extracted with EtOAc (3.times.20 mL). The combined organic
extracts were concentrated and the residue was purified by flash
chromatography (silica gel, cHex/EtOAc 7:3) to give intermediate
100 as a white solid (377 mg, 42%). The other regioisomer was
collected in mixture with the unreacted intermediate 99. This crude
mixture was repurified by flash chromatography (silica gel,
CH.sub.2Cl.sub.2/NH.sub.3(0.5 in MeOH) 95:5) to give intermediate
101 as a white solid (193.1 mg, 22%).
Intermediate 100:
[0612] NMR (.sup.1H, CDCl.sub.3): .delta. 8.36 (d, 1H), 8.28 (d,
1H), 6.87 (s, 1H), 6.86 (d, 2H), 4.46 (s, 2H), 4.05 (dd, 2H), 3.91
(s, 6H), 3.43 (dd, 2H).
[0613] MS (m/z): 349 [MH].sup.+.
Intermediate 101:
[0614] NMR (.sup.1H, DMSO): .delta. 8.55 (d, 1H), 7.19 (d, 1H),
6.88 (d, 1H), 6.83 (d, 1H), 6.78 (dd, 1H), 4.29 (s, 2H), 3.88 (dd,
2H), 3.70 (s, 3H), 3.69 (s, 3H), 3.28 (dd, 2H).
[0615] MS (m/z): 349 [MH].sup.+.
Intermediate 102
1-{[3,4-Bis(methyloxy)phenyl]methyl}-3-(4-bromo-2-pyrimidinyl)-2-imidazoli-
dinone
[0616] To a suspension of intermediate 100 (50 mg, 0.144 mmol) in
propionitrile (2 mL), at r.t., under N.sub.2, was added TMSBr (38
.mu.L, 2 eq). The reaction mixture was subjected to microwave
irradiation (2.times.10 min, T=100.degree. C.). 2N NaOH and EtOAc
were added to the reaction mixture and the two phases were
separated. The aqueous layer was further extracted with EtOAc
(3.times.10 mL) and the combined organic extracts were concentrated
in vacuo. The residue was purified on an SCX cartridge (100%
CH.sub.2Cl.sub.2.fwdarw.NH.sub.3 (0.5 in MeOH)) to give the title
compound as a white solid (43 mg, 76%).
[0617] NMR (.sup.1H, CDCl.sub.3): .delta. 8.27 (m, 2H), 6.81-6.83
(m, 3H), 4.24 (s, 2H), 4.01 (t, 2H), 3.88 (s, 3H), 3.87 (s, 3H),
3.40 (t, 2H).
[0618] MS (m/z): 393 [MH].sup.+.
Intermediate 103
1-{[3,4-Bis(methyloxy)phenyl]methyl}-3-(4-{6-methyl-1-[2-methyl-4-(methylo-
xy)phenyl]-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl}-2-pyrimidinyl)-2-imi-
dazolidinone
[0619] To a solution of intermediate 102 (43 mg, 0.112 mmol) and
intermediate 93 (50 mg, 1.5 eq) in a 1:1 mixture of EtOH/toluene (4
mL), at r.t., under N.sub.2, were added Pd(PPh.sub.3).sub.4 (13 mg,
0.1 eq), tetra-n-butylammonium bromide (4 mg, 0.1 eq) and 2N
Na.sub.2CO.sub.3 (1.6 ml, 28.5 eq). The reaction mixture was heated
at 100.degree. C. for 2 hr. It was cooled down to r.t. and poured
into water. EtOAc was added and the phases were separated. The
aqueous layer was further extracted with EtOAc (2.times.10 mL). The
combined organic extracts were dried over anh. Na.sub.2SO.sub.4,
the solids were filtered and the solvent evaporated. The residue
was purified by flash chromatography (silica gel, cHex/EtOAc 9:1)
to give the title compound as a yellow solid (71 mg,
quantitative).
[0620] NMR (.sup.1H, CDCl.sub.3): .delta. 8.61 (dd, 1H), 8.24 (dd,
1H), 7.18-7.26 (m, 4H), 6.76-6.85 (m, 3H), 4.46 (s, 2H), 4.13 (t,
2H), 3.80-3.88 (m, 11H), 3.59 (t, 2H), 3.44 (t, 2H), 2.38 (s, 3H),
2.25 (s, 3H).
[0621] MS (m/z): 567 [MH].sup.+.
Intermediate 104
1-{[3,4-Bis(methyloxy)phenyl]methyl}-3-(2-bromo-4-pyrimidinyl)-2-imidazoli-
dinone
[0622] To a suspension of intermediate 101 (188 mg, 0.54 mmol) in
propionitrile (2 mL), at r.t., under N.sub.2, was added TMSBr (143
.mu.L, 2 eq). The reaction mixture was subjected to microwave
irradiation (10 min, P=155 W, T=100.degree. C., p=60 psi). 2N NaOH
was added and the reaction mixture was concentrated in vacuo. The
residue was purified on a MEGA Bond Elut silica cartridge
(CH.sub.2Cl.sub.2/MeOH 95:5) to give the title compound as a yellow
solid (33 mg, 16%).
[0623] NMR (.sup.1H, DMSO-d.sub.6): .delta. 8.44 (d, 1H), 7.35 (d,
1H), 6.80-6.90 (m, 3H), 4.31 (s, 2H), 3.90 (t, 2H), 3.73 (s, 3H),
3.72 (s, 3H), 3.22-3.34 (m, 2H).
[0624] MS (m/z): 393 [MH].sup.+.
Intermediate 105
1-{[3,4-Bis(methyloxy)phenyl]methyl}-3-(2-{6-methyl-1-[2-methyl-4-(methylo-
xy)phenyl]-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl}-4-pyrimidinyl)-2-imi-
dazolidinone
[0625] To a solution of intermediate 104 (33 mg, 0.084 mmol) and
intermediate 93 (37 mg, 1.5 eq) in a 1:1 mixture of EtOH/toluene (3
mL) were added Pd(PPh.sub.3).sub.4 (10 mg, 0.1 eq),
tetra-n-butylammonium bromide (3 mg, 0.1 eq) and 2N
Na.sub.2CO.sub.3 (1.2 mL, 28.5 eq). The reaction mixture was heated
at 100.degree. C. for 2.5 hr. It was cooled down to r.t. and poured
into water. EtOAc was added and the phases were separated. The
aqueous layer was further extracted with EtOAc (2.times.10 mL). The
combined organic extracts were dried over anh. Na.sub.2SO.sub.4,
the solids were filtered and the solvent evaporated. The residue
was purified by flash chromatography (silica gel,
CH.sub.2Cl.sub.2/MeOH 95:5) and on a Strata NH.sub.2 deactivated
silica cartridge (cHex/EtOAc 1:0.fwdarw.cHex/EtOAc 0:1) to give 13
mg of the title compound still contaminated by unidentified
by-products. This crude mixture was used in the next step without
further purification.
[0626] NMR (.sup.1H, CDCl.sub.3): .delta. 8.73 (d, 1H), 7.43-7.69
(m, 4H), 7.17 (d, 1H), 6.75-6.92 (m, 2H), 6.70 (s, 1H), 4.47 (s,
2H), 4.06-4.15 (m, 2H), 3.80-3.91 (m, 8H), 3.80 (s, 3H), 3.55-3.63
(m, 2H), 3.40 (m, 2H), 2.35 (s, 3H), 2.24 (s, 3H).
[0627] MS (m/z): 567 [MH].sup.+.
Intermediate 106
1-{6-Methyl-1-[2-methyl-4-(methyloxy)phenyl]-2,3-dihydro-1H-pyrrolo[2,3-b]-
pyridin-4-yl}-1H-1,2,4-triazol-3-amine
[0628] A suspension of intermediate 5 (50 mg, 0.13 mmol),
1H-1,2,4-triazol-3-amine (22 mg, 2 eq), CuI (145 mg, 6 eq),
K.sub.2CO.sub.3 (37 mg, 2.1 eq) and
1-2-N,N'-dimethylcyclohexanediamine (106 mg, 6 eq) in anh. NMP (5
mL) at r.t., under N.sub.2, was subjected to microwave irradiation
(3.times.45 min, 150.degree. C.). Sat.aq. NaCl (15 mL) was then
added and the reaction mixture extracted with CH.sub.2Cl.sub.2
(2.times.15 mL). The combined organic extracts were dried over anh.
Na.sub.2SO.sub.4, the solids were filtered and the solvents
evaporated in vacuo The crude compound thus obtained was purified
on an SCX cartridge (cHex/EtOAc 1:1.fwdarw.EtOAc/MeOH 9:1) to give
the title compound as a white solid (20 mg, 46%).
[0629] NMR (.sup.1H, CDCl.sub.3): .delta. 8.7 (s, 1H), 7.2 (d, 1H),
6.8 (d, 1H), 6.7 (dd, 2H), 6.67 (s, 1H), 5.75 (bs, 2H), 3.75 (t,
2H), 3.7 (s, 3H), 3.4 (t, 2H), 2.2 (s, 3H), 2.2 (s, 3H).
[0630] MS (m/z): 337 [MH].sup.+.
Intermediate 107
N-(2-Chloroethyl)-N'-(1-{6-methyl-1-[2-methyl-4-(methyloxy)phenyl]-2,3-dih-
ydro-1H-pyrrolo[2,3-b]pyridin-4-yl}-1H-1,2,4-triazol-3-yl)urea
[0631] To a solution of intermediate 106 (20 mg, 0.06 mmol) in anh.
DMF (2 mL), at 0.degree. C., under N.sub.2, was added 3-chloroethyl
isocyanate (0.5 mL, excess) and the reaction mixture was stirred at
r.t. for 6 days. H.sub.2O (15 mL) was then added and the mixture
extracted with CH.sub.2Cl.sub.2 (2.times.15 mL). The combined
organic extracts were dried over anh. Na.sub.2SO.sub.4, the solids
were filtered and the solvents evaporated in vacuo. The crude
product was purified on a MEGA Bond Elut silica cartridge
(cHex/EtOAc 3:7.fwdarw.7:3) to give the title compound as a white
solid (30 mg, 100%).
[0632] MS (m/z): 442 [MH].sup.+.
Intermediate 108
1-{1-[2-Chloro-3-(2-hydroxypropyl)-6-methyl-4-pyridinyl]-1H-pyrazol-3-yl}--
3-{[4-(methyloxy)phenyl]methyl}-2-imidazolidinone
[0633] To a clear solution of intermediate 43 (160 mg, 0.36 mmol)
in anh THF (2 mL), cooled at 0.degree. C., was added 3.0 M
MeMgBr/Et.sub.2O (0.18 mL, 1.5 eq). The reaction mixture was
stirred at 0.degree. C. for 1 h and then slowly warmed to r.t.
After 1 h, the reaction was complete. EtOAc and sat.aq. NH.sub.4Cl
were added and the phases were separated. The organic layer was
washed with sat.aq. NaCl and dried over anh. Na.sub.2SO.sub.4, the
solids were filtered and the solvent evaporated. The crude product
was purified by flash chromatography (silica gel, EtOAc/cHex
1:1.fwdarw.6:4) to give the title compound as a white solid (138
mg, 84%).
[0634] NMR (.sup.1H, CDCl.sub.3): .delta. 7.85 (bs, 1H), 7.65 (d,
1H), 7.21 (d, 2H), 7.1 (d, 1H), 6.88 (d, 2H), 4.45 (q, 1H), 4.3 (m,
1H), 3.9 (t, 2H), 3.7 (s, 3H), 3.4 (t, 2H), 2.95 (d, 2H), 2.5 (s,
3H), 1.25 (d, 3H).
[0635] MS (m/z): 456 [MH].sup.+.
Intermediate 109
1-{1-[2-Chloro-3-(2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}propyl)-6-met-
hyl-4-pyridinyl]-1H-pyrazol-3-yl}-3-{[4-(methyloxy)phenyl]methyl}-2-imidaz-
olidinone
[0636] To a clear solution of intermediate 108 (135 mg, 0.3 mmol)
in anh CH.sub.2Cl.sub.2 (2 mL), at 0.degree. C., under N.sub.2,
were added 2,6-lutidine (77 .mu.L, 2.2 eq) and
tert-butyldimethylsilyl triflate (100 .mu.L, 1.5 eq). The reaction
mixture was stirred at r.t. for 4 hr. Sat.aq. NH.sub.4Cl was added,
the phases were separated and the organic layer was washed with
sat.aq. NaCl and dried over anh. Na.sub.2SO.sub.4. The solids were
filtered and the solvent evaporated. The crude product was purified
by flash chromatography (silica gel, EtOAc/cHex 1:1) to give the
title compound as a white solid (130 mg, 76%).
[0637] NMR (.sup.1H, CDCl.sub.3): .delta. 8.35 (bs, 1H), 7.19 (m,
3H), 7.00 (bs, 1H), 6.87 (d, 2H), 4.40 (s, 2H), 4.36 (m, 1H), 3.89
(m, 2H), 3.79 (s, 3H), 3.36 (t, 2H), 2.96 (m, 2H), 2.50 (s, 3H),
1.23 (d, 3H), 0.70 (s, 9H), -0.06 (s, 3H), -0.33 (s, 3H).
[0638] MS (m/z): 570 [MH].sup.+.
Intermediate 110
1-[1-(3-(2-{[(1,1-Dimethylethyl)(dimethyl)silyl]oxy}propyl)-6-methyl-2-{[2-
-methyl-4-(methyloxy)phenyl]amino}-4-pyridinyl)-1H-pyrazol-3-yl]-3-{[4-(me-
thyloxy)phenyl]methyl}-2-imidazolidinone
[0639] To a mixture of intermediate 109 (130 mg, 0.227 mmol),
Pd.sub.2(DBA).sub.3 (20.8 mg, 10% mol), K.sub.3PO.sub.4 (145 mg, 3
eq), 2-(Dicyclohexylphosphino)-2'-methylbiphenyl (24.8 mg, 30% mol)
and 4-methoxy-2-methylaniline (47 mg, 1.5 eq), at r.t., under
N.sub.2, was added anh. DME (2 mL). The reaction mixture was
stirred at 90.degree. C. for 3 hr. The mixture was cooled to r.t.
and more Pd.sub.2(DBA).sub.3 (20.8 mg, 10% mol) and
2-(Dicyclohexylphosphino)-2'-methylbiphenyl (24.8 mg, 30% mol) were
added. The reaction was heated at 90.degree. C. for an additional 2
hr and left overnight at r.t. After an addition of
Pd.sub.2(DBA).sub.3 (20.8 mg, 10% mol) and
2-(Dicyclohexylphosphino)-2'-methylbiphenyl (24.8 mg, 30% mol), the
reaction mixture was heated for an additional 2 hr at 90.degree. C.
Then it was cooled to r.t., treated with water and EtOAc, and the
phases were separated. The organic layer was dried over anh.
Na.sub.2SO.sub.4, the solids were filtered and the solvent
concentrated in vacuo. The crude product was purified by flash
chromatography (silica gel, cHex/EtOAc 8:2.fwdarw.7:3) to give the
title compound as a yellow oil (84 mg), still contaminated with the
unreacted aniline. The mixture was used in the next step without
further purification.
[0640] MS (m/z): 671 [MH].sup.+.
Intermediate 111
1-[1-(3-(2-Hydroxypropyl)-6-methyl-2-{[2-methyl-4-(methyloxy)phenyl]amino}-
-4-pyridinyl)-1H-pyrazol-3-yl]-3-{[4-(methyloxy)phenyl]methyl}-2-imidazoli-
dinone
[0641] To a solution of intermediate 110 (80 mg, 0.12 mmol) in anh.
THF (2.5 mL), at r.t., under N.sub.2, was added Et.sub.3N.3HF (156
.mu.L, 8 eq) and the reaction mixture was stirred at r.t. for 18
hr. EtOAc and water were added, the phases were separated and the
organic layer was dried over anh. Na.sub.2SO.sub.4. The solids were
filtered and the solvent evaporated. The crude product was purified
by flash chromatography (silica gel, cHex/EtOAc 1:1) to give the
title compound as a pale yellow solid (23 mg, 18%, two steps).
[0642] (.sup.1H CDCl.sub.3): .delta. 7.63 (d, 1H), 7.57 (d, 1H),
7.21 (d, 2H), 7.00 (d, 1H), 6.87 (d, 2H), 6.74 (s, 1H), 6.72 (m,
2H), 6.44 (s, 1H), 4.74 (m, 1H), 4.40 (s, 2H), 4.35 (m, 1H), 3.87
(m, 2H), 3.78 (s, 3H), 3.77 (s, 3H), 3.36 (t, 2H), 2.81 (d, 1H),
2.78 (d, 1H), 2.34 (s, 3H), 2.22 (s, 3H), 1.33 (d, 3H).
[0643] MS (m/z): 557 [MH].sup.+.
Intermediate 112
1-(1-{2,6-Dimethyl-1-[2-methyl-4-(methyloxy)phenyl]-2,3-dihydro-1H-pyrrolo-
[2,3-b]pyridin-4-yl}-1H-pyrazol-3-yl)-3-{[4-(methyloxy)phenyl]methyl}-2-im-
idazolidinone
[0644] To a clear solution of intermediate 111 (23 mg, 0.04 mmol)
in anh. CH.sub.2Cl.sub.2 (1 mL), at r.t., under N.sub.2, were added
Et.sub.3N (10 .mu.L, 2 eq), triphenylphosphine (21.7 mg, 2 eq) and
I.sub.2 (21 mg, 2 eq) and the reaction mixture was stirred at r.t.
for 2 hr. CH.sub.2Cl.sub.2 and water were added, the phases were
separated, the organic layer dried over anh. Na.sub.2SO.sub.4, the
solids were filtered and the solvent evaporated. The crude product
was purified by flash chromatography (cHex/EtOAc 1:1) to give the
title compound as white solid (10 mg, 46%).
[0645] NMR (.sup.1H, CDCl.sub.3): .delta. 7.80 (d, 1H), 7.21 (d,
2H), 7.09 (d, 1H), 6.99 (d, 1H), 6.88 (d, 2H), 6.81 (d, 1H), 6.76
(dd, 1H), 6.53 (s, 1H), 4.41 (s, 2H), 4.35 (m, 1H), 3.91 (t, 2H),
3.79 (s, 6H), 3.63 (dd, 1H), 3.42 (t, 2H), 2.96 (dd, 1H), 2.28 (s,
3H), 2.17 (s, 3H), 1.18 (d, 3H).
[0646] MS (m/z): 539 [MH].sup.+.
Intermediate 113
Methyl (4,6-dichloro-2-methyl-5-pyrimidinyl)acetate
[0647] Sodium (1.74 g, 3 eq) was added portionwise to anh. MeOH (60
mL), at 0.degree. C., under N.sub.2. After consumption of metallic
sodium, acetamidine hydrochloride (7.06 g, 3 eq) was added. After
20 min. of stirring the precipitated NaCl was filtered off. A
solution of 2-ethoxycarbonyl-succinic acid diethyl ester (6.04 g,
24.5 mmol) in anhydrous CH.sub.3OH (20 mL) was added to the
solution of free acetamidine and the mixture was stirred at r.t.
for 2 days. The reaction mixture was concentrated to dryness in
vacuo and the yellow foam (8.69 g) obtained was then mixed with
POCl.sub.3 (6 eq) and CH.sub.3CN (80 mL) and heated at reflux for
18 hours. The resulting solution was cooled to r.t. and poured
slowly into ice/water and conc. NH.sub.4OH with vigorous stirring.
The product was extracted with EtOAc (3.times.50 mL). The combined
organic extracts were washed with brine, dried over anh.
Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The crude oil
was purified by flash chromatography (silica gel, cHex/EtOAc 8:2).
The title compound was obtained as a yellow solid (98% in two
steps)
[0648] NMR (.sup.1H, CDCl.sub.3): .delta. 5.85 (m, 1H), 5.15 (dq,
1H), 5.11 (dq, 1H), 3.61 (dt, 2H), 2.67 (s, 3H).
[0649] MS (m/z): 202 [M].sup.+ (2C1).
Intermediate 114
2-(4,6-Dichloro-2-methyl-5-pyrimidinyl)ethanol
[0650] To a solution of intermediate 113 (4.0 g, 0.017 mol) in anh.
THF (60 mL), at -78.degree. C., under N.sub.2, was added DIBAI-H
1M/THF (52.5 mL, 3 eq) dropwise. After the addition was complete,
the reaction mixture was stirred at -30.degree. C. for 3 hr. A
Rochelle salt solution was then added at 0.degree. C. and the
phases were separated. The aqueous layer was extracted with EtOAc
(2.times.50 mL) and the combined organic extracts were dried over
anh. Na.sub.2SO.sub.4. The solids were filtered and the solvent
evaporated. The title compound was obtained as a clear oil (3.1 gr,
89%) and was used in the next step without further
purification.
[0651] NMR (.sup.1H, CDCl.sub.3): .delta. 4.90 (t, 2H), 3.15 (t,
2H), 2.64 (s, 3H), 1.70 (bs, 1H).
[0652] MS (m/z): 207 [MH].sup.+
Intermediate 115
4,6-Dichloro-5-(2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}ethyl)-2-methyl-
pyrimidine
[0653] To a solution of intermediate 114 (3.1 g, 0.015 mol) in anh.
DMF (100 mL), at 0.degree. C., under N.sub.2, were added imidazole
(17 g, 17 eq), t-butyldimethylsilyl chloride (6.35 gr, 2.8 eq) and
DMAP (catalytic amount). The solution was stirred at r.t. for 18
hr. EtOAc (100 mL) and sat.aq. NH.sub.4Cl (50 mL) were added and
the phases were separated. The organic layer was washed with
sat.aq. NaCl (2.times.100 mL) and dried over anh. Na.sub.2SO.sub.4.
The solids were filtered and the solvent evaporated. The crude
compound was purified by flash chromatography (silica gel,
cHex/EtOAc 9:1) to give the title compound as a clear oil (4.6 g,
95%).
[0654] NMR (.sup.1H, CDCl.sub.3): .delta. 3.86 (t, 2H), 3.12 (t,
2H), 2.66 (s, 3H), 0.85 (s, 9H), 0.01 (s, 6H).
[0655] MS (m/z): 321 [MH].sup.+
Intermediate 116
N-[2,4-Bis(trifluoromethyl)phenyl]-6-chloro-5-(2-{[(1,1-dimethylethyl)(dim-
ethyl)-silyl]oxy}ethyl)-2-methyl-4-pyrimidinamine
[0656] To a solution of 2,4-bis-trifluoromethyl-aniline (984 .mu.L,
1 eq) in anh. DMF (15 mL), at 0.degree. C., under N.sub.2, was
added NaH 80%/oil (400 mg, 2.2 eq). The reaction mixture was
stirred at 0.degree. C. for 30 min and was then added to a solution
of intermediate 115 (2 g, 6 mmol) in anh. DMF (15 mL) at r.t.,
under N.sub.2. The reaction mixture was stirred at r.t. for 30 min.
The excess NaH was carefully destroyed with sat.aq. NaCl and the
reaction mixture was diluted with EtOAc. The phases were separated,
the organic layer was washed with sat.aq. NaCl (2.times.30 mL) and
dried over anh. Na.sub.2SO.sub.4. The solids were filtered and the
solvent evaporated. The crude compound was purified by flash
chromatography (silica gel, cHex/EtOAc 95:5.fwdarw.90:10). The
title compound was obtained as a clear oil (1.84 g, 56%).
[0657] NMR (.sup.1H, CDCl.sub.3): .delta. 8.61 (d, 1H), 8.04 (bs,
1H), 7.86 (s, 1H), 7.79 (d, 1H), 4.95 (t, 2H), 3.95 (t, 2H), 2.53
(s, 3H), 0.73 (s, 9H), -0.90 (s, 6H).
[0658] MS (m/z): 514 [MH].sup.+
Intermediate 117
2-(4-{[2,4-Bis(trifluoromethyl)phenyl]amino}-6-chloro-2-methyl-5-pyrimidin-
yl)ethanol
[0659] To a solution of intermediate 116 (1.84 g, 3.58 mmol) in
anh. DMF (30 mL), at r.t., under N.sub.2, was added Et.sub.3N.3HF
(2.4 mL, 3 eq). The reaction mixture was stirred at r.t. for 18 hr.
It was then diluted with cold sat.aq. NaCl (50 mL) and extracted
with EtOAc (3.times.50 mL). The combined organic extracts were
dried over anh. Na.sub.2SO.sub.4. The solids were filtered and the
solvent evaporated. The title compound was obtained as a clear oil
(1.4 gr, 98%) and was used in the next step without further
purification.
[0660] NMR (.sup.1H, CDCl.sub.3): .delta. 8.59 (bs, 1H), 8.22 (d,
1H), 7.84 (s, 1H), 7.75 (d, 1H), 4.06 (t, 2H), 3.01 (t, 2H), 2.50
(s, 3H)
[0661] MS (m/z): 400 [MH].sup.+
Intermediate 118
7-[2,4-Bis(trifluoromethyl)phenyl]-4-chloro-2-methyl-6,7-dihydro-5H-pyrrol-
o[2,3-d]pyrimidine
[0662] To a solution of intermediate 117 (514 mg, 1.29 mmol) in
anh. CH.sub.2Cl.sub.2 (20 mL), at 0.degree. C., under N.sub.2, were
added Et.sub.3N (712 .mu.L, 4 eq) and methanesulfonyl chloride (197
.mu.L, 2 eq) and the reaction mixture was stirred at r.t. for 18
hr. Water (20 mL) was then added and the phases were separated. The
aqueous layer was extracted with CH.sub.2Cl.sub.2 (2.times.20 mL)
and the combined organic extracts were dried over anh.
Na.sub.2SO.sub.4. The solids were filtered and the solvent
evaporated. The crude product was purified by flash chromatography
(silica gel, cHex/EtOAc 8:2) to give the title compound as a white
solid (430 mg, 87%).
[0663] NMR (.sup.1H, CDCl.sub.3): .delta. 8.04 (s, 1H), 7.93 (s,
1H), 7.53 (d, 1H), 4.00 (t, 2H), 3.24 (t, 2H), 2.42 (s, 3H).
[0664] MS (m/z): 381 [MH].sup.+.
Intermediate 119
2-{4-Chloro-6-[(2,4-dichlorophenyl)amino]-2-methyl-5-pyrimidinyl}ethanol
[0665] Intermediate 114 (1.34 g, 6.47 mmol) and 2,4-dichloroaniline
(1.06 g, 1 eq) were heated in a sealed vial, at 100.degree. C.,
under N.sub.2, for 18 hr. A 1:1 mixture of H.sub.2O/MeOH was added
and a white precipitate was formed. The solids were filtered and
dried to give the title compound as a white solid (960 mg,
44%).
[0666] MS (m/z): 332 [M].sup.+.
Intermediate 120
4-Chloro-7-(2,4-dichlorophenyl)-2-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyri-
midine
[0667] To a solution of intermediate 119 (960 mg, 2.87 mmol) in
anh. CH.sub.2Cl.sub.2 (10 mL), at 0.degree. C., under N.sub.2, were
added Et.sub.3N (1.21 mL, 3 eq) and MsCl (0.5 ml, 2.3 eq). The
reaction mixture was kept at r.t. for 4 hr. Then Et.sub.3N (0.6 mL,
2 eq) was added and the mixture was refluxed for 3 hr. The reaction
mixture was diluted with CH.sub.2Cl.sub.2 and washed with 10% HCl
(15 mL). The organic phases were separated and washed with sat.aq.
NaCl. It was dried over anh. Na.sub.2SO.sub.4, the solids were
filtered and the solvent evaporated. The title compound was
obtained as a white solid (900 mg, quantitative yield) and was used
as such in the next step without further purification.
[0668] NMR (.sup.1H, CDCl.sub.3): .delta. 7.45 (d, 1H), 7.3 (d,
2H), 4.05 (t, 2H), 3.16 (t, 2H), 2.45 (s, 3H).
[0669] MS (m/z): 315 [MH].sup.+.
Intermediate 121
3-{6-Methyl-1-[2-methyl-4-(methyloxy)phenyl]-2,3-dihydro-1H-pyrrolo[2,3-b]-
pyridin-4-yl}aniline
[0670] A suspension of intermediate 5 (100 mg, 0.263 mmol),
3-aminophenylboronic acid (61 mg, 1.5 eq), Pd(PPh.sub.3).sub.4 (30
mg, 0.1 eq), TBAB (8 mg, 0.1 eq) and 2N Na.sub.2CO.sub.3 (3.7 ml,
28.5 eq), at r.t., under N.sub.2, in a 1:1 mixture of anh.
EtOH/Toluene (10 mL) was heated at 100.degree. C. for 2.5 h. It was
cooled down to r.t. and poured into water. EtOAc was added and the
phases were separated. The aqueous layer was further extracted with
EtOAc (2.times.10 mL). The combined organic extracts were dried
over anh. Na.sub.2SO.sub.4, the solids were filtered and the
solvent evaporated. The residue was purified on an SCX cartridge
(100% CH.sub.2Cl.sub.2.fwdarw.NH.sub.3 (0.5 in MeOH)) and on a MEGA
Bond Elut silica cartridge (CH.sub.2Cl.sub.2/MeOH 95:5) to give the
title compound as a white solid (91 mg, quantitative yield).
[0671] NMR (.sup.1H, DMSO-d.sub.6): .delta. 7.18 (d, 1H), 7.09 (t,
1H), 6.87 (d, 1H), 6.81 (dd, 1H), 6.76 (d, 1H), 6.69 (d, 2H), 6.61
(d, 2H), 6.41 (s, 1H), 5.18 (bs, 2H), 3.8 (m, 5H), 3.15 (t, 2H),
2.2 (s, 6H).
[0672] MS (m/z): 346 [MH].sup.+.
Intermediate 122
N-(2-Chloroethyl)-N'-(3-{6-methyl-1-[2-methyl-4-(methyloxy)phenyl]-2,3-dih-
ydro-1H-pyrrolo[2,3-b]pyridin-4-yl}phenyl)urea
[0673] To a solution of intermediate 121 (91 mg, 0.26 mmol) in anh.
THF (3 mL), at r.t., under N.sub.2, was added 2-chloroethyl
isocyanate (51 .mu.L, 2 eq). The reaction mixture was stirred at
r.t. for 2 hr. It was evaporated to dryness and the residue was
purified by flash chromatography (silica gel, cHex/EtOAc
7:3.fwdarw.EtOAc/Et.sub.3N 1:0.02) to give the title compound as a
white solid (113.4 mg, 97%).
[0674] NMR (.sup.1H, DMSO-d.sub.6): .delta. 8.76 (s, 1H), 7.69 (s,
1H), 7.28 (m, 2H), 7.14 (d, 1H), 7.05 (t, 1H), 8.23 (d, 1H), 6.74
(dd, 1H), 6.4 (m, 2H), 3.75 (m, 5H), 3.6 (m, 2H), 3.4 (m, 2H), 3.1
(t, 2H), 2.15 (s, 3H), 2.15 (s, 3H).
[0675] MS (m/z): 451 [MH].sup.+.
Intermediate 123
5-Methyl-1-{6-methyl-1-[2-methyl-4-(methyloxy)phenyl]-2,3-dihydro-1H-pyrro-
lo[2,3-b]pyridin-4-yl}-1H-pyrazol-3-amine
[0676] A solution of intermediate 5 (200 mg, 0.52 mmol),
5-methyl-3-aminopyrazole (200 mg, 2 eq), CuI (285 mg, 3 eq),
K.sub.2CO.sub.3 (150 mg, 2.1 eq),
N--N'-dimethyltranscyclohexandiamine (213 mg, 3 eq) in anh. NMP (1
mL), was heated at 150.degree. C. for 36 hr. H.sub.2O (50 mL) was
then added and the solution extracted with CH.sub.2Cl.sub.2
(3.times.25 mL). The organic layer was dried over anh.
Na.sub.2SO.sub.4, the solids were filtered and the solvents
evaporated in vacuo. The crude compound thus obtained was purified
by flash chromatography (silica gel, cHex/EtOAc 9:1.fwdarw.3:7) to
give the title compound as a white solid (60 mg, 33%).
[0677] NMR (.sup.1H, CDCl.sub.3): 7.15 (d, 1H); 6.85 (d, 1H); 6.75
(m, 1H); 6.45 (s, 1H); 5.48 (s, 1H); 4.74 (s, 2H); 3.71 (s, 3H);
3.23 (t, 2H); 3.12 (t, 2H); 2.20 (s, 3H), 2.11 (s, 6H) .delta..
[0678] MS (m/z): 350 [MH].sup.+.
Intermediate 124
N-(2-Chloroethyl)-N'-(1-{6-methyl-1-[2-methyl-4-(methyloxy)phenyl]-2,3-dih-
ydro-1H-pyrrolo[2,3-b]pyridin-4-yl}-1H-1,2,4-triazol-3-yl)urea
[0679] To a solution of intermediate 123 (60 mg, 0.17 mmol) in anh.
DMF (2 mL), at 0.degree. C., under N.sub.2, was added 2-chloroethyl
isocyanate (0.2 mL, excess) and the reaction mixture was stirred at
r.t. for 16 hr. H.sub.2O (10 mL) was then added and the solution
extracted with CH.sub.2Cl.sub.2 (2.times.10 mL). The combined
organic extracts was dried over anh. Na.sub.2SO.sub.4, the solids
were filtered and the solvents evaporated in vacuo. The crude
product was purified on an SCX cartridge (CH.sub.2Cl.sub.2, then
0.05 M NH.sub.3/MeOH) to give the title compound as a white solid
(30 mg, 40%).
[0680] MS (m/z): 455 [MH].sup.+.
Intermediate 125
1-Acetyl-3-[1-(1-[4-[(difluoromethyl)oxy]-2-methylphenyl]-6-methyl-2,3-dih-
ydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-3-yl]-2-imidazolidinone
[0681] To a solution of intermediate 29 (2.87 g, 4.63 mmols) in
anh. DMF (80 mL), under N.sub.2, at r.t., was added NaH 60%/oil
(0.240 g, 1.2 eq). The reaction mixture was stirred at r.t. for 10
min, then the flask was sealed with a rubber septum.
CF.sub.2Br.sub.2 (2.5 mL, 6 eq) was added and the mixture heated at
60.degree. C. for 3 hr. The mixture was cooled down to r.t.,
quenched with sat.aq. NaHCO.sub.3 and extracted with
CH.sub.2Cl.sub.2 (1.times.50 mL). The organic layer was washed with
sat.aq. NaCl and dried over anh. Na.sub.2SO.sub.4. The solids were
filtered and the solvent evaporated. The residue was purified by
flash chromatography twice (silica gel, 2.5% MeOH/CH.sub.2Cl.sub.2)
to give 554 mg of a crude compound still contaminated by side
products. It was re-purified by fraction lynx chromatography
(M+H=483) and the resulting fractions (174 mg), still contaminated,
were re-purified by flash chromatography (silica gel, 2%
MeOH/CH.sub.2Cl.sub.2) to give the title compound (76 mg, 3.4%) as
a white solid.
[0682] NMR (.sup.1H, CDCl.sub.3): .delta. 7.93 (d, 1H), 7.23 (dd,
1H), 7.1-7.0 (m, 3H), 6.63 (s, 1H), 6.54 (t, 1H), 4.07 (m, 4H),
4.03 (t, 2H), 3.53 (t, 2H), 2.63 (s, 3H), 2.40 (bs, 3H), 2.31 (s,
3H).
Example 1
Synthesis of Compounds of General Formula (II),
##STR00038##
[0683] in which [0684] Y is --CR.sub.7; [0685] W is a W2
derivative:
[0685] ##STR00039## [0686] Z is a pyrazolyl, phenyl, pyridyl,
pyrimidinyl, trazolyl, derivative and
[0686] ##STR00040## [0687] m is an integer from 0 to 2; [0688] q is
an integer from 0 to 4.
Example 1-1
1-{1-[1-(4-Methoxy-2-methylphenyl)-6-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]p-
yridin-4-yl]-1H-pyrazol-3-yl}imidazolidin-2-one
[0689] In a sealed vial, at r.t., under N.sub.2, are mixed together
intermediate 5 (60 mg, 0.158 mmol), CuI (6 mg, 0.2 eq) and
K.sub.2CO.sub.3 (4.5 mg, 2.5 eq). A solution of dodecane (14.3
.mu.L, 0.4 eq), trans-cyclohexanediamine (14 .mu.L, 0.6 eq) and
intermediate 8 (48 mg, 2 eq) in anh. NMP (5 mL) was added and the
reaction mixture was stirred at 130.degree. C. for 3.5 hr. It was
then cooled down to r.t. and poured in EtOAc/H.sub.2O. The phases
were separated and the aqueous layer was extracted with EtOAc
(2.times.10 mL). The combined organic extracts were dried over anh.
Na.sub.2SO.sub.4, the solids were filtered and the solvent
evaporated. The crude product was purified by flash chromatography
(EtOAc/cHex 6:4, then 1:1, then 3:7) followed by an SCX cartridge
(100% MeOH, then 2M NH.sub.3/MeOH) to give the title compound as a
white solid (34 mg, 53%).
[0690] Alternatively, to a suspension of CuI (8 mg, 0.02 eq) in
anh. DMF (1.8 mL), at r.t., under N.sub.2, was added
(1R,2R)--N,N'-dimethyl-1,2-cyclohexanediamine (90 mg, 0.3 eq) and
the blue solution obtained stirred at r.t. for 1.5 hr. Intermediate
8 (0.80 g, 2.5 eq) and K.sub.2CO.sub.3 (0.87 g, 3.0 eq) were added
followed by intermediate 92 (0.7 g, 21 mmol) in anh. DMF (1.8 mL).
The resulting mixture was heated at 125.degree. C. for 30 hr. The
mixture was cooled at 60.degree. C. and water (10 mL) was added
dropwise. The suspension was stirred at room temperature for 1 hr
and the white precipitate was filtered and washed once with a 1:2
mixture of DMF/water (10 mL), then twice with water (10 mL). The
collected solid was dried at 80.degree. C. for 24 hr. The crude
solid thus obtained was dissolved at r.t. in a 9:1 mixture of
CH.sub.2Cl.sub.2/MeOH (10 mL). The solution was filtered through a
carbon pad and the cake washed with the same solvent (10 mL).
Heptane (20 mL) was added dropwise at r.t., the resulting
suspension was left standing for 2 hr, filtered and washed with
MeOH. The collected solid was dried at 80.degree. C. for 24 hr to
obtain the title compound (410 mg, 48%) as a white solid.
Example 1-2
1-{1-[1-(4-Methoxy-2-methylphenyl)-6-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]p-
yridin-4-yl]-1H-pyrazol-3-yl}-3-methylimidazolidin-2-one
[0691] To a solution of example 1 (20 mg, 0.05 mmol) in anh. THF (1
mL), at r.t., under N.sub.2, was added KOt-Bu (5 mg, 1 eq) and the
reaction mixture was stirred for 15 min. Methyl iodide (6 .mu.L, 2
eq) was then added and the reaction mixture was stirred at r.t. for
3 hr. It was then poured into EtOAc/H.sub.2O and the phases were
separated. The aqueous layer was extracted with EtOAc (2.times.20
mL) and the combined organic extracts were dried over anh.
Na.sub.2SO.sub.4. The solids were filtered and the solvent
evaporated. The crude product was purified by flash chromatography
(silica gel, cHex/EtOAc 1:1) to give the title compound as a yellow
solid (6 mg, 29%).
Example 1-3
1-{1-[1-(2,4-Dichlorophenyl)-6-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-
-4-yl]-1H-pyrazol-3-yl}imidazolidin-2-one
[0692] To a solution of intermediate 37 (25 mg, 0.062 mmol) and
1-(1H-pyrazol-3-yl)-2-imidazolidinone (18.8 mg, 2 eq) in anh. NMP
(2 mL), at r.t., under N.sub.2, were added K.sub.2CO.sub.3 (26 mg,
3 eq), CuI (1.2 mg, 0.1 eq) and (1R,2R)-diaminoethylcyclohexane
(2.9 mg, 0.3 eq) and the reaction mixture was stirred at
100.degree. C. for 1 hr, at 120.degree. C. for 1 hr, at 150.degree.
C. for 1 hr and at 180.degree. C. for 2 hr. The reaction mixture
was then cooled to r.t., then partitioned between EtOAc/sat.aq.
NaCl (100 mL/50 mL). The phases were separated and the organic
layer was dried over anh. Na.sub.2SO.sub.4, the solids were
filtered, the solvent evaporated and the crude product was purified
by flash chromatography (silica gel, cHex/EtOAc 2:8) to give the
title compound as a white solid (2 mg, 7%).
Example 1-4
1-(1-{1-[2,4-Bis(trifluoromethyl)phenyl]-6-methyl-2,3-dihydro-1H-pyrrolo[2-
,3-b]pyridin-4-yl}-1H-pyrazol-3-yl)-2-imidazolidinone
[0693] To a solution of intermediate 81 (120 mg, 0.19 mmol) in TFA
(12 mL), at r.t., under N.sub.2, was added anisole (61 .mu.L, 3 eq)
and the reaction mixture was stirred at 80.degree. C. for 2 hr. The
solution was concentrated in vacuo. The residue was diluted with
CH.sub.2Cl.sub.2 and washed with sat.aq. NaHCO.sub.3. The organic
layer was dried over anh. Na.sub.2SO.sub.4, the solids were
filtered and the solvent evaporated. The crude product was purified
by flash chromatography
(CH.sub.2Cl.sub.2.fwdarw.CH.sub.2Cl.sub.2/MeOH 95:5) to give the
title compound as a white solid (80 mg, 84%).
Example 1-5
1-{1-[1-(4-Hydroxy-2-methylphenyl)-6-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]p-
yridin-4-yl]-1H-pyrazol-3-yl}-2-imidazolidinone
[0694] To a solution of example 1 (131 mg, 0.324 mmol) in anh.
CH.sub.2Cl.sub.2 (6.5 mL), at 0.degree. C., under N.sub.2, was
added BBr.sub.3 1M/CH.sub.2Cl.sub.2 (1.6 mL, 5 eq) and the reaction
mixture was stirred at 0.degree. C. for 3 hr. MeOH (5 mL) was
slowly added and the solvents were evaporated. The residue was
taken up in CH.sub.2Cl.sub.2 and the organic layer was washed with
sat.aq. NaHCO.sub.3 (2.times.20 mL) and dried over anh.
Na.sub.2SO.sub.4. The solids were filtered and the solvent
evaporated. The crude compound was purified by flash chromatography
(silica gel, 100% EtOAc.fwdarw.5% MeOH/EtOAc) to give the title
compound as a yellow solid (65 mg, 51%).
Example 1-6
1-Acetyl-3-(1-{6-methyl-1-[2-methyl-4-(methyloxy)phenyl]-2,3-dihydro-1H-py-
rrolo[2,3-b]pyridin-4-yl}-1H-pyrazol-3-yl)-2-imidazolidinone
[0695] To a solution of example 1 (205 mg, 0.507 mmol) in anh. DMF
(10 mL), at r.t., under N.sub.2, was added NaH 60%/oil (24 mg, 1.2
eq). The reaction mixture was stirred at r.t. for 20 min. It was
then cooled to 0.degree. C. and acetyl chloride (72 .mu.L, 2 eq)
was added slowly. The reaction mixture was stirred at 0.degree. C.
for 15 min (a white precipitate formed) and at r.t. for 30 min. It
was then poured into EtOAc/sat.aq. NaCl and the phases were
separated. The organic layer was washed with sat.aq. NaCl
(2.times.20 mL) and the combined aqueous phases extracted back with
CH.sub.2Cl.sub.2 (2.times.20 mL). The combined organic extracts
were dried over anh. Na.sub.2SO.sub.4, the solids were filtered and
the solvent evaporated. The crude compound was purified by flash
chromatography (silica gel, 2.5% MeOH/CH.sub.2Cl.sub.2). The title
compound was obtained as a yellow solid (190 mg, 84%)
Example 1-7
1-(1-{1-[4-(Ethyloxy)-2-methylphenyl]-6-methyl-2,3-dihydro-1H-pyrrolo[2,3--
b]pyridin-4-yl}-1H-pyrazol-3-yl)-2-imidazolidinone
[0696] To a solution of intermediate 30 (5 mg, 0.011 mmol) in an
anh. 3:1 mixture of MeOH/CH.sub.2Cl.sub.2 (1 mL), at r.t., under
N.sub.2, was added Cs.sub.2CO.sub.3 (18 mg, 5 eq) and the reaction
mixture was stirred at r.t. for 1 hr. The solvent was evaporated
and the residue purified by flash chromatography (MEGA-BondElut,
500 mg, cHex/EtOAc 1:1) to give the title compound (2.3 mg, 50%) as
a white solid.
Example 1-8
1-[1-(6-Methyl-1-{2-methyl-4-[(1-methylethyl)oxy]phenyl}-2,3-dihydro-1H-py-
rrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-3-yl]-2-imidazolidinone
[0697] To a solution of intermediate 31 (11 mg, 0.023 mmol) in an
anh. 3:1 mixture of MeOH/CH.sub.2Cl.sub.2 (1 mL), at r.t., under
N.sub.2, was added Cs.sub.2CO.sub.3 (38 mg, 5 eq) and the reaction
mixture was stirred at r.t. for 2 hr. The solvent was evaporated
and the residue purified by flash chromatography (MEGA-BondElut, 1
gr, cHex/EtOAc 1:1) to give the title compound (2.1 mg, 21%) as a
white solid.
Example 1-9
1-[1-(6-Methyl-1-{2-methyl-4-[(trifluoromethyl)oxy]phenyl}-2,3-dihydro-1H--
pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-3-yl]-2-imidazolidinone
[0698] To a solution of intermediate 48 (140 mg, 0.242 mmol) in TFA
(3.0 mL), under N.sub.2, was added anisole (263 .mu.L, 10 eq) and
the reaction mixture was stirred and heated at 80.degree. C. for 2
hr. It was then cooled down to r.t., TFA was evaporated and the
reaction mixture was partitioned between CH.sub.2Cl.sub.2/sat.aq.
NaHCO.sub.3. The phases were separated and the organic layer was
washed with sat. aq. NaCl (2.times.10 mL). It was dried over anh.
Na.sub.2SO.sub.4, the solids were filtered and the solvent
evaporated. The crude product was purified by flash chromatography
(silica gel, CH.sub.2Cl.sub.2/MeOH 95:5) to give the title compound
as a white solid (110 mg, 99%).
Example 1-10
3-Methyl-4-{6-methyl-4-[3-(2-oxo-1-imidazolidinyl)-1H-pyrazol-1-yl]-2,3-di-
hydro-1H-pyrrolo[2,3-b]pyridin-1-yl}benzonitrile
[0699] To a solution of intermediate 51 (120 mg, 0.23 mmol) in TFA
(15 mL), at r.t., under N.sub.2, was added anisole (75 .mu.L, 3 eq)
and the reaction mixture was stirred at 80.degree. C. for 1.5 hr.
The solution was concentrated in vacuo. The residue was diluted
with CH.sub.2Cl.sub.2 and washed with a sat.aq. NaHCO.sub.3. The
organic layer was dried over anh. Na.sub.2SO.sub.4, the solids were
filtered and the solvent evaporated. The crude product was purified
on an SCX cartridge (CH.sub.2Cl.sub.2.fwdarw.CH.sub.2Cl.sub.2/MeOH
95:5) to give the title compound as a white solid (58 mg, 63%).
Example 1-11
1-(1-{6-Methyl-1-[2-methyl-4-(1H-pyrazol-1-yl)phenyl]-2,3-dihydro-1H-pyrro-
lo[2,3-b]pyridin-4-yl}-1H-pyrazol-3-yl)-2-imidazolidinone
[0700] To a solution of intermediate 54 (95 mg, 0.169 mmol) in TFA
(2.0 mL), under N.sub.2, was added anisole (184 .mu.L, 10 eq) and
the reaction mixture was stirred and heated at 80.degree. C. for 2
hr. It was then cooled down to r.t., TFA was evaporated and the
reaction mixture was partitioned between CH.sub.2Cl.sub.2/sat.aq.
NaHCO.sub.3. The phases were separated and the organic layer was
washed with sat.aq. NaCl (2.times.10 mL). It was dried over anh.
Na.sub.2SO.sub.4, the solids were filtered and the solvent
evaporated. The crude product was purified by flash chromatography
(silica gel, CH.sub.2Cl.sub.2/MeOH 95:5) to give the title compound
as a white solid (77 mg, 99%).
Example 1-12
4-{6-Methyl-4-[3-(2-oxo-1-imidazolidinyl)-1H-pyrazol-1-yl]-2,3-dihydro-1H--
pyrrolo[2,3-b]pyridin-1-yl}-3-(trifluoromethyl)benzonitrile
[0701] To a solution of intermediate 57 (70 mg, 0.122 mmol) in TFA
(2.0 mL), under N.sub.2, was added anisole (133 .mu.L, 10 eq) and
the reaction mixture was stirred and heated at 80.degree. C. for 2
hr. It was then cooled down to r.t., TFA was evaporated and the
crude product was directly purified on an SCX cartridge (100%
CH.sub.2Cl.sub.2.fwdarw.CH.sub.2Cl.sub.2/MeOH and then 2.0M
Et.sub.3N/MeOH) to give the title compound as a white solid (55 mg,
99%).
Example 1-13
1-(1-{1-[2-(Difluoromethyl)-4-(methyloxy)phenyl]-6-methyl-2,3-dihydro-1H-p-
yrrolo[2,3-b]pyridin-4-yl}-1H-pyrazol-3-yl)-2-imidazolidinone
[0702] To a solution of intermediate 60 (19.6 mg, 0.035 mmol) in
TFA (4 mL), at r.t., under N.sub.2, was added anisole (12 .mu.L,
0.003 eq). The reaction mixture was stirred for 2 hr. Sat.aq.
NaHCO.sub.3 was added until neutral pH and the mixture was
evaporated to dryness. The residue was purified on an SCX cartridge
(0.5M NH.sub.3/MeOH) to give the title compound as a white foam
(7.2 mg, 47%).
Example 1-14
4-{6-Methyl-4-[3-(2-oxo-1-imidazolidinyl)-1H-pyrazol-1-yl]-2,3-dihydro-1H--
pyrrolo[2,3-b]pyridin-1-yl}-3-[(trifluoromethyl)oxy]benzonitrile
[0703] To a solution of intermediate 63 (115 mg, 0.19 mmol) in TFA
(12 mL), at r.t., under N.sub.2, was added anisole (61 .mu.L, 3 eq)
and the reaction mixture was stirred at 80.degree. C. for 1.5 hr.
The solution was concentrated in vacuo. The residue was diluted
with CH.sub.2Cl.sub.2 and washed with sat.aq. NaHCO.sub.3. The
organic layer was dried over anh. Na.sub.2SO.sub.4, the solids were
filtered and the solvent evaporated. The crude product was purified
on an SCX cartridge (CH.sub.2Cl.sub.2.fwdarw.CH.sub.2Cl.sub.2/MeOH
95:5) to give the title compound as a white solid (52.9 mg,
59%).
Example 1-15
3-Ethyl-4-{6-methyl-4-[3-(2-oxo-1-imidazolidinyl)-1H-pyrazol-1-yl]-2,3-dih-
ydro-1H-pyrrolo[2,3-b]pyridin-1-yl}benzonitrile
[0704] To a solution of intermediate 66 (70 mg, 0.13 mmol) in TFA
(9 mL), at r.t., under N.sub.2, was added anisole (42 .mu.L, 3 eq)
and the reaction mixture was stirred at 80.degree. C. for 1 hr. The
solution was concentrated in vacuo. The residue was diluted with
CH.sub.2Cl.sub.2 and washed with sat.aq.NaHCO.sub.3. The organic
layer was dried over anh. Na.sub.2SO.sub.4, the solids were
filtered and the solvent evaporated. The crude product was purified
on an SCX cartridge (100%
CH.sub.2Cl.sub.2.fwdarw.CH.sub.2Cl.sub.2/MeOH 95:5) to give the
title compound as a white solid (29 mg, 54%).
Example 1-16
1-(1-{6-Methyl-1-[2-(methyloxy)-4-(1H-pyrazol-1-yl)phenyl]-2,3-dihydro-1H--
pyrrolo[2,3-b]pyridin-4-yl}-1H-pyrazol-3-yl)-2-imidazolidinone
[0705] To a solution of intermediate 69 (72 mg, 0.12 mmol) in TFA
(7.5 mL), at r.t., under N.sub.2, was added anisole (41 .mu.L, 3
eq) and the reaction mixture was stirred at 80.degree. C. for 1.5
hr. The solution was concentrated in vacuo. The residue was diluted
with CH.sub.2Cl.sub.2 and washed with sat.aq. NaHCO.sub.3. The
organic layer was dried over anh. Na.sub.2SO.sub.4, the solids were
filtered and the solvent evaporated. The crude product was purified
on an SCX cartridge (CH.sub.2Cl.sub.2/0.5M NH3/MeOH 95:5) to give
the title compound as a white solid (35 mg, 64%).
Example 1-17
1-{1-[6-Methyl-1-(6-methyl-1,3-benzodioxol-5-yl)-2,3-dihydro-1H-pyrrolo[2,-
3-b]pyridin-4-yl]-1H-pyrazol-3-yl}-2-imidazolidinone
[0706] To a solution of intermediate 72 (41 mg, 0.076 mmol) in TFA
(4.7 mL), at r.t., under N.sub.2, was added anisole (25 .mu.L, 3
eq) and the reaction mixture was stirred at 80.degree. C. for 1.5
hr. The solution was concentrated in vacuo. The residue was diluted
with CH.sub.2Cl.sub.2 and washed with sat.aq. NaHCO.sub.3. The
organic layer was dried over anh. Na.sub.2SO.sub.4, the solids were
filtered and the solvent evaporated. The crude product was purified
on an SCX cartridge (100%
CH.sub.2Cl.sub.2.fwdarw.CH.sub.2Cl.sub.2/MeOH 98:2) to give the
title compound as a white solid (25 mg, 79%).
Example 1-18
1-(1-{6-Methyl-1-[2,4,6-tris(methyloxy)phenyl]-2,3-dihydro-1H-pyrrolo[2,3--
b]pyridin-4-yl}-1H-pyrazol-3-yl)-2-imidazolidinone
[0707] To intermediate 75 (16 mg, 0.028 mmol) were added TFA (1 mL)
and anisole (10 .mu.L, 3 eq). The reaction mixture was stirred at
r.t. for 3 hr, and the solvent was evaporated under reduced
pressure. The crude mixture was partitioned between
CH.sub.2Cl.sub.2/sat.aq. NaHCO.sub.3. The phases were separated and
the organic layer was dried over anh. Na.sub.2SO.sub.4, the solids
were filtered and the solvent evaporated. The crude product was
purified by flash chromatography (silica gel, 100%
CH.sub.2Cl.sub.2.fwdarw.CH.sub.2Cl.sub.2/MeOH 97:3) followed by a
further purification on an SCX SPE cartridge (100% CH.sub.2Cl.sub.2
to CH.sub.2Cl.sub.2/MeOH/2M NH.sub.3 in MeOH 80:19:1) to give the
title compound as a white solid (9.5 mg, 71%).
Example 1-19
1-{1-[6-Methyl-1-(6-methyl-1,3-benzodioxol-5-yl)-2,3-dihydro-1H-pyrrolo[2,-
3-b]pyridin-4-yl]-1H-pyrazol-3-yl}-2-imidazolidinone
[0708] To a solution of intermediate 78 (20 mg, 0.037 mmol) in TFA
(2.3 mL), at r.t., under N.sub.2, was added anisole (12 .mu.L, 3
eq.) and the reaction mixture was stirred at 80.degree. C. for 2
hr. The solution was concentrated in vacuo. The residue was diluted
with CH.sub.2Cl.sub.2 and washed with sat.aq. NaHCO.sub.3. The
organic layer was dried over anh. Na.sub.2SO.sub.4, the solids were
filtered and the solvent evaporated. The crude product was purified
on an SCX cartridge (CH.sub.2Cl.sub.2.fwdarw.CH.sub.2Cl.sub.2/MeOH
98:2) to give the title compound as a white solid (12.4 mg,
76%).
Example 1-20
1-(6-{6-Methyl-1-[2-methyl-4-(methyloxy)phenyl]-2,3-dihydro-1H-pyrrolo[2,3-
-b]pyridin-4-yl}-2-pyridinyl)-2-imidazolidinone
[0709] To a solution of intermediate 97 (30 mg, 1 eq) in TFA (0.75
ml), at r.t., under N.sub.2, were added Anisole (18.3 .mu.L, 3 eq)
and a drop of H.sub.2SO.sub.4. The reaction mixture was refluxed
for 3 h. It was concentrated and then partitioned between EtOAc and
NaHCO.sub.3ss. The phases were separated and the organic layer was
washed with sat.aq. NaCl. It was dried over anh. Na2SO4, the solids
were filtered and the solvent evaporated. The compound was obtained
as a white solid (22 mg, 98%).
Example 1-21
1-(4-{6-Methyl-1-[2-methyl-4-(methyloxy)phenyl]-2,3-dihydro-1H-pyrrolo[2,3-
-b]pyridin-4-yl}-2-pyrimidinyl)-2-imidazolidinone
[0710] To a solution of intermediate 103 (71 mg, 0.125 mmol) in TFA
(1 mL), at r.t., under N.sub.2, was added anisole (50 .mu.L, 3.7
eq). The reaction mixture was refluxed for 3 hr. No traces of the
desired product were detected by MS analysis. To the cooled
reaction mixture was added conc. H.sub.2SO.sub.4 (2 drops). The
reaction mixture was refluxed for 75 min, cooled down to r.t. and
neutralized with solid Na.sub.2CO.sub.3. The solvents were
evaporated and the residue was purified on a MEGA Bond Elut silica
cartridge (CH.sub.2Cl.sub.2/Et.sub.2O/EtOAc
1:1:2.fwdarw.CH.sub.2Cl.sub.2/MeOH/Et.sub.3N 1:1:0.02) to give the
title compound as a yellow solid (24.2 mg, 47%).
Example 1-22
1-(2-{6-Methyl-1-[2-methyl-4-(methyloxy)phenyl]-2,3-dihydro-1H-pyrrolo[2,3-
-b]pyridin-4-yl}-4-pyrimidinyl)-2-imidazolidinone
[0711] To a solution of intermediate 105 (13 mg, 0.023 mmol) in TFA
(1 mL), at r.t., under N.sub.2, was added anisole (10 .mu.L, 4 eq)
and conc. H.sub.2SO.sub.4 (2 drops). The reaction mixture was
refluxed for 2 hr and neutralized with solid NaHCO.sub.3. The
reaction mixture was partitioned between EtOAc and water. The
aqueous layer was further extracted with EtOAc (3.times.10 mL) and
the combined organic extracts were concentrated in vacuo. The
residue was purified by flash chromatography (silica gel, 100%
CH.sub.2Cl.sub.2.fwdarw.CH.sub.2Cl.sub.2/MeOH 95:5) and on an SCX
cartridge (100% CH.sub.2Cl.sub.2.fwdarw.NH.sub.3 (0.5 in MeOH)) to
give the title compound as a white solid (2.8 mg, 10%, 2
steps).
Example 1-23
1-(1-{6-Methyl-1-[2-methyl-4-(methyloxy)phenyl]-2,3-dihydro-1H-pyrrolo[2,3-
-b]pyridin-4-yl}-1H-pyrazol-3-yl)-2-imidazolidinone
[0712] To a solution of intermediate 107 (30 mg, 0.06 mmol) in anh.
THF (2 mL), at r.t., under N.sub.2, was added KOt-Bu (9 mg, 1.2 eq)
and the reaction mixture was stirred for 1 hr. Water (0.5 mL) was
added and the solvent was evaporated. The aqueous phase was diluted
with H.sub.2O and extracted with CH.sub.2Cl.sub.2 (3.times.20 mL).
The combined organic extracts were dried over anh.
Na.sub.2SO.sub.4. The solids were filtered and the solvent
evaporated. The crude product was purified on a MEGA Bond Elut
silica cartridge (100% EtOAc.fwdarw.EtOAc/MeOH 9:1) to give the
title compound as a white solid (6 mg, 25%).
Example 1-24
1-(1-{2,6-Dimethyl-1-[2-methyl-4-(methyloxy)phenyl]-2,3-dihydro-1H-pyrrolo-
[2,3-b]pyridin-4-yl}-1H-pyrazol-3-yl)-2-imidazolidinone
[0713] To a solution of intermediate 112 (10 mg, 0.018 mmol) in TFA
(1.1 mL), at r.t., under N.sub.2, was added anisole (10 .mu.L, 5
eq) and the reaction mixture was stirred at 80.degree. C. for 1.5
hr. The solution was then concentrated in vacuo. The residue was
diluted with CH.sub.2Cl.sub.2, washed with sat.aq. NaHCO.sub.3 and
the phases were separated. The organic layer was dried over anh.
Na.sub.2SO.sub.4, the solids were filtered and the solvent
evaporated. The crude product was purified on a MEGA Bond Elut
silica cartridge (100%
CH.sub.2Cl.sub.2.fwdarw.CH.sub.2Cl.sub.2/MeOH 98:2) to give the
title compound (racemate) as a white solid (6 mg, 80%).
Example 1-25
1-(3-{6-Methyl-1-[2-methyl-4-(methyloxy)phenyl]-2,3-dihydro-1H-pyrrolo[2,3-
-b]pyridin-4-yl}phenyl)-2-imidazolidinone
[0714] To a suspension of intermediate 122 (60 mg, 0.13 mmol) in
anh. THF (3 mL), at r.t., under N.sub.2, was added t-BuOK (18 mg,
1.2 eq). The reaction mixture was stirred at r.t. for 3 hr. Sat.aq.
NH.sub.4Cl and EtOAc were added and the phases were separated. The
aqueous layer was further extracted with EtOAc (2.times.10 mL). The
combined organic extracts were dried over anh. Na.sub.2SO.sub.4,
the solids were filtered and the solvent evaporated. The residue
was purified by flash chromatography (silica gel, cHex/EtOAc
8:2.fwdarw.100% EtOAc) to give the desired compound still
contaminated with aliphatic impurities. This crude product was
further purified by preparative HPLC (Column: X Terra MS C18 5 mm,
30.times.75 mm, Mobile phase: A: H2O+0.1% TFA, B: CH3CN+0.1% TFA,
Gradient: 10% (B) for 1 min, from 10% (B) to 90% (B) in 12 min,
Flow rate (ml/min):43, UV wavelength range (nm):200-400 Mass range
(amu):100-900, Ionization: ES+) to give the title compound as a
white solid (31.3 mg, 58%).
Example 1-26
1-(5-Methyl-1-{6-methyl-1-[2-methyl-4-(methyloxy)phenyl]-2,3-dihydro-1H-py-
rrolo[2,3-b]pyridin-4-yl}-1H-pyrazol-3-yl)-2-imidazolidinone
[0715] To a solution of intermediate 124 (35 mg, 0.072 mmol) in
anh. THF (2 mL), at r.t., under N.sub.2, was added t-BuOK (9.8 mg,
1.2 eq) and the reaction mixture was stirred at r.t. for 18 hr.
Water (0.5 mL) was added and the solvent was evaporated. The
aqueous phase was diluted with H.sub.2O and extracted with
CH.sub.2Cl.sub.2 (3.times.10 mL). The combined organic extracts
were dried over anh. Na.sub.2SO.sub.4. The solids were filtered and
the solvent evaporated. The crude product was purified on a MEGA
Bond Elut silica cartridge (EtOAc/cHex 2:8.fwdarw.3:7) to give the
title compound as a white solid (12 mg, 39%).
Example 1-27
1-[1-(1-{4-[(difluoromethyl)oxy}-2-methylphenyl]-6-methyl-2,3-dihydro-1H-p-
yrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-3-yl]-2-imidazolidinone
[0716] To a suspension of intermediate 125 (76 mg, 0.156 mmol) in a
3:1 mixture of MeOH/CH.sub.2Cl.sub.2 (10 mL), at r.t., was added
Cs.sub.2CO.sub.3 (0.257 g, 5 eq). The mixture was stirred at r.t.
for 1 hr. The solvent was evaporated and the residue purified by
flash chromatography (silica gel, 2% MeOH/CH.sub.2Cl.sub.2) to give
the title compound (45 mg, 71%) as white solid.
[0717] All the analytical data are set forth in the following Table
1-1 and in which:
R.sub.1 is --CH.sub.3;
[0718] R.sub.5 is hydrogen; R.sub.6 is hydrogen, R.sub.7 is
hydrogen; D corresponds to --CR.sub.8R.sub.9; G corresponds to
--CR.sub.10R.sub.11; R.sub.8, R.sub.9, R.sub.10, R.sub.11 are all
hydrogen, except for example 1-24 where R.sub.10 is a methyl
group.
TABLE-US-00001 Cpd. No. R R.sub.12 Z Analytical Data 1-1
2-methyl-4-methoxy- phenyl H ##STR00041## NMR (.sup.1H,
CDCl.sub.3): .delta. 8.29 (d. 1H), 7.15 (d, 1H), 7.04 (s, 1H), 6.85
(d, 1H), 6.79-6.74 (m, 3H), 3.91 (t, 2H), 3.82 (t, 2H), 3.75 (s,
3H), 3.44 (t, 4H), 2.17 (s, 3H), 2.15 (s, 3H) Structure confirmed
by NOE experiment MS (m/z): 405 [MH].sup.+ 1-2 2-methyl-4-methoxy-
phenyl CH.sub.3 ##STR00042## NMR (.sup.1H, CDCl.sub.3): .delta.
7.76 (d, 1H), 7.15 (d, 1H), 6.93 (d, 1H), 6.77 (d, 1H), 6.75 (dd,
1H), 6.52 (s, 1H), 3.96 (t, 2H), 3.84 (t, 2H), 3.77 (s, 3H), 3.50
(t, 2H), 3.42 (t, 2H), 3.89 (s, 3H), 2.28 (s, 3H), 2.20 (s, 3H) MS
(m/z): 419 [MH].sup.+ 1-3 2,4-dichloro-phenyl H ##STR00043## NMR
(.sup.1H, CDCl.sub.3): .delta. 7.82.delta. (s, 1H), 7.44 (s, 1H),
7.42 (s, 1H), 7.26 (s, 1H), 6.95 (s, 1H), 6.66 (s, 1H), 4.57 (bs,
1H), 4.09 (t, 1H), 3.96 (t, 1H), 3.61 (t, 1H), 3.48 (t, 1H), 2.34
(s, 3H). Structure confirmed by NOE experiment MS (m/z): 429
[M].sup.+ 1-4 2,4-bis-trifluoromethyl- phenyl H ##STR00044## NMR
(.sup.1H, CDCl.sub.3): .delta. 7.96 (s, 1H), 7.83 (d, 1H), 7.80
(bs, 1H), 7.61 (d, 1H), 6.97 (d, 1H), 6.70 (s, 1H), 4.66 (bs, 1H),
4.08 (t, 2H), 3.91 (t, 2H), 3.61 (t, 2H), 3.50 (t, 2H), 2.31 (s,
3H). MS (m/z): 497 [MH].sup.+ 1-5 2-methyl-4-hydroxy- phenyl H
##STR00045## NMR (.sup.1H, DMSO-d.sub.6): .delta. 9.31 (bs, 1H),
8.31 (d, 1H), 7.07 (bs, 1H), 7.04 (d, 1H), 6.78 (d, 1H), 6.75 (s,
1H), 6.68 (d, 1H), 6.62 (dd, 1H), 3.93 (t, 2H), 3.81 (t, 2H), 3.46
(m, 4H), 3.18 (s, 3H), 2.10 (s, 3H). MS (m/z): 391 [MH].sup.+. 1-6
2-methyl-4-methoxy- phenyl Ac ##STR00046## NMR (.sup.1H,
CDCl.sub.3): .delta. 7.85 (d, 1H), 7.15 (d, 1H), 6.95 (d, 1H), 6.80
(d, 1H), 6.75 (dd, 1H), 6.55 (s, 1H), 4.00 (m, 4H), 3.85 (t, 2H),
3.80 (s, 3H), 3.45 (t, 2H), 2.60 (s, 3H), 2.30 (s, 3H), 2.20 (s,
3H). MS (m/z): 447 [MH].sup.+. 1-7 2-methyl-4-ethoxy-phenyl H
##STR00047## NMR (.sup.1H,): .delta. 7.82 (d, 1H), 7.15 (d, 1H),
6.90 (d, 1H), 6.78 (d, 1H), 6.75 (dd, 1H), 6.70 (dd, 1H), 4.70 (bs,
1H), 4.2-4.0 (m, 4H), 3.80 (t, 2H), 3.60 (t, 2H), 3.40 (t, 2H),
2.30 (s, 3H), 2.25 (s, 2H), 1.45 (t, 3H). Structure confirmed by
NOE experiment MS (m/z): 419 [MH].sup.+. 1-8 2-methyl-4-isopropoxy-
phenyl H ##STR00048## NMR (.sup.1H,): .delta. 7.90 (d, 1H), 7.10
(d, 1H), 6.90 (d, 1H), 6.8-6.7 (m, 2H), 6.55 (s, 1H), 4.60 (bs,
1H), 4.50 (m, 1H), 4.10 (t, 2H), 3.90 (t, 2H), 3.60 (t, 2H), 3.45
(t, 2H), 2.30 (s, 3H), 2.20 (s, 3H), 1.26 (d, 6H). MS (m/z): 475
[MH].sup.+. 1-9 2-methyl-4- trifluoromethyloxy-phenyl H
##STR00049## NMR (.sup.1H, CDCl.sub.3): .delta. 7.84 (d, 1H), 7.30
(d, 1H), 7.12 (s, 1H), 7.09 (d, 1H), 6.98 (d, 1H), 6.63 (s, 1H),
4.68 (s, 1H), 4.10 (t, 2H), 3.91 (t, 2H), 3.63 (t, 2H), 3.50 (t,
2H), 2.36 (s, 3H), 2.29 (s, 3H). MS (m/z): 459 [MH].sup.+. 1-10
2-methyl-4-cyano-phenyl H ##STR00050## NMR (.sup.1H, CDCl.sub.3):
.delta. 7.82 (d, 1H), 7.54 (bs, 1H), 7.48 (dd, 1H), 7.36 (d, 1H),
6.96 (d, 1H), 6.67 (s, 1H), 4.55 (bs, 1H), 4.11 (t, 2H), 3.95 (t,
2H), 3.62 (t, 2H), 3.49 (t, 2H), 2.34 (s, 3H), 2.29 (s, 3H). MS
(m/z): 400 [MH].sup.+. 1-11 2-methyl-4-(pyrazol-1-yl)- phenyl H
##STR00051## NMR (.sup.1H, CDCl.sub.3): .delta. 7.90 (d, 1H), 7.84
(d, 1H), 7.72 (d, 1H), 7.68 (m, 1H), 7.64 (m, 1H), 7.37 (d, 1H),
6.97 (d, 1H), 6.62 (s, 1H), 6.45 (t, 1H), 4.77 (s, 1H), 4.11 (t,
2H), 3.94 (t, 2H), 3.63 (t, 2H), 3.50 (t, 2H), 2.34 (s, 6H). MS
(m/z): 441 [MH].sup.+. 1-12 2-trifluoromethyl-4-cyano- phenyl H
##STR00052## NMR (.sup.1H, CDCl.sub.3): .delta. 8.01 (d, 1H), 7.85
(d, 1H), 7.84 (dd, 1H), 7.69 (d, 1H), 7.00 (d, 1H), 6.75 (s, 1H),
4.65 (s, 1H), 4.10 (t, 2H), 3.98 (t, 2H), 3.64 (t, 2H), 3.51 (t,
2H), 2.36 (s, 3H). MS (m/z): 454 [MH].sup.+. 1-13
2-difluoromethyl-4- methoxy H ##STR00053## NMR (.sup.1H,
CDCl.sub.3): .delta. 7.84 (d, 1H), 7.21 (m, 2H), 7.02 (dd, 1H),
6.87 (t, 1H, J.sub.(H--F) = 57 Hz), 6.97 (d, 1H), 6.64 (s, 1H),
4.84 (bs, 1H), 4.13 (t, 2H), 3.93 (t, 2H), 3.9 (s, 3H), 3.66 (t,
2H), 3.53 (t, 2H), 2.33 (s, 3H). MS (m/z): 441 [MH].sup.+. 1-14
2-trifluoromethyloxy-4- cyano-phenyl H ##STR00054## NMR (.sup.1H,
CDCl.sub.3): .delta. 8.05 (d, 1H), 7.84 (m, 1H), 7.54 (bs, 1H), 7.5
(m, 1H), 6.98 (m, 1H), 6.78 (s, 1H),4.63 (bs, 1H), 4.11 (m, 4H),
3.62 (t, 2H), 3.48 (t, 2H), 2.41 (s, 3H). MS (m/z): 470 [MH].sup.+.
1-15 2-ethyl-4-cyano-phenyl H ##STR00055## NMR (.sup.1H,
CDCl.sub.3): .delta. 7.82 (d, 1H), 7.6 (bs, 1H), 7.49 (m, 1H), 7.34
(m, 1H), 6.96 (d, 1H), 6.65 (s, 1H), 4.7 (bs, 1H), 4.11 (t, 2H),
3.92 (t, 2H), 3.62 (t, 2H), 3.49 (t, 2H), 2.66 (m, 2H), 2.41 (s,
3H), 1.22 (t, 3H). MS (m/z): 414 [MH].sup.+. 1-16 2-methoxy-4-
(pyrazol-1-yl)-phenyl H ##STR00056## NMR (.sup.1H, CDCl.sub.3):
.delta. 7.89 (d, 1H), 7.82 (d, 1H), 7.69 (d, 1H), 7.58 (d, 1H),
7.42 (d, 1H), 7.16 (dd, 1H), 6.94 (d, 1H), 6.62 (s, 1H), 6.44 (t,
1H), 4.68 (bs, 1H), 4.13-3.66 (t/t, 4H), 3.89 (s, 3H), 3.93-3.53
(t/t, 4H), 2.34 (s, 3H). MS (m/z): 457 [MH].sup.+. 1-17
2-methyl-4,5- benzodioxolyl H ##STR00057## NMR (.sup.1H,
CDCl.sub.3): .delta. 7.8 (d, 1H), 6.95 (d, 1H), 6.8 (s/s, 2H), 6.5
(s, 1H), 5.95 (s, 2H), 4.5 (bs, 1H), 4.1-3.5 (t/t, 4H), 3.8-3.6
(t/t, 4H), 2.2 (s, 3H), 2.1 (s, 3H). MS (m/z): 419 [MH].sup.+. 1-18
2,4,6-trimethoxy-phenyl H ##STR00058## NMR (.sup.1H, DMSO-d.sub.6):
.delta. 8.26 (bs, 1H), 7.04 (bs, 1H), 6.76 (bs, 1H), 6.65 (bs, 1H),
6.29 (bs, 1H), 3.92-3.46 (t,t, 4H), 3.81-3.46 (t,t, 4H), 3.79 (s,
3H), 3.69 (s, 6H), 2.13 (s, 3H). MS (m/z): 451 [MH].sup.+. 1-19
2-methyl-3,4- benzodioxolyl H ##STR00059## NMR (.sup.1H,
CDCl.sub.3): .delta. 7.81 (d, 1H), 6.94 (d, 1H), 6.75 (dd, 2H),
6.56 (s, 1H), 5.95 (s, 2H), 4.61 (bs, 1H), 4.09 (t, 2H), 3.84 (t,
2H), 3.60 (t, 2H), 3.43 (t, 2H), 2.31 (s, 3H), 2.08 (s, 3H). MS
(m/z): 419 [MH].sup.+ 1-20 2-methyl-4-methoxy- phenyl H
##STR00060## NMR (.sup.1H, CDCl.sub.3): 8.15 (d, 1H), 7.77 (t, 1H),
7.42 (d, 1H), 7.14 (d, 1H), 6.86 (d, 1H), 6.8 (m, 1H), 6.79 (s,
1H), 4.22 (t, 2H), 3.84 (t, 2H), 3.78 (s, 3H), 3.51 (m, 4H), 2.26
(s, 3H), 2.21 (s, 3H).delta.. MS (m/z): 416 [MH].sup.+. 1-21
2-methyl-4-methoxy- phenyl H ##STR00061## NMR (.sup.1H,
DMSO-d.sub.6): .delta. 8.62 (d, 1H), 8.1 (d, 1H), 7.65 (bs, 1H),
7.21 (s, 1H), 7.18 (d, 1H), 6.86 (d, 1H), 6.79 (d, 1H), 4.13 (t,
2H), 3.85 (t, 2H), 3.75 (s, 3H), 3.57 (t, 2H), 3.47 (t, 2H), 2.21
(s, 3H), 2.16 (s, 3H). Structure confirmed by NOE experiment MS
(m/z): 417 [MH].sup.+. 1-22 2-methyl-4-methoxy- phenyl H
##STR00062## NMR (.sup.1H, CDCl.sub.3): .delta. 8.77 (d, 1H), 7.29
(d, 1H), 7.2 (d, 1H), 6.83 (d, 1H), 6.76 (dd, 1H), 6.71 (s, 1H),
4.95 (bs, 1H), 4.28 (t, 2H), 3.93 (t, 2H), 3.81 (s, 3H), 3.61 (t,
2H), 3.58 (t, 2H), 2.37 (s, 3H), 2.25 (s, 3H). Structure confirmed
by NOE experiment MS (m/z): 417 [MH].sup.+. 1-23
2-methyl-4-methoxy- phenyl H ##STR00063## NMR (.sup.1H,
CDCl.sub.3): .delta. 8.98 (s, 1H), 7.14 (d, 1H), 7.05 (s, 1H), 6.83
(d, 1H), 6.76 (m, 2H), 3.89 (t, 2H), 3.37 (t, 2H), 3.82 (t, 2H),
3.41 (t, 2H), 3.71 (s, 3H), 2.17 (s, 3H), 2.11 (s, 3H). Structure
confirmed by NOE experiment MS (m/z): 406 [MH].sup.+. 1-24
2-methyl-4-methoxy- phenyl H ##STR00064## NMR (.sup.1H,
CDCl.sub.3): .delta. 7.80 (d, 1H), 7.09 (d, 1H), 6.93 (d, 1H), 6.81
(d, 1H), 6.77 (dd, 1H), 6.53 (s, 1H), 4.56 (bs, 1H), 4.25 (m, 1H),
4.10 (t, 2H), 3.79 (s, 3H), 3.61 (m, 3H), 2.97 (dd, 1H), 2.27 (s,
3H), 2.17 (s, 3H), 1.21 (d, 3H). MS (m/z): 419 [MH].sup.+. 1-25
2-methyl-4-methoxy- phenyl ##STR00065## NMR (.sup.1H,
DMSO-d.sub.6): .delta. 7.79 (s, 1H), 7.6 (d, 1H), 7.43 (t, 1H), 7.2
(d, 2H), 7.02 (bs, 1H), 6.89 (d, 1H), 6.83 (dd, 1H), 6.49 (s, 1H),
3.85 (t, 2H), 3.8 (t, 2H), 3.77 (s, 3H), 3.4 (t, 2H), 3.2 (t, 2H),
2.21 (s, 6H). MS (m/z): 415 [MH].sup.+. 1-26 2-methyl-4-methoxy-
phenyl H ##STR00066## NMR (.sup.1H, CDCl.sub.3): .delta. 7.18 (d,
1H); 6.9 (d, 1H); 7.85 (d, 1H); 6.77 (m, 1H); 6.53 (s, 2H); 6.43
(s, 1H); 3.80 (t, 2H); 3.75 (s, 3H); 3.41 (t, 2H); 3.3 (s, 3H);
3.15 (t, 2H); 2.34 (s, 3H), 2.18 (s, 3H), 2.17 (s, 3H). MS (m/z):
418.2 [MH].sup.+. 1-27 2-methyl-4-difluoro- methyloxyphenyl H
##STR00067## NMR (1H, CDCl.sub.3): .delta. 7.87 (d, 1H), 7.30 (dd,
1H), 7.08 (d, 1H), 7.01 (dd, 1H), 7.00 (d, 1H), 6.64 (s, 1H), 6.53
(t, 1H), 4.66 (s, 1H), 4.14 (t, 2H), 3.92 (t, 2H), 3.66 (t, (2H),
3.51 (t, 2H), 2.38 (bs, 3H), 2.31 (s, 3H). MS (m/z): 441
[MH].sup.+
Example 2
Synthesis of Compounds of General Formula (II)
##STR00068##
[0719] in which [0720] Y is --CR.sub.7; [0721] W is a W9
derivative:
[0721] ##STR00069## [0722] Z is a pyrazolyl derivative
[0722] ##STR00070## [0723] m is an integer from 0 to 2; [0724] n is
an integer from 0 to 6.
Example 2-1
1-{1-[1-(4-Methoxy-2-methylphenyl)-6-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]p-
yridin-4-yl]-1H-pyrazol-3-yl}pyrrolidin-2-one
[0725] In a sealed vial, at r.t., under N.sub.2, are mixed together
intermediate 5 (50 mg, 0.16 mmol), CuI (6 mg, 0.2 eq) and
K.sub.2CO.sub.3 (46 mg, 2.1 eq). A solution of dodecane (14.5
.mu.L, 0.4 eq), trans-cyclohexanediamine (11.5 .mu.L, 0.6 eq) and
intermediate 10 (30 mg, 1.2 eq) in anh. NMP (1.5 mL) was added and
the reaction mixture was subjected to microwave irradiation
(150.degree. C.) for three cycles (5 min, 10 min, 15 min). It was
then cooled down to r.t. and poured in EtOAc/H.sub.2O. The phases
were separated and the aqueous layer was extracted with EtOAc
(2.times.10 mL). The combined organic extracts were dried over anh.
Na.sub.2SO.sub.4, the solids were filtered and the solvent
evaporated. The crude product was purified on a first SCX cartridge
(cHex/EtOAc 9:1), a second SCX cartridge (CH.sub.2Cl.sub.2/MeOH
9:1) and finally preparative HPLC (Column: X Terra MS C18 5 um,
50.times.4.6 mm, Mobile phase: A: H2O+0.1% TFA.; B: CH3CN+0.1% TFA,
Gradient: 10% (B) for 1 min, from 10% (B) to 90% (B) in 12 min,
Flow rate: 1 ml/min, UV wavelength range: 200-400 nm, Mass range:
150-900 amu, Ionization: ES+) to give the title compound as a pale
yellow solid (21 mg, 35%)
[0726] All the analytical data are set forth in the following Table
2-1 and in which: [0727] R.sub.1 is --CH.sub.3; [0728] R.sub.5 is
hydrogen; [0729] R.sub.6 is hydrogen, [0730] R.sub.7 is hydrogen;
[0731] D corresponds to --CR.sub.8R.sub.9; [0732] G corresponds to
--CR.sub.10R.sub.11; [0733] R.sub.8, R.sub.9, R.sub.10, R.sub.11
are all hydrogen.
TABLE-US-00002 [0733] Cpd. No. R Analytical Data 2-1
2-methyl-4-methoxy- NMR (.sup.1H, DMSO): .delta. 8.35 (d, 1H),
phenyl 7.20 (d, 1H), 6.95 (d, 1H), 6.85 (d, 1H), 6.75 (m, 2H), 3.90
(m, 4H), 3.70 (s, 3H), 3.45 (t, 2H), 2.50 (m, 2H), 2.15 (s, 3H),
2.10 (m, 2H), 2.10 (s, 3H). MS (m/z): 404 [MH].sup.+
Example 3
Synthesis of Compounds of General Formula (II),
##STR00071##
[0734] in which [0735] Y is --CR.sub.7; [0736] W is a W3
derivative:
[0736] ##STR00072## [0737] Z is a pyrazolyl derivative
[0737] ##STR00073## [0738] m is an integer from 0 to 2; [0739] n is
an integer from 0 to 6.
Example 3-1
1-{1-[1-(4-Methoxy-2-methylphenyl)-6-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]p-
yridin-4-yl]-1H-pyrazol-3-yl}tetrahydropyrimidin-2(1H)-one
[0740] In a sealed vial, at r.t., under N.sub.2, are mixed together
intermediate 5 (15 mg, 0.04 mmol), CuI (1.5 mg, 0.2 eq) and
K.sub.2CO.sub.3 (11.6 mg, 2.1 eq). A solution of dodecane (2 .mu.L,
0.2 eq), trans-cyclohexanediamine (2 .mu.L, 0.3 eq) and
intermediate 13 (8 mg, 1 eq) in anh. NMP (2 mL) was added and the
reaction mixture was stirred at 130.degree. C. for 6 hr. It was
then cooled down to r.t. and poured in EtOAc/H.sub.2O. The phases
were separated and the aqueous layer was extracted with EtOAc
(2.times.10 mL). The combined organic extracts were dried over anh.
Na.sub.2SO.sub.4, the solids were filtered and the solvent
evaporated The crude product was purified on an SCX cartridge
(EtOAc/cHex 6:4, then 100% EtOAc, then, 5% MeOH/EtOAc) to give the
title compound as a white solid (5.1 mg, 25%)
[0741] All the analytical data are set forth in the following Table
3-1 and in which: [0742] R.sub.1 is --CH.sub.3; [0743] R.sub.5 is
hydrogen; [0744] R.sub.6 is hydrogen, [0745] R.sub.7 is hydrogen;
[0746] R.sub.12 is hydrogen; [0747] D corresponds to
--CR.sub.8R.sub.3; [0748] G corresponds to --CR.sub.10R.sub.11;
[0749] R.sub.8, R.sub.9, R.sub.10, R.sub.11 are all hydrogen.
TABLE-US-00003 [0749] Cpd. No. R Analytical Data 3-1
2-methyl-4-methoxy- NMR (.sup.1H, CDCl.sub.3): .delta. 7.80 (d,
1H), 7.2 (d, phenyl 1H), 7.0 (d, 1H), 6.80 (d, 1H), 6.75 (dd, 1H),
6.60 (s, 1H), 4.95 (bs, 1H), 4.05 (dd, 2H), 3.90 (t, 2H), 3.80 (s,
3H), 3.45 (t, 2H), 3.40 (bm, 2H), 2.45 (s, 3H), 2.25 (s, 3H), 2.05
(m, 2H). MS (m/z): 419 [MH].sup.+
Example 4
Synthesis of Compounds of General Formula (II),
##STR00074##
[0750] in which [0751] Y is --CR.sub.7; [0752] W is a W11
derivative:
[0752] ##STR00075## [0753] Z is a pyrazolyl derivative
[0753] ##STR00076## [0754] m is an integer from 0 to 2; [0755] q is
an integer from 0 to 4.
Example 4-1
3-(1-{6-Methyl-1-[2-methyl-4-(methyloxy)phenyl]-2,3-dihydro-1H-pyrrolo[2,3-
-b]pyridin-4-yl}-1H-pyrazol-3-yl)-1,3-oxazolidin-2-one
[0756] To a vial under N.sub.2 were added intermediate 5 (38 mg,
0.1 mmol), intermediate 16 (15 mg, 0.1 mmol), CuI (1.9 mg, 0.1 eq),
(1R,2R)-diaminomethylcyclohexane (4.3 mg, 0.3 eq), K.sub.2CO.sub.3
(41 mg, 0.3 mmol) and anh. NMP (1 mL). The vial was sealed and the
reaction mixture was stirred at 130.degree. C. for 4 hr. It was
poured into water/EtOAc. The phases were separated and the aqueous
layer was further extracted with EtOAc (2.times.10 mL). The
combined organic extracts were dried over anh. Na.sub.2SO.sub.4,
the solids were filtered and the solvent evaporated. The residue
was purified by flash chromatography (silica gel, EtOAc/cHex 1:1)
to give the title compound as a white solid (20 mg, 49%).
[0757] All the analytical data are set forth in the following Table
4-1 and in which: [0758] R.sub.1 is --CH.sub.3; [0759] R.sub.5 is
hydrogen; [0760] R.sub.6 is hydrogen, [0761] R.sub.7 is hydrogen;
[0762] D corresponds to --CR.sub.8R.sub.9; [0763] G corresponds to
--CR.sub.10R.sub.11; [0764] R.sub.8, R.sub.9, R.sub.10, R.sub.11
are all hydrogen.
TABLE-US-00004 [0764] Cpd. No. R Analytical Data 4-1
2-methyl-4-methoxy- NMR (.sup.1H, CDCl.sub.3): .delta. 7.85 (d,
1H), phenyl 7.16 (d, 1H), 6.93 (d, 1H), 6.81 (d, 1H), 6.77 (dd,
1H), 6.55 (s, 1H), 4.54 (t, 2H), 4.2 (t, 2H), 3.87 (t, 2H), 3.8 (s,
3H), 3.44 (t, 2H), 2.32 (s, 3H), 2.24 (s, 3H). MS (m/z): 406
[MH].sup.+.
Example 5
Synthesis of Compounds of General Formula (II),
##STR00077##
[0765] in which [0766] Y is --CR.sub.7; [0767] W is a W10
derivative:
[0767] ##STR00078## [0768] Z is a pyrazolyl derivative
[0768] ##STR00079## [0769] m is an integer from 0 to 2; [0770] q is
an integer from 0 to 4.
Example 5-1
Methyl
5-(1-{6-methyl-1-[2-methyl-4-(methyloxy)phenyl]-2,3-dihydro-1H-pyrr-
olo[2,3-b]pyridin-4-yl}-1H-pyrazol-3-yl)-1,2,5-thiadiazolidine-2-carboxyla-
te 1,1-dioxide)
[0771] To a vial under N.sub.2 were added intermediate 21 (20 mg,
0.052 mmol), (methoxycarbonylsulfamoyl)triethylammonium hydroxide
inner salt (40 mg, 3.2 eq) and anh. THF (1 mL). The reaction
mixture was refluxed for 1 hr. It was cooled down to r.t. and
diluted with CH.sub.2Cl.sub.2. 1N HCl was added and the phases were
separated. The aqueous layer was further extracted with
CH.sub.2Cl.sub.2 (3.times.10 mL). The combined organic extracts
were concentrated and the residue was purified by flash
chromatography (silica gel, cHex/EtOAc 7:3) to give the title
compound as a white solid (8.2 mg, 32%).
Example 5-2
4-[3-(1,1-Dioxido-1,2,5-thiadiazolidin-2-yl)-1H-pyrazol-1-yl]-6-methyl-1-[-
2-methyl-4-(methyloxy)phenyl]-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine
[0772] To a solution of example 5-1 (7.2 mg, 0.0144 mmol) in anh.
MeOH (1 mL) and anh. CH.sub.2Cl.sub.2 (2 mL), at r.t., under
N.sub.2, was added 25% NaOH (40 .mu.L). The reaction mixture was
stirred at r.t. for 30 min. It was then poured into sat.aq.
NaHCO.sub.3 and CH.sub.2Cl.sub.2 was added. The phases were
separated and the aqueous layer was further extracted with
CH.sub.2Cl.sub.2 (2.times.10 mL). The combined organic extracts
were dried over anh. Na.sub.2SO.sub.4, the solids were filtered and
the solvent evaporated to give the title compound (6.4 mg,
quantitative yield) as a white solid.
[0773] All the analytical data are set forth in the following Table
5-1 and in which: [0774] R.sub.1 is --CH.sub.3; [0775] R.sub.5 is
hydrogen; [0776] R.sub.6 is hydrogen, [0777] R.sub.7 is hydrogen;
[0778] D corresponds to --CR.sub.8R.sub.9; [0779] G corresponds to
--CR.sub.10R.sub.11; [0780] R.sub.8, R.sub.9, R.sub.10, R.sub.11
are all hydrogen.
TABLE-US-00005 [0780] Cpd. No. R R.sub.12 Analytical Data 5-1
2-methyl-4- CO.sub.2Me NMR (.sup.1H, CDCl.sub.3): .delta. 7.88 (d,
1H), methoxy- 7.17 (d, 1H), 6.82 (d, 1H), 6.77 (dd, 1H), phenyl
6.51 (s, 1H), 6.5 (d, 1H), 4.1 (bst, 4H), 3.95 (s, 3H), 3.87 (t,
2H), 3.81 (s, 3H), 3.46 (t, 2H), 2.32 (s, 3H), 2.24 (s, 3H). MS
(m/z): 499 [MH].sup.+ 5-2 2-methyl- H NMR (.sup.1H, DMSO-d.sub.6):
.delta. 8.37 (d, 1H), 4-methoxy- 7.71 (bs, 1H), 7.15 (d, 1H), 6.84
(d, phenyl 1H), 6.76 (dd, 1H), 6.74 (s, 1H), 6.31 (d, 1H), 3.93 (t,
2H), 3.82 (t, 2H), 3.74 (s, 3H), 3.50 (t, 2H), 3.42 (t, 2H), 2.16
(s, 3H), 2.13 (s, 3H). MS (m/z): 441 [MH].sup.+
Example 6
Synthesis of Compounds of General Formula (II),
##STR00080##
[0781] in which [0782] Y is --CR.sub.7; [0783] W is a W12
derivative:
[0783] ##STR00081## [0784] Z is a pyrazolyl derivative
[0784] ##STR00082## [0785] m is an integer from 0 to 2; [0786] n is
an integer from 0 to 6.
Example 6-1
4-[3-(1,1-Dioxido-2-isothiazolidinyl)-1H-pyrazol-1-yl]-6-methyl-1-[2-methy-
l-4-(methyloxy)phenyl]-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine
[0787] Intermediate 22 (10 mg, 0.022 mmol) and POCl.sub.3 (1 mL)
were mixed together in a vial under N.sub.2. The reaction mixture
was refluxed for 1 hr. Sat.aq. NaHCO.sub.3 was added until neutral
pH and the mixture was partitioned between water and EtOAc. The two
phases were separated and the aqueous layer was further extracted
with EtOAc (3.times.10 mL). The combined organic extracts were
concentrated and the residue was purified by flash chromatography
(silica gel, cHex/EtOAc 1:1.fwdarw.EtOAc/sol. NH.sub.3 in MeOH (0.5
M) 7:3) to give the title compound as a white solid (4.2 mg,
50%).
[0788] All the analytical data are set forth in the following Table
6-1 and in which: [0789] R.sub.1 is --CH.sub.3; [0790] R.sub.5 is
hydrogen; [0791] R.sub.6 is hydrogen, [0792] R.sub.7 is hydrogen;
[0793] D corresponds to --CR.sub.8R.sub.9; [0794] G corresponds to
--CR.sub.10R.sub.11; [0795] R.sub.8, R.sub.9, R.sub.10, R.sub.11
are all hydrogen.
TABLE-US-00006 [0795] Cpd. No. R Analytical Data 6-1
2-methyl-4-methoxy- NMR (.sup.1H, CDCl.sub.3): .delta. 7.84 (d,
1H), phenyl 7.16 (d, 1H), 6.82 (d, 1H), 6.77 (dd, 1H), 6.52 (s,
1H), 6.51 (d, 1H), 3.98 (t, 2H), 3.87 (t, 2H), 3.80 (s, 3H), 3.46
(m, 2H), 3.37 (t, 2H), 2.57 (m, 2H), 2.32 (s, 3H), 2.23 (s, 3H). IR
(film, cm.sup.-1): -- MS (m/z): 439 [M].sup.+.
Example 7
Synthesis of Compounds of General Formula (II),
##STR00083##
[0796] in which [0797] Y is --CR.sub.7; [0798] W is a W13
derivative:
[0798] ##STR00084## [0799] Z is a pyrazolyl derivative
[0799] ##STR00085## [0800] m is an integer from 0 to 2; [0801] q is
an integer from 0 to 4.
Example 7-1
3-Methyl-1-(1-{6-methyl-1-[2-methyl-4-(methyloxy)phenyl]-2,3-dihydro-1H-py-
rrolo[2,3-b]pyridin-4-yl}-1H-pyrazol-3-yl)-2(1H)-pyridinone
[0802] A solution of intermediate 5 (20 mg, 0.05 mmol),
intermediate 26 (14 mg, 2 eq), CuI (10 mg, 1 eq), K.sub.2CO.sub.3
(15 mg, 2.1 eq) and N--N'-dimethyl trans-cyclohexanediamine (9 mg,
1 eq) in anh. NMP (1 mL) at r.t., was heated at 150.degree. C. for
18 hr. Sat.aq. NH.sub.4Cl (10 mL) was then added and the solution
extracted with CH.sub.2Cl.sub.2 (25 mL). The organic layer was
dried over anh. Na.sub.2SO.sub.4, the solids were filtered and the
solvents evaporated in vacuo The crude compound thus obtained was
purified by flash chromatography (silica gel, cHex/EtOAc 1:9) to
give 5.5 mg (44%) of the title compound as a white solid.
[0803] All the analytical data are set forth in the following Table
7-1 and in which: [0804] R.sub.1 is --CH.sub.3; [0805] R.sub.5 is
hydrogen; [0806] R.sub.6 is hydrogen, [0807] R.sub.7 is hydrogen;
[0808] D corresponds to --CR.sub.8R.sub.9; [0809] G corresponds to
--CR.sub.10R.sub.11; [0810] R.sub.8, R.sub.9, R.sub.10, R.sub.11
are all hydrogen.
TABLE-US-00007 [0810] Cpd. No. R Analytical Data 7-1 2-methyl- NMR
(.sup.1H, CDCl.sub.3): .delta. 8.00 (dd, 1H), 4-methoxy- 7.9 (d,
1H), 7.3 (m, 2H), 7.25 (d, 1H), phenyl 6.8 (m, 2H), 6.7 (s, 1H),
6.2 (t, 1H), 3.9 (t, 2H), 3.4 (t, 2H), 3.7 (s, 3H), 2.4 (s, 3H),
2.3 (s, 3H), 2.25 (s, 3H), MS (m/z): 428 [MH].sup.+.
Example 8
Synthesis of Compounds of General Formula (II),
##STR00086##
[0811] in which [0812] Y is --CR.sub.7; [0813] W is a W14
derivative:
[0813] ##STR00087## [0814] Z is a pyrazolyl derivative
[0814] ##STR00088## [0815] m is an integer from 0 to 2; [0816] p is
an integer from 0 to 3.
Example 8-1
2-(1-{6-Methyl-1-[2-methyl-4-(methyloxy)phenyl]-2,3-dihydro-1H-pyrrolo[2,3-
-b]pyridin-4-yl}-1H-pyrazol-3-yl)-3(2H)-pyridazinone
[0817] A solution of intermediate 5 (25 mg, 0.06 mmol),
intermediate 28 (20 mg, 2 eq), CuI (10 mg, 1 eq), K.sub.2CO.sub.3
(15 mg, 2.1 eq) and N--N'-dimethyl trans-cyclohexanediamine (9 mg,
1 eq) in anh. NMP (1 mL) was heated at 150.degree. C. for 3 days.
Sat.aq. NH.sub.4Cl (10 mL) was then added and the solution
extracted with CH.sub.2Cl.sub.2 (25 ml). The organic layer was
dried over anh. Na.sub.2SO.sub.4, the solids were filtered and the
solvents evaporated in vacuo. The crude compound thus obtained was
purified by flash chromatography (silica gel, cHex/EtOAc 1:9) to
give 6 mg (24%) of the title compound as a white solid.
[0818] All the analytical data are set forth in the following Table
8-1 and in which: [0819] R.sub.1 is --CH.sub.3; [0820] R.sub.5 is
hydrogen; [0821] R.sub.6 is hydrogen, [0822] R.sub.7 is hydrogen;
[0823] D corresponds to --CR.sub.8R.sub.9; [0824] G corresponds to
--CR.sub.10R.sub.11; [0825] R.sub.8, R.sub.9, R.sub.10, R.sub.11
are all hydrogen.
TABLE-US-00008 [0825] Cpd. No. R Analytical Data 8-1 2-methyl-4-
NMR (.sup.1H, CDCl.sub.3): .delta. 7.96 (dd-d, 2H), methoxy-phenyl
7.27 (dd, 1H), 7.16 (d, 1H), 6.98 (d, 1H), 6.82 (d, 1H), 6.77 (dd,
1H), 6.64 (s, 1H), 3.88 (t, 2H), 3.8 (s, 3H), 3.46 (t, 2H), 2.33
(s, 3H), 2.23 (s, 3H). MS (m/z): 415 [MH].sup.+.
Example 9
Synthesis of Compounds of General Formula (II),
##STR00089##
[0826] in which [0827] Y is --CR.sub.7; [0828] W is a W1
derivative:
##STR00090##
[0829] Z is a pyrazolyl derivative
##STR00091## [0830] m is an integer from 0 to 2.
Example 9-1
1-(1-{6-Methyl-1-[2-methyl-4-(methyloxy)phenyl]-2,3-dihydro-1H-pyrrolo[2,3-
-b]pyridin-4-yl}-1H-pyrazol-3-yl)-1,3-dihydro-2H-imidazol-2-one
[0831] To a solution of intermediate 24 (50 mg, 0.1 mmol), in anh.
CH.sub.2Cl.sub.2 (2 mL) was added HCl N (200 .mu.L). The reaction
mixture was stirred at rt. for 45 min. It was then neutralized with
1M NaHCO.sub.3 (1 mL) and the solvents were evaporated in vacuo.
The crude compound thus obtained was purified by flash
chromatography (silica gel, cHex/EtOAc 1:1) to give 18 mg (45%) of
the title compound as a white solid.
[0832] All the analytical data are set forth in the following Table
9-1 and in which: [0833] R.sub.1 is --CH.sub.3; [0834] R.sub.5 is
hydrogen; [0835] R.sub.6 is hydrogen, [0836] R.sub.7 is hydrogen;
[0837] R.sub.12 is hydrogen; [0838] D corresponds to
--CR.sub.8R.sub.9; [0839] G corresponds to --CR.sub.10R.sub.11;
[0840] R.sub.8, R.sub.9, R.sub.10, R.sub.11 are all hydrogen.
TABLE-US-00009 [0840] Cpd. No. R Analytical Data 9-1
2-methyl-4-methoxy- NMR (.sup.1H, CDCl.sub.3): .delta. 7.85 (d,
1H), phenyl 7.79 (bs, 1H), 7.12 (d, 1H), 7.03 (d, 1H), 6.96 (m,
1H), 6.76 (d, 1H), 6.72 (dd, 1H), 6.52 (s, 1H), 6.33 (m, 1H), 3.82
(t, 2H), 3.74 (s, 3H), 3.41 (t, 2H), 3.27 (s, 3H), 2.18 (s, 3H). MS
(m/z): 403 [MH].sup.+.
Example 10
Synthesis of Compounds of General Formula (II),
##STR00092##
[0841] in which [0842] Y is --CR.sub.7; [0843] W is a W2
derivative:
[0843] ##STR00093## [0844] Z is a pyrazolyl derivative
[0844] ##STR00094## [0845] m is an integer from 0 to 2; [0846] q is
an integer from 0 to 4.
Example 10-1
1-(1-{6-Methyl-1-[2-methyl-4-(methyloxy)phenyl]-1H-pyrrolo[2,3-b]pyridin-4-
-yl}-1H-pyrazol-3-yl)-2-imidazolidinone
[0847] To a solution of example 1 (90 mg, 0.223 mmol) in anh.
CH.sub.2Cl.sub.2 (6 mL) at r.t., under N.sub.2, was added DDQ (56
mg, 5 eq). The reaction mixture was stirred at r.t. for 24 hr. The
solvent was evaporated in vacuo. The crude compound thus obtained
was purified by flash chromatography (silica gel, cHex/EtOAc 1:1)
to give 14.8 mg of a white solid, which was further purified by
Mass Direct Autoprep (Fraction Lynks), affording the title compound
as white solid (9 mg, 10%).
[0848] All the analytical data are set forth in the following Table
10-1 and in which:
R.sub.1 is --CH.sub.3;
[0849] R.sub.5 is hydrogen; R.sub.6 is hydrogen, R.sub.7 is
hydrogen; R.sub.12 is hydrogen; D corresponds to --CR.sub.8; G
corresponds to --CR.sub.10; D and G are double bonded; R.sub.8,
R.sub.10 are all hydrogen.
TABLE-US-00010 Cpd. No. R Analytical Data 10-1 2-methyl-4-methoxy-
NMR (.sup.1H, CDCl.sub.3): 8.57 (d, 1H), 7.42 (d, phenyl 1H), 7.37
(s, 1H), 7.21 (d, 1H), 7.18 (d, 1H), 7.09 (bs, 1H), 6.97 (d, 1H),
6.89 (dd, 1H), 4.00 (m, 2H), 3.81 (s, 3H), 3.48 (m, 2H), 2.46 (s,
3H), 1.95 (s, 3H).delta.. MS (m/z): 403 [MH].sup.+.
Example 11
Synthesis of Compounds of General Formula (II),
##STR00095##
[0850] in which [0851] Y is nitrogen; [0852] W is a W2 derivative
for example 11-1:
[0852] ##STR00096## [0853] is a W11 derivative for example 11-2
[0853] ##STR00097## [0854] Z is a pyrazolyl derivative
[0854] ##STR00098## [0855] m is an integer from 0 to 2; [0856] q is
an integer from 0 to 4.
Example 11-1
141-{7-[2,4-bis(trifluoromethyl)phenyl]-2-methyl-6,7-dihydro-5H-pyrrolo[2,-
3-d]pyrimidin-4-yl}-1H-pyrazol-3-yl)-2-imidazolidinone
[0857] To a solution of intermediate 8 (7 mg, 2 eq) in anh. DMF
(3.5 mL), at r.t., under N.sub.2, was added NaH 60%/oil (2 mg, 2
eq). The reaction mixture was stirred at r.t. for 20 min. A
solution of intermediate 118 (8 mg, 0.021 mmol) in anh. DMF (3 mL)
was added to the reaction mixture and it was heated at 80.degree.
C. for 5 hr. Water and EtOAc were added and the phases were
separated. The aqueous layer was further extracted with EtOAc
(2.times.10 mL). The combined organic extracts were dried over anh.
Na.sub.2SO.sub.4, the solids were filtered and the solvent
evaporated. The residue was purified on a MEGA Bond Elut silica
cartridge (100% cHex.fwdarw.100% EtOAc) to give the title compound
as a white solid (1.2 mg, 12%).
Example 11-2
1-{1-[7-(2,4-Dichlorophenyl)-2-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimid-
in-4-yl]-1H-pyrazol-3-yl}-2-pyrrolidinone
[0858] To a suspension of NaH 60%/oil (5 mg, 3.0 eq) in anh. DMF (1
mL) at r.t., under N.sub.2, was added intermediate 10 (30 mg, 3
eq). The reaction mixture was stirred at 80.degree. C. for 30 min.
Intermediate 120 (20 mg, 0.064 mmol) was then added and the
reaction mixture was heated at 100.degree. C. for 5 h. It was then
cooled down to r.t., poured into EtOAc, washed with sat.aq. NaCl
(3.times.10 mL) and dried over anh. Na.sub.2SO.sub.4. The solid was
filtered and the solvent evaporated. The crude product was purified
by flash chromatography (silica gel, cHex/EtOAc 7:3) to give the
title compound as white solid (10 mg, 35%).
[0859] All the analytical data are set forth in the following Table
11-1 and in which: [0860] R.sub.1 is --CH.sub.3; [0861] R.sub.5 is
hydrogen; [0862] R.sub.6 is hydrogen, [0863] R.sub.12 is hydrogen;
[0864] D corresponds to --CR.sub.8R.sub.9; [0865] G corresponds to
--CR.sub.10R.sub.11; [0866] R.sub.8, R.sub.9, R.sub.10, R.sub.11
are all hydrogen.
TABLE-US-00011 [0866] Cpd. No. R W Analytical Data 11-1
2,4-bis-tri- fluoro- methyl- phenyl ##STR00099## NMR (.sup.1H,
CDCl.sub.3): .delta. 8.43 (d, 1H), 7.94 (d, 1H), 7.83(dd, 1H), 7.45
(d, 1H), 6.88 (d, 1H), 4.05 (t, 2H), 3.89 (t, 2H), 3.85 (t, 2H),
3.85 (t, 2H), 2.35 (s, 3H). MS (m/z): 498 [MH].sup.+. 11-2
2,4-dichloro- phenyl ##STR00100## NMR (.sup.1H, CDCl.sub.3):
.delta. 8.50 (d, 1H), 7.47 (d, 1H), 7.34 (d, 1H), 7.29 (dd, 1H),
7.08 (d, 1H), 4.08 (m, 4H), 3.60 (t, 4H), 2.60 (t, 2H), 2.42 (s,
2H), 2.19 (t, 2H). MS(m/z): 429 [MH].sup.+.
Example 12
CRF Binding Activity
[0867] CRF binding affinity has been determined in vitro by the
compounds' ability to displace .sup.125I-oCRF and
.sup.125I-Sauvagine for CRF1 and CRF2 SPA, respectively, from
recombinant human CRF receptors expressed in Chinese Hamster Ovary
(CHO) cell membranes. For membrane preparation, CHO cells from
confluent T-flasks were collected in SPA buffer (HEPES/KOH 50 mM,
EDTA 2 mM, MgCl.sub.2 10 mM, pH 7.4) in 50 mL centrifuge tubes,
homogenized with a Polytron and centrifuged (50'000 g for 5 min at
4.degree. C.: Beckman centrifuge with JA20 rotor). The pellet was
resuspended, homogenized and centrifuged as before.
[0868] The SPA experiment has been carried out in Optiplate by the
addition of 100 .mu.L the reagent mixture to 1 .mu.L of compound
dilution (100% DMSO solution) per well. The assay mixture was
prepared by mixing SPA buffer, WGA SPA beads (2.5 mg/mL), BSA (1
mg/mL) and membranes (50 and 5 .mu.g of protein/mL for CRF1 and
CRF2 respectively) and 50 .mu.M of radioligand.
[0869] The plate was incubated overnight (>18 hrs) at room
temperature and read with the Packard Topcount with a WGA-SPA
.sup.125I counting protocol.
Example 13
CRF Functional Assay
[0870] Compounds of the invention were characterised in a
functional assay for the determination of their inhibitory effect.
Human CRF--CHO cells were stimulated with CRF and the receptor
activation was evaluated by measuring the accumulation of cAMP. CHO
cells from a confluent T-flask were resuspended with culture medium
without G418 and dispensed in a 96-well plate, 25'000 c/well, 100
.mu.L/well and incubated overnight. After the incubation the medium
was replaced with 100 .mu.L of cAMP IBMX buffer warmed at
37.degree. C. (5 mM KCl, 5 mM NaHCO.sub.3, 154 mM NaCl, 5 mM HEPES,
2.3 mM CaCl.sub.2, 1 mM MgCl.sub.2, 1 g/L glucose, pH 7.4
additioned by 1 mg/mL BSA and 1 mM IBMX) and 1 .mu.L of antagonist
dilution in neat DMSO. After 10 additional minutes of incubation at
37.degree. C. in a plate incubator without CO2, 1 .mu.L of agonist
dilution in neat DMSO was added. As before, the plate was incubated
for 10 minutes and then cAMP cellular content was measured by using
the Amersham RPA 538 kit.
[0871] All publications, including but not limited to patents and
patent applications, cited in this specification are herein
incorporated by reference as if each individual publication were
specifically and individually indicated to be incorporated by
reference herein as though fully set forth.
[0872] It is to be understood that the present invention covers all
combinations of particular and preferred groups described herein
above.
[0873] The application of which this description and claims forms
part may be used as a basis for priority in respect of any
subsequent application. The claims of such subsequent application
may be directed to any feature or combination of features described
herein. They may take the form of product, composition, process, or
use claims and may include, by way of example and without
limitation, the following claims:
* * * * *