U.S. patent application number 14/589056 was filed with the patent office on 2015-04-30 for pyrazole derivatives as jak inhibitors.
The applicant listed for this patent is ALMIRALL, S.A.. Invention is credited to Jordi BACH TANA, Paul Robert EASTWOOD, Victor GIULIO MATASSA, Jacob GONZALEZ RODRIGUES, Lluis Miquel PAGES SANTACANA, Joan TALTAVULL MOLL.
Application Number | 20150118186 14/589056 |
Document ID | / |
Family ID | 43706312 |
Filed Date | 2015-04-30 |
United States Patent
Application |
20150118186 |
Kind Code |
A1 |
BACH TANA; Jordi ; et
al. |
April 30, 2015 |
PYRAZOLE DERIVATIVES AS JAK INHIBITORS
Abstract
New pyrazole derivatives having the chemical structure of
formula (I) are disclosed; as well as process for theft
preparation, pharmaceutical compositions comprising them and their
use in therapy as inhibitors of Janus Kinases (JAK).
##STR00001##
Inventors: |
BACH TANA; Jordi;
(Barcelona, ES) ; PAGES SANTACANA; Lluis Miquel;
(Barcelona, ES) ; TALTAVULL MOLL; Joan;
(Barcelona, ES) ; EASTWOOD; Paul Robert;
(Barcelona, ES) ; GONZALEZ RODRIGUES; Jacob;
(Barcelona, ES) ; GIULIO MATASSA; Victor;
(Barcelona, ES) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
ALMIRALL, S.A. |
Barcelona |
|
ES |
|
|
Family ID: |
43706312 |
Appl. No.: |
14/589056 |
Filed: |
January 5, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13579344 |
Sep 21, 2012 |
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PCT/EP2011/000792 |
Feb 18, 2011 |
|
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14589056 |
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61306051 |
Feb 19, 2010 |
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61371081 |
Aug 5, 2010 |
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Current U.S.
Class: |
424/85.6 ;
424/143.1; 424/158.1; 424/172.1; 424/85.7; 514/167; 514/171;
514/249; 514/255.05; 514/256; 514/300; 544/295; 544/328; 544/350;
544/405; 546/121 |
Current CPC
Class: |
A61K 45/06 20130101;
A61P 35/02 20180101; A61P 17/06 20180101; A61P 37/02 20180101; A61P
11/00 20180101; C07D 487/04 20130101; A61K 31/4985 20130101; A61P
11/06 20180101; A61P 11/02 20180101; A61P 35/00 20180101; A61P
27/02 20180101; A61P 27/14 20180101; A61P 1/04 20180101; A61K
31/497 20130101; A61P 29/00 20180101; A61P 43/00 20180101; A61K
31/437 20130101; C07D 471/04 20130101; A61P 37/00 20180101; A61P
37/06 20180101; A61K 31/506 20130101; A61P 19/02 20180101; A61P
17/00 20180101; A61P 25/00 20180101 |
Class at
Publication: |
424/85.6 ;
544/328; 514/256; 546/121; 514/300; 544/295; 514/249; 544/350;
544/405; 514/255.05; 514/171; 424/158.1; 424/143.1; 424/172.1;
514/167; 424/85.7 |
International
Class: |
C07D 487/04 20060101
C07D487/04; A61K 31/506 20060101 A61K031/506; A61K 45/06 20060101
A61K045/06; A61K 31/4985 20060101 A61K031/4985; A61K 31/497
20060101 A61K031/497; C07D 471/04 20060101 C07D471/04; A61K 31/437
20060101 A61K031/437 |
Foreign Application Data
Date |
Code |
Application Number |
Feb 18, 2010 |
EP |
10382039.5 |
Aug 5, 2010 |
EP |
10382217.7 |
Claims
1-43. (canceled)
44. A compound chosen from:
N-(Cyclohexylmethyl)-2-pyrazolo[1,5-a]pyrazin-3-ylpyrimidin-4-amine;
(S)--N-(1-phenylethyl)-2-(pyrazolo[1,5-a]pyrazin-3-yl)pyrimidin-4-amine;
N-Benzyl-2-pyrazolo[1,5-a]pyrazin-3-ylpyrimidin-4-amine;
N-(2,2-Dimethylpropyl)-2-pyrazolo[1,5-a]pyrazin-3-ylpyrimidin-4-amine;
3-Oxo-3-{(3R)-3-[(2-pyrazolo[1,5-a]pyrazin-3-ylpyrimidin-4-yl)amino]piper-
idin-1-yl}propanenitrile;
6-{(3R)-3-[(2-Pyrazolo[1,5-a]pyrazin-3-ylpyrimidin-4-yl)amino]piperidin-1-
-yl}nicotinonitrile;
2-Pyrazolo[1,5-a]pyrazin-3-yl-N-[(3R)-1-(3,3,3-trifluoropropanoyl)piperid-
in-3-yl]pyrimidin-4-amine;
3-{(3R)-3-[Methyl(2-pyrazolo[1,5-a]pyrazin-3-ylpyrimidin-4-yl)amino]piper-
idin-1-yl}-3-oxopropanenitrile;
3-{(3R)-3-[(5-Chloro-2-pyrazolo[1,5-a]pyrazin-3-ylpyrimidin-4-yl)amino]pi-
peridin-1-yl}-3-oxopropanenitrile;
3-{(3R)-3-[(5-Fluoro-2-pyrazolo[1,5-a]pyrazin-3-ylpyrimidin-4-yl)amino]pi-
peridin-1-yl}-3-oxopropanenitrile;
5-Fluoro-2-pyrazolo[1,5-a]pyrazin-3-yl-N-[(3R)-1-(3,3,3-trifluoropropanoy-
l)piperidin-3-yl]pyrimidin-4-amine;
3-{(3R)-3-[(5-Methyl-2-pyrazolo[1,5-a]pyrazin-3-ylpyrimidin-4-yl)amino]pi-
peridin-1-yl}-3-oxopropanenitrile;
(S)--N-(1-(5-Fluoropyridin-2-yl)ethyl)-2-(pyrazolo[1,5-a]pyrazin-3-yl)pyr-
imidin-4-amine;
N-((5-Fluoropyridin-2-yl)methyl)-2-(pyrazolo[1,5-a]pyrazin-3-yl)pyrimidin-
-4-amine;
5-Chloro-N-((5-fluoropyridin-2-yl)methyl)-2-(pyrazolo[1,5-a]pyra-
zin-3-yl)pyrimidin-4-amine;
N.sup.4-(4,4-Difluorocyclohexyl)-2-(pyrazolo[1,5-a]pyrazin-3-yl)pyrimidin-
e-4,5-diamine;
(S)-5-Chloro-N-(1-(5-fluoropyridin-2-yl)ethyl)-2-(pyrazolo[1,5-a]pyrazin--
3-yl)pyrimidin-4-amine;
2-(Pyrazolo[1,5-a]pyrazin-3-yl)-N.sup.4-(tetrahydro-2H-pyran-4-yl)pyrimid-
ine-4,5-diamine;
(R)-3-Oxo-3-(3-(6-(pyrazolo[1,5-a]pyrazin-3-yl)pyrazin-2-ylamino)piperidi-
n-1-yl)propanenitrile; or a pharmaceutically acceptable salt, or
N-oxide, or stereoisomer thereof.
45. A compound of formula (I), or a pharmaceutically acceptable
salt, or N-oxide, or stereoisomer thereof: ##STR00102## wherein T
is --CR.sub.9; m is chosen from 0, 1, 2, or 3; Z is chosen from an
oxygen atom or NR.sub.5; W is a nitrogen atom; X and Y are
independently chosen from a nitrogen atom or --CR.sub.9, wherein
one of X or Y is a nitrogen atom and the remaining X or Y group is
--CR.sub.9; R.sub.1, R.sub.2, R.sub.3, R.sub.4 and R.sub.9 are each
independently chosen from a hydrogen atom, halogen atoms, cyano,
linear or branched C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.4 alkenyl,
C.sub.2-C.sub.4 alkynyl, C.sub.1-C.sub.4 halo alkyl,
C.sub.1-C.sub.4 hydroxyalkyl, C.sub.3-C.sub.10 cycloalkyl,
C.sub.3-C.sub.10 cycloalkenyl, monocyclic or polycyclic
C.sub.5-C.sub.14 aryl, 5- to 14-membered heteroaryl containing at
least one heteroatom chosen from O, S or N, 5- to 14-membered
heterocyclyl containing at least one heteroatom chosen from O, S or
N, bicyclyl containing a monocyclic C.sub.5-C.sub.9 aryl or
heteroaryl bonded directly to a 5- to 9-membered cycloalkyl or
heterocyclyl, wherein the heteroaryl or heterocyclyl contain at
least one heteroatom chosen from O, S or N, an aza-bicycloalkyl
comprising up to 12 carbon atoms, or aza-bicycloalkenyl comprising
up to 12 carbon atoms, wherein each of the alkenyl, alkynyl,
haloalkyl, hydroxyalkyl, cycloalkyl, cycloalkenyl, aryl,
heteroaryl, heterocyclyl, bicyclyl, aza-bicycloalkyl and
aza-bicycloalkenyl is independently unsubstituted or substituted by
at least one substituent chosen from Ra, and each of the alkyl
groups is independently unsubstituted or substituted by at least
one Rb; or R.sub.1, R.sub.2, R.sub.3, R.sub.4 and R.sub.9 are each
independently chosen from a --SR.sub.13; --SOR.sub.13,
--S(O).sub.2R.sub.13, --S(O).sub.2NR.sub.13R.sub.14,
--NR.sub.13S(O).sub.2R.sub.14, --NR.sub.13S(O).sub.2NR.sub.14,
--(CH.sub.2).sub.nOR.sub.13, --C(O)OR.sub.13, --O--C(O)R.sub.13,
--C(O)--(CH.sub.2).sub.n--R.sub.13, --NR.sub.13R.sub.14,
--C(O)--(CH.sub.2).sub.n--NR.sub.13R.sub.14,
--NR.sub.13C(O)--(CH.sub.2).sub.n--R.sub.14 or
--NR.sub.13C(O)--(CH.sub.2).sub.n--NR.sub.14R.sub.15, wherein each
n is independently chosen from 0, 1, or 2; or when two adjacent
--CR.sub.9 groups are present, both adjacent --CR.sub.9 and the
carbon atoms to which they are bonded optionally form a
C.sub.5-C.sub.12 aryl group or a 4- to 12-membered heteroaryl,
cycloalkyl or heterocyclyl group, wherein the heteroaryl and
heterocyclyl contain at least one heteroatom chosen from O, S or N,
and wherein the aryl, heteroaryl, cycloalkyl and heterocyclyl are
independently unsubstituted or substituted by at least one
substituent chosen from halogen atoms, linear or branched
C.sub.1-C.sub.6 alkyl, monocyclic or polycyclic C.sub.5-C.sub.14
aryl, 5- to 14-membered heteroaryl containing at least one
heteroatom chosen from O, S or N, or 5- to 14-membered heterocyclyl
containing at least one heteroatom chosen from O, S or N, wherein
the alkyl, the aryl, the heteroaryl and the heterocyclyl
substituents are independently unsubstituted or substituted by at
least one substituent chosen from halogen atoms, hydroxyl, cyano,
linear or branched C.sub.1-C.sub.6 alkyl or C.sub.1-C.sub.4
haloalkyl; R.sub.5 is chosen from a hydrogen atom, linear or
branched C.sub.1-C.sub.6 alkyl unsubstituted or substituted by at
least one substituent chosen from hydroxyl, cyano, C.sub.1-C.sub.4
haloalkyl, C.sub.1-C.sub.4 hydroxyalkyl, C.sub.3-C.sub.10,
cycloalkyl, phenyl or 6-membered, saturated N-containing
heterocyclyl ring, or R.sub.5 is chosen from --S(O).sub.2R.sub.10,
--S(O).sub.2NR.sub.10R.sub.11, --C(O)OR.sub.10,
--C(O)--(CH.sub.2).sub.n--R.sub.10, or
--C(O)--(CH.sub.2).sub.n--NR.sub.10R.sub.11; R.sub.6 and R.sub.7
are each independently chosen from a hydrogen atom or linear or
branched C.sub.1-C.sub.6 alkyl independently unsubstituted or
substituted by at least one substituent chosen from hydroxyl,
cyano, C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4 hydroxyalkyl,
C.sub.1-C.sub.4 alkoxycarbonyl, C.sub.3-C.sub.7 cycloalkyl, phenyl
or 6-membered, saturated N-containing heterocyclyl ring; R.sub.8 is
chosen from a hydrogen atom, halogen atoms, cyano, linear or
branched C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.4 alkenyl,
C.sub.2-C.sub.4 alkynyl, C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4
hydroxyalkyl, C.sub.3-C.sub.10 cycloalkyl, C.sub.3-C.sub.10
cycloalkenyl, monocyclic or polycyclic C.sub.5-C.sub.14 aryl, 5- to
14-membered heteroaryl containing at least one heteroatom chosen
from O, S or N, 5- to 14-membered heterocyclyl containing at least
one heteroatom chosen from O, S or N, bicyclyl containing a
monocyclic C.sub.5-C.sub.9 aryl or heteroaryl bonded directly to a
5- to 9-membered cycloalkyl or heterocyclyl, wherein the heteroaryl
or heterocyclyl contain at least one heteroatom chosen from O, S or
N, an aza-bicycloalkyl comprising up to 12 carbon atoms, or
aza-bicycloalkenyl comprising up to 12 carbon atoms, wherein each
of the alkenyl, alkynyl, haloalkyl, hydroxyalkyl, cycloalkyl,
cycloalkenyl, aryl, heteroaryl, heterocyclyl, bicyclyl,
aza-bicycloalkyl and aza-bicycloalkenyl is independently
unsubstituted or substituted by at least one substituent chosen
from Ra, --(C.sub.1-C.sub.4 alkyl)-CN, or
--(C.sub.1-C.sub.4alkyl)-C(O)NR'R'' wherein R' and R'' are the same
or different and are independently chosen from hydrogen atoms or
linear or branched C.sub.1-C.sub.4 alkyl; and each of the alkyl
groups is independently unsubstituted or substituted by at least
one Rb; and when R.sub.8 is a 5- to 7-membered heterocyclyl
containing one nitrogen atom, the heterocyclyl is substituted by at
least one substituent, and wherein the substitution is at least on
the ring nitrogen of the heterocyclyl, with the proviso that the
substituent on the ring nitrogen of the heterocyclyl is not
tert-butoxycarbonyl; or R.sub.8 is chosen from --SR.sub.13,
--SOR.sub.13, --S(O).sub.2R.sub.13, --S(O).sub.2NR.sub.13R.sub.14,
--NR.sub.13S(O).sub.2R.sub.14, --NR.sub.13S(O).sub.2NR.sub.14,
--(CH.sub.2).sub.nOR.sub.13, --C(O)OR.sub.13, --O--C(O)R.sub.13,
--C(O)--(CH.sub.2).sub.n--R.sub.13, --NR.sub.13R.sub.14,
--C(O)--(CH.sub.2).sub.n--NR.sub.13R.sub.14,
--NR.sub.13C(O)--(CH.sub.2).sub.n--R.sub.14, or
--NR.sub.13C(O)--(CH.sub.2).sub.n--NR.sub.14R.sub.15, wherein each
n is independently chosen from 0, 1, or 2, or R.sub.8 together with
R.sub.5 and the nitrogen atom to which R.sub.5 is bonded form a 4-
to 10-membered, saturated heterocyclyl group, wherein the
heterocyclyl contains one or two nitrogen atoms, and is substituted
by linear or branched C.sub.1-C.sub.6 alkyl, monocyclic or
polycyclic C.sub.5-C.sub.14 aryl, 5- to 14-membered heteroaryl
containing at least one heteroatom chosen from O, S or N, 5- to
14-membered heterocyclyl containing at least one heteroatom chosen
from O, S or N, --SO.sub.2R.sub.10,
--C(O)--(CH.sub.2).sub.n--R.sub.10, or
--C(O)--(CH.sub.2).sub.n--NR.sub.10R.sub.11, wherein each n is
independently chosen from 0, 1, or 2, wherein each of the alkyl,
aryl, heteroaryl and heterocyclyl is independently unsubstituted or
substituted by at least one substituent chosen from halogen atoms,
hydroxyl, cyano, linear or branched C.sub.1-C.sub.6 alkyl, or
C.sub.1-C.sub.4 haloalkyl, and wherein each of the alkyl groups is
independently unsubstituted or substituted by at least one
substituent chosen from halogen atoms, hydroxyl, cyano or
C.sub.1-C.sub.4 haloalkyl; with the proviso that when m is zero,
R.sub.8 is not --SR.sub.13, --SOR.sub.13, --S(O).sub.2R.sub.13,
--S(O).sub.2NR.sub.13R.sub.14, --NR.sub.13S(O).sub.2R.sub.14,
--NR.sub.13S(O).sub.2NR.sub.14, --(CH.sub.2).sub.nOR.sub.13,
--O--C(O)R.sub.13, --NR.sub.13R.sub.14,
--NR.sub.13C(O)--(CH.sub.2).sub.n--R.sub.14, or
--NR.sub.13C(O)--(CH.sub.2).sub.n--NR.sub.14R.sub.15; wherein each
Ra is independently chosen from halogen atoms, cyano, hydroxyl,
linear or branched C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.4
haloalkyl, C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4 hydroxyalkyl,
C.sub.3-C.sub.7 cycloalkyl or a C.sub.3-C.sub.7 cycloalkenyl
unsubstituted or substituted by at least one Re, monocyclic or
polycyclic C.sub.5-C.sub.14 aryl unsubstituted or substituted by at
least one Re, 5- to 14-membered heteroaryl containing at least one
heteroatom chosen from O, S or N unsubstituted or substituted by at
least one Re, 5- to 14-membered heterocyclyl containing at least
one heteroatom chosen from O, S or N unsubstituted or substituted
by at least one substituent chosen from Re, --SR.sub.10,
--SOR.sub.10, --S(O).sub.2R.sub.10, --S(O).sub.2NR.sub.10R.sub.11,
--NR.sub.10S(O).sub.2R.sub.11, --NR.sub.10S(O).sub.2NR.sub.11,
--(CH.sub.2).sub.nOR.sub.10, --C(O)OR.sub.10, --O--C(O)R.sub.10 a
--C(O)--(CH.sub.2).sub.n--R.sub.10, --NR.sub.10R.sub.11,
--C(O)--(CH.sub.2).sub.n--NR.sub.10R.sub.11, a
--NR.sub.10C(O)--(CH.sub.2).sub.n--R.sub.11 or
--NR.sub.10C(O)--(CH.sub.2).sub.n--NR.sub.11R.sub.12, wherein each
n is independently chosen from 0, 1, or 2; each Rb is independently
chosen from cyano, C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4
alkoxy, C.sub.1-C.sub.4 hydroxyalkyl, C.sub.3-C.sub.7 cycloalkyl or
a C.sub.3-C.sub.7 cycloalkenyl unsubstituted or substituted by at
least one Re, monocyclic or polycyclic C.sub.5-C.sub.14aryl
unsubstituted or substituted by at least one Re, 5- to 14-membered
heteroaryl containing at least one heteroatom chosen from O, S or
N, unsubstituted or substituted by at least one Re, 5- to
14-membered heterocyclyl containing at least one heteroatom chosen
from O, S or N, unsubstituted or substituted by at least one
substituent chosen from Re, --SR.sub.10, --SOR.sub.10,
--S(O).sub.2R.sub.10, --S(O).sub.2NR.sub.10R.sub.11,
--NR.sub.10S(O).sub.2R.sub.11, --NR.sub.10S(O).sub.2NR.sub.11,
--(CH.sub.2).sub.nOR.sub.10, --C(O)OR.sub.10, --O--C(O)R.sub.10,
--C(O)--(CH.sub.2).sub.n--R.sub.10, --NR.sub.10R.sub.11,
--C(O)--(CH.sub.2).sub.n--NR.sub.10R.sub.1, a
--NR.sub.10C(O)--(CH.sub.2).sub.n--R.sub.11, or
--NR.sub.10C(O)--(CH.sub.2).sub.n--NR.sub.11R.sub.12, wherein each
n is independently chosen from 0, 1 or 2; R.sub.10, R.sub.11 and
R.sub.12 are each independently chosen from a hydrogen atom, cyano,
linear or branched C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.4
haloalkyl, C.sub.1-C.sub.4 hydroxyalkyl, C.sub.1-C.sub.4
alkoxycarbonyl, C.sub.3-C.sub.7 cycloalkyl, phenyl, 5- to
6-membered monocyclic heteroaryl containing 1, 2, or 3 heteroatoms
chosen from N, O or S, 5- to 6-membered, heterocyclyl containing 1,
2, or 3 nitrogen atoms, bicyclyl containing a monocyclic
C.sub.5-C.sub.6 aryl or heteroaryl bonded directly to a 5- to
6-membered cycloalkyl or heterocyclyl, wherein the heteroaryl or
heterocyclyl contains 1, 2, or 3 nitrogen atoms, and wherein each
of the haloalkyl, hydroxyalkyl, alkoxycarbonyl, cycloalkyl, phenyl,
heteroaryl, heterocyclyl and bicyclyl is independently
unsubstituted or substituted by at least one Rc, and each of the
alkyl groups is independently unsubstituted or substituted by at
least one Rd; each Rc is independently chosen from halogen atoms,
hydroxyl, cyano, linear or branched C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4
hydroxyalkyl, C.sub.3-C.sub.7 cycloalkyl, phenyl, 5- to 6-membered
monocyclic heteroaryl containing 1, 2, or 3 nitrogen atoms, 5- to
6-membered heterocyclyl containing 1, 2, or 3 nitrogen atoms, or
C.sub.3-C.sub.7 heterocycloalkyl ketone containing 1, 2, or 3
nitrogen atoms, wherein each phenyl is independently unsubstituted
or substituted by at least one halogen atom, and each of the
heteroaryl, heterocyclyl and heterocycloalkyl ketone are
independently unsubstituted or substituted by at least one linear
or branched C.sub.1-C.sub.3 alkyl; each Rd is independently chosen
from cyano, C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4 alkoxy,
C.sub.1-C.sub.4 hydroxyalkyl, C.sub.3-C.sub.7 cycloalkyl, phenyl,
5- to 6-membered monocyclic heteroaryl containing 1, 2, or 3
nitrogen atoms, 5- to 6-membered heterocyclyl containing 1, 2, or 3
nitrogen atoms, or C.sub.3-C.sub.7 heterocycloalkyl ketone
containing 1, 2, or 3 nitrogen atoms, wherein each phenyl is
independently unsubstituted or substituted by at least one halogen
atom, and each of the heteroaryl, heterocyclyl and heterocycloalkyl
ketone are independently unsubstituted or substituted by at least
one linear or branched C.sub.1-C.sub.3 alkyl; each Re is
independently chosen from halogen atoms, hydroxyl, cyano, linear or
branched C.sub.1-C.sub.6 alkyl, or C.sub.1-C.sub.4 haloalkyl;
R.sub.13, R.sub.14, and R.sub.15 are each independently chosen from
a hydrogen atom, cyano, linear or branched C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4 hydroxyalkyl,
C.sub.1-C.sub.4 alkoxycarbonyl, C.sub.3-C.sub.7 cycloalkyl,
monocyclic or polycyclic C.sub.5-C.sub.14 aryl, 5- to 14-membered
heteroaryl containing at least one heteroatom chosen from O, S or
N, or 5- to 14-membered heterocyclyl containing at least one
heteroatom chosen from O, S or N, wherein each of the haloalkyl,
hydroxyalkyl, alkoxycarbonyl, cycloalkyl, aryl, heteroaryl and
heterocyclyl is independently unsubstituted or substituted by at
least one Ra, and each of the alkyl groups is independently
unsubstituted or substituted by at least one Rb.
46. A compound according to claim 45, wherein Y is --CR.sub.9.
47. A pharmaceutical composition comprising the compound according
to claim 45 and a pharmaceutically acceptable diluent or
carrier.
48. A composition comprising: (i) a compound according to claim 45;
and (ii) at least one other compound chosen from: Dyhydrofolate
reductase inhibitors; DHODH inhibitors; Immunomodulators;
Inhibitors of DNA synthesis and repair; Anti-alpha 4 integrin
antibodies; Alpha 4 integrin antagonists; Corticoids and
glucocorticoids; Fumaric acid esters; Anti-TNF alpha antibodies;
Soluble TNF alpha receptors; Anti-CD20 monoclonal antibodies;
Anti-CD52; Anti-CD25; Anti-CD88; Anti-IL12R/IL23R; Calcineurin
inhibitors; IMPDH inhibitors; Cannabinoid receptor agonists;
Chemokine CCR1 antagonists; Chemokine CCR2 antagonists; NF-kappaB
activation inhibitors; S1P receptor agonists; S1P liase inhibitors;
Syk inhibitors; PKC inhibitors; M3 antagonist; Long-acting beta
adrenergic agonist; Vitamin D derivatives; Phosphosdiesterase IV
inhibitors; p38 Inhibitors; MEK inhibitors; PI3K.delta..gamma.
inhibitors; Interferons comprising Interferon beta 1a and
Interferon beta 1b; or Interferon alpha.
49. A method of treating a pathological condition or disease
susceptible to amelioration by inhibition of Janus kinases
comprising administering to a subject in need thereof an effective
amount of the composition according to claim 48 for simultaneous,
separate or sequential use in the treatment of the human or animal
body.
50. The compound according to claim 45, wherein Z is NR.sub.5.
51. The compound according to claim 45, wherein R.sub.8 is chosen
from a linear or branched C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.4
haloalkyl, C.sub.3-C.sub.7 cycloalkyl, phenyl, 5- to 6-membered
monocyclic heteroaryl containing 1, 2, or 3 heteroatoms chosen from
N, O or S, 5- to 7-membered heterocyclyl containing 1, 2, or 3
heteroatoms chosen from N, O or S, or --(CH.sub.2).sub.nOR.sub.13
wherein n is chosen from 0 or 1 and R.sub.13 is chosen from linear
or branched C.sub.1-C.sub.6 alkyl or C.sub.1-C.sub.4 haloalkyl;
wherein each of the haloalkyl, cycloalkyl, phenyl, heteroaryl and
heterocyclyl is independently unsubstituted or substituted by at
least one Ra; and each of the alkyl groups is independently
unsubstituted or substituted by at least one Rb; each Ra is
independently chosen from halogen atoms, cyano, hydroxyl, linear or
branched C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.4 haloalkyl,
C.sub.1-C.sub.4 alkoxy, C.sub.3-C.sub.7 cycloalkyl unsubstituted or
substituted by at least one Re, phenyl unsubstituted or substituted
by at least one Re, 5- to 6-membered monocyclic heteroaryl
containing 1, 2, or 3 heteroatoms chosen from N, O or S,
unsubstituted or substituted by at least one Re, 6-membered,
saturated N-containing heterocyclyl ring, unsubstituted or
substituted by at least one substituent chosen from Re,
--C(O)OR.sub.10, or --C(O)--(CH.sub.2).sub.n--R.sub.10 wherein n is
chosen from 0 or 1, each Rb is independently chosen from cyano,
C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4 alkoxy, C.sub.3-C.sub.7
cycloalkyl unsubstituted or substituted by at least one Re, phenyl
unsubstituted or substituted by at least one Re, 5- to 6-membered
monocyclic heteroaryl containing 1, 2, or 3 heteroatoms chosen from
N, O or S, unsubstituted or substituted by at least one Re,
6-membered, saturated N-containing heterocyclyl ring, unsubstituted
or substituted by at least one substituent chosen from Re,
--C(O)OR.sub.10, or --C(O)--(CH.sub.2).sub.n--R.sub.10 wherein n is
chosen from 0 or 1; each R.sub.10 group in --C(O)OR.sub.10 is
independently chosen from a hydrogen atom, linear or branched
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.4 haloalkyl, C.sub.3-C.sub.7
cycloalkyl, phenyl, 5- to 6-membered monocyclic heteroaryl
containing 1, 2, or 3 heteroatoms chosen from N, O or S, or 5- to
6-membered, saturated N-containing heterocyclyl ring; and each
R.sub.10 group in --C(O)--(CH.sub.2).sub.n--R.sub.10 is
independently chosen from cyano, linear or branched C.sub.1-C.sub.6
alkyl, C.sub.1-C.sub.4 haloalkyl, C.sub.3-C.sub.7 cycloalkyl,
phenyl, 5- to 6-membered monocyclic heteroaryl containing 1, 2, or
3 heteroatoms chosen from N, O or S, or 5- to 6-membered, saturated
N-containing heterocyclyl ring; wherein the cycloalkyl, phenyl,
heteroaryl and heterocyclyl are independently unsubstituted or
substituted by at least one substituent chosen from hydroxyl,
cyano, linear or branched C.sub.1-C.sub.6 alkyl or C.sub.1-C.sub.4
haloalkyl.
52. The compound according to 45, wherein R.sub.8 is chosen from a
linear or branched C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.4
haloalkyl, C.sub.3-C.sub.7 cycloalkyl, phenyl, 5- to 7-membered
heterocyclyl containing 1, 2, or 3 heteroatoms chosen from N, O or
S, or --(CH.sub.2).sub.nOR.sub.13; wherein each of the haloalkyl,
cycloalkyl, phenyl, and heterocyclyl is unsubstituted or
substituted by at least one Ra; and each of the alkyl groups is
independently unsubstituted or substituted by at least one Rb; each
Ra is independently chosen from halogen atoms, cyano, hydroxyl,
linear or branched C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.4
haloalkyl, 5- to 6-membered monocyclic heteroaryl containing 1, 2,
or 3 heteroatoms chosen from N, O or S, unsubstituted or
substituted by at least one substituent chosen from halogen atoms,
hydroxyl, cyano, linear or branched C.sub.1-C.sub.6 alkyl or
C.sub.1-C.sub.4 haloalkyl; and each Rb is independently chosen from
cyano, C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4 alkoxy,
C.sub.3-C.sub.7 cycloalkyl unsubstituted or substituted by at least
one substituent chosen from halogen atoms, hydroxyl, or cyano;
phenyl unsubstituted or substituted by at least one substituent
chosen from halogen atoms, hydroxyl group, cyano, or linear or
branched C.sub.1-C.sub.6 alkyl.
53. The compound according to claim 45, wherein R.sub.1 is chosen
from a hydrogen atom, halogen atoms, cyano, linear or branched
C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.7 cycloalkyl, or
NR.sub.13R.sub.14, wherein R.sub.13 and R.sub.14 are the same or
different and each is independently chosen from a hydrogen atom,
linear or branched C.sub.1-C.sub.6 alkyl, or C.sub.1-C.sub.4
haloalkyl.
54. The compound according to claim 45, wherein R.sub.2 is chosen
from a hydrogen atom, halogen atoms, cyano, linear or branched
C.sub.1-C.sub.6 alkyl, or C.sub.3-C.sub.7 cycloalkyl.
55. The compound according to claim 45, wherein R.sub.3 is chosen
from a hydrogen atom, halogen atoms, cyano, linear or branched
C.sub.1-C.sub.6 alkyl, or C.sub.3-C.sub.7 cycloalkyl.
56. The compound according to claim 45, wherein R.sub.4 is chosen
from a hydrogen atom, halogen atoms, cyano, linear or branched
C.sub.1-C.sub.6 alkyl, or C.sub.3-C.sub.7 cycloalkyl.
57. The compound according to claim 45, wherein R.sub.5 is chosen
from a hydrogen atom, linear or branched C.sub.1-C.sub.4 alkyl
unsubstituted or substituted by at least one substituent chosen
from hydroxyl, C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4
hydroxyalkyl, or C.sub.3-C.sub.7 cycloalkyl.
58. The compound according to claim 45, wherein R.sub.6 and R.sub.7
are chosen from a hydrogen atom or linear or branched
C.sub.1-C.sub.6 alkyl.
59. The compound according to claim 45, wherein R.sub.9 is chosen
from a hydrogen atom, halogen atoms, hydroxyl, cyano, linear or
branched C.sub.1-C.sub.6 alkyl, or --NH.sub.2.
60. The compound according to claim 45, wherein: R.sub.1 is chosen
from a hydrogen atom, halogen atoms, hydroxyl, cyano, linear or
branched C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.4 haloalkyl,
C.sub.1-C.sub.4 hydroxyalkyl, C.sub.3-C.sub.10 cycloalkyl, or
NR.sub.13R.sub.14; wherein R.sub.13 and R.sub.14 are the same or
different and each is independently chosen from a hydrogen atom,
linear or branched C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.4
haloalkyl, or C.sub.1-C.sub.4 hydroxyalkyl; R.sub.2, R.sub.3 and
R.sub.4 are the same or different and each is independently chosen
from a hydrogen atom, halogen atoms, hydroxyl, cyano, linear or
branched C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.4 haloalkyl,
C.sub.1-C.sub.4 hydroxyalkyl, or C.sub.3-C.sub.10 cycloalkyl;
R.sub.5 is chosen from a hydrogen atom, linear or branched
C.sub.1-C.sub.6 alkyl unsubstituted or substituted by at least one
substituent chosen from a hydroxyl, cyano, C.sub.1-C.sub.4
haloalkyl, C.sub.1-C.sub.4 hydroxyalkyl, C.sub.3-C.sub.10
cycloalkyl, phenyl, or 6-membered, saturated N-containing
heterocyclyl ring; R.sub.6 and R.sub.7 are the same or different
and each is independently chosen from a hydrogen atom or linear or
branched C.sub.1-C.sub.6 alkyl independently unsubstituted or
substituted by at least one substituent chosen from C.sub.1-C.sub.4
haloalkyl or C.sub.1-C.sub.4 hydroxyalkyl; R.sub.9 is chosen from a
hydrogen atom, halogen atoms, hydroxyl, cyano, linear or branched
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4
hydroxyalkyl, or NR.sub.13R.sub.14; wherein R.sub.13 and R.sub.14
are the same or different and each is independently chosen from a
hydrogen atom, linear or branched C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.4 haloalkyl, or C.sub.1-C.sub.4 hydroxyalkyl; R.sub.8
is chosen from linear or branched C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.4 haloalkyl, C.sub.3-C.sub.7 cycloalkyl, phenyl, 5-
to 6-membered monocyclic heteroaryl containing 1, 2, or 3
heteroatoms chosen from N, O or S, 5- to 7-membered heterocyclyl
group containing 1, 2 or 3 heteroatoms chosen from N, O or S, or
--(CH.sub.2).sub.nOR.sub.13 wherein n is chosen from 0 or 1 and
R.sub.13 is linear or branched C.sub.1-C.sub.6 alkyl or
C.sub.1-C.sub.4 haloalkyl; wherein each of the haloalkyl,
cycloalkyl, phenyl, heteroaryl and heterocyclyl is independently
unsubstituted or substituted by at least one Ra; and each of the
alkyl groups is independently unsubstituted or substituted by at
least one Rb; each Ra is independently chosen from halogen atoms,
cyano, hydroxyl, linear or branched C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4 alkoxy, C.sub.3-C.sub.7
cycloalkyl unsubstituted or substituted by at least one Re, phenyl
unsubstituted or substituted by at least one Re, 5- to 6-membered
monocyclic heteroaryl containing 1, 2, or 3 heteroatoms chosen from
N, O or S, unsubstituted or substituted by one or more Re, or
6-membered, saturated N-containing heterocyclyl ring, unsubstituted
or substituted by at least one substituent chosen from Re,
--C(O)OR.sub.10, or --C(O)--(CH.sub.2).sub.n--R.sub.10 wherein n is
chosen from 0 or 1, each Rb is independently chosen from cyano,
C.sub.1-C.sub.4 haloalkyl, a C.sub.1-C.sub.4 alkoxy, a
C.sub.3-C.sub.7 cycloalkyl unsubstituted or substituted by at least
one Re, phenyl unsubstituted or substituted by at least one Re, 5-
to 6-membered monocyclic heteroaryl containing 1, 2, or 3
heteroatoms chosen from N, O or S, unsubstituted or substituted by
at least one Re, 6-membered, saturated N-containing heterocyclyl
ring, unsubstituted or substituted by at least one substituent
chosen from Re, --C(O)OR.sub.10, or
--C(O)--(CH.sub.2).sub.n--R.sub.10 wherein n is chosen from 0 or 1;
each R.sub.10 group in --C(O)OR.sub.10 is independently chosen from
a hydrogen atom, linear or branched C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.4 haloalkyl, C.sub.3-C.sub.7 cycloalkyl, phenyl, 5-
to 6-membered monocyclic heteroaryl containing 1, 2, or 3
heteroatoms chosen from N, O or S, or 5- to 6-membered, saturated
N-containing heterocyclyl ring; and each R.sub.10 group in
--C(O)--(CH.sub.2).sub.n--R.sub.10 is independently chosen from
cyano, linear or branched C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.4
haloalkyl, C.sub.3-C.sub.7 cycloalkyl, phenyl, 5- to 6-membered
monocyclic heteroaryl containing 1, 2, or 3 heteroatoms chosen from
N, O or S, or 5- to 6-membered, saturated N-containing heterocyclyl
ring; wherein the cycloalkyl, phenyl, heteroaryl and heterocyclyl
are independently unsubstituted or substituted by at least one
substituent chosen from hydroxyl, cyano, linear or branched
C.sub.1-C.sub.6 alkyl or C.sub.1-C.sub.4 haloalkyl.
61. The compound according to 60, wherein Z is NR.sub.5.
62. The compound according to 60, wherein: m is chosen from 0, 1,
or 2; Z is NR.sub.5; R.sub.1 is chosen from a hydrogen atom or
--NH.sub.2; R.sub.2, R.sub.4, R.sub.5, R.sub.6, and R.sub.7 are
each independently chosen from a hydrogen atom or linear or
branched C.sub.1-C.sub.3 alkyl; R.sub.3 is chosen from a hydrogen
atom, cyano, or linear or branched C.sub.1-C.sub.3 alkyl; R.sub.8
is chosen from linear or branched C.sub.1-C.sub.6 alkyl;
C.sub.1-C.sub.4 haloalkyl; C.sub.3-C.sub.7 cycloalkyl unsubstituted
or substituted by at least one substituent chosen from halogen
atoms or hydroxyl; phenyl unsubstituted or substituted by at least
one halogen atom; --(CH.sub.2).sub.n--OR.sub.13 wherein n is chosen
from 0 or 1 and R.sub.13 is a linear or branched C.sub.1-C.sub.3
alkyl; pyridyl unsubstituted or substituted by at least one
substituent chosen from halogen atoms, hydroxyl, or cyano;
tetrahydropyranyl, unsubstituted or substituted by at least one
substituent chosen from halogen atoms or hydroxyl; piperidinyl
unsubstituted or substituted by at least one substituent chosen
from linear or branched C.sub.1-C.sub.3 alkyl or halogen atoms; or
1,2,4-triazolyl; and R.sub.9 is chosen from a hydrogen atom,
halogen atoms, or a linear or branched C.sub.1-C.sub.3 alkyl group,
or --NH.sub.2.
63. The compound according to 62, wherein R.sub.8 is chosen from a
linear or branched C.sub.1-C.sub.6 alkyl; C.sub.1-C.sub.4
haloalkyl; C.sub.3-C.sub.7 cycloalkyl unsubstituted or substituted
by at least one substituent chosen from halogen atoms or hydroxyl;
phenyl unsubstituted or substituted by at least one halogen atom;
--(CH.sub.2).sub.n--OR.sub.3 wherein n is chosen from 0 or 1 and
R.sub.13 is a linear or branched C.sub.1-C.sub.3 alkyl; pyridyl
unsubstituted or substituted by at least one substituent chosen
from halogen atoms, hydroxyl, or cyano; tetrahydropyranyl
unsubstituted or substituted by at least one substituent chosen
from halogen atoms or hydroxyl; piperidinyl substituted by at least
one substituent, wherein the substitution is at least on the ring
nitrogen of the piperidinyl and is chosen from linear or branched
C.sub.1-C.sub.3 alkyl or halogen atoms; or 1,2,4-triazolyl.
64. The compound according to claim 45, wherein: m is chosen from
0, 1, or 2; Z is NR.sub.5; R.sub.1 is chosen from a hydrogen atom
or --NH.sub.2; R.sub.2, R.sub.4, R.sub.5, R.sub.6, and R.sub.7 are
each independently chosen from a hydrogen atom or linear or
branched C.sub.1-C.sub.3 alkyl; R.sub.3 is chosen from a hydrogen
atom, cyano, or linear or branched C.sub.1-C.sub.3 alkyl; R.sub.8
is chosen from linear or branched C.sub.1-C.sub.6 alkyl;
C.sub.1-C.sub.4 haloalkyl; C.sub.3-C.sub.7 cycloalkyl unsubstituted
or substituted by at least one hydroxyl; phenyl unsubstituted or
substituted by at least one halogen atom;
--(CH.sub.2).sub.n--OR.sub.13 wherein n is chosen from 0 or 1 and
R.sub.13 is a linear or branched C.sub.1-C.sub.3 alkyl; piperidinyl
unsubstituted or substituted by at least one pyridyl, wherein the
pyridyl is unsubstituted or substituted by at least one cyano; or
--C(O)--(CH.sub.2).sub.n--R.sub.13, wherein n is chosen from 0 or 1
and R.sub.13 is chosen from cyano, linear or branched
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.4 haloalkyl, or
C.sub.3-C.sub.7 cycloalkyl; and R.sub.9 is chosen from a hydrogen
atom, halogen atoms, or linear or branched C.sub.1-C.sub.3
alkyl.
65. The compound according to claim 45, wherein the compound is of
formula (I-a): ##STR00103## wherein m is chosen from 0, 1 or 2; X
is a nitrogen atom; R.sub.1 is chosen from a hydrogen atom or
--NH.sub.2; R.sub.3 is chosen from a hydrogen atom, cyano, or
linear or branched C.sub.1-C.sub.3 alkyl; R.sub.2, R.sub.4,
R.sub.5, R.sub.6 and R.sub.7 are each independently chosen from a
hydrogen atom or linear or branched C.sub.1-C.sub.3 alkyl; R.sub.8
is chosen from linear or branched C.sub.1-C.sub.6 alkyl;
C.sub.1-C.sub.4 haloalkyl; C.sub.3-C.sub.7 cycloalkyl unsubstituted
or substituted by at least one hydroxyl; phenyl unsubstituted or
substituted by at least one halogen atom;
--(CH.sub.2).sub.n--OR.sub.13 wherein n is chosen from 0 or 1 and
R.sub.13 is linear or branched C.sub.1-C.sub.3 alkyl; piperidinyl
unsubstituted or substituted by at least one pyridyl, wherein the
pyridyl is unsubstituted or substituted by at least one cyano; or
--C(O)--(CH.sub.2).sub.n--R.sub.13, wherein n is chosen from 0 or 1
and R.sub.13 is chosen from cyano, linear or branched
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.4 haloalkyl or C.sub.3-C.sub.7
cycloalkyl; and R.sub.9 is chosen from a hydrogen atom, halogen
atoms, or linear or branched C.sub.1-C.sub.3 alkyl.
66. The compound according to 65, wherein: m is chosen from 0 or 1;
R.sub.1, R.sub.2 and R.sub.4 are hydrogen atoms; R.sub.3 is chosen
from a hydrogen atom or cyano; R.sub.8 is chosen from linear or
branched C.sub.1-C.sub.6 alkyl; C.sub.1-C.sub.4 haloalkyl;
C.sub.3-C.sub.7 cycloalkyl unsubstituted or substituted by at least
one hydroxyl; phenyl unsubstituted or substituted by at least one
halogen atom; --(CH.sub.2).sub.n--OR.sub.13 wherein n is chosen
from 0 or 1 and R.sub.13 is linear or branched C.sub.1-C.sub.3
alkyl; piperidinyl unsubstituted or substituted by at least one
substituent chosen from pyridyl, wherein the pyridyl is
unsubstituted or substituted by at least one cyano; or
--C(O)--(CH.sub.2).sub.n--R.sub.13, wherein n is chosen from 0 or 1
and R.sub.13 is chosen from cyano, linear or branched
C.sub.1-C.sub.3 alkyl, or C.sub.1-C.sub.4 haloalkyl.
67. A method of treating a pathological condition or disease
susceptible to amelioration by inhibition of Janus kinases
comprising administering to a subject in need thereof an effective
amount of a compound according to claim 45.
68. The method according to claim 67, wherein the pathological
condition or disease is chosen from myeloproliferative disorders,
leukemia, lymphoid malignancies and solid tumors, bone marrow and
organ transplant rejection, immune-mediated diseases, or
inflammatory diseases.
69. The method according to claim 68, wherein the pathological
condition or disease is chosen from myeloproliferative disorders,
leukemia, or lymphoid malignancies and solid tumors.
70. The method according to claim 68, wherein the pathological
condition or disease is chosen from bone marrow and organ
transplant rejection, immune-mediated diseases, or inflammatory
diseases.
71. The method according to claim 67, wherein the pathological
condition or disease is chosen from rheumatoid arthritis, multiple
sclerosis, inflammatory bowel disease, dry eye, uveitis, allergic
conjunctivitis, allergic rhinitis, asthma, chronic obstructive
pulmonary disease, atopic dermatitis, or psoriasis.
72. The compound according to claim 45, wherein the compound is of
formula (I-b): ##STR00104## wherein m is chosen from 0, 1, or 2; X
is a nitrogen atom; R.sub.1 is chosen from a hydrogen atom or
--NH.sub.2; R.sub.2, R.sub.4, R.sub.5, R.sub.6 and R.sub.7 are each
independently chosen from a hydrogen atom or linear or branched
C.sub.1-C.sub.3 alkyl; R.sub.8 is chosen from linear or branched
C.sub.1-C.sub.6 alkyl; C.sub.1-C.sub.4 haloalkyl; C.sub.3-C.sub.7
cycloalkyl unsubstituted or substituted by at least one hydroxyl;
phenyl unsubstituted or substituted by at least one halogen atom;
(CH.sub.2).sub.n--OR.sub.13 wherein n is chosen from 0 or 1 and
R.sub.13 is a linear or branched C.sub.1-C.sub.3 alkyl; piperidinyl
unsubstituted or substituted by at least one substituent chosen
from pyridyl, wherein the pyridyl is unsubstituted or substituted
by at least one cyano; or --C(O)--(CH.sub.2).sub.n--R.sub.13,
wherein n is chosen from 0 or 1 and R.sub.13 is chosen from cyano,
linear or branched C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.4 haloalkyl
or C.sub.3-C.sub.7 cycloalkyl; and R.sub.9 is chosen from a
hydrogen atom, halogen atoms, or linear or branched C.sub.1-C.sub.3
alkyl.
73. The compound according to claim 72, wherein m is chosen from 0
or 1; R.sub.1 and R.sub.2 are hydrogen atoms; R.sub.8 is chosen
from linear or branched C.sub.1-C.sub.6 alkyl; C.sub.3-C.sub.7
cycloalkyl unsubstituted or substituted by at least one hydroxyl;
phenyl unsubstituted or substituted by at least one halogen atom;
piperidinyl unsubstituted or substituted by at least one pyridyl,
wherein the pyridyl is unsubstituted or substituted by at least one
cyano; or --C(O)--(CH.sub.2).sub.n--R.sub.13, wherein n is chosen
from 0 or 1 and R.sub.13 is chosen from cyano, linear or branched
C.sub.1-C.sub.3 alkyl or C.sub.1-C.sub.3 haloalkyl.
Description
[0001] Cytokines have critical functions in regulating many aspects
of immunity and inflammation, ranging from the development and
differentiation of immune cells to the suppression of immune
responses. Type I and type II cytokine receptors lack intrinsic
enzymatic activity capable of mediating signal transduction, and
thus require association with tyrosine kinases for this purpose.
The JAK family of kinases comprises four different members, namely
JAK1, JAK2, JAK3 and TYK2, which bind to type I and type II
cytokine receptors for controlling signal transduction (Murray P J,
(2007). The JAK-STAT signalling pathway: input and output
integration. J Immunol, 178: 2623). Each of the JAK kinases is
selective for the receptors of certain cytokines. In this regard,
JAK-deficient cell lines and mice have validated the essential role
of each JAK protein in receptor signalling: JAK1 in class II
cytokine receptors (IFN and IL-10 family), those sharing the gp130
chain (IL-6 family) and the common gamma chain (IL-2, IL-4, IL-7,
IL-9, IL-15 and IL-21) (Rodig et at. (1998). Disruption of the JAK1
gene demonstrates obligatory and nonredundant roles of the Jaks in
cytokine-induced biological response. Cell, 93:373; Guschin et at.
(1995). A major role for the protein tyrosine kinase JAK1 in the
JAK/STAT signal transduction pathway in response to interleukin-6.
EMBO J. 14: 1421; Briscoe et at. (1996). Kinase-negative mutants of
JAK1 can sustain interferon-gamma-inducible gene expression but not
an antiviral state. EMBO J. 15:799); JAK2 in hematopoietic factors
(Epo, Tpo, GM-CSF, IL-3, IL-5) and type II IFNs (Parganas et al.,
(1998). JAK2 is essential for signalling through a variety of
cytokine receptors. Cell, 93:385); JAK3 in receptors sharing the
common gamma chain (IL-2 family) (Park et al., (1995).
Developmental defects of lymphoid cells in JAK3 kinase-deficient
mice. Immunity, 3:771; Thomis et al., (1995). Defects in B
lymphocyte maturation and T lymphocyte activation in mice lacking
JAK3. Science, 270:794; Russell et al, (1995). Mutation of JAK3 in
a patient with SCID: Essential role of JAK3 in lymphoid
development. Science, 270:797); and Tyk2 in the receptors of IL-12,
IL-23, IL-13 and type I IFNs (Karaghiosoff et al., (2000). Partial
impairment of cytokine responses in Tyk2-deficient mice. Immunity,
13:549; Shimoda et al., (2000). Tyk2 plays a restricted role in
IFNg signaling, although it is required for IL-12-mediated T cell
function. Immunity, 13:561; Minegishi et al., (2006). Human
Tyrosine kinase 2 deficiency reveals its requisite roles in
multiple cytokine signals involved in innate and acquired immunity.
Immunity, 25:745).
[0002] Receptor stimulation leads sequentially to JAK activation by
phosphorylation, receptor phosphorylation, STAT protein recruitment
and STAT activation and dimerization. The STAT dimer then functions
as a transcription factor, translocating to the nucleus and
activating the transcription of multiple response genes. There are
seven STAT proteins identified: STAT1, STAT2, STAT3, STAT4, STAT5a,
STAT5b and STAT6. Each particular cytokine receptor associates
preferentially with a particular STAT protein. Some associations
are independent of cell type (ex: IFNg-STAT1) while others may be
cell type dependent (Murray P J, (2007). The JAK-STAT signaling
pathway: input and output integration. J Immunol, 178: 2623).
[0003] The phenotype of deficient mice has provided insights on the
function of each JAK and the cytokine receptors signaling through
them. JAK3 associates exclusively with the common gamma chain of
the receptors for IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21
cytokines. By virtue of this exclusive association, JAK3 knock out
mice and common gamma chain deficient mice have an identical
phenotype (Thomis et al., (1995). Defects in B lymphocyte
maturation and T lymphocyte activation in mice lacking JAK3.
Science, 270:794; DiSanto et at., (1995). Lymphoid development in
mice with a targeted deletion of the interleukin 2 receptor gamma
chain. PNAS, 92:377). Moreover, this phenotype is shared to a great
extent with SCID patients that hold mutations/defects in the common
gamma chain or JAK3 genes (O'Shea et al, (2004). JAK3 and the
pathogenesis of severe combined immunodeficiency. Mol Immunol, 41:
727). JAK3-deficient mice are viable but display abnormal
lymphopoiesis which leads to a reduced thymus size (10-100 fold
smaller than wild type). JAK3-deficient peripheral T cells are
unresponsive and have an activated/memory cell phenotype (Baird et
al, (1998). T cell development and activation in JAK3-deficient
mice. J. Leuk. Biol. 63: 669). The thymic defect in these mice
strongly resembles that seen in IL-7 and IL-7 receptor knockout
mice, suggesting that the absence of IL-7 signaling accounts for
this defect in JAK3 -/-mice (von Freeden-Jeffry et al, (1995).
Lymphopenia in Interleukin (IL)-7 Gene-deleted Mice Identifies IL-7
as a non-redundant Cytokine. J Exp Med, 181:1519; Peschon et al,
(1994). Early lymphocyte expansion is severely impaired in
interleukin 7 receptor-deficient mice. J Exp Med, 180: 1955). These
mice, like SCID humans, have no NK cells, probably due to the
absence of IL-15 signaling, a survival factor for these cells. JAK3
knockout mice, unlike SCID patients, show deficient B cell
lymphopoiesis while in human patients, B cells are present in
circulation but are not responsive leading to hypoglobulinemia
(O'Shea et al, (2004). JAK3 and the pathogenesis of severe combined
immunodeficiency. Mol Immunol, 41: 727). This is explained by
species-specific differences in IL-7 function in B and T cell
development in mice and humans. On the other hand, Grossman et al.
(1999. Dysregulated myelopoiesis in mice lacking JAK3. Blood,
94:932:939) have shown that the loss of JAK3 in the T-cell
compartment drives the expansion of the myeloid lineages leading to
dysregulated myelopoiesis.
[0004] JAK2-deficient mice are embrionically lethal, due to the
absence of definitive erythropoiesis. Myeloid progenitors fail to
respond to Epo, Tpo, IL-3 or GM-CSF, while G-CSF and IL-6 signaling
are not affected. JAK2 is not required for the generation,
amplification or functional differentiation of lymphoid progenitors
(Parganas et al., (1998). JAK2 is essential for signaling through a
variety of cytokine receptors. Cell, 93:385).
[0005] JAK1-deficient mice die perinatally due to a nursing defect.
JAK1 binds exclusively to the gp130 chain shared by the IL-6
cytokine family (i.e. LIF, CNTF, OSM, CT-1) and along with JAK3, is
an essential component of the receptors sharing the common gamma
chain, by binding to the non-shared receptor subunit. In this
regard, JAK1-deficient mice show similar hematopoiesis defects as
JAK3-deficient mice. In addition, they show defective responses to
neurotrophic factors and to all interferons (class II cytokine
receptors) (Rodig et al, (1998). Disruption of the JAK1 gene
demonstrates obligatory and non-redundant roles of the Jaks in
cytokine-induced biological response. Cell, 93:373).
[0006] Finally, Tyk2-deficient mice show an impaired response to
IL-12 and IL-23 and only partially impaired to IFN-alpha
(Karaghiosoff et al., (2000). Partial impairment of cytokine
responses in Tyk2-deficient mice. Immunity, 13:549; Shimoda et al.,
(2000). Tyk2 plays a restricted role in IFNg signaling, although it
is required for IL-12-mediated T cell function. Immunity, 13:561).
However, human Tyk2 deficiency demonstrates that Tyk2 is involved
in the signaling from IFN-.alpha., IL-6, IL-10, IL-12 and IL-23
(Minegishi et al., (2006). Human Tyrosine kinase 2 deficiency
reveals its requisite roles in multiple cytokine signals involved
in innate and acquired immunity. Immunity, 25:745).
[0007] The role of JAK kinases in transducing the signal from a
myriad of cytokines makes them potential targets for the treatment
of diseases in which cytokines have a pathogenic role, such as
inflammatory diseases, including but not limited to allergies and
asthma, chronic obstructive pulmonary disease (COPD), psoriasis,
autoimmune diseases such as rheumatoid arthritis, amyotrophic
lateral sclerosis and multiple sclerosis, uveitis, transplant
rejection, as well as in solid and hematologic malignancies such as
myeloproliferative disorders, leukemia and lymphomas.
[0008] Inhibition of JAK kinases, especially JAK1 and JAK3, could
give rise to potent immunosuppression which could be used
therapeutically to prevent transplant rejection. In this regard,
the JAK inhibitor CP-690,550 (tasocitinib) has shown efficacy in
several animal models of transplantation (heretopic heart
transplantation in mice, cardiac allografts implanted in the ear of
mice, renal allotransplantation in cynomolgous monkeys, aorta and
tracheal transplantation in rats) by prolonging the mean survival
time of grafts (West K (2009). CP-690,550, a JAK3 inhibitor as an
immunosuppressant for the treatment of rheumatoid arthritis,
transplant rejection, psoriasis and other immune-mediated
disorders. Curr. Op. Invest. Drugs 10: 491).
[0009] In rheumatoid joints, an imbalance between pro and
anti-inflammatory cytokine activities favours the induction of
autoimmunity, followed by chronic inflammation and tissue
destruction. In this regard, the pathogenic role of IL-6 in
rheumatoid arthritis (RA) has been validated clinically by the use
of the anti-IL-6R antibody tocilizumab. IL-6 activates the
transcription factor STAT3, through the use of JAK1 binding to the
gp130 receptor chain (Heinrich et al., (2003). Principles of
interleukin (IL)-6-type cytokine signaling and its regulation.
Biochem J. 374: 1). Constitutive STAT3 mediates the abnormal growth
and survival properties of RA synoviocytes (Ivashkiv and Hu (2003).
The JAK/STAT pathway in rheumatoid arthritis: pathogenic or
protective? Arth & Rheum. 48:2092). Other cytokines that have
been implicated in the pathogenesis of arthritis include IL-12 and
IL-23, implicated in Th1 and Th17 cell proliferation, respectively;
IL-15, and GM-CSF (McInnes and Schett, (2007). Cytokines in the
pathogenesis of rheumatoid arthritis. Nature Rew Immunol. 7:429.).
The receptors for these cytokines also utilize JAK proteins for
signal transduction, making JAK inhibitors potential pleiotropic
drugs in this pathology. Consequently, administration of several
JAK inhibitors in animal models of murine collagen-induced
arthritis and rat adjuvant-induced arthritis has shown to reduce
inflammation, and tissue destruction (Milici et al., (2008).
Cartilage preservation by inhibition of Janus kinase 3 in two
rodent models of rheumatoid arthritis. Arth. Res. 10:R14).
[0010] Inflammatory bowel disease (IBD) encloses two major forms of
intestinal inflammation: ulcerative colitis and Crohn's disease.
Growing evidence has shown that multiple cytokines, including
interleukins and interferons, are involved in the pathogenesis of
IBD (Strober et al, (2002). The immunology of mucosal models of
inflammation. Annu Rev Immunol. 20: 495). Activation of the
IL-6STAT3 cascade in lamina propia T cells has been shown to induce
prolonged survival of pathogenic T cells (Atreya et al, (2000).
Blockade of interleukin 6 trans signaling suppresses T-cell
resistance against apoptosis in chronic intestinal inflammation:
Evidence in Crohn's disease and experimental colitis in vivo.
Nature Med. 6:583). Specifically, STAT3 has been shown to be
constitutively active in intestinal T cells of Crohn's disease
patients and a JAK inhibitor has been shown to block the
constitutive activation of STAT3 in these cells (Lovato et al,
(2003). Constitutive STAT3 activation in intestinal T cells from
patients with Crohn's disease. J Biol Chem. 278:16777). These
observations indicate that the JAK-STAT pathway plays a pathogenic
role in IBD and that a JAK inhibitor could be therapeutic in this
setting.
[0011] Multiple sclerosis is an autoimmune demyelinating disease
characterized by the formation of plaques in the white matter. The
role of cytokines in the generation of multiple sclerosis has long
been known. Potential therapies include blockade of IFN-g, IL-6,
IL-12 and IL-23 (Steinman L. (2008). Nuanced roles of cytokines in
three major human brain disorders. J Clin Invest. 118:3557),
cytokines that signal through the JAK-STAT pathways. Use of
tyrphostin, a JAK inhibitor, has been shown to inhibit
IL-12-induced phosphorylation of STAT3, and to reduce the incidence
and severity of active and passive experimental autoimmune
encephalitis (EAE) (Bright et al., (1999) Tyrphostin B42 inhibits
IL-12-induced tyrosine phosphorylation and activation of Janus
kinase-2 and prevents experimental allergic encephalomyelitis. J
Immunol. 162:6255). Another multikinase inhibitor, CEP701, has been
shown to reduce secretion of TNF-alpha, IL-6 and IL-23 as well as
the levels of phospho-STAT1, STAT3, and STATS in peripheral DCs of
mice with EAE, significantly improving the clinical course of EAE
in mice (Skarica et al, (2009). Signal transduction inhibition of
APCs diminishes Th17 and Th1 responses in experimental autoimmune
encephalomyelitis. J. Immunol. 182:4192.).
[0012] Psoriasis is a skin inflammatory disease which involves a
process of immune cell infiltration and activation that culminates
in epithelial remodeling. The current theory behind the cause of
psoriasis states the existence of a cytokine network that governs
the interaction between immune and epithelial cells (Nickoloff B J.
(2007). Cracking the cytokine code in psoriasis, Nat Med, 13:242).
In this regard, IL-23 produced by dendritic cells is found elevated
in psoriatic skin, along with IL-12. IL-23 induces the formation of
Th17 cells which in turn produce IL-17 and IL-22, the last one
being responsible for epidermis thickening. IL-23 and IL-22 induce
the phosphorylation of STAT-3, which is found abundantly in
psoriatic skin. JAK inhibitors may thus be therapeutic in this
setting. In accordance, a JAK1/3 inhibitor, R348, has been found to
attenuate psoriasiform skin inflammation in a spontaneous T
cell-dependent mouse model of psoriasis (Chang et al., (2009). JAK3
inhibition significantly attenuates psoriasiform skin inflammation
on CD18 mutant PL/J mice. J Immunol. 183:2183).
[0013] Th2 cytokine-driven diseases such as allergy and asthma
could also be a target of JAK inhibitors. IL-4 promotes Th2
differentiation, regulates B-cell function and immunoglobulin class
switching, regulates eotaxin production, induces expression of IgE
receptor and MHC II on B cells, and stimulates mast cells. Other
Th2 cytokines like IL-5 and IL-13 can also contribute to eosinophil
recruitment in bronchoalveolar lavage by stimulating eotaxin
production. Pharmacological inhibition of JAK has been shown to
reduce the expression of IgE receptor and MHCII induced by IL-4
stimulation on B cells (Kudlacz et al., (2008). The JAK3 inhibitor
CP-690,550 is a potent anti-inflammatory agent in a murine model of
pulmonary eosinophilia. European J. Pharm. 582: 154). Furthermore,
JAK3-deficient mice display poor eosinophil recruitment and mucus
secretion to the airway lumen upon OVA challenge, as compared to
wild type mice (Malaviya et al, (2000). Treatment of allergic
asthma by targeting Janus kinase 3-dependent leukotriene synthesis
in mast cells with
4-(3',5'-dibromo-4'-hydroxyphenyl)amino-6,7-dimethoxyquinazoline
(WHI-P97). JPET 295:912.). In this regard, systemic administration
of the CP-690,550 JAK inhibitor in mice has been shown to reduce
the eosinophil count as well as the levels of eotaxin and IL13 in
BAL in a murine model of pulmonary eosinophilia (Kudlacz et al.,
(2008). The JAK3 inhibitor CP-690,550 is a potent anti-inflammatory
agent in a murine model of pulmonary eosinophilia. European J.
Pharm. 582:154).
[0014] There is increasing evidence that cytokines play a
pathogenetic role in ocular inflammatory disease such as uveitis or
dry eye syndrome. Some cytokines implicated in experimental
autoimmune uveitis, such as IL-2, IL-6, IL-12 and IFNg, would be
amenable to JAK inhibition (Vallochi et al, (2007). The role of
cytokines in the regulation of ocular autoimmune inflammation.
Cytok Growth Factors Rev. 18:135). In this regard, drugs or
biologicals that interfere with IL-2 signaling such as cyclosporine
or anti-IL-2 receptor antibody (daclizumab) have shown efficacy in
the treatment of keratoconjuctivitis sicca and refractory uveitis,
respectively (Lim et al, (2006). Biologic therapies for
inflammatory eye disease. Clin Exp Opht 34:365). Similarly,
allergic conjunctivitis, a common allergic eye disease
characterized by conjuctival congestion, mast cell activation and
eosinophil infiltration, could benefit from JAK inhibition.
STAT6-deficient mice, showing decreased TH2-mediated immune
responses which are normally triggered by IL-4, do not develop the
classical early and late phase responses, suggesting that IL-4
pathway abrogation through JAK inhibition may be therapeutic in
this setting (Ozaki et al, (2005). The control of allergic
conjunctivitis by suppression of cytokine signaling (SOCS)3 and
SOCS5 in a murine model. J Immunol, 175:5489).
[0015] There is growing evidence of the critical role of STAT3
activity in processes involved in tumorigenesis like cell cycle
dysregulation, promotion of uncontrolled growth, induction of
survival factors and inhibition of apoptosis (Siddiquee et al.,
(2008). STAT3 as a target for inducing apoptosis in solid and
haematological tumors. Cell Res. 18: 254). Antagonism of STAT3 by
means of dominant-negative mutants or antisense oligonucleotides
has shown to promote apoptosis of cancer cells, inhibition of
angiogenesis and up-regulation of host immunocompetence. Inhibition
of constitutively active STAT3 in human tumors by means of JAK
inhibitors may provide a therapeutic option to the treatment of
this disease. In this regard, the use of the JAK inhibitor
tyrphostin has been shown to induce apoptosis of malignant cells
and inhibit cell proliferation in vitro and in vivo (Meydan et al.,
(1996). Inhibition of acute lymphoblastic leukemia by a JAK-2
inhibitor. Nature, 379:645).
[0016] Hematological malignancies with dysregulated JAK-STAT
pathways may benefit from JAK inhibition. Recent studies have
implicated dysregulation of JAK2 kinase activity by chromosomal
translocations and mutations within the pseudokinase domain (such
as the JAK2V617F mutation) in a spectrum of myeloproliferative
diseases (Ihle and Gililand, 2007), including polycythemia vera,
myelofibrosis and essential thrombocythemia. In this regard,
several JAK inhibitors that tackle JAK2 potently, such as TG-101209
(Pardanani et al., (2007). TG101209, a small molecular
JAK2-selective inhibitor potently inhibits myeloproliferative
disorder-associated JAK2V617F and MPLW515L/K mutations Leukemia.
21:1658-68), TG101348 (Wernig et al, (2008). Efficacy of TG101348,
a selective JAK2 inhibitor, in treatment of a murine model of
JAK2V617F-induced polycythemia vera. Cancer Cell, 13: 311), CEP701,
(Hexner et al, (2008). Lestaurtinib (CEP701) is a JAK2 inhibitor
that suppresses JAK2STATS signaling and the proliferation of
primary erythroid cells from patients with myeloproliferative
disorders. Blood, 111: 5663), CP-690,550 (Manshouri et al, (2008).
The JAK kinase inhibitor CP-690,550 suppresses the growth of human
polycythemia vera cells carrying the JAK2V617F mutation. Cancer
Sci, 99:1265), and CYT387 (Pardanani et al., (2009). CYT387, a
selective JAK1/JAK2 inhibitor: invitro assessment of kinase
selectivity and preclinical studies using cell lines and primary
cells from polycythemia vera patients. Leukemia, 23:1441) have been
proposed for treating myeloproliferative diseases on the basis of
their antiproliferative activity on cells carrying the JAK2V617F
mutation. Similarly, T-cell leukemia due to human T-cell leukemia
virus (HTLV-1) transformation is associated with JAK3 and STAT5
constitutive activation (Migone et al, (1995). Constitutively
activated JAK-STAT pathway in T cells transformed with HTLV-I.
Science, 269: 79) and JAK inhibitors may be therapeutic in this
setting (Tomita et al, (2006). Inhibition of constitutively active
JAK-STAT pathway suppresses cell growth of human T-cell leukemia
virus type I-infected T cell lines and primary adult T-cell
leukemia cells. Retrovirology, 3:22). JAK1-activating mutations
have also been identified in adult acute lymphoblastic leukemia of
T cell origin (Flex et al, (2008). Somatically acquired JAK1
mutations in adult acute lymphoblastic leukemia. J. Exp. Med.
205:751-8) pointing to this kinase as a target for the development
of novel antileukemic drugs.
[0017] Conditions in which targeting of the JAK pathway or
modulation of the JAK kinases, particularly JAK1, JAK2 and JAK3
kinases, are contemplated to be therapeutically useful for the
treatment or prevention of diseases include: neoplastic diseases
(e.g. leukemia, lymphomas, solid tumors); transplant rejection,
bone marrow transplant applications (e.g., graft-versus-host
disease); autoimmune diseases (e.g. diabetes, multiple sclerosis,
rheumatoid arthritis, inflammatory bowel disease); respiratory
inflammation diseases (e.g. asthma, chronic obstructive pulmonary
disease), inflammation-linked ocular diseases or allergic eye
diseases (e.g. dry eye, glaucoma, uveitis, diabetic retinopathy,
allergic conjunctivitis or age-related macular degeneration) and
skin inflammatory diseases (e.g., atopic dermatitis or
psoriasis).
[0018] In view of the numerous conditions that are contemplated to
benefit by treatment involving modulation of the JAK pathway or of
the JAK kinases it is immediately apparent that new compounds that
modulate JAK pathways and use of these compounds should provide
substantial therapeutic benefits to a wide variety of patients.
[0019] Provided herein are novel heteroaryl imidazolone derivatives
for use in the treatment of conditions in which targeting of the
JAK pathway or inhibition of JAK kinases can be therapeutically
useful.
[0020] The compounds described in the present invention are
simultaneously potent JAK1, JAK2 and JAK3 inhibitors, i.e. pan-JAK
inhibitors. This property makes them useful for the treatment or
prevention of pathological conditions or diseases such as
myeloproliferative disorders (such as polycythemia vera, essential
thrombocythemia or myelofibrosis), leukemia, lymphomas and solid
tumors; bone marrow and organ transplant rejection; or
immune-mediated diseases such as autoimmune and inflammation
diseases, including rheumatoid arthritis, multiple sclerosis,
inflammatory bowel disease (such as ulcerative colitis or Crohn's
disease), inflammation-linked ocular diseases or allergic eye
diseases (such as dry eye, uveitis, or allergic conjunctivitis),
allergic rhinitis, asthma, chronic obstructive pulmonary disease
(COPD), and skin inflammatory diseases (such as atopic dermatitis
or psoriasis).
[0021] It has now been found that certain pyrazole derivatives are
novel and potent JAK inhibitors and can therefore be used in the
treatment or prevention of these diseases.
[0022] Thus the present invention is directed to compounds which
are pyrazole derivatives of formula (I), or a pharmaceutically
acceptable salt, or solvate, or N-oxide, or stereoisomer or
deuterated derivative thereof:
##STR00002##
wherein m is 0 or an integer from 1 to 3; Z represents an oxygen
atom or a group NR.sub.5; W represents a nitrogen atom or a
--CR.sub.3 group; X, Y and T independently represent a nitrogen
atom or a --CR.sub.9 group, wherein when one of X, Y or T
represents a nitrogen atom the remaining represent a --CR.sub.9
group; R.sub.1, R.sub.2, R.sub.3, R.sub.4 and R.sub.9 each
independently represent a hydrogen atom, a halogen atom, a cyano
group, a linear or branched C.sub.1-C.sub.6 alkyl group, a
C.sub.2-C.sub.4 alkenyl group, a C.sub.2-C.sub.4 alkynyl group, a
C.sub.1-C.sub.4 haloalkyl group, a C.sub.1-C.sub.4 hydroxyalkyl
group, a C.sub.3-C.sub.10 cycloalkyl group, a C.sub.3-C.sub.10
cycloalkenyl group, a monocyclic or polycyclic C.sub.5-C.sub.14
aryl group, a 5- to 14-membered heteroaryl group containing at
least one heteroatom selected from O, S and N, a 5- to 14-membered
heterocyclyl group containing at least one heteroatom selected from
O, S and N, a bicyclyl group containing a monocyclic
C.sub.5-C.sub.9 aryl or heteroaryl group bonded directly to a 5- to
9-membered cycloalkyl or heterocyclyl group, said heteroaryl or
heterocyclyl group containing at least one heteroatom selected from
O, S and N, an aza-bicycloalkyl group having up to 12 carbon atoms
or an aza-bicycloalkenyl group having up to 12 carbon atoms, [0023]
wherein the alkenyl, alkynyl, haloalkyl, hydroxyalkyl, cycloalkyl,
cycloalkenyl, aryl, heteroaryl, heterocyclyl, bicyclyl,
aza-bicycloalkyl and aza-bicycloalkenyl groups are unsubstituted or
substituted by one or more substituents selected from substituents
Ra, and the alkyl groups are unsubstituted or substituted by one or
more substituents selected from Rb; or R.sub.1, R.sub.2, R.sub.3,
R.sub.4 and R.sub.9 independently represent a --SR.sub.13 group, a
--SOR.sub.13 group, a --S(O).sub.2R.sub.13 group, a
--S(O).sub.2NR.sub.13R.sub.14 group, a
--NR.sub.13S(O).sub.2R.sub.14 group, a
--NR.sub.13S(O).sub.2NR.sub.14 group, a --(CH.sub.2).sub.nOR.sub.13
group, a --C(O)OR.sub.13 group, a --O--C(O)R.sub.13 group, a
--C(O)--(CH.sub.2).sub.n--R.sub.13 group, a --NR.sub.13R.sub.14
group, a --C(O)--(CH.sub.2).sub.n--NR.sub.13R.sub.14group, a
--NR.sub.13C(O)--(CH.sub.2).sub.n--R.sub.14group or a
--NR.sub.13C(O)--(CH.sub.2).sub.n--NR.sub.14R.sub.15 group, wherein
each n is 0, 1 or 2; or in the case when two adjacent --CR.sub.9
groups are present, two adjacent --CR.sub.9 groups and the carbon
atoms to which they are bonded optionally form a C.sub.5-C.sub.12
aryl group or a 4- to 12-membered heteroaryl, cycloalkyl or
heterocyclyl group, said heteroaryl and heterocyclyl groups
containing at least one heteroatom selected from O, S and N, the
aryl, heteroaryl, cycloalkyl and heterocyclyl groups being
unsubstituted or substituted by one or more substituents selected
from a halogen atom, a linear or branched C.sub.1-C.sub.6 alkyl
group, a monocyclic or polycyclic C.sub.5-C.sub.14aryl group, a 5-
to 14-membered heteroaryl group containing at least one heteroatom
selected from O, S and N, or a 5- to 14-membered heterocyclyl group
containing at least one heteroatom selected from O, S and N,
wherein the alkyl, the aryl, the heteroaryl and the heterocyclyl
substituents are unsubstituted or substituted by one or more
substituents selected from a halogen atom, a hydroxyl group, a
cyano group, a linear or branched C.sub.1-C.sub.6 alkyl group or a
C.sub.1-C.sub.4 haloalkyl group; R.sub.5 represents a hydrogen
atom, a linear or branched C.sub.1-C.sub.6 alkyl group optionally
substituted by one or more substituents selected from a hydroxyl
group, a cyano group, a C.sub.1-C.sub.4 haloalkyl group, a
C.sub.1-C.sub.4 hydroxyalkyl group, a C.sub.3-C.sub.10 cycloalkyl
group, a phenyl group or a 6 membered, saturated N-containing
heterocyclyl ring, or R.sub.5 represents a --S(O).sub.2R.sub.10
group, a --S(O).sub.2NR.sub.10R.sub.11 group, a --C(O)OR.sub.10
group, a --C(O)--(CH.sub.2).sub.n--R.sub.10 group, or a
--C(O)--(CH.sub.2).sub.n--NR.sub.10R.sub.11 group; R.sub.6 and
R.sub.7 each independently represents a hydrogen atom or a linear
or branched C.sub.1-C.sub.6 alkyl group optionally substituted by
one or more substituents selected from a hydroxyl group, a cyano
group, a C.sub.1-C.sub.4 haloalkyl group, a C.sub.1-C.sub.4
hydroxyalkyl group, a C.sub.1-C.sub.4 alkoxycarbonyl group, a
C.sub.3-C.sub.7 cycloalkyl group, a phenyl group or a 6 membered,
saturated N-containing heterocyclyl ring; R.sub.8 represents a
hydrogen atom, a halogen atom, a cyano group, a linear or branched
C.sub.1-C.sub.6 alkyl group, a C.sub.2-C.sub.4 alkenyl group, a
C.sub.2-C.sub.4 alkynyl group, a C.sub.1-C.sub.4 haloalkyl group, a
C.sub.1-C.sub.4 hydroxyalkyl group, a C.sub.3-C.sub.10 cycloalkyl
group, a C.sub.3-C.sub.10 cycloalkenyl group, a monocyclic or
polycyclic C.sub.5-C.sub.14aryl group, a 5- to 14-membered
heteroaryl group containing at least one heteroatom selected from
O, S and N, a 5- to 14-membered heterocyclyl group containing at
least one heteroatom selected from O, S and N, a bicyclyl group
containing a monocyclic C.sub.5-C.sub.9 aryl or heteroaryl group
bonded directly to a 5- to 9-membered cycloalkyl or heterocyclyl
group, said heteroaryl or heterocyclyl group containing at least
one heteroatom selected from O, S and N, an aza-bicycloalkyl group
having up to 12 carbon atoms or a aza-bicycloalkenyl group having
up to 12 carbon atoms, [0024] wherein the alkenyl, alkynyl,
haloalkyl, hydroxyalkyl, cycloalkyl, cycloalkenyl, aryl,
heteroaryl, heterocyclyl, bicyclyl, aza-bicycloalkyl and
aza-bicycloalkenyl groups are unsubstituted or substituted by one
or more substituents selected from Ra, --(C.sub.1-C.sub.4 alkyl)-CN
groups, or --(C.sub.1-C.sub.4 alkyl)-C(O)NR'R'' groups wherein R'
and R'' are the same or different and are selected from hydrogen
atoms and linear or branched C.sub.1-C.sub.4 alkyl groups; and the
alkyl groups are unsubstituted or substituted by one or more
substituents selected from Rb; or R.sub.8 represents a --SR.sub.13
group, a --SOR.sub.13 group, a --S(O).sub.2R.sub.13 group, a
--S(O).sub.2NR.sub.13R.sub.14 group, a
--NR.sub.13S(O).sub.2R.sub.14 group, a
--NR.sub.13S(O).sub.2NR.sub.14 group, a --(CH.sub.2).sub.nOR.sub.13
group, a --C(O)OR.sub.13 group, a --O--C(O)R.sub.13 group, a
--C(O)--(CH.sub.2).sub.n--R.sub.13 group, a --NR.sub.13R.sub.14
group, a --C(O)--(CH.sub.2).sub.n--NR.sub.13R.sub.14 group, a
--NR.sub.13C(O)--(CH.sub.2).sub.n--R.sub.14 group, or a
--NR.sub.13C(O)--(CH.sub.2).sub.n--NR.sub.14R.sub.15group, wherein
each n is 0, 1 or 2, or R.sub.8 together with R.sub.5 and the
nitrogen atom to which R.sub.5 is bonded form a 4- to 10-membered,
saturated heterocyclyl group, which contains, as heteroatoms, one
or two nitrogen atoms and which is substituted by a linear or
branched C.sub.1-C.sub.6 alkyl group, a monocyclic or polycyclic
C.sub.5-C.sub.14 aryl group, a 5- to 14-membered heteroaryl group
containing at least one heteroatom selected from O, S and N, a 5-
to 14-membered heterocyclyl group containing at least one
heteroatom selected from O, S and N, a --SO.sub.2R.sub.10group, a
--C(O)--(CH.sub.2).sub.n--R.sub.10group, or a
--C(O)--(CH.sub.2).sub.n--NR.sub.10R.sub.11 group, wherein each n
is 0, 1 or 2, [0025] wherein the alkyl, aryl, heteroaryl and
heterocyclyl groups are unsubstituted or substituted by one or more
substituents selected from a halogen atom, a hydroxyl group, a
cyano group, a linear or branched C.sub.1-C.sub.6 alkyl group or a
C.sub.1-C.sub.4 haloalkyl group, and wherein the alkyl groups are
unsubstituted or substituted by one or more substituents selected
from a halogen atom, a hydroxyl group, a cyano group or a
C.sub.1-C.sub.4 haloalkyl group; provided that when m is zero,
R.sub.8 is other than a --SR.sub.13 group, a --SOR.sub.13 group, a
--S(O).sub.2R.sub.13 group, a --S(O).sub.2NR.sub.13R.sub.14 group,
a --NR.sub.13S(O).sub.2R.sub.14 group, a
--NR.sub.13S(O).sub.2NR.sub.14 group, a --(CH.sub.2).sub.nOR.sub.13
group, a --O--C(O)R.sub.13 group, a --NR.sub.13R.sub.14 group, a
--NR.sub.13C(O)--(CH.sub.2).sub.n--R.sub.14group, or a
--NR.sub.13C(O)--(CH.sub.2).sub.n--NR.sub.14R.sub.15group,
wherein
[0026] Ra is a halogen atom, a cyano group, a hydroxyl group, a
linear or branched C.sub.1-C.sub.6 alkyl group, a C.sub.1-C.sub.4
haloalkyl group, C.sub.1-C.sub.4 alkoxy group, a C.sub.1-C.sub.4
hydroxyalkyl group, a C.sub.3-C.sub.7 cycloalkyl or a
C.sub.3-C.sub.7 cycloalkenyl group unsubstituted or substituted by
one or more substituents selected from substituents Re, a
monocyclic or polycyclic C.sub.5-C.sub.14 aryl group unsubstituted
or substituted by one or more substituents selected from
substituents Re, a 5- to 14-membered heteroaryl group containing at
least one heteroatom selected from O, S and N unsubstituted or
substituted by one or more substituents selected from substituents
Re, a 5- to 14-membered heterocyclyl group containing at least one
heteroatom selected from O, S and N unsubstituted or substituted by
one or more substituents selected from substituents Re, a
--SR.sub.10 group, a --SOR.sub.10 group, a --S(O).sub.2R.sub.10
group, a --S(O).sub.2NR.sub.10R.sub.11 group, a
--NR.sub.10S(O).sub.2R.sub.11 group, a
--NR.sub.10S(O).sub.2NR.sub.11 group, a --(CH.sub.2).sub.nOR.sub.10
group, a --C(O)OR.sub.10 group, a --O--C(O)R.sub.10 group,
a --C(O)--(CH.sub.2).sub.n--R.sub.10 group, a --NR.sub.10R.sub.11
group, a --C(O)--(CH.sub.2).sub.n--NR.sub.10R.sub.11 group, [0027]
a --NR.sub.10C(O)--(CH.sub.2).sub.n--R.sub.11group or a
--NR.sub.10C(O)--(CH.sub.2).sub.n--NR.sub.11R.sub.12group, wherein
each n is 0, 1 or 2; Rb is a cyano group, a C.sub.1-C.sub.4
haloalkyl group, C.sub.1-C.sub.4 alkoxy group, a C.sub.1-C.sub.4
hydroxyalkyl group, a C.sub.3-C.sub.7 cycloalkyl or a
C.sub.3-C.sub.7 cycloalkenyl group unsubstituted or substituted by
one or more substituents selected from substituents Re, a
monocyclic or polycyclic C.sub.5-C.sub.14 aryl group unsubstituted
or substituted by one or more substituents selected from
substituents Re, a 5- to 14-membered heteroaryl group containing at
least one heteroatom selected from O, S and N unsubstituted or
substituted by one or more substituents selected from substituents
Re, a 5- to 14-membered heterocyclyl group containing at least one
heteroatom selected from O, S and N unsubstituted or substituted by
one or more substituents selected from substituents Re, a
--SR.sub.10 group, a --SOR.sub.10 group, a --S(O).sub.2R.sub.10
group, a --S(O).sub.2NR.sub.10R.sub.11 group, a
--NR.sub.10S(O).sub.2R.sub.11 group, a
--NR.sub.10S(O).sub.2NR.sub.11 group, a --(CH.sub.2).sub.nOR.sub.10
group, a --C(O)OR.sub.10 group, a --O--C(O)R.sub.10 group, a
--C(O)--(CH.sub.2).sub.n--R.sub.10 group, a --NR.sub.10R.sub.11
group, a --C(O)--(CH.sub.2).sub.n--NR.sub.10R.sub.11 group, a
--NR.sub.10C(O)--(CH.sub.2).sub.n--R.sub.11group or a
--NR.sub.10C(O)--(CF.sub.12).sub.n--NR.sub.11R.sub.12group, wherein
each n is 0, 1 or 2; R.sub.10, R.sub.11and R.sub.12 each
independently represents a hydrogen atom, a cyano group, a linear
or branched C.sub.1-C.sub.6 alkyl group, a C.sub.1-C.sub.4
haloalkyl group, a C.sub.1-C.sub.4 hydroxyalkyl group, a
C.sub.1-C.sub.4 alkoxycarbonyl group, a C.sub.3-C.sub.7 cycloalkyl
group, a phenyl group, a 5- to 6-membered monocyclic heteroaryl
group containing 1, 2 or 3 heteroatoms selected from N, O and S, a
5- to 6-membered, heterocyclyl group containing 1, 2 or 3 nitrogen
atoms, a bicyclyl group containing a monocyclic C.sub.5-C.sub.6
aryl or heteroaryl group bonded directly to a 5- to 6-membered
cycloalkyl or heterocyclyl group which heteroaryl or heterocyclyl
group contains 1, 2 or 3 nitrogen atoms, the haloalkyl,
hydroxyalkyl, alkoxycarbonyl, cycloalkyl, phenyl, heteroaryl,
heterocyclyl and bicyclyl group being unsubstituted or substituted
by one or more substituents selected from substituents Rc, and the
alkyl groups being unsubstituted or substituted by one or more
substituents selected from substituents Rd; Rc is a halogen atom, a
hydroxyl group, a cyano group, a linear or branched C.sub.1-C.sub.6
alkyl group, a C.sub.1-C.sub.4 haloalkyl group, a C.sub.1-C.sub.4
alkoxy group, a C.sub.1-C.sub.4 hydroxyalkyl group, a
C.sub.3-C.sub.7 cycloalkyl group, a phenyl group, a 5- to
6-membered monocyclic heteroaryl group containing 1, 2 or 3
nitrogen atoms, a 5- to 6-membered heterocyclyl group containing 1,
2 or 3 nitrogen atoms, or a C.sub.3-C.sub.7 heterocycloalkyl ketone
group containing 1, 2 or 3 nitrogen atoms, said phenyl group being
unsubstituted or substituted by one or more halogen atoms, and said
heteroaryl, heterocyclyl and heterocycloalkyl ketone groups being
unsubstituted or substituted by one or more linear or branched
C.sub.1-C.sub.3 alkyl groups; Rd is a cyano group, a
C.sub.1-C.sub.4 haloalkyl group, a C.sub.1-C.sub.4 alkoxy group, a
C.sub.1-C.sub.4 hydroxyalkyl group, a C.sub.3-C.sub.7 cycloalkyl
group, a phenyl group, a 5- to 6-membered monocyclic heteroaryl
group containing 1, 2 or 3 nitrogen atoms, a 5- to 6-membered
heterocyclyl group containing 1, 2 or 3 nitrogen atoms, or a
C.sub.3-C.sub.7 heterocycloalkyl ketone group containing 1, 2 or 3
nitrogen atoms, said phenyl group being unsubstituted or
substituted by one or more halogen atoms, and said heteroaryl,
heterocyclyl and heterocycloalkyl ketone groups being unsubstituted
or substituted by one or more linear or branched C.sub.1-C.sub.3
alkyl groups; Re is a halogen atom, a hydroxyl group, a cyano
group, a linear or branched C.sub.1-C.sub.6 alkyl group or a
C.sub.1-C.sub.4 haloalkyl group; R.sub.13, R.sub.14, and R.sub.15
each independently represents a hydrogen atom, a cyano group, a
linear or branched C.sub.1-C.sub.6 alkyl group, a C.sub.1-C.sub.4
haloalkyl group, a C.sub.1-C.sub.4 hydroxyalkyl group, a
C.sub.1-C.sub.4 alkoxycarbonyl group, a C.sub.3-C.sub.7 cycloalkyl
group, a monocyclic or polycyclic C.sub.5-C.sub.14 aryl group, a 5-
to 14-membered heteroaryl group containing at least one heteroatom
selected from O, S and N, or a 5- to 14-membered heterocyclyl group
containing at least one heteroatom selected from O, S and N, [0028]
wherein the haloalkyl, hydroxyalkyl, alkoxycarbonyl, cycloalkyl,
aryl, heteroaryl and heterocyclyl groups are unsubstituted or
substituted by one or more substituents selected from the
substituents Ra, and the alkyl groups are optionally substituted by
one or more substitutents selected from Rb, for use in the
treatment of a pathological condition or disease susceptible to
amelioration by inhibition of Janus kinases (JAK).
[0029] The invention further provides new pyrazole derivatives of
formula (I), or a pharmaceutically acceptable salt, or solvate, or
N-oxide, or stereoisomer or deuterated derivative thereof, wherein
T represents a CR.sub.9 group and m, Z, W, X, Y and R.sub.1 to
R.sub.9 are as defined above.
[0030] In one embodiment, in the compound of formula (I) both Y and
T represent a --CR.sub.9 group and m, Z, W, X and R.sub.1 to
R.sub.9 are as defined above.
[0031] In another embodiment, in the compound of formula (I) Y
represents N, X and T represent a --CR.sub.9 group and m, Z, W and
R.sub.1 to R.sub.9 are as defined above, provided that when R.sub.8
represents a 5- to 7-membered heterocyclyl group containing one
nitrogen atom, said heterocyclyl group is substituted by one or
more substituents, wherein said substitution is at least on the
ring nitrogen of the heterocyclyl group, and provided that this
substituent on the ring nitrogen of the heterocyclyl group is other
than a tert-butoxycarbonyl group.
[0032] The invention further provides synthetic processes and
intermediates described herein, which are useful for preparing said
compounds.
[0033] The invention also provides a pharmaceutical composition
comprising the compounds of the invention and a
pharmaceutically-acceptable diluent or carrier.
[0034] The pathological condition or disease susceptible to
amelioration by inhibition of Janus Kinases (JAK) is, in
particular, selected from myeloproliferative disorders, leukemia,
lymphoid malignancies and solid tumors; bone marrow and organ
transplant rejection; immune-mediated diseases and inflammatory
diseases, for example from myeloproliferative disorders, leukemia,
lymphoid malignancies and solid tumors; bone marrow and organ
transplant rejection; and immune-mediated diseases. More
particularly the pathological condition or disease is selected from
rheumatoid arthritis, multiple sclerosis, inflammatory bowel
disease, dry eye, uveitis, allergic conjunctivitis, allergic
rhinitis, asthma, chronic obstructive pulmonary disease (COPD),
atopic dermatitis and psoriasis.
[0035] In one aspect, the compounds of formula (I) may be used in
the treatment of myeloproliferative disorders, leukemia, lymphoid
malignancies and solid tumors. In this aspect, the treatment is
typically effected by inhibition of Janus Kinases in the subject.
In another aspect, the compounds of formula (I) may be used in the
treatment of bone marrow and organ transplant rejection;
immune-mediated diseases and inflammatory diseases, for example
from bone marrow and organ transplant rejection; and
immune-mediated diseases, e.g. bone marrow and organ transplant
rejection.
[0036] The invention also provides a pyrazole derivative of formula
(I) as defined herein, or a pharmaceutically acceptable salt, or
solvate, or N-oxide, or stereoisomer or deuterated derivative
thereof for use in inhibiting Janus Kinases. In particular, the
invention provides a pyrazole derivative of formula (I) as defined
herein, or a pharmaceutically acceptable salt, or solvate, or
N-oxide, or stereoisomer or deuterated derivative thereof for
treating a pathological condition or disease as described above,
wherein the treatment is by inhibition of Janus Kinases.
[0037] The invention also provides a method of treatment of a
pathological condition or disease susceptible to amelioration by
inhibition of Janus Kinases (JAK), in particular wherein the
pathological condition or disease is selected from
myeloproliferative disorders, leukemia, lymphoid malignancies and
solid tumors; bone marrow and organ transplant rejection;
immune-mediated diseases and inflammatory diseases, for example
from myeloproliferative disorders, leukemia, lymphoid malignancies
and solid tumors; bone marrow and organ transplant rejection; and
immune-mediated diseases, more particularly wherein the
pathological condition or disease is selected from rheumatoid
arthritis, multiple sclerosis, inflammatory bowel disease, dry eye,
uveitis, allergic conjunctivitis, allergic rhinitis, asthma,
chronic obstructive pulmonary disease (COPD), atopic dermatitis and
psoriasis; comprising administering a therapeutically effective
amount of the compounds defined herein or a pharmaceutical
composition comprising a compound as defined herein in association
with a pharmaceutically acceptable diluent or carrier. to a subject
in need of such treatment. In particular, the treatment is effected
by inhibition of Janus Kinases in the subject.
[0038] The invention also provides a method of inhibiting Janus
kinases in a subject in need thereof, which comprises administering
to said subject a therapeutically effective amount of a compound as
defined herein, or a pharmaceutical composition comprising a
compound as defined herein in association with a pharmaceutically
acceptable diluent or carrier to a subject in need of such
treatment.
[0039] The invention also provides a combination product comprising
(i) a compound as described herein; and (ii) one or more additional
active substances which are known to be useful in the treatment of
myeloproliferative disorders (such as polycythemia vera, essential
thrombocythemia or myelofibrosis), leukemia, lymphoid malignancies
and solid tumors; bone marrow and organ transplant rejection;
immune-mediated diseases and inflammatory diseases, for example
from myeloproliferative disorders, leukemia, lymphoid malignancies
and solid tumors; bone marrow and organ transplant rejection; and
immune-mediated diseases, more particularly wherein the
pathological condition or disease is selected from rheumatoid
arthritis, multiple sclerosis, inflammatory bowel disease (such as
ulcerative colitis or Crohn's disease), dry eye, uveitis, allergic
conjunctivitis, allergic rhinitis, asthma, chronic obstructive
pulmonary disease (COPD), atopic dermatitis and psoriasis.
[0040] As used herein the term C.sub.1-C.sub.6 alkyl embraces
optionally substituted, linear or branched radicals having 1 to 6
carbon atoms, preferably 1 to 4 carbon atoms. Examples include
methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl, t-butyl,
n-pentyl, 1-methylbutyl, 2-methylbutyl, isopentyl; 1-ethylpropyl,
1,1-dimethylpropyl, 1,2-dimethylpropyl, n-hexyl, 1-ethylbutyl,
2-ethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl,
1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl,
2-methylpentyl, 3-methylpentyl and iso-hexyl radicals.
[0041] As used herein, the term C.sub.2-C.sub.4 alkenyl embraces
optionally substituted, linear or branched, mono or polyunsaturated
radicals having 2 to 4 carbon atoms. Examples include vinyl, allyl,
1-propenyl, isopropenyl, 1-butenyl, 2-butenyl and 3-butenyl
radicals.
[0042] As used herein, the term C.sub.2-C.sub.4 alkynyl embraces
optionally substituted, linear or branched, mono or polyunsaturated
radicals having 2 to 4 carbon atoms. Examples include 1-propynyl,
2-propynyl, 1-butynyl, 2-butynyl and 3-butynyl radicals.
[0043] When it is mentioned that alkyl, alkenyl or alkynyl radicals
may be optionally substituted it is meant to include linear or
branched alkyl, alkenyl or alkynyl radicals as defined above, which
may be unsubstituted or substituted in any position by one or more
substituents, for example by 1, 2 or 3 substituents. When two or
more substituents are present, each substituent may be the same or
different.
[0044] A said optionally substituted alkenyl group is typically
unsubstituted or substituted by 1, 2 or 3 substituents which may be
the same or different. Typically, substituents on an alkenyl group
are themselves unsubstituted. Preferred substituents on the alkenyl
groups are halogen atoms and hydroxy groups, and are more
preferably halogen atoms.
[0045] A said optionally substituted alkynyl group is typically
unsubstituted or substituted by 1, 2 or 3 substituents which may be
the same or different. Typically, substituents on an alkynyl group
are themselves unsubstituted. Preferred substituents on the alkynyl
groups are halogen atoms and hydroxy groups, and are more
preferably halogen atoms.
[0046] As used herein, the term C.sub.1-C.sub.4 haloalkyl group is
an alkyl group, for example a C.sub.1-4 or C.sub.1-2 alkyl group,
which is bonded to one or more, preferably 1, 2 or 3 halogen atoms.
Preferably, said haloalkyl group is chosen from --CCl.sub.3 and
--CF.sub.3.
[0047] As used herein, the term C.sub.1-C.sub.4 hydroxyalkyl
embraces linear or branched alkyl radicals having 1 to 4 carbon
atoms, any one of which may be substituted by one or more,
preferably 1 or 2, more preferably 1 hydroxyl radicals. Examples of
such radicals include hydroxymethyl, hydroxyethyl, hydroxypropyl,
and hydroxybutyl.
[0048] As used herein, the term C.sub.1-C.sub.4 alkoxy (or
alkyloxy) embraces optionally substituted, linear or branched
oxy-containing radicals each having alkyl portions of 1 to 4 carbon
atoms. An alkoxy group is typically unsubstituted or substituted by
1, 2 or 3 substituents which may be the same or different.
Typically, the substituents on an alkoxy group are themselves
unsubstituted. Preferred alkoxy radicals include methoxy, ethoxy,
n-propoxy, i-propoxy, n-butoxy, sec-butoxy, t-butoxy,
trifluoromethoxy, difluoromethoxy, hydroxymethoxy, 2-hydroxyethoxy
and 2-hydroxypropoxy.
[0049] As used herein, the term C.sub.1-C.sub.4alkoxycarbonyl group
embraces radicals of formula --C(O)O(C.sub.1-C.sub.4alkyl), wherein
said C.sub.1-C.sub.4 alkyl is a linear or branched hydrocarbon
radical having 1 to 4 carbon atoms. Examples include
methoxycarbonyl, ethoxycarbonyl, n-propyloxycarbonyl,
i-propyloxycarbonyl, n-butyloxycarbonyl, sec-butyloxycarbonyl and
tert-butyloxycarbonyl radicals.
[0050] As used herein, the term C.sub.3-C.sub.10 cycloalkyl
embraces saturated monocyclic or polycyclic carbocyclic radicals
having from 3 to 10 carbon atoms, preferably from 3 to 7 carbon
atoms. A C.sub.3-C.sub.10 cycloalkyl radical is typically
unsubstituted or substituted by 1, 2 or 3 substituents which may be
the same or different. When a C.sub.3-C.sub.10 cycloalkyl radical
carries 2 or more substituents, the substituents may be the same or
different. Typically the substituents on a C.sub.3-C.sub.10
cycloalkyl group are themselves unsubstituted. Polycyclic
cycloalkyl radicals contains two or more fused cycloalkyl groups,
preferably two cycloalkyl groups. Typically, polycyclic cycloalkyl
radicals are selected from decahydronaphthyl (decalyl),
bicyclo[2.2.2]octyl, adamantly, camphyl or bornyl groups. Examples
of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl and
cyclodecyl.
[0051] As used herein, the term C.sub.3-C.sub.10 cycloalkenyl
embraces partially unsaturated carbocyclic radicals having from 3
to 10 carbon atoms, preferably from 3 to 7 carbon atoms. A
C.sub.3-C.sub.10 cycloalkenyl radical is typically unsubstituted or
substituted by 1, 2 or 3 substituents which may be the same or
different. When a C.sub.3-C.sub.10 cycloalkenyl radical carries 2
or more substituents, the substituents may be the same or
different. Typically, the substituents on a cycloalkenyl group are
themselves unsubstituted. Examples include cyclobutenyl,
cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl,
cyclononenyl and cyclodecenyl.
[0052] As used herein, the term C.sub.5-C.sub.14 aryl radical
embraces typically a C.sub.5-C.sub.14, preferably C.sub.6-C.sub.14,
more preferably C.sub.6-C.sub.10 monocyclic or polycyclic aryl
radical such as phenyl, naphthyl, anthranyl and phenanthryl. Phenyl
is preferred. A said optionally substituted C.sub.5-C.sub.14 aryl
radical is typically unsubstituted or substituted by 1, 2 or 3
substituents which may be the same or different. When a
C.sub.5-C.sub.14 aryl radical carries 2 or more substituents, the
substituents may be the same or different. Unless otherwise
specified, the substituents on a C.sub.5-C.sub.14 aryl group are
typically themselves unsubstituted.
[0053] As used herein, the term 5- to 14-membered heteroaryl
radical embraces typically a 5- to 14-membered ring system,
preferably a 5- to 10-membered ring system, more-preferably a 5- to
6-membered ring system, comprising at least one heteroaromatic ring
and containing at least one heteroatom selected from O, S and N. A
5- to 14-membered heteroaryl radical may be a single ring or two or
more fused rings wherein at least one ring contains a
heteroatom.
[0054] A said optionally substituted 5- to 14-membered heteroaryl
radical is typically unsubstituted or substituted by 1, 2 or 3
substituents which may be the same or different. When a 5- to
14-membered heteroaryl radical carries 2 or more substituents, the
substituents may be the same or different. Unless otherwise
specified, the substituents on a 5- to 14-membered heteroaryl
radical are typically themselves unsubstituted.
[0055] Examples include pyridyl, pyrazinyl, pyrimidinyl,
pyridazinyl, furyl, benzofuranyl, oxadiazolyl, oxazolyl,
isoxazolyl, benzoxazolyl, imidazolyl, benzimidazolyl, thiazolyl,
thiadiazolyl, thienyl, pyrrolyl, pyridinyl, benzothiazolyl,
indolyl, indazolyl, purinyl, quinolyl, isoquinolyl, phthalazinyl,
naphthyridinyl, quinoxalinyl, quinazolinyl, quinolizinyl,
cinnolinyl, triazolyl, indolizinyl, indolinyl, isoindolinyl,
isoindolyl, imidazolidinyl, pteridinyl, thianthrenyl, pyrazolyl,
2H-pyrazolo[3,4-d]pyrimidinyl, 1H-pyrazolo[3,4-d]pyrimidinyl,
thieno[2,3-d]pyrimidinyl and the various pyrrolopyridyl
radicals.
[0056] As used herein, the term 5- to 14-membered heterocyclyl
radical embraces typically a non-aromatic, saturated or unsaturated
C.sub.5-C.sub.14 carbocyclic ring system, preferably
C.sub.5-C.sub.10 carbocyclic ring system, more preferably
C.sub.5-C.sub.6 carbocyclic ring system, in which one or more, for
example 1, 2, 3 or 4 of the carbon atoms preferably 1 or 2 of the
carbon atoms are replaced by a heteroatom selected from N, O and S.
A heterocyclyl radical may be a single ring or two or more fused
rings wherein at least one ring contains a heteroatom. When a 5 to
14-membered heterocyclyl radical carries 2 or more substituents,
the substituents may be the same or different.
[0057] A said optionally substituted 5- to 14-membered heterocyclyl
radical is typically unsubstituted or substituted by 1, 2 or 3
substituents which may be the same or different. Typically, the
substituents on a 5 to 14-membered heterocyclyl radical are
themselves unsubstituted.
[0058] Examples of 5- to 14-membered heterocyclyl radicals include
piperidyl, pyrrolidyl, pyrrolinyl, piperazinyl, morpholinyl,
thiomorpholinyl, pyrrolyl, pyrazolinyl, pirazolidinyl,
quinuclidinyl, triazolyl, pyrazolyl, tetrazolyl, imidazolidinyl,
imidazolyl, oxiranyl, 4,5-dihydro-oxazolyl, 2-benzofuran-1(3H)-one,
1,3-dioxol-2-one, 3-aza-tetrahydrofuranyl and tetrahydropyranyl,
for example piperidyl, pyrrolidyl, pyrrolinyl, piperazinyl,
morpholinyl, thiomorpholinyl, pyrrolyl, pyrazolinyl, pirazolidinyl,
quinuclidinyl, triazolyl, pyrazolyl, tetrazolyl, imidazolidinyl,
imidazolyl, oxiranyl, 4,5-dihydro-oxazolyl, 2-benzofuran-1(3H)-one,
1,3-dioxol-2-one and 3-aza-tetrahydrofuranyl.
[0059] Where a 5- to 14-membered heterocyclyl radical carries 2 or
more substituents, the substituents may be the same or
different.
[0060] As used herein, the term 6-membered saturated N-containing
heterocyclic group is a C.sub.6 saturated carbocyclic ring system
in which one of the carbon atoms is replaced by N and optionally in
which 1, 2, or 3, preferably 1 or 2, further carbon atoms are
replaced by heteroatoms selected from N and O.
[0061] A said 6-membered saturated N-containing heterocyclic group
is typically unsubstituted or substituted by 1, 2 or 3 substituents
which may be the same or different. Typically, the substituents on
a 6-membered saturated N-containing heterocyclic group are
themselves unsubstituted, unless otherwise specified.
[0062] Examples of 6-membered saturated N-containing heterocyclic
group include piperidyl and piperazinyl.
[0063] As used herein, the term C.sub.3-C.sub.7 heterocycloalkyl
ketone group embraces typically a non-aromatic, saturated or
unsaturated C.sub.3-C.sub.7 carbocyclic ring system, in which one
of the carbon atoms is replaced by a C.dbd.O group and 1, 2 or 3,
preferably 1 or 2, more preferably 1, further carbon atoms
preferably are replaced by N. Examples include pyridone groups.
[0064] As used herein, the term aza-bicycloalkyl group having up to
12 carbon atoms denotes a fused ring system consisting of a
cycloalkyl group and a N-containing heterocyclyl group, as defined
herein.
[0065] As used herein, the term aza-bicycloalkenyl group having up
to 12 carbon atoms embraces an aza-bicycloalkyl group, as defined
herein, containing at least one unsaturated carbon-carbon bond.
[0066] As used herein, a bicyclyl group containing a monocyclic
C.sub.5-C.sub.9 aryl or heteroaryl group bonded directly to a 5- to
9-membered cycloalkyl or heterocyclyl group typically refers to
groups where a monocyclic C.sub.5-C.sub.9 aryl or heteroaryl group
is bonded to a 5- to 9-membered cycloalkyl or heterocyclyl group by
a single bond. Examples include biphenyl groups or chromanyl
groups.
[0067] As used herein, some of the atoms, radicals, moieties,
chains and cycles present in the general structures of the
invention are "optionally substituted". This means that these
atoms, radicals, moieties, chains and cycles can be either
unsubstituted or substituted in any position by one or more, for
example 1, 2, 3 or 4, substituents, whereby the hydrogen atoms
bound to the unsubstituted atoms, radicals, moieties, chains and
cycles are replaced by chemically acceptable atoms, radicals,
moieties, chains and cycles. When two or more substituents are
present, each substituent may be the same or different. The
substituents are typically themselves unsubstituted.
[0068] Typically when a cyclic radical is bridged by an alkylene or
alkylenedioxy radical, the bridging alkylene radical is bonded to
the ring at non-adjacent atoms.
[0069] As used herein, the term halogen atom embraces chlorine,
fluorine, bromine and iodine atoms. A halogen atom is typically a
fluorine, chlorine or bromine atom, most preferably chlorine or
fluorine. The term halo when used as a prefix has the same
meaning.
[0070] As used herein, the term pharmaceutically acceptable salt
embraces salts with a pharmaceutically acceptable acid or base.
Pharmaceutically acceptable acids include both inorganic acids, for
example hydrochloric, sulphuric, phosphoric, diphosphoric,
hydrobromic, hydroiodic and nitric acid and organic acids, for
example citric, fumaric, maleic, malic, mandelic, ascorbic, oxalic,
succinic, tartaric, benzoic, acetic, methanesulphonic,
ethanesulphonic, benzenesulphonic or p-toluenesulphonic acid.
Pharmaceutically acceptable bases include alkali metal (e.g. sodium
or potassium) and alkali earth metal (e.g. calcium or magnesium)
hydroxides and organic bases, for example alkyl amines, arylalkyl
amines and heterocyclyl amines.
[0071] Other preferred salts according to the invention are
quaternary ammonium compounds wherein an equivalent of an anion
(X-) is associated with the positive charge of the N atom. X- may
be an anion of various mineral acids such as, for example,
chloride, bromide, iodide, sulphate, nitrate, phosphate, or an
anion of an organic acid such as, for example, acetate, maleate,
fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate,
trifluoroacetate, methanesulphonate and p-toluenesulphonate. X- is
preferably an anion selected from chloride, bromide, iodide,
sulphate, nitrate, acetate, maleate, oxalate, succinate or
trifluoroacetate. More preferably X- is chloride, bromide,
trifluoroacetate or methanesulphonate.
[0072] As used herein, an N-oxide is formed from the tertiary basic
amines or imines present in the molecule, using a convenient
oxidising agent.
[0073] As used herein, the term solvate means a compound which
further includes a stoichiometric or non-stoichiometric amount of
solvent such as water, acetone, ethanol, methanol, dichloromethane,
2-propanol, or the like, bound by non-covalent intermolecular
forces. When the solvent is water, the term hydrate is used instead
of solvate.
[0074] As used herein, the term deuterated derivative embraces
compounds of the invention where in a particular position at least
one hydrogen atom is replaced by deuterium. Deuterium (D or
.sup.2H) is a stable isotope of hydrogen which is present at a
natural abundance of 0.015 molar %.
[0075] Hydrogen deuterium exchange (deuterium incorporation)-is a
chemical reaction in which a covalently bonded hydrogen atom is
replaced by a deuterium atom. Said exchange (incorporation)
reaction can be total or partial.
[0076] Typically, a deuterated derivative of a compound of the
invention has an isotopic enrichment factor (ratio between the
isotopic abundance and the natural abundance of that isotope, i.e.
the percentage of incorporation of deuterium at a given position in
a molecule in the place of hydrogen) for each deuterium present at
a site designated as a potential site of deuteration on the
compound of at least 3500 (52.5% deuterium incorporation).
[0077] In a preferred embodiment, the isotopic enrichment factor is
at least 5000 (75% deuterium). In a more preferred embodiment, the
isotopic enrichment factor is at least 6333.3 (95% deuterium
incorporation). In a most preferred embodiment, the isotopic
enrichment factor is at least 6633.3 (99.5%-deuterium
incorporation). It is understood that the isotopic enrichment
factor of each deuterium present at a site designated as a site of
deuteration is independent from the other deuteration sites.
[0078] The isotopic enrichment factor can be determined using
conventional analytical methods known too en ordinary skilled in
the art, including mass spectrometry (MS) and nuclear magnetic
resonance (NMR).
[0079] Typically, the compounds of formula (I) are other than
[0080]
trans-5-cyano-3-[6-(4-hydroxycyclohexylamino)pyridin-2-yl]pyrazolo[1,5-a]-
pyridine, [0081]
trans-5-cyano-3-[6-(4-hydroxycyclohexyl-N-methylamino)pyridin-2-yl]pyrazo-
lo[1,5-a]pyridine, [0082]
trans-5-cyano-3-[6-(N-ethyl-N-(4-hydroxycyclohexyl)amino)pyridin-2-yl]pyr-
azolo[1,5-a]pyridine, [0083]
5-cyano-3-[6-(piperidin-4-ylamino)pyridin-2-yl]pyrazolo[1,5-a]pyridine,
[0084]
5-cyano-3-[6-(methyl(piperidin-4-yl)amino)pyridin-2-yl]pyrazolo[1,-
5-a]pyridine, [0085]
5-cyano-3-[6-(1-(2-cyanoacetyl)piperidin-3-ylamino)pyridin-2-yl]pyrazolo[-
1,5-a]pyridine, [0086]
(R)-5-cyano-3-[6-(1-(2-cyanoacetyl)piperidin-3-ylamino)pyridin-2-yl]pyraz-
olo[1,5-a]pyridine, and [0087]
(R)-5-cyano-3-[6-(N-methyl-1-(2-cyanoacetyl)piperidin-3-ylamino)pyridin-2-
-yl]pyrazolo[1,5-a]pyridine, and salts of the above compounds; and
[0088]
3-[6-(1-Hydroxymethylcyclopentylamino)pyridin-2-yl]pyrazolo[1,5-a]pyridin-
e [0089]
3-[6-(4-hydroxymethylpiperidin-1-yl)pyridin-2-yl]pyrazolo[1,5-a]p-
yridine, [0090]
3-[6-(3-hydroxycyclohexylamino)pyridin-2-yl]pyrazolo[1,5-a]pyridine,
[0091]
trans-3-[6-(4-hydroxycyclohexyl-N-methylamino)pyridin-2-yl]pyrazol-
o[1,5-a]pyridine, [0092]
3-[6-(1-ethoxycarbonylpiperidin-4-ylamino)pyridin-2-yl]pyrazolo[1,5-a]pyr-
idine, [0093]
trans-3-[6-(4-aminocyclohexylamino)pyridin-2-yl]pyrazolo[1,5-a]pyridine,
[0094]
trans-3-[6-(4-hydroxycyclohexylamino)pyridin-2-yl]pyrazolo[1,5-a]p-
yridine, [0095]
3-[6-(tetrahydro-4H-piran-4-ylamino)pyridin-2-yl]pyrazolo[1,5-a]pyridine,
[0096]
3-[6-(N-methylcyclohexylamino)pyridin-2-yl]pyrazolo[1,5-a]pyridine-
, [0097]
3-[6-(3-hydroxymethylpiperidin-1-yl)pyridin-2-yl]pyrazolo[1,5-a]p-
yridine, [0098]
3-[6-(1-methylpiperidin-4-ylamino)pyridin-2-yl]pyrazolo[1,5-a]pyridine,
[0099]
3-[6-(2,2,6,6-tetramethylpiperidin-4-ylamino)pyridin-2-yl]pyrazolo-
[1,5-a]pyridine, [0100]
3-[6-(2-phenylpropan-2-amino)pyridin-2-yl]pyrazolo[1,5-a]pyridine,
[0101]
(S)-3-[6-(1-phenylethylamino)pyridin-2-yl]pyrazolo[1,5-a]pyridine,
[0102] 3-[6-(1-benzylamino)pyridin-2-yl]pyrazolo[1,5-a]pyridine,
[0103]
(S)-3-[6-(1-cyclohexylethylamino)pyridin-2-yl]pyrazolo[1,5-a]pyridine,
[0104]
(S)-3-[6-(1-methoxypropan-2-ylamino)pyridin-2-yl]pyrazolo[1,5-a]py-
ridine, [0105]
3-[6-(methylamino)pyridin-2-yl]pyrazolo[1,5-a]pyridine, [0106]
3-[6-(phenylamino)pyridin-2-yl]pyrazolo[1,5-a]pyridine, [0107]
3-[6-(pyridin-3-ylamino)pyridin-2-yl]pyrazolo[1,5-a]pyridine,
[0108]
3-[6-(pyridin-4-ylamino)pyridin-2-yl]pyrazolo[1,5-a]pyridine,
[0109]
trans-3-[6-(4-aminocyclohexylamino)pyridin-2-yl]-5-cyanopyrazolo[1,5-a]py-
ridine, [0110]
5-cyano-(S)-3-[6-(1-phenylethylamino)pyridin-2-yl]pyrazolo[1,5-a]pyridine-
, [0111]
5-cyano-3-[6-(4-hydroxybutylamino)pyridin-2-yl]pyrazolo[1,5-a]pyr-
idine [0112]
5-cyano-3-[6-(N-methyl-(3-hydroxypropyl)amino)pyridin-2-yl]pyrazolo[1,5-a-
]pyridine, [0113]
3-[6-(3-aminocyclohexylamino)pyridin-2-yl]-5-cyanopyrazolo[1,5-a]pyridine-
, [0114]
5-cyano-3-[6-(N-methyl-N-(2-methylamino)ethylamino)pyridin-2-yl]p-
yrazolo[1,5-a]pyridine, [0115]
5-cyano-3-[6-((1-ethoxycarbonyl)piperidin-3-ylamino)pyridin-2-yl]pyrazolo-
[1,5-a]pyridine, [0116]
3-[6-(2-aminoethylamino)pyridin-2-yl]-5-cyanopyrazolo[1,5-a]pyridine,
[0117]
(S)-5-cyano-3-[6-(2-hydroxymethylpyrrolidin-1-yl)pyridin-2-yl]pyra-
zolo[1,5-a]pyridine, [0118]
(R)-5-cyano-3-[6-(2-hydroxymethylpyrrolidin-1-yl)pyridin-2-yl]pyrazolo[1,-
5-a]pyridine, [0119]
5-cyano-3-[6-(N-ethyl-N-(4-hydroxybutyl)amino)pyridin-2-yl]pyrazolo[1,5-a-
]pyridine, [0120]
5-cyano-3-[6-(3-hydroxypropylamino)pyridin-2-yl]pyrazolo[1,5-a]pyridine,
[0121]
(S)-5-cyano-3-[6-(1-(ethoxycarbonyl)piperidin-3-ylamino)pyridin-2--
yl]pyrazolo[1,5-a]pyridine [0122]
trans-3-[6-(4-acetylaminocyclohexylamino)pyridin-2-yl]pyrazolo[1,5-a]pyri-
dine [0123]
trans-3-[6-(4-methanosulfonylaminocyclohexylamino)pyridin-2-yl]pyrazolo[1-
,5-a]pyridine [0124]
3-[6-(3-(2-oxopyrrolidin-1-yl)phenylamino)pyridin-2-yl]pyrazolo[1,5-a]pyr-
idine [0125]
3-[6-(N-cyclohexylamino)pyridin-2-yl]pyrazolo[1,5-a]pyridine,
[0126]
3-[6-(N-(2-methylcyclohexyl)amino)pyridin-2-yl]pyrazolo[1,5-a]pyri-
dine, [0127]
3-[6-(4-acetylaminophenylamino)pyridin-2-yl]pyrazolo[1,5-a]pyridine,
[0128]
3-[6-(3-acetylaminophenylamino)pyridin-2-yl]pyrazolo[1,5-a]pyridin-
e, [0129]
3-[6-((3-methylaminocarbonyl)phenylamino)pyridin-2-yl]pyrazolo[1-
,5-a]pyridine, [0130]
3-[6-(3-hydroxyphenyl-N-methylamino)pyridin-2-yl]pyrazolo[1,5-a]pyridine
[0131]
3-[6-(N-cyclopropylcarbonylamino)pyridin-2-yl]pyrazolo[1,5-a]pyrid-
ine [0132]
(S)-3-[6-(1-phenylethylamino)pyridin-2-yl]-5-hydroxymethylpyraz-
olo[1,5-a]pyridine [0133]
3-[6-(piperidin-4-ylamino)pyridin-2-yl]pyrazolo[1,5-a]pyridine
[0134]
3-[6-(piperidin-4-ylamino)pyridin-2-yl]-5-carboxypyrazolo[1,5-a]pyridine,
[0135]
3-[6-(1-acetylpiperidin-4-ylamino)pyridin-2-yl]pyrazolo[1,5-a]pyri-
dine [0136]
5-cyano-3-[6-((1-acetyl)piperidin-3-ylamino)pyridin-2-yl]pyrazolo[1,5-a]p-
yridine [0137]
(S)-5-cyano-3-[6-(piperidin-3-ylamino)pyridin-2-yl]pyrazolo[1,5-a]pyridin-
e. The salts and solvates of these compounds may also be excluded
from the compounds of formula (I).
[0138] The above compounds are disclosed in WO 2010/072823.
Typically, the compounds of formula (I) exclude the compounds
disclosed in WO 2010/072823, including the salts, solvates and
stereoisomers disclosed therein.
[0139] For example, the compounds defined herein may exclude
compounds of formula (I) wherein
R.sub.1, R.sub.2 and R.sub.4 each represent a hydrogen atom; W
represents a --CR.sub.3 group; Z represents a group --NR.sub.5; X,
Y and T each represent a group --CR.sub.9, wherein R.sub.9
represents a hydrogen atom; R.sub.3 represents hydrogen, halogen,
C.sub.1-4alkyl, haloC.sub.1-4alkyl, hydroxyC.sub.1-4alkyl,
R.sub.27--C.sub.1-4alkyl halogen, cyano, --C(O)--NR.sub.24R.sub.24,
--C(O)R.sub.25, --C(O)OR.sub.25, --OR.sub.24, --S(O).sub.2R.sub.25,
--S(O).sub.2NR.sub.24R.sub.24, --NR.sub.24R.sub.24, --NHCOR.sub.24,
--N(C.sub.1-4alkyl)COR.sub.24, --NHCONR.sub.24R.sub.24,
--N(C.sub.1-4alkyl)CONR.sub.24R.sub.24, --NHC(O)OR.sub.35,
--N(C.sub.1-4alkyl)C(O)OR.sub.35, --NHS(O).sub.2R.sub.25,
N(C.sub.1-4alkyl)S(O).sub.2R.sub.25, or Cy.sub.1, wherein Cy.sub.1
is optionally substituted with one or more substituents selected
from R.sub.28; R.sub.5 represents a hydrogen atom, C.sub.1-4alkyl,
hydroxyC.sub.1-4alkyl or C.sub.1-4 alkyl substituted with a group
selected from cyano, hydroxyl or Cy.sub.1, wherein Cy.sub.1 is
optionally substituted with one or more R.sub.28, for example
R.sub.5 may represent a hydrogen atom, C.sub.1-4alkyl,
haloC.sub.1-4alkyl, hydroxyC.sub.1-4alkyl or
R.sub.27--C.sub.1-4alkyl or Cy.sub.2, wherein Cy.sub.2 is
optionally substituted with one or more R.sub.28; the group
--(CR.sub.6R.sub.7).sub.m--R.sub.8 represents C.sub.1-4alkyl,
C.sub.1-4haloalkyl, hydroxyC.sub.1-4alkyl,
R.sub.211-C.sub.1-4alkyl, --CONR.sub.209R.sub.209, --COR.sub.210,
--C(O)OR.sub.210, --S(O).sub.2R.sub.210,
--SO.sub.2NR.sub.209R.sub.209 or Cy.sub.3, wherein Cy.sub.3 is
optionally substituted with one or more R.sub.212; or R.sub.5
together with R.sub.8 and the nitrogen atom to which they are
bonded form a Cy.sub.4 group, wherein Cy.sub.4 is optionally
substituted with one or more R.sub.212; each R.sub.24 independently
represents hydrogen or R.sub.25; each R.sub.25 independently
represents C.sub.1-4alkyl, haloC.sub.1-4alkyl,
C.sub.1-4alkoxyC.sub.1-4alkyl, hydroxyC.sub.1-4alkyl,
cyanoC.sub.1-4alkyl, Cy.sub.1-C.sub.1-4alkyl, or Cy.sub.1, wherein
Cy.sub.1 is optionally substituted with one or more R.sub.28; each
R.sub.35 independently represents C.sub.1-4alkyl,
C.sub.1-4alkoxyC.sub.1-4alkyl, hydroxyC.sub.1-4alkyl,
cyanoC.sub.1-4 alkyl or Cy.sub.1-C.sub.1-4alkyl, wherein Cy.sub.1
is optionally substituted with one or more R.sub.28; for example
each R.sub.35 may independently represent C.sub.1-4alkyl,
haloC.sub.1-4alkyl, hydroxyC.sub.1-4alkyl, cyanoC.sub.1-4alkyl,
Cy.sub.1-C.sub.1-4alkyl, or Cy.sub.1 wherein Cy.sub.1 is optionally
substituted with one or more R.sub.28; each R.sub.28 independently
represents C.sub.1-4alkyl, haloC.sub.1-4alkyl,
C.sub.1-4alkoxyC.sub.1-4alkyl, hydroxyC.sub.1-4alkyl,
cyanoC.sub.1-4alkyl, halogen or hydroxyl; R.sub.27 represents a
cyano group, --C(O)--NR.sub.24R.sub.24, --C(O)R.sub.25,
--C(O)OR.sub.25, --OR.sub.24, --S(O).sub.2R.sub.25,
--S(O).sub.2NR.sub.24R.sub.24, --NR.sub.24R.sub.24, --NHCOR.sub.24,
--N(C.sub.1-4alkyl)COR.sub.24, --NHCONR.sub.24R.sub.24,
--N(C.sub.1-4alkyl)CONR.sub.24R.sub.24, --NHC(O)OR.sub.25,
--N(C.sub.1-4alkyl)C(O)OR.sub.25, --NHS(O).sub.2R.sub.25,
N(C.sub.1-4alkyl)S(O).sub.2R.sub.25, or Cy.sub.1, wherein Cy.sub.1
is optionally substituted with one or more substituents selected
from R.sub.28; each R.sub.209 independently represents hydrogen or
R.sub.210; each R.sub.210 independently represents C.sub.1-4alkyl,
haloC.sub.1-4alkyl, hydroxyC.sub.1-4alkyl,
R.sub.211--C.sub.1-4alkyl or Cy.sub.5, wherein Cy.sub.5 is
optionally substituted with one or more substituents selected from
R.sub.213; R.sub.211 represents halogen, cyano,
--CONR.sub.214R.sub.214, --COR.sub.215, --C(O)OR.sub.215,
--OR.sub.214, --SO.sub.2R.sub.215, --SO.sub.2NR.sub.214R.sub.214,
--NR.sub.214R.sub.214, --NHCOR.sub.214,
--N(C.sub.1-4alkyl)COR.sub.214, --NHCONR.sub.214R.sub.214,
--N(C.sub.1-4alkyl)CONR.sub.214R.sub.214, --NHC(O)OR.sub.215,
--N(C.sub.1-4alkyl)C(O)OR.sub.215, --NHS(O).sub.2R.sub.215,
N(C.sub.1-4alkyl)S(O).sub.2R.sub.215, or Cy.sub.5, wherein Cy.sub.5
is optionally substituted with one or more substituents selected
from R.sub.213; for example R.sub.211 may represent halogen, cyano,
--CONR.sub.214R.sub.214, --COR.sub.215, --C(O)OR.sub.215,
--OR.sub.214, --SO.sub.2R.sub.215, --OCONR.sub.214R.sub.214,
--SO.sub.2NR.sub.214R.sub.214, --NR.sub.214R.sub.214,
--NHCOR.sub.214, --N(C.sub.1-4alkyl)COR.sub.214,
--NHCONR.sub.214R.sub.214,
--N(C.sub.1-4alkyl)CONR.sub.214R.sub.214, --NHC(O)OR.sub.215,
--N(C.sub.1-4alkyl)C(O)OR.sub.215, --NHS(O).sub.2R.sub.215,
N(C.sub.1-4alkyl)S(O).sub.2R.sub.215, or Cy.sub.5, wherein Cy.sub.5
is optionally substituted with one or more substituents selected
from R.sub.213, each R.sub.212 independently represents
C.sub.1-4alkyl, haloC.sub.1-4alkyl, hydroxyC.sub.1-4alkyl,
R.sub.211--C.sub.1-4alkyl or R.sub.212 represents any of the
meanings described for R.sub.211; each R.sub.213 independently
represents C.sub.1-4alkyl, C.sub.1-4haloalkyl,
C.sub.1-4alkoxyC.sub.1-4alkyl, hydroxyC.sub.1-4alkyl,
cyanoC.sub.1-4alkyl, halogen, cyano, --CONR.sub.216R.sub.216,
--COR.sub.217, --C(O)OR.sub.217, --OR.sub.216,
--OCONR.sub.216R.sub.216, --S(O).sub.2R.sub.217,
--SO.sub.2NR.sub.216R.sub.216, --NR.sub.216R.sub.216,
--NHCOR.sub.216, --N(C.sub.1-4alkyl)COR.sub.216,
--NHCONR.sub.216R.sub.216,
--N(C.sub.1-4alkyl)CONR.sub.216R.sub.216, --NHC(O)OR.sub.217,
--N(C.sub.1-4alkyl)C(O)OR.sub.217, --NHS(O).sub.2R.sub.217,
N(C.sub.1-4alkyl)S(O).sub.2R.sub.217; each R.sub.214 independently
represents hydrogen or R.sub.215; each R.sub.215 independently
represents C.sub.1-4alkyl, haloC.sub.1-4alkyl,
C.sub.1-4alkoxyC.sub.1-4alkyl, hydroxyC.sub.1-4alkyl,
cyanoC.sub.1-4alkyl, Cy.sub.5-C.sub.1-4alkyl or Cy.sub.5, wherein
Cy.sub.5 is optionally substituted with one or more R.sub.213; each
R.sub.216 independently represents hydrogen or R.sub.217; each
R.sub.217 independently represents C.sub.1-4alkyl,
haloC.sub.1-4alkyl, C.sub.1-4alkoxyC.sub.1-4alkyl,
hydroxyC.sub.1-4alkyl or cyanoC.sub.1-4alkyl; Cy1 represents a 3-
to 7-membered monocyclic carbocyclic ring that is saturated,
partially unsaturated or aromatic, and which optionally contains
from 1 to 3 heteroatoms independently selected from N, S and O,
wherein said ring is bonded to the rest of the molecule through any
available C or N atom, and wherein one or more C or S ring atoms
are optionally oxidized forming CO, SO or SO2 groups; Cy2
represents a 3- to 7-membered monocyclic carbocyclic ring that is
saturated, partially unsaturated or aromatic, and which optionally
contains from 1 to 3 heteroatoms independently selected from N, S
and O, wherein said ring is bonded to the rest of the molecule
through any available C atom, and wherein one or more C or S ring
atoms are optionally oxidized forming CO, SO or SO2 groups; Cy3
represents a 3- to 7-membered monocyclic or 8- to 12-membered
bicyclic carbocyclic ring that is saturated, partially unsaturated
or aromatic, and which optionally contains from 1 to 4 heteroatoms
independently selected from N, S and O, wherein said ring is bonded
to the rest of the molecule through any available C atom, and
wherein one or more C or S ring atoms are optionally oxidized
forming CO, SO or SO2 groups; Cy4 represents a 3- to 7-membered
monocyclic heterocyclic ring that is saturated or partially
unsaturated, which is optionally fused to a 5- or 6-membered
carbocyclic or heterocyclic ring that is saturated, partially
unsaturated or aromatic, wherein Cy4 optionally contains from 1 to
4 heteroatoms in total independently selected from N, S and O; and
wherein one or more C or S atoms of Cy4 are optionally oxidized
forming CO, SO or SO2 groups; and Cy5 represents a 3- to 7-membered
monocyclic or 8- to 12-membered bicyclic carbocyclic ring that is
saturated, partially unsaturated or aromatic, and which optionally
contains from 1 to 4 heteroatoms independently selected from N, S
and O, wherein said ring is bonded to the rest of the molecule
through any available C or N atom, and wherein one or more C or S
ring atoms are optionally oxidized forming CO, SO or SO2 groups, as
well as the salts and solvates of these compounds, in particular
the salts, solvates and stereoisomers of these compounds.
[0140] Typically, the compounds of formula (I) are other than
[0141]
1-[4-[4-[(5-chloro-4-pyrazolo[1,5-a]pyridin-3-yl-pyrimidin-2-yl)amino]-3--
methoxy-phenyl]piperazin-I-yl]ethanone; [0142]
5-chloro-N-(2-methoxy-4-(piperazin-I-yl)phenyl)-4-(pyrazolo[1,5-a]pyridin-
-3-yl)pyrimidin-2-amine; [0143]
1-[4-[4-[(5-chloro-4-pyrazolo[1,5-a]pyridin-3-yl-pyrimidin-2-yl)amino]-3--
methoxy-phenyl]piperazin-I-yl]-2-hydroxy-ethanone; [0144]
(2R)-1-[4-[4-[(5-chloro-4-pyrazolo[1,5-a]pyridin-3-yl-pyrimidin-2-yl)amin-
o]-3-methoxy-phenyl]piperazin-I-yl]-2-hydroxy-propan-I-one; [0145]
(2S)-1-[4-[4-[(5-chloro-4-pyrazolo[1,5-a]pyridin-3-yl-pyrimidin-2-yl)amin-
o]-3-methoxy-phenyl]piperazin-I-yl]-2-hydroxy-propan-I-one; [0146]
1-[4-[4-[(5-chloro-4-pyrazolo[1,5-a]pyridin-3-yl-pyrimidin-2-yl)amino]-3--
methoxy-phenyl]piperazin-I-yl]-2-methylamino-ethanone; [0147]
2-[4-[4-[(5-chloro-4-pyrazolo[1,5-a]pyridin-3-yl-pyrimidin-2-yl)amino]-3--
methoxy-phenyl]piperazin-1-yl]ethanol; [0148]
(2S)-1-(3-(4-(5-chloro-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-ylamino-
)-3-methoxyphenyl)azetidin-1-yl)-2-hydroxypropan-1-one; [0149]
(2R)-1-(3-(4-(5-chloro-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-ylamino-
)-3-methoxyphenyl)azetidin-1-yl)-2-hydroxypropan-1-one; [0150]
5-chloro-N-[2-methoxy-4-(4-piperidyl)phenyl]-4-pyrazolo[1,5-a]pyridin-3-y-
l-pyrimidin-2-amine; [0151]
1-[4-[4-[(5-chloro-4-pyrazolo[1,5-a]pyridin-3-yl-pyrimidin-2-yl)amino]-3--
methoxy-phenyl]-1-piperidyl]-2-hydroxy-ethanone; [0152]
(2R)-1-[4-[4-[5-chloro-4-pyrazolo[1,5-a]pyridin-3-yl-pyrimidin-2-yl)amino-
]-3-methoxy-phenyl]-1-piperidyl]-2-hydroxy-propan-1-one; [0153]
(2S)-1-[4-[4-[(5-chloro-4-pyrazolo[1,5-a]pyridin-3-yl-pyrimidin-2-yl)amin-
o]-3-methoxy-phenyl]-1-piperidyl]-2-hydroxy-propan-1-one; [0154]
5-chloro-N-(2-methoxy-5-piperazin-1-yl-phenyl)-4-pyrazolo[1,5-a]pyridin-3-
-yl-pyrimidin-2-amine; [0155]
2-[4-[(5-chloro-4-pyrazolo[1,5-a]pyridin-3-yl-pyrimidin-2-yl)amino]-3-met-
hoxy-phenyl]propane-1,3-diol; [0156]
5-chloro-N-[2-methoxy-4-(9-oxa-3,7-diazabicyclo[3.3.1]nonan-7-yl)phenyl]--
4-pyrazolo[1,5-a]pyridin-3-yl-pyrimidin-2-amine; [0157]
1-[4-[3-[(5-chloro-4-pyrazolo[1,5-a]pyridin-3-yl-pyrimidin-2-yl)amino]-4--
methoxy-phenyl]piperazin-1-yl]-2-(methylamino)ethanone; [0158]
1-[4-[3-[(5-chloro-4-pyrazolo[1,5-a]pyridin-3-yl-pyrimidin-2-yl)amino]-4--
methoxy-phenyl]piperazin-1-yl]-2-(dimethylamino)ethanone; [0159]
N-[3-[(5-chloro-4-pyrazolo[1,5-a]pyridin-3-yl-pyrimidin-2-yl)amino]-4-met-
hoxy-phenyl]-2-(dimethylamino)acetamide; [0160]
1-[6-[(5-chloro-4-pyrazolo[1,5-a]pyridin-3-yl-pyrimidin-2-yl)amino]-5-met-
hoxy-indolin-1-yl]ethanone; [0161]
N-(5-chloro-4-pyrazolo[1,5-a]pyridin-3-yl-pyrimidin-2-yl)-5-methoxy-indol-
in-6-amine; [0162]
1-[6-[(5-chloro-4-pyrazolo[1,5-a]pyridin-3-yl-pyrimidin-2-yl)amino]-5-met-
hoxy-indolin-1-yl]-2-(methylamino)ethanone; [0163]
1-[6-[(5-chloro-4-pyrazolo[1,5-a]pyridin-3-yl-pyrimidin-2-yl)amino]-5-met-
hoxy-indolin-1-yl]-2-(dimethylamino)ethanone; [0164]
1-[4-[3-methoxy-4-[(5-methyl-4-pyrazolo[1,5-a]pyridin-3-yl-pyrimidin-2-yl-
)amino]phenyl]piperazin-1-yl]ethanone; [0165]
N-(2-methoxy-4-piperazin-1-yl-phenyl)-5-methyl-4-pyrazolo[1,5-a]pyridin-3-
-yl-pyrimidin-2-amine; [0166]
1-[4-[3-methoxy-4-[5-methyl-4-pyrazolo[1,5-a]pyridin-3-yl-pyrimidin-2-yl)-
amino]phenyl]piperazin-1-yl]-2-(methylamino)ethanone; [0167]
2-[4-[3-methoxy-4-[(5-methyl-4-pyrazolo[1,5-a]pyridin-3-yl-pyrimidin-2-yl-
)amino]phenyl]piperazin-1-yl]ethanol; [0168]
N-[2-methoxy-4-(4-piperidyl)phenyl]-5-methyl-4-pyrazolo[1,5-a]pyridin-3-y-
l-pyrimidin-2-amine; [0169]
2-hydroxy-1-[4-[3-methoxy-4-[(5-methyl-4-pyrazolo[1,5-a]pyridin-3-yl-pyri-
midin-2-yl)amino]phenyl]-1-piperidyl]ethanone; [0170]
(2R)-2-hydroxy-1-[4-[3-methoxy-4-[(5-methyl-4-pyrazolo[1,5-a]pyridine-3-y-
l-pyrimidin-2-yl)amino]phenyl]-1-piperidyl]propan-1-one; [0171]
(2S)-2-hydroxy-1-[4-[3-methoxy-4-[(5-methyl-4-pyrazolo[1,5-a]pyridine-3-y-
l-pyrimidin-2-yl)amino]phenyl]-1-piperidyl]propan-1-one; [0172]
N-(2-methoxy-5-piperazin-1-yl-phenyl)-5-methyl-4-pyrazolo[1,5-a]pyridin-3-
-yl-pyrimidin-2-amine; [0173]
1-[4-[4-methoxy-3-[(5-methyl-4-pyrazolo[1,5-a]pyridin-3-yl-pyrimidin-2-yl-
)amino]phenyl]piperazin-1-yl]-2-(methylamino)ethanone; [0174]
1-[5-methoxy-6-[(5-methyl-4-pyrazolo[1,5-a]pyridin-3-yl-pyrimidin-2-yl)am-
ino]indolin-1-yl]ethanone; [0175]
2-(dimethylamino)-1-[5-methoxy-6-[(5-methyl-4-pyrazolo[1,5-a]pyridin-3-yl-
-pyrimidin-2-yl)amino]indolin-1-yl]ethanone; [0176]
1-[4-[4-[(5-fluoro-4-pyrazolo[1,5-a]pyridin-3-yl-pyrimidin-2-yl)amino]-3--
methoxy-phenyl]piperzain-1-yl]ethanone; [0177]
5-fluoro-N-(2-methoxy-4-piperazin-1-yl-phenyl)-4-pyrazolo[1,5-a]pyridin-3-
-yl-pyrimidin-2-amine; [0178]
1-[4-[4-[(5-fluoro-4-pyrazolo[1,5-a]pyridin-3-yl-pyrimidin-2-yl)amino]-3--
methoxy-phenyl]piperazin-1-yl]-2-(methylamino)ethanone; [0179]
5-fluoro-N-[2-methoxy-4-(4-piperidyl)phenyl]-4-pyrazolo[1,5-a]pyridin-3-y-
l-pyrimidin-2-amine; [0180]
5-fluoro-N-(2-methoxy-5-piperazin-1-yl-phenyl)-4-pyrazolo[1,5-a]pyridin-3-
-yl-pyrimidin-2-amine; [0181]
2-(dimethylamino)-1-[6-[5-fluoro-4-pyrazolo[1,5-a]pyridin-3-yl-pyrimidin--
2-yl)amino]-5-methoxy-indolin-1-yl]ethanone; [0182]
5-chloro-N-[2-methoxy-5-(9-oxa-3,7-diazabicyclo[3.3.1]nonan-7-yl)phenyl]--
4-pyrazolo[1,5-a]pyridin-3-yl-pyrimidin-2-amine; [0183]
2-[[4-[(5-chloro-4-pyrazolo[1,5-a]pyridin-3-yl-pyrimidin-2-yl)amino]-3-me-
thoxy-phenyl]methyl]propane-I,3-diol; [0184]
2-[4-[4-[(5-chloro-4-pyrazolo[1,5-a]pyridin-3-yl-pyrimidin-2-yl)amino]-3--
methoxy-phenyl]piperazin-1-yl]-2-methyl-propan-I-ol; [0185]
2-[4-[3-methoxy-4-[(5-methyl-4-pyrazolo[1,5-a]pyridin-3-yl-pyrimidin-2-yl-
)amino]phenyl]piperazin-1-yl]-2-methyl-propan-I-ol; [0186]
1-[4-[3-methoxy-4-[(5-methyl-4-pyrazolo[1,5-a]pyridin-3-yl-pyrimidin-2-yl-
)amino]phenyl]-1-piperidyl]ethanone; [0187]
1-[4-[4-[(5-cyclopropyl-4-pyrazolo[1,5-a]pyridin-3-yl-pyrimidin-2-yl)amin-
o]-3-methoxy-phenyl]piperazin-I-yl]ethanone; [0188]
2-(dimethylamino)-1-[4-[4-methoxy-3-[(5-methyl-4-pyrazolo[1,5-a]pyridin-3-
-yl-pyrimidin-2-yl)amino]phenyl]piperazin-I-yl]ethanone; [0189]
1-[4-[3-methoxy-4-[(5-methyl-4-pyrazolo[1,5-a]pyridin-3-yl-pyrimidin-2-yl-
)amino]phenyl]-1-piperidyl]-2-(methylamino)ethanone; [0190]
1-[4-[4-[(5-fluoro-4-pyrazolo[1,5-a]pyridin-3-yl-pyrimidin-2-yl)amino]-3--
methoxy-phenyl]-I-piperidyl]-2-(methylamino)ethanone; [0191]
2-[4-(I-acetyl-4-piperidyl)-2-methoxy-anilino]-4-pyrazolo[1,5-a]pyridin-3-
-yl-pyrimidine-5-carbonitrile; [0192]
2-[4-[1-(2-hydroxyacetyl)-4-piperidyl]-2-methoxy-anilino]-4-pyrazolo[1,5--
a]pyridin-3-yl-pyrimidine-5-carbonitrile and pharmaceutically
acceptable salts thereof. These compounds are typically excluded
from the scope of the invention for use in the production of an
anti-proliferative effect in a human or animal, for example for use
in the treatment of a disease or medical condition mediated alone
or in part by insulin-like growth factor receptor (IGF-1R) tyrosine
kinase, for example for use in the prevention or treatment of those
tumours which are sensitive to inhibition of insulin-like growth
factor-1 receptor (IGF-1R) tyrosine kinase, involved in the signal
transduction steps which lead to the proliferation and/or survival
of tumour cells, for example for use in the treatment of cancer.
These compounds are typically excluded from the scope of the
invention when used in combination with methotrexate.
[0193] The above compounds are disclosed in WO 2010/049731.
Typically, the compounds of formula (I) exclude the compounds
disclosed in WO 2010/049731, including the salts disclosed
therein.
[0194] Typically, the compounds defined herein are other than
compounds of formula (I) and pharmaceutically acceptable salts
thereof in which: [0195] m is 0; [0196] Z is NH; [0197] W is
CR.sup.1b' [0198] X is CR.sup.2', wherein R.sup.2'represents a
halogen atom, a cyano group, a trifluoromethyl group, a cyclopropyl
group or an unsubstituted C.sub.1-C.sub.3 alkyl group; [0199] Y is
CH; [0200] T is a nitrogen atom; [0201] R.sub.1 and R.sub.2 are
both H; [0202] R.sub.4 is R.sup.1a'; [0203] R.sub.8 represents a
moiety
[0203] ##STR00003## [0204] wherein [0205] R.sup.3' represents
hydroxy, cyano, halogeno, (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.4)alkoxy, (C.sub.1-C.sub.4)haloalkyl or
(C.sub.1-C.sub.4)hydroxyalkyl; [0206] each R.sup.4', which may be
the same or different, is selected from hydroxy, cyano, halogeno,
formyl, carboxy, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.4)alkoxy,
(C.sub.2-C.sub.6)alkanoyl, (C.sub.1-C.sub.6)alkoxycarbonyl,
(C.sub.3-C.sub.7)cycloalkyl, (C.sub.3-C.sub.7)cycloalkylcarbonyl,
amino, (C.sub.1-C.sub.6)alkylamino,
di-[(C.sub.1-C.sub.6)alkyl]amino, carbamoyl,
(C.sub.1-C.sub.6)alkylcarbamoyl,
di-[(C.sub.1-C.sub.6)alkyl]carbamoyl, sulfamoyl,
(C.sub.1-C.sub.6)alkylsulfamoyl,
di-[(C.sub.1-C.sub.6)alkyl]sulfamoyl, --S(O).sub.m'R' wherein R' is
selected from hydrogen and (C.sub.1-C.sub.6)alkyl and m' represents
0, 1 or 2, --N(R'')C(O)R' wherein R' is as defined above and R'' is
selected from hydrogen and (C.sub.1-C.sub.6)alkyl and --X-Q wherein
X is a direct bond and Q represents a saturated 5-, 6-, 7-, 8-, 9-
or 10-membered heterocyclic ring comprising at least one ring
heteroatom selected from nitrogen, oxygen and sulfur, [0207] or two
R.sup.4' groups on adjacent carbon atoms of the phenyl ring,
together with the carbon atoms to which they are attached, form a
saturated or unsaturated monocyclic 5- or 6-membered heterocyclic
ring comprising at least one ring heteroatom selected from
nitrogen, oxygen and sulfur, each of which groups or rings within
R.sup.4 may be optionally substituted by one or more substituents
independently selected from hydroxy, halogeno, cyano, formyl,
carboxy, (C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.7)cycloalkyl,
(C.sub.3-C.sub.7)cycloalkylcarbonyl, (C.sub.1-C.sub.6)alkoxy,
amino, (C.sub.1-C.sub.6)alkylamino,
di-[(C.sub.1-C.sub.6)alkyl]amino, (C.sub.2-C.sub.6)alkanoyl,
(C.sub.1-C.sub.6)alkoxycarbonyl, carbamoyl,
(C.sub.1-C.sub.6)alkylcarbamoyl,
di-[(C.sub.1-C.sub.6)alkyl]carbamoyl, sulfamoyl,
(C.sub.1-C.sub.6)alkylsulfamoyl,
di-[(C.sub.1-C.sub.6)alkyl]sulfamoyl, --S(O).sub.m'R' wherein R'
and m' are each as defined above, --N(R'')C(O)R' wherein R' and R''
are each as defined above, and --X-Q wherein X and Q are each as
defined above, any of which substituents may be optionally
substituted by one or more further substituents independently
selected from (C.sub.1-C.sub.4)alkyl, (C.sub.1-C.sub.4)alkoxy,
hydroxy, halogeno, cyano, hydroxy (C.sub.1-C.sub.4)alkyl, and
--X-Q' wherein X as defined above and Q' represents a saturated 5-
or 6-membered heterocyclic ring comprising at least one ring
nitrogen atom; and [0208] each R.sup.1a'and R.sup.1b', which may be
the same or different, is selected from hydrogen, halogeno, cyano,
(C.sub.1-C.sub.6)alkyl, amino, (C.sub.1-C.sub.6)alkylamino and
di-[(C.sub.1-C.sub.6)alkyl]amino, each of which groups within
R.sup.1a'and R.sup.1b' may be optionally substituted by one or more
substituents independently selected from hydroxy, halogeno, cyano,
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.4)alkoxy, amino,
(C.sub.1-C.sub.6)alkylamino, di-[(C.sub.1-C.sub.6)alkyl]amino,
--N(R'')C(O)R' wherein R' and R'' are as defined above, and a
saturated monocyclic 5-, 6-, 7- or 8-membered ring optionally
comprising one or more heteroatoms independently selected from
nitrogen, oxygen and sulfur.
[0209] These compounds are typically excluded from the scope of the
invention for use in the production of an anti-proliferative effect
in a human or animal, for example for use in the treatment of a
disease or medical condition mediated alone or in part by
insulin-like growth factor receptor (IGF-1R) tyrosine kinase, for
example for use in the prevention or treatment of those tumours
which are sensitive to inhibition of insulin-like growth factor-1
receptor (IGF-1R) tyrosine kinase, involved in the signal
transduction steps which lead to the proliferation and/or survival
of tumour cells, for example for use in the treatment of cancer.
These compounds are typically excluded from the scope of the
invention when used in combination with methotrexate.
[0210] Typically, in the compound of formula (I) R.sub.1 represents
a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a
linear or branched C.sub.1-C.sub.6 alkyl group, a C.sub.1-C.sub.4
haloalkyl group, a C.sub.1-C.sub.4 hydroxyalkyl group, a
C.sub.3-C.sub.10 cycloalkyl group or a --NR'R'' group; wherein R'
and R'' are the same or different and each represents a hydrogen
atom, a linear or branched C.sub.1-C.sub.6 alkyl group, a
C.sub.1-C.sub.4 haloalkyl group or C.sub.1-C.sub.4 hydroxyalkyl
group;
R.sub.2, R.sub.3 and R.sub.4 are the same or different and each
represent a hydrogen atom, a halogen atom, a hydroxyl group, a
cyano group, a linear or branched C.sub.1-C.sub.6 alkyl group, a
C.sub.1-C.sub.4 haloalkyl group, a C.sub.1-C.sub.4 hydroxyalkyl
group, or a C.sub.3-C.sub.11, cycloalkyl group; R.sub.5 represents
a hydrogen atom, a linear or branched C.sub.1-C.sub.6 alkyl group
optionally substituted by one or more substituents selected from a
hydroxyl group, a cyano group, a C.sub.1-C.sub.4 haloalkyl group, a
C.sub.1-C.sub.4 hydroxyalkyl group or a C.sub.3-C.sub.10 cycloalkyl
group; or R.sub.5 together with R.sub.8 and the nitrogen atom to
which R.sub.5 is bonded form a 5- to 9-membered, saturated
heterocyclyl group, which contains, as heteroatoms, one or two
nitrogen atoms and which heterocyclyl ring is unsubstituted or
substituted by a --C(O)--(CH.sub.2).sub.n--R group or a
--C(O)--(CH.sub.2).sub.n--NR'R'' group, wherein n is 0, 1 or 2, R
represents a hydrogen atom, or a linear or branched C.sub.1-C.sub.6
alkyl group, a C.sub.1-C.sub.4 haloalkyl group, a C.sub.1-C.sub.4
hydroxyalkyl group, or a cyano group and R' and R'' are the same or
different and each represents a hydrogen atom, a linear or branched
C.sub.1-C.sub.6 alkyl group, a C.sub.1-C.sub.4 haloalkyl group, or
C.sub.1-C.sub.4 hydroxyalkyl group; R.sub.6 and R.sub.7 are the
same or different and each represent a hydrogen atom, a linear or
branched C.sub.1-C.sub.6 alkyl group, a C.sub.1-C.sub.4 haloalkyl
group or a C.sub.1-C.sub.4 hydroxyalkyl group; R.sub.9 represents a
hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a
linear or branched C.sub.1-C.sub.6 alkyl group, a C.sub.1-C.sub.4
haloalkyl group, a C.sub.1-C.sub.4 hydroxyalkyl group, a 5- to
10-membered heterocyclyl group, or a 5- to 10-membered heteroaryl
group, wherein said heterocyclyl and heteroaryl groups are
unsubstituted or substituted by one or more substituents selected
from a halogen atom, a linear or branched C.sub.1-C.sub.6 alkyl
group, a cyano group, a hydroxyl group or a C.sub.1-C.sub.4 alkoxy
group; or R.sub.9 represents a --C(O)--O--R' group or a
--C(O)--(CH.sub.2).sub.n--NR'R'' group, wherein n is 0, 1 or 2, and
R' and R'' are the same or different and each represents a hydrogen
atom, a linear or branched C.sub.1-C.sub.6 alkyl group, a
C.sub.1-C.sub.4 haloalkyl group, or C.sub.1-C.sub.4 hydroxyalkyl
group; or in the case when two adjacent --CR.sub.9 groups are
present, the two adjacent --CR.sub.9 groups and the carbon atoms to
which they are bonded optionally form a C.sub.6-C.sub.10 aryl group
which is unsubstituted or substituted by one or more substituents
selected from a halogen atom, a linear or branched C.sub.1-C.sub.6
alkyl group, a hydroxy group or a C.sub.1-C.sub.4 alkoxy group;
R.sub.8 represents a hydrogen atom, a linear or branched
C.sub.1-C.sub.6 alkyl group, a C.sub.1-C.sub.4 haloalkyl group, a
C.sub.1-C.sub.4 hydroxyalkyl group, a C.sub.3-C.sub.10, cycloalkyl
group, a C.sub.6-C.sub.10 aryl group, a 5- to 10-membered
heteroaryl group containing 1, 2 or 3 heteroatoms selected from N,
O and S, a 5- to 10-membered heterocyclyl group containing 1, 2 or
3 heteroatoms selected from N, O and S, -L-Het-R''', -L-A,
-A-SO.sub.2--R', -A-SO--R''', -A-A', -A-L-C(O)NR'R'', -A-L-CN,
-A-C(O)--Het'-L-CN, -A-C(O)--NR'R'', -A-C(O).sub.Z-A'',
-A-C(O)--R''', -A-CO.sub.2--R', -A-C(O).sub.Z-L-A''',
-A-C(O).sub.Z-L-R''', -A-C(O).sub.Z-L-CN, or -A-C(O).sub.Z-L-Het-R'
group, wherein z is 1 or 2, R' and R'' are the same or different
and each represents a hydrogen atom or linear or a branched
C.sub.1-C.sub.6 alkyl group, a C.sub.1-C.sub.4 haloalkyl group or a
C.sub.1-C.sub.4 hydroxyalkyl group, and R''' represents a linear or
branched C.sub.1-C.sub.6 alkyl group, a C.sub.1-C.sub.4 haloalkyl
group or a C.sub.1-C.sub.4 hydroxyalkyl group, the heterocyclyl and
heteroaryl groups being optionally fused to a phenyl group, and
wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl groups
being unsubstituted or substituted by one or more substituents
selected from a halogen atom, a hydroxyl group, a cyano group, a
linear or branched C.sub.1-C.sub.6 alkyl group, or a
C.sub.1-C.sub.4 alkoxy group, and wherein L is a linear or branched
C.sub.1-C.sub.6 alkylene group, Het represents O or NR.sup.IV, and
Het' represents NR.sup.IV, wherein R.sup.IV is a hydrogen atom, a
linear or branched C.sub.1-C.sub.4 alkyl group, a C.sub.1-C.sub.4
haloalkyl group, or C.sub.1-C.sub.4 hydroxyalkyl group, A, A', A''
and A''' are the same or different and each represent a
C.sub.3-C.sub.10 cycloalkyl group, a 5- to 10-membered heterocyclyl
group, a C.sub.6-C.sub.10aryl group, or a 5- to 10-membered
heteroaryl group, the cycloalkyl, heterocyclyl, aryl and heteroaryl
groups being unsubstituted or substituted by one or more
substituents selected from a halogen atom, a hydroxyl group, a
cyano group, a linear or branched C.sub.1-C.sub.6 alkyl group, or a
C.sub.1-C.sub.4 alkoxy group.
[0211] Alternatively, in the compounds of formula (I), R.sub.9
represents a hydrogen atom, a halogen atom, a hydroxyl group, a
cyano group, a linear or branched C.sub.1-C.sub.6 alkyl group, a
C.sub.1-C.sub.4 haloalkyl group, a C.sub.1-C.sub.4 hydroxyalkyl
group or a --NR'R'' group; wherein R' and R'' are the same or
different and each represents a hydrogen atom, a linear or branched
C.sub.1-C.sub.6 alkyl group, a C.sub.1-C.sub.4 haloalkyl group or
C.sub.1-C.sub.4 hydroxyalkyl group, and R.sub.1, R.sub.2, R.sub.3,
R.sub.4, R.sub.5, R.sub.6, R.sub.7, R.sub.8, L, Het, A, A', A'' and
A''' are as defined above.
[0212] Preferably, in the compound of formula (I) Z is a NR.sub.5
group, wherein R.sub.5 represents a hydrogen atom, a linear or
branched C.sub.1-C.sub.6 alkyl group optionally substituted by one
or more substituents selected from a hydroxyl group, a cyano group,
a C.sub.1-C.sub.4 haloalkyl group, a C.sub.1-C.sub.4 hydroxyalkyl
group, a C.sub.3-C.sub.10 cycloalkyl group, a phenyl group or a 6
membered, saturated N-containing heterocyclyl ring, or R.sub.5
represents a --S(O).sub.2R.sub.10 group, a
--S(O).sub.2NR.sub.10R.sub.11 group, a --C(O)OR.sub.10 group, a
--C(O)--(CH.sub.2).sub.n--R.sub.10 group, or a
--C(O)--(CH.sub.2).sub.n--NR.sub.10R.sub.11 group, wherein n is 0,
1 or 2 and R.sub.10 and R.sub.11 are as defined before.
[0213] Typically, in the compound of formula (I), Y represents a
--CR.sub.9 group. Typically, in the compound of formula (I), T
represents a --CR.sub.9 group. Preferably, both Y and T represent a
--CR.sub.9 group.
[0214] Typically, in the compound of formula (I), at least one of
X, Y and T, preferably at least one of X and Y, represents N.
[0215] In the compound of formula (I), Y may represent N, in which
case X and T each represent a --CR.sub.9 group.
[0216] When Y represents N and R.sub.8 represents a 5- to
7-membered heterocyclyl group containing one nitrogen atom,
typically said heterocyclyl group is substituted by one or more
substituents, wherein said substitution is at least on the ring
nitrogen atom of the heterocyclyl group, and wherein this
substituent is other than a tert-butoxycarbonyl group. Preferred
substituents for an R.sub.8 heterocyclyl group are defined herein.
Preferably, when Y represents N and R.sub.8 represents a 5- to
7-membered heterocyclyl group containing one nitrogen atom, said
heterocyclyl group is a piperidinyl group which is substituted by
one or more substituents, wherein said substitution is at least on
the ring nitrogen of the piperidinyl group, the substituents being
selected from [0217] a linear or branched C.sub.1-C.sub.3 alkyl
group; [0218] a halogen atom; [0219] a pyridyl group, which pyridyl
group is unsubstituted or substituted by one or more cyano groups;
[0220] a 1,2,4-triazolyl group; and [0221] a
--C(O)--(CH.sub.2).sub.n--R'' group, wherein n is 0 or 1 and R'' is
a cyano group, a linear or branched C.sub.1-C.sub.6 alkyl group, a
C.sub.1-C.sub.4 haloalkyl group or a C.sub.3-C.sub.7 cycloalkyl
group.
[0222] Typically, in the compound of formula (I) R.sub.1 represents
a hydrogen atom, a halogen atom, a cyano group, a linear or
branched C.sub.1-C.sub.6 alkyl group, a C.sub.3-C.sub.7 cycloalkyl
group or a --NR'R'' group, wherein R' and R'' are the same or
different and each represents a hydrogen atom, a linear or branched
C.sub.1-C.sub.6 alkyl group, a C.sub.1-C.sub.4 haloalkyl group;
preferably R.sub.1 represents a hydrogen atom or a --NH.sub.2
group; more preferably R.sub.1 represents a hydrogen atom.
[0223] Typically, in the compound of formula (I) R.sub.2 represents
a hydrogen atom, a halogen atom, a cyano group, a linear or
branched C.sub.1-C.sub.6 alkyl group or a C.sub.3-C.sub.7
cycloalkyl group; preferably R.sub.2 represents a hydrogen atom or
a linear or branched C.sub.1-C.sub.3 alkyl group; more preferably
R.sub.2 represents a hydrogen atom.
[0224] Typically, in the compound of formula (I) R.sub.3 represents
a hydrogen atom, a halogen atom, a cyano group, a linear or
branched C.sub.1-C.sub.6 alkyl group or a C.sub.3-C.sub.7
cycloalkyl group; preferably R.sub.3 represents a hydrogen atom, a
cyano group or a linear or branched C.sub.1-C.sub.3 alkyl group;
more preferably R.sub.3 represents a hydrogen atom or a cyano
group.
[0225] Typically, in the compound of formula (I) R.sub.4 represents
a hydrogen atom, a halogen atom, a cyano group, a linear or
branched C.sub.1-C.sub.6 alkyl group or a C.sub.3-C.sub.7
cycloalkyl group; preferably R.sub.4 represents a hydrogen atom or
a linear or branched C.sub.1-C.sub.3 alkyl group; more preferably
R.sub.4 represents a hydrogen atom.
[0226] Typically, in the compound of formula (I) Z is NR.sub.5 and
R.sub.5 represents a hydrogen atom, a linear or branched
C.sub.1-C.sub.4 alkyl group optionally substituted by one or more
substituents selected from a hydroxyl group, a C.sub.1-C.sub.4
haloalkyl group, a C.sub.1-C.sub.4 hydroxyalkyl group or a
C.sub.3-C.sub.7 cycloalkyl group; preferably R.sub.5 represents a
hydrogen atom or a linear or branched C.sub.1-C.sub.3 alkyl group;
more preferably R.sub.5 represents a hydrogen atom.
[0227] Typically, in the compound of formula (I) R.sub.6 and
R.sub.7 independently represent a hydrogen atom or a linear or
branched C.sub.1-C.sub.6 alkyl group; preferably R.sub.6 and
R.sub.7 independently represent a hydrogen atom or a linear or
branched C.sub.1-C.sub.3 alkyl group.
[0228] Typically, in the compound of formula (I) R.sub.8 represents
a linear or branched C.sub.1-C.sub.6alkyl group, a C.sub.1-C.sub.4
haloalkyl group, a C.sub.1-C.sub.4 hydroxyalkyl group, a
C.sub.3-C.sub.10 cycloalkyl group, a C.sub.6-C.sub.10 aryl group, a
5- to 10-membered heteroaryl group containing 1, 2 or 3 heteroatoms
selected from N, O and S, a 5- to 10-membered heterocyclyl group
containing 1, 2 or 3 heteroatoms selected from N, O and S,
-L-Het-R''', -L-A, -A-A', -A-L-C(O)NR'R'', -A-L-CN,
-A-C(O)--Het'-L-CN, -A-C(O)--NR'R'', -A-C(O).sub.Z-A'',
-A-C(O)--R''', -A-CO.sub.2--R', -A-C(O).sub.Z-L-A''',
-A-C(O).sub.Z-L-R''', -A-C(O).sub.Z-L-CN, or -A-C(O).sub.Z-L-Het-R'
group, wherein z is 1 or 2, R' and R'' are the same or different
and each represents a hydrogen atom or linear or a branched
C.sub.1-C.sub.6 alkyl group, a C.sub.1-C.sub.4 haloalkyl group or a
C.sub.1-C.sub.4 hydroxyalkyl group, and R''' represents a linear or
branched C.sub.1-C.sub.6 alkyl group, a C.sub.1-C.sub.4 haloalkyl
group or a C.sub.1-C.sub.4 hydroxyalkyl group, the heterocyclyl and
heteroaryl groups being optionally fused to a phenyl group, and
wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl groups
being unsubstituted or substituted by one or more substituents
selected from a halogen atom, a hydroxyl group, a cyano group, a
linear or branched C.sub.1-C.sub.4 alkyl group, or a
C.sub.1-C.sub.4 alkoxy group. Typically, L is a linear or branched
C.sub.1-C.sub.6 alkylene group. Preferably, L is a linear or
branched C.sub.1-C.sub.5 alkylene group; more preferably, L is a
linear or branched C.sub.1-C.sub.3 alkylene group.
[0229] Typically, Het represents O or NR.sup.IV and Het' represents
NR.sup.IV, wherein R.sup.IV is a hydrogen atom or a linear or
branched C.sub.1-C.sub.4 alkyl group, preferably a hydrogen atom or
a straight or branched C.sub.1-C.sub.2 alkyl group. Preferably, Het
represents O.
[0230] Typically, A, A', A'' and A''' are the same or different and
each represent a C.sub.3-C.sub.6 cycloalkyl, 5- to 6-membered
heterocyclyl, phenyl, 5- to 6-membered heteroaryl group, the
cycloalkyl, heterocyclyl, phenyl and heteroaryl groups being
unsubstituted or substituted by 1, 2 or 3 halogen atoms, or
hydroxyl, cyano, linear or branched C.sub.1-C.sub.2 alkyl, or
C.sub.1-C.sub.2 alkoxy groups.
[0231] Typically, A is a 5- to 6-membered heterocyclyl group,
phenyl or C.sub.3-C.sub.6 cycloalkyl group, said heterocyclyl,
phenyl and cycloalkyl groups being unsubstituted or substituted by
1, 2 or 3, preferably 1 or 2, halogen atoms or hydroxyl or
C.sub.1-C.sub.2 alkyl groups. Preferably, A is a piperidinyl,
phenyl or cyclohexyl group, which piperidinyl, phenyl and
cyclohexyl groups are unsubstituted or substituted by one halogen
atom, or hydroxyl group or C.sub.1-C.sub.2 alkyl group,
[0232] Typically, A' is phenyl group or a 5- or 6-membered
heteroaryl group, which phenyl and heteroaryl groups are
unsubstituted or substituted by 1, 2 or 3 halogen atoms, or cyano,
hydroxy or C.sub.1-C.sub.2 alkyl groups. Preferably, A' is a
phenyl, pyridinyl or triazolyl group, for example a phenyl or
pyridinyl group, which is unsubstituted or substituted by 1 or 2
halogen atoms or cyano groups.
[0233] Typically, A'' is a 5- to 6-membered heterocyclyl,
C.sub.3-C.sub.6 cycloalkyl or 5- or 6-membered heteroaryl group,
which heterocyclyl, cycloalkyl and heteroaryl groups are
unsubstituted or substituted by 1, 2 or 3, halogen atoms, or cyano,
hydroxy or C.sub.1-C.sub.2 alkyl groups. Preferably, A'' is a
pyrrolidinyl, cyclopropyl or pyridinyl group, which pyrrolidinyl,
cyclopropyl and pyridinyl groups are unsubstituted or substituted
by 1 or 2 halogen atoms or cyano groups.
[0234] Typically, A''' is a 5- to 6-membered heteroaryl group,
which heteroaryl group is unsubstituted or substituted by 1, 2 or
3, preferably 1 or 2 halogen atoms or hydroxy or C.sub.1-C.sub.2
alkyl groups. Preferably, A''' is an imidazolyl group.
[0235] Preferably in the compounds of formula (I), R.sub.8
represents a hydrogen atom, a linear or branched C.sub.1-C.sub.6
alkyl group, a C.sub.1-C.sub.4 haloalkyl group, a C.sub.1-C.sub.4
hydroxyalkyl group, a C.sub.3-C.sub.10 cycloalkyl group, a
C.sub.6-C.sub.10aryl group, a 5- to 10-membered heteroaryl group
containing 1, 2 or 3 heteroatoms selected from N, O and S, a 5- to
10-membered heterocyclyl group containing 1, 2 or 3 heteroatoms
selected from N, O and S, -L-Het-R''', -L-A, -A-A', -A-L-CN,
-A-C(O)--R''', -A-C(O).sub.Z-L-R''', -A-C(O).sub.Z-L-CN, or
-A-C(O).sub.Z-L-Het-R' group, wherein z is 1 or 2 and R'''
represents a linear or branched C.sub.1-C.sub.3 alkyl group, a
C.sub.1-C.sub.3 haloalkyl group or a C.sub.1-C.sub.3 hydroxyalkyl
group, and wherein the cycloalkyl, heterocyclyl, aryl and
heteroaryl groups are unsubstituted or substituted by one or more
substituents selected from a halogen atom, a hydroxyl group, a
cyano group, a linear or branched C.sub.1-C.sub.6 alkyl group, or a
C.sub.1-C.sub.4 alkoxy group, and wherein
L is a linear or branched C.sub.1-C.sub.3 alkylene group, Het
represents O or NR.sup.IV, wherein R.sup.IV is a hydrogen atom, a
linear or branched C.sub.1-C.sub.4 alkyl group, a C.sub.1-C.sub.4
haloalkyl group, or C.sub.1-C.sub.4 hydroxyalkyl group, A and A'
are the same or different and each represents a C.sub.3-C.sub.10
cycloalkyl group, a 5- to 10-membered heterocyclyl group, a
C.sub.6-C.sub.10 aryl group, or a 5- to 10-membered heteroaryl
group, the cycloalkyl, heterocyclyl, aryl and heteroaryl groups
being unsubstituted or substituted by one or more substituents
selected from a halogen atom, a hydroxyl group, a cyano group, a
linear or branched C.sub.1-C.sub.6 alkyl group, or a
C.sub.1-C.sub.4 alkoxy group.
[0236] Preferably, in the compound of formula (I) R.sub.8
represents a linear or branched C.sub.1-C.sub.6 alkyl group, a
C.sub.1-C.sub.4 haloalkyl group, a C.sub.3-C.sub.7 cycloalkyl
group, a phenyl group, a 5- to 6-membered monocyclic heteroaryl
group containing 1, 2 or 3 heteroatoms selected from N, O and S, a
5- to 7-membered heterocyclyl group containing 1, 2 or 3
heteroatoms selected from N, O and S, or a --(CH.sub.2).sub.nOR
group wherein n is 0 or 1 and R represents a linear or branched
C.sub.1-C.sub.6 alkyl group or a C.sub.1-C.sub.4 haloalkyl group;
[0237] wherein the haloalkyl, cycloalkyl, phenyl, heteroaryl and
heterocyclyl groups are unsubstituted or substituted by one or more
substituents selected from Ra; and the alkyl group is unsubstituted
or substituted by one or more substituents selected from Rb; [0238]
Ra is a halogen atom; a cyano group; a hydroxyl group; a linear or
branched C.sub.1-C.sub.6 alkyl group; a C.sub.1-C.sub.4 haloalkyl
group; a C.sub.1-C.sub.4 alkoxy group; a C.sub.3-C.sub.7 cycloalkyl
group unsubstituted or substituted by one or more substituents
selected from substituents Re; a phenyl group unsubstituted or
substituted by one or more substituents selected from substituents
Re; a 5- to 6-membered monocyclic heteroaryl group containing 1, 2
or 3 heteroatoms selected from N, O and S unsubstituted or
substituted by one or more substituents selected from substituents
Re; a 6 membered, saturated N-containing heterocyclyl ring,
unsubstituted or substituted by one or more substituents selected
from substituents Re; a --C(O)OR' group or a
--C(O)--(CH.sub.2).sub.n--R'' group wherein n is 0 or 1, [0239] Rb
is a cyano group; a C.sub.1-C.sub.4 haloalkyl group; a
C.sub.1-C.sub.4 alkoxy group; a C.sub.3-C.sub.7 cycloalkyl group
unsubstituted or substituted by one or more substituents selected
from substituents Re; a phenyl group unsubstituted or substituted
by one or more substituents selected from substituents Re; a 5- to
6-membered monocyclic heteroaryl group containing 1, 2 or 3
heteroatoms selected from N, O and S unsubstituted or substituted
by one or more substituents selected from substituents Re; a 6
membered, saturated N-containing heterocyclyl ring, unsubstituted
or substituted by one or more substituents selected from
substituents Re; a --C(O)OR' group or a
--C(O)--(CH.sub.2).sub.n--R'' group wherein n is 0 or 1, [0240] Re
is a halogen atom, a hydroxyl group, a cyano group, a linear or
branched C.sub.1-C.sub.6 alkyl group or a C.sub.1-C.sub.4 haloalkyl
group; [0241] R' is a hydrogen atom, a linear or branched
C.sub.1-C.sub.6 alkyl group, a C.sub.1-C.sub.4 haloalkyl group, a
C.sub.3-C.sub.7 cycloalkyl group, a phenyl group, a 5- to
6-membered monocyclic heteroaryl group containing 1, 2 or 3
heteroatoms selected from N, O and S or a 5- to 6-membered,
saturated N-containing heterocyclyl ring; and [0242] R'' is a cyano
group, a linear or branched C.sub.1-C.sub.6 alkyl group, a
C.sub.1-C.sub.4 haloalkyl group, a C.sub.3-C.sub.7 cycloalkyl
group, a phenyl group, a 5- to 6-membered monocyclic heteroaryl
group containing 1, 2 or 3 heteroatoms selected from N, O and S or
a 5- to 6-membered, saturated N-containing heterocyclyl ring;
wherein the cycloalkyl, phenyl, heteroaryl and heterocyclyl groups
are unsubstituted or substituted by one or more substituents
selected from a hydroxyl group, a cyano group, a linear or branched
C.sub.1-C.sub.6 alkyl group or a C.sub.1-C.sub.4 haloalkyl
group.
[0243] More preferably, in the compound of formula (I) R.sub.8
represents a linear or branched C.sub.1-C.sub.6 alkyl group, a
C.sub.1-C.sub.4 haloalkyl group, a C.sub.3-C.sub.7 cycloalkyl
group, a phenyl group, a 5- to 6-membered monocyclic heteroaryl
group containing 1, 2 or 3 heteroatoms selected form N, O and S, a
5- to 7-membered heterocyclyl group containing 1, 2 or 3
heteroatoms selected from N, O and S, or a --(CH.sub.2).sub.nOR
group wherein n is 0 or 1 and R represents a linear or branched
C.sub.1-C.sub.6 alkyl group or a C.sub.1-C.sub.4 haloalkyl group,
for example R.sub.8 represents a linear or branched C.sub.1-C.sub.6
alkyl group, a C.sub.1-C.sub.4 haloalkyl group, a C.sub.3-C.sub.7
cycloalkyl group, a phenyl group, a 5- to 7-membered heterocyclyl
group containing 1, 2 or 3 heteroatoms selected from N, O and S, or
a --(CH.sub.2).sub.nOR group wherein n is 0 or 1 and R represents a
linear or branched C.sub.1-C.sub.6 alkyl group or a C.sub.1-C.sub.4
haloalkyl group; [0244] wherein the haloalkyl, cycloalkyl, phenyl,
heteroaryl and heterocyclyl groups are unsubstituted or substituted
by one or more substituents selected from Ra; and the alkyl group
is unsubstituted or substituted by one or more substituents
selected from Rb; [0245] Ra is a halogen atom; a cyano group; a
hydroxyl group; a linear or branched C.sub.1-C.sub.6 alkyl group; a
C.sub.1-C.sub.4 haloalkyl group; a 5- to 6-membered monocyclic
heteroaryl group containing 1, 2 or 3 heteroatoms selected from N,
O and S unsubstituted or substituted by one or more substituents
selected from a halogen atom, a hydroxyl group, a cyano group, a
linear or branched C.sub.1-C.sub.6 alkyl group or a C.sub.1-C.sub.4
haloalkyl group; a --C(O)OR' group or a
--C(O)--(CH.sub.2).sub.n--R'' group wherein n is 0 or 1, [0246] Rb
is a cyano group; a C.sub.1-C.sub.4 haloalkyl group; a
C.sub.1-C.sub.4 alkoxy group; a C.sub.3-C.sub.7 cycloalkyl group
unsubstituted or substituted by one or more substituents selected
from a halogen atom, a hydroxyl group or a cyano group; a phenyl
group unsubstituted or substituted by one or more substituents
selected from a halogen atom, a hydroxyl group, a cyano group or a
linear or branched C.sub.1-C.sub.6 alkyl group; a --C(O)OR' group
or a --C(O)--(CH.sub.2).sub.n--R'' group wherein n is 0 or 1,
[0247] R' is a hydrogen atom, a linear or branched C.sub.1-C.sub.6
alkyl group, a C.sub.1-C.sub.4 haloalkyl group or a C.sub.3-C.sub.7
cycloalkyl group; and [0248] R'' is a cyano group, a linear or
branched C.sub.1-C.sub.6 alkyl group, a C.sub.1-C.sub.4 haloalkyl
group or a C.sub.3-C.sub.7 cycloalkyl group.
[0249] In one embodiment, R.sub.8 represents a linear or branched
C.sub.1-C.sub.6 alkyl group, a C.sub.1-C.sub.4 haloalkyl group, a
C.sub.3-C.sub.7 cycloalkyl group, a 6-membered heterocyclyl group
containing 1, 2 or 3 heteroatoms selected from N, O and S, or a
--(CH.sub.2).sub.nOR group wherein n is 0 or 1 and R represents a
linear or branched C.sub.1-C.sub.6 alkyl group or a C.sub.1-C.sub.4
haloalkyl group; in particular, R.sub.8 may represent a 6-membered
heterocyclyl group containing 1, 2 or 3 heteroatoms selected from
N, O and S; [0250] wherein the haloalkyl, cycloalkyl and
heterocyclyl groups are unsubstituted or substituted by one or more
substituents selected from Ra; and the alkyl group is unsubstituted
or substituted by one or more substituents selected from Rb,
wherein Ra and Rb are as defined above.
[0251] More preferably, when R.sub.8 is an alkyl or haloalkyl
group, it is an unsubstituted alkyl or haloalkyl group; when
R.sub.8 is a cycloalkyl or phenyl group, it is unsubstituted or
substituted by one or more substituents selected from a halogen
atom, a cyano group, a hydroxyl group, a linear or branched
C.sub.1-C.sub.6 alkyl group, a C.sub.1-C.sub.4 haloalkyl group, a
--C(O)OR' group or a --C(O)--(CH.sub.2).sub.n--R'' group wherein n
is 0 or 1, R' is a hydrogen atom, a linear or branched
C.sub.1-C.sub.3 alkyl group or a C.sub.1-C.sub.3 haloalkyl group
and R'' is a cyano group, a linear or branched C.sub.1-C.sub.3
alkyl group or a C.sub.1-C.sub.3 haloalkyl group; and when R.sub.8
is a heteroaryl or heterocyclyl group it is unsubstituted or
substituted with one or more substituents selected from Ra, wherein
Ra is as defined above.
[0252] Preferably, when R.sub.8 is a heteroaryl group, it is a 5-
to 6-membered heteroaryl group containing one or two nitrogen
atoms. Pyridyl is preferred. Preferably, when R.sub.8 is a
heteroaryl group it is unsubstituted or substituted with one or
more halogen atoms.
[0253] When R.sub.8 is a heterocyclyl group it is preferably a 5-
or 6-membered heterocyclyl group, e.g. a 6-membered heterocyclyl
group, containing one or two heteroatoms selected from N and O,
more preferably containing one or two nitrogen atoms. Preferred
examples are piperidinyl and tetrahydropyranyl. Piperidinyl is
preferred. Preferably, the heterocyclyl group is linked to the rest
of the molecule via a ring carbon atom, in other words it is linked
to the group --Z--(CR.sub.6R.sub.7).sub.m-- via a ring carbon atom.
Substituents on a piperidinyl group may be present on any ring atom
but are preferably present on the nitrogen atom. Preferably, at
least one substituent is present on the ring nitrogen atom.
[0254] Most preferably, R.sub.8 represents a linear or branched
C.sub.1-C.sub.6 alkyl group; a C.sub.1-C.sub.4 haloalkyl group; a
C.sub.3-C.sub.7 cycloalkyl group, which cycloalkyl group is
unsubstituted or substituted by one or more substituents selected
from halogen atoms and hydroxyl groups; a phenyl group, which
phenyl group is unsubstituted or substituted by one or more halogen
atoms; a --(CH.sub.2).sub.n--OR group wherein n is 0 or 1 and R
represents a linear or branched C.sub.1-C.sub.3 alkyl group; a
pyridyl group, which pyridyl group is unsubstituted or substituted
by one or more substituents selected from halogen atoms and
hydroxyl groups; a tetrahydropyranyl group, which tetrahydropyranyl
group is unsubstituted or substituted by one or more substituents
selected from halogen atoms and hydroxyl groups; or a piperidinyl
group, which piperidinyl group is unsubstituted or substituted by
one or more substituents selected from [0255] a linear or branched
C.sub.1-C.sub.3 alkyl group; [0256] a halogen atom; [0257] a
pyridyl group, which pyridyl group is unsubstituted or substituted
by one or more cyano groups; [0258] a 1,2,4-triazolyl group; and
[0259] a --C(O)--(CH.sub.2).sub.n--R'' group, wherein n is 0 or 1
and R'' is a cyano group, a linear or branched C.sub.1-C.sub.6
alkyl group, a C.sub.1-C.sub.4 haloalkyl group or a C.sub.3-C.sub.7
cycloalkyl group.
[0260] For example, R.sub.8 may represent a linear or branched
C.sub.1-C.sub.6 alkyl group; a C.sub.1-C.sub.4 haloalkyl group; a
C.sub.3-C.sub.7 cycloalkyl group, which cycloalkyl group is
unsubstituted or substituted by one or more hydroxyl groups; a
phenyl group, which phenyl group is unsubstituted or substituted by
one or more halogen atoms; a (CH.sub.2).sub.n--OR group wherein n
is 0 or 1 and R represents a linear or branched C.sub.1-C.sub.3
alkyl group; or a piperidinyl group, which piperidinyl group is
unsubstituted or substituted by one or more substituents selected
from [0261] a pyridyl group, which pyridyl group is unsubstituted
or substituted by one or more cyano groups; and [0262] a
--C(O)--(CH.sub.2).sub.n--R'' group, wherein n is 0 or 1 and R'' is
a cyano group, a linear or branched C.sub.1-C.sub.6 alkyl group, a
C.sub.1-C.sub.4 haloalkyl group or a C.sub.3-C.sub.7 cycloalkyl
group.
[0263] Alternatively, R.sub.8 may represent a linear or branched
C.sub.1-C.sub.6 alkyl group; a C.sub.1-C.sub.4 haloalkyl group; a
C.sub.3-C.sub.7 cycloalkyl group, which cycloalkyl group is
unsubstituted or substituted by one or more substituents selected
from halogen atoms and hydroxyl groups; a --(CH.sub.2).sub.n--OR
group wherein n is 0 or 1 and R represents a linear or branched
C.sub.1-C.sub.3 alkyl group; a tetrahydropyranyl group, which
tetrahydropyranyl group is unsubstituted or substituted by one or
more substituents selected from halogen atoms and hydroxyl groups;
or a piperidinyl group, which piperidinyl group is unsubstituted or
substituted by one or more substituents selected from [0264] a
linear or branched C.sub.1-C.sub.3 alkyl group; [0265] a halogen
atom; [0266] a pyridyl group, which pyridyl group is unsubstituted
or substituted by one or more cyano groups; [0267] a
1,2,4-triazolyl group; and [0268] a --C(O)--(CH.sub.2).sub.n--R''
group, wherein n is 0 or 1 and R'' is a cyano group, a linear or
branched C.sub.1-C.sub.6 alkyl group, a C.sub.1-C.sub.4 haloalkyl
group or a C.sub.3-C.sub.7 cycloalkyl group.
[0269] Particularly preferred substituents on the piperidinyl group
at R.sub.8 are substituents selected from [0270] a pyridyl group,
which pyridyl group is unsubstituted or substituted by one or more
cyano groups; [0271] a 1,2,4-triazolyl group, and [0272] a
--C(O)--(CH.sub.2).sub.n--R'' group, wherein n is 0 or 1 and R'' is
a cyano group or a linear or branched C.sub.1-C.sub.3 alkyl
group.
[0273] For example, preferred substituents on the piperidinyl group
at R.sub.8 are substituents selected from [0274] a pyridyl group,
which pyridyl group is unsubstituted or substituted by one or more
cyano groups; and [0275] a --C(O)--(CH.sub.2).sub.n--R'' group,
wherein n is 0 or 1 and R'' is a cyano group or a linear or
branched C.sub.1-C.sub.3 alkyl group.
[0276] In one embodiment R.sub.8 represents a 6-membered
heterocyclyl group, e.g. a tetrahydropyranyl group or a piperidinyl
group, e.g. a piperidinyl group. Preferred substituents on these
groups are defined above.
[0277] In one embodiment, when R.sub.8 represents a 5- to
7-membered heterocyclyl group containing one nitrogen atom, said
heterocyclyl group is substituted by one or more substituents,
wherein said substitution is at least on the ring nitrogen atom of
the heterocyclyl group, and wherein this substituent is other than
a tert-butoxycarbonyl group. Preferably, said heterocyclyl group is
a piperidinyl group which is substituted by one or more
substituents, wherein said substitution is at least on the ring
nitrogen of the piperidinyl group, the substituents being selected
from [0278] a linear or branched C.sub.1-C.sub.3 alkyl group;
[0279] a halogen atom; [0280] a pyridyl group, which pyridyl group
is unsubstituted or substituted by one or more cyano groups; [0281]
a 1,2,4-triazolyl group; and [0282] a --C(O)--(CH.sub.2).sub.n--R''
group, wherein n is 0 or 1 and R'' is a cyano group, a linear or
branched C.sub.1-C.sub.6 alkyl group, a C.sub.1-C.sub.4 haloalkyl
group or a C.sub.3-C.sub.7 cycloalkyl group.
[0283] Preferred substituents are selected from [0284] a pyridyl
group, which pyridyl group is unsubstituted or substituted by one
or more cyano groups; [0285] a 1,2,4-triazolyl group, and [0286] a
--C(O)--(CH.sub.2).sub.n--R'' group, wherein n is 0 or 1 and R'' is
a cyano group or a linear or branched C.sub.1-C.sub.3 alkyl
group.
[0287] Typically, in the compound of formula (I) R.sub.9 represents
a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group or
a linear or branched C.sub.1-C.sub.6 alkyl group; preferably
R.sub.9 represents a hydrogen atom, a halogen atom or a linear or
branched C.sub.1-C.sub.3 alkyl group.
[0288] Typically, in the compounds of formula (I), m is 0, 1 or 2,
preferably 0 or 1.
[0289] In a particularly preferred embodiment, the compound of the
invention is of formula (I-c)
##STR00004##
wherein m is 0 or an integer from 1 to 3; Z represents an oxygen
atom or a NR.sub.5 group; W represents a nitrogen atom or a
--CR.sub.3 group; X and Y independently represent a nitrogen atom
or a --CR.sub.9 group, wherein at least one of X and Y represents a
nitrogen atom, and the other represents a --CR.sub.9 group; R.sub.1
represents a hydrogen atom, a halogen atom, a hydroxyl group, a
cyano group, a linear or branched C.sub.1-C.sub.6 alkyl group, a
C.sub.1-C.sub.4 haloalkyl group, a C.sub.1-C.sub.4 hydroxyalkyl
group, a C.sub.3-C.sub.10 cycloalkyl group or a --NR'R'' group;
wherein R' and R'' are the same or different and each represents a
hydrogen atom, a linear or branched C.sub.1-C.sub.6 alkyl group, a
C.sub.1-C.sub.4 haloalkyl group or C.sub.1-C.sub.4 hydroxyalkyl
group; R.sub.2, R.sub.3 and R.sub.4 are the same or different and
each represent an hydrogen atom, a halogen atom, a hydroxyl group,
a cyano group, a linear or branched C.sub.1-C.sub.6 alkyl group, a
C.sub.1-C.sub.4 haloalkyl group, a C.sub.1-C.sub.4 hydroxyalkyl
group, or a C.sub.3-C.sub.10 cycloalkyl group; R.sub.5 represents a
hydrogen atom, a linear or branched C.sub.1-C.sub.6 alkyl group
unsubstituted or substituted by one or more substituents selected
from a hydroxyl group, a cyano group, a C.sub.1-C.sub.4 haloalkyl
group, a C.sub.1-C.sub.4 hydroxyalkyl group, a C.sub.3-C.sub.10
cycloalkyl group, a phenyl group, a pyridyl group or a 6 membered,
saturated N-containing heterocyclyl ring; R.sub.6 and R.sub.7 are
the same or different and each represent a hydrogen atom, a linear
or branched C.sub.1-C.sub.6 alkyl group, a C.sub.1-C.sub.4
haloalkyl group or a C.sub.1-C.sub.4 hydroxyalkyl group; R.sub.9
represents a hydrogen atom, a halogen atom, a hydroxyl group, a
cyano group, a linear or branched C.sub.1-C.sub.6 alkyl group, a
C.sub.1-C.sub.4 haloalkyl group, a C.sub.1-C.sub.4 hydroxyalkyl
group or a --NR'R'' group; wherein R' and R'' are the same or
different and each represents a hydrogen atom, a linear or branched
C.sub.1-C.sub.6 alkyl group, a C.sub.1-C.sub.4 haloalkyl group or
C.sub.1-C.sub.4 hydroxyalkyl group; R.sub.8 represents a linear or
branched C.sub.1-C.sub.6 alkyl group, a C.sub.1-C.sub.4 haloalkyl
group, a C.sub.3-C.sub.7 cycloalkyl group, a phenyl group, a 5- to
6-membered monocyclic heteroaryl group containing 1, 2 or 3
heteroatoms selected from N, O and S, a 5- to 7-membered
heterocyclyl group containing 1, 2 or 3 heteroatoms selected from
N, O and S, or a --(CH.sub.2).sub.nOR group wherein n is 0 or 1 and
R represents a linear or branched C.sub.1-C.sub.6 alkyl group or a
C.sub.1-C.sub.4 haloalkyl group; [0290] wherein the haloalkyl,
cycloalkyl, phenyl, heteroaryl and heterocyclyl groups are
unsubstituted or substituted by one or more substituents selected
from Ra; and the alkyl group is unsubstituted or substituted by one
or more substituents selected from Rb; [0291] Ra is a halogen atom;
a cyano group; a hydroxyl group; a linear or branched
C.sub.1-C.sub.6 alkyl group; a C.sub.1-C.sub.4 haloalkyl group; a
C.sub.1-C.sub.4 alkoxy group; a C.sub.3-C.sub.7 cycloalkyl group
unsubstituted or substituted by one or more substituents selected
from substituents Re; a phenyl group unsubstituted or substituted
by one or more substituents selected from substituents Re; a 5- to
6-membered monocyclic heteroaryl group containing 1, 2 or 3
heteroatoms selected from N, O and S unsubstituted or substituted
by one or more substituents selected from substituents Re; a 6
membered, saturated N-containing heterocyclyl ring, unsubstituted
or substituted by one or more substituents selected from
substituents Re; a --C(O)OR' group or a
--C(O)--(CH.sub.2).sub.n--R'' group wherein n is 0 or 1, [0292] Rb
is a cyano group; a C.sub.1-C.sub.4 haloalkyl group; a
C.sub.1-C.sub.4 alkoxy group; a C.sub.3-C.sub.7 cycloalkyl group
unsubstituted or substituted by one or more substituents selected
from substituents Re; a phenyl group unsubstituted or substituted
by one or more substituents selected from substituents Re; a 5- to
6-membered monocyclic heteroaryl group containing 1, 2 or 3
heteroatoms selected from N, O and S unsubstituted or substituted
by one or more substituents selected from substituents Re; a 6
membered, saturated N-containing heterocyclyl ring, unsubstituted
or substituted by one or more substituents selected from
substituents Re; a --C(O)OR' group or a
--C(O)--(CH.sub.2).sub.n--R'' group wherein n is 0 or 1; [0293] Re
is a halogen atom, a hydroxyl group, a cyano group, a linear or
branched C.sub.1-C.sub.6 alkyl group or a C.sub.1-C.sub.4 haloalkyl
group; [0294] R' is a hydrogen atom, a linear or branched
C.sub.1-C.sub.6 alkyl group, a C.sub.1-C.sub.4 haloalkyl group, a
C.sub.3-C.sub.7 cycloalkyl group, a phenyl group, a 5- to
6-membered monocyclic heteroaryl group containing 1, 2 or 3
heteroatoms selected from N, O and S or a 5- to 6-membered,
saturated N-containing heterocyclyl ring; and [0295] R'' is a cyano
group, a linear or branched C.sub.1-C.sub.6 alkyl group, a
C.sub.1-C.sub.4 haloalkyl group, a C.sub.3-C.sub.7 cycloalkyl
group, a phenyl group, a 5- to 6-membered monocyclic heteroaryl
group containing 1, 2 or 3 heteroatoms selected from N, O and S or
a 5- to 6-membered, saturated N-containing heterocyclyl ring;
wherein the cycloalkyl, phenyl, heteroaryl and heterocyclyl groups
are unsubstituted or substituted by one or more substituents
selected from a hydroxyl group, a cyano group, a linear or branched
C.sub.1-C.sub.6 alkyl group or a C.sub.1-C.sub.4 haloalkyl
group.
[0296] In the compounds of formula (I-c), when Y is N and R.sub.8
represents a 5- to 7-membered heterocyclyl group containing one
nitrogen atom, said heterocyclyl group is typically substituted by
one or more substituents, wherein said substitution is at least on
the ring nitrogen of the heterocyclyl group, and this substituent
on the ring nitrogen of the heterocyclyl group is typically other
than a tert-butoxycarbonyl group.
[0297] Preferred substituents for the compounds of formula (I-c)
are defined above with regard to formula (I) and are further
described in more detail below.
[0298] Typically, in the compound of formula (I-c), X and Y
independently represent a nitrogen atom or a --CR.sub.9 group,
wherein at least one of X and Y represents a nitrogen atom, and the
other represents a --CR.sub.9 group. Typically, when X represents a
nitrogen atom, Y represents a --CR.sub.9 group. Typically, when X
represents a --CR.sub.9 group, Y represents a nitrogen atom.
[0299] Typically, in the compound of the invention of formula
(I-c), Z is a NR.sub.5 group, wherein R.sub.5 represents a hydrogen
atom or a linear or branched C.sub.1-C.sub.6 alkyl group
unsubstituted or substituted by one or more substituents selected
from a hydroxyl group, a cyano group, a C.sub.1-C.sub.4 haloalkyl
group, a C.sub.1-C.sub.4 hydroxyalkyl group, a C.sub.3-C.sub.10
cycloalkyl group, a phenyl group, a pyridyl group or a 6 membered,
saturated N-containing heterocyclyl ring.
[0300] Typically, in the compound of the invention of formula (I-c)
R.sub.1 represents a hydrogen atom, a halogen atom, a cyano group,
a linear or branched C.sub.1-C.sub.6 alkyl group, a C.sub.3-C.sub.7
cycloalkyl group or a --NR'R'' group, wherein R' and R'' are the
same or different and each represents a hydrogen atom, a linear or
branched C.sub.1-C.sub.6 alkyl group or a C.sub.1-C.sub.4 haloalkyl
group; preferably R.sub.1 represents a hydrogen atom, a linear or
branched C.sub.1-C.sub.3 alkyl group or a --NH.sub.2 group; more
preferably R.sub.1 represents a hydrogen atom.
[0301] Typically, in the compound of the invention of formula (I-c)
R.sub.2 represents a hydrogen atom, a halogen atom, a cyano group,
a linear or branched C.sub.1-C.sub.6 alkyl group or a
C.sub.3-C.sub.7 cycloalkyl group; preferably R.sub.2 represents a
hydrogen atom or a linear or branched C.sub.1-C.sub.3 alkyl group;
more preferably R.sub.2 represents a hydrogen atom.
[0302] Typically, in the compound of the invention of formula (I-c)
R.sub.3 represents a hydrogen atom, a halogen atom, a cyano group,
a linear or branched C.sub.1-C.sub.6 alkyl group or a
C.sub.3-C.sub.7 cycloalkyl group; preferably R.sub.3 represents a
hydrogen atom, a cyano group or a linear or branched
C.sub.1-C.sub.3 alkyl group; more preferably R.sub.3 represents a
hydrogen atom or a cyano group.
[0303] Typically, in the compound of the invention of formula (I-c)
R.sub.4 represents a hydrogen atom, a halogen atom, a cyano group,
a linear or branched C.sub.1-C.sub.6 alkyl group or a
C.sub.3-C.sub.7 cycloalkyl group; preferably R.sub.4 represents a
hydrogen atom or a linear or branched C.sub.1-C.sub.3 alkyl group;
more preferably R.sub.4 represents a hydrogen atom.
[0304] Typically, in the compound of the invention of formula (I-c)
R.sub.5 represents a hydrogen atom or a linear or branched
C.sub.1-C.sub.4 alkyl group unsubstituted or substituted by one or
more substituents selected from a hydroxyl group, a C.sub.1-C.sub.4
haloalkyl group, a C.sub.1-C.sub.4 hydroxyalkyl group or a
C.sub.3-C.sub.7 cycloalkyl group; preferably R.sub.5 represents a
hydrogen atom or a linear or branched C.sub.1-C.sub.3 alkyl group;
more preferably R.sub.5 represents a hydrogen atom.
[0305] Typically, in the compound of the invention of formula (I-c)
R.sub.6 and R.sub.7 independently represent a hydrogen atom or a
linear or branched C.sub.1-C.sub.6 alkyl group; preferably R.sub.6
and R.sub.7 independently represent a hydrogen atom or a linear or
branched C.sub.1-C.sub.3 alkyl group.
[0306] Typically, in the compound of the invention of formula (I-c)
R.sub.8 represents a linear or branched C.sub.1-C.sub.6 alkyl
group, a C.sub.1-C.sub.4 haloalkyl group, a C.sub.3-C.sub.7
cycloalkyl group, a phenyl group, a 5- to 6-membered monocyclic
heteroaryl group containing 1, 2 or 3 heteroatoms selected from N,
O and S, a 5- to 7-membered heterocyclyl group containing 1, 2 or 3
heteroatoms selected from N, O and S, or a --(CH.sub.2).sub.nOR
group wherein n is 0 or 1 and R represents a linear or branched
C.sub.1-C.sub.6 alkyl group or a C.sub.1-C.sub.4 haloalkyl group;
[0307] wherein the haloalkyl, cycloalkyl, phenyl, heteroaryl and
heterocyclyl groups are unsubstituted or substituted by one or more
substituents selected from Ra; and the alkyl group is unsubstituted
or substituted by one or more substituents selected from Rb; [0308]
Ra is a halogen atom; a cyano group; a hydroxyl group; a linear or
branched C.sub.1-C.sub.6 alkyl group; a C.sub.1-C.sub.4 haloalkyl
group; a C.sub.1-C.sub.4 alkoxy group; a C.sub.3-C.sub.7 cycloalkyl
group unsubstituted or substituted by one or more substituents
selected from substituents Re; a phenyl group unsubstituted or
substituted by one or more substituents selected from substituents
Re; a 5- to 6-membered monocyclic heteroaryl group containing 1, 2
or 3 heteroatoms selected from N, O and S unsubstituted or
substituted by one or more substituents selected from substituents
Re; a 6 membered, saturated N-containing heterocyclyl ring,
unsubstituted or substituted by one or more substituents selected
from substituents Re; a --C(O)OR' group or a
--C(O)--(CH.sub.2).sub.n--R'' group wherein n is 0 or [0309] Rb is
a cyano group; a C.sub.1-C.sub.4 haloalkyl group; a C.sub.1-C.sub.4
alkoxy group; a C.sub.3-C.sub.7 cycloalkyl group unsubstituted or
substituted by one or more substituents selected from substituents
Re; a phenyl group unsubstituted or substituted by one or more
substituents selected from substituents Re; a 5- to 6-membered
monocyclic heteroaryl group containing 1, 2 or 3 heteroatoms
selected from N, O and S unsubstituted or substituted by one or
more substituents selected from substituents Re; a 6 membered,
saturated N-containing heterocyclyl ring, unsubstituted or
substituted by one or more substituents selected from substituents
Re; a --C(O)OR' group or a --C(O)--(CH.sub.2).sub.n--R'' group
wherein n is 0 or 1; [0310] Re is a halogen atom, a hydroxyl group,
a cyano group, a linear or branched C.sub.1-C.sub.6 alkyl group or
a C.sub.1-C.sub.4 haloalkyl group; [0311] R' is a hydrogen atom, a
linear or branched C.sub.1-C.sub.6 alkyl group, a C.sub.1-C.sub.4
haloalkyl group, a C.sub.3-C.sub.7 cycloalkyl group, a phenyl
group, a 5- to 6-membered monocyclic heteroaryl group containing 1,
2 or 3 heteroatoms selected from N, O and S or a 5- to 6-membered,
saturated N-containing heterocyclyl ring; and [0312] R'' is a cyano
group, a linear or branched C.sub.1-C.sub.6 alkyl group, a
C.sub.1-C.sub.4 haloalkyl group, a C.sub.3-C.sub.7 cycloalkyl
group, a phenyl group, a 5- to 6-membered monocyclic heteroaryl
group containing 1, 2 or 3 heteroatoms selected from N, O and S or
a 5- to 6-membered, saturated N-containing heterocyclyl ring;
wherein the cycloalkyl, phenyl, heteroaryl and heterocyclyl groups
are unsubstituted or substituted by one or more substituents
selected from a hydroxyl group, a cyano group, a linear or branched
C.sub.1-C.sub.6 alkyl group or a C.sub.1-C.sub.4 haloalkyl
group.
[0313] When R.sub.8 represents a 5- to 7-membered heterocyclyl
group containing one nitrogen atom, said heterocyclyl group is
typically substituted by one or more substituents, wherein said
substitution is at least on the ring nitrogen of the heterocyclyl
group, and this substituent on the ring nitrogen of the
heterocyclyl group is typically other than a tert-butoxycarbonyl
group.
[0314] Preferably, in the compound of the invention of formula
(I-c) R.sub.8 represents a linear or branched C.sub.1-C.sub.6 alkyl
group, a C.sub.1-C.sub.4 haloalkyl group, a C.sub.3-C.sub.7
cycloalkyl group, a phenyl group, a 5- to 6-membered monocyclic
heteroaryl group containing 1, 2 or 3 heteroatoms selected form N,
O and S, a 5- to 7-membered heterocyclyl group containing 1, 2 or 3
heteroatoms selected from N, O and S, or a --(CH.sub.2).sub.nOR
group wherein n is 0 or 1 and R represents a linear or branched
C.sub.1-C.sub.6 alkyl group or a C.sub.1-C.sub.4 haloalkyl group;
[0315] wherein the haloalkyl, cycloalkyl, phenyl, heteroaryl and
heterocyclyl groups are unsubstituted or substituted by one or more
substituents selected from Ra; and the alkyl group is unsubstituted
or substituted by one or more substituents selected from Rb; [0316]
Ra is a halogen atom; a cyano group; a hydroxyl group; a linear or
branched C.sub.1-C.sub.6 alkyl group; a C.sub.1-C.sub.4 haloalkyl
group; a 5- to 6-membered monocyclic heteroaryl group containing 1,
2 or 3 heteroatoms selected from N, O and S unsubstituted or
substituted by one or more substituents selected from a halogen
atom, a hydroxyl group, a cyano group, a linear or branched
C.sub.1-C.sub.6 alkyl group or a C.sub.1-C.sub.4 haloalkyl group; a
--C(O)OR' group or a --C(O)--(CH.sub.2).sub.n--R'' group wherein n
is 0 or 1, [0317] Rb is a cyano group; a C.sub.1-C.sub.4 haloalkyl
group; a C.sub.1-C.sub.4 alkoxy group; a C.sub.3-C.sub.7 cycloalkyl
group unsubstituted or substituted by one or more substituents
selected from a halogen atom, a hydroxyl group or a cyano group; a
phenyl group unsubstituted or substituted by one or more
substituents selected from a halogen atom, a hydroxyl group, a
cyano group or a linear or branched C.sub.1-C.sub.6 alkyl group; a
--C(O)OR' group or a --C(O)--(CH.sub.2).sub.n--R'' group wherein n
is 0 or 1, [0318] R' is a hydrogen atom, a linear or branched
C.sub.1-C.sub.6 alkyl group, a C.sub.1-C.sub.4 haloalkyl group or a
C.sub.3-C.sub.7 cycloalkyl group; and [0319] R'' is a cyano group,
a linear or branched C.sub.1-C.sub.6 alkyl group, a C.sub.1-C.sub.4
haloalkyl group or a C.sub.3-C.sub.7 cycloalkyl group.
[0320] In one embodiment, in the compounds of formula (I-c) R.sub.8
represents a linear or branched C.sub.1-C.sub.6 alkyl group, a
C.sub.1-C.sub.4 haloalkyl group, a C.sub.3-C.sub.7 cycloalkyl
group, a 6-membered heterocyclyl group containing 1, 2 or 3
heteroatoms selected from N, O and S, or a --(CH.sub.2).sub.nOR
group wherein n is 0 or 1 and R represents a linear or branched
C.sub.1-C.sub.6 alkyl group or a C.sub.1-C.sub.4 haloalkyl group;
in particular, R.sub.8 may represent a 6-membered heterocyclyl
group containing 1, 2 or 3 heteroatoms selected from N, O and S;
[0321] wherein the haloalkyl, cycloalkyl and heterocyclyl groups
are unsubstituted or substituted by one or more substituents
selected from Ra; and the alkyl group is unsubstituted or
substituted by one or more substituents selected from Rb, wherein
Ra and Rb are as defined above.
[0322] More preferably, in the compound of the invention of formula
(I-c) when R.sub.8 is an alkyl or haloalkyl group, it is an
unsubstituted alkyl or haloalkyl group; when R.sub.8 is a
cycloalkyl, phenyl or pyridyl group, it is unsubstituted or
substituted by one or more substituents selected from a halogen
atom, a cyano group, a hydroxyl group, a linear or branched
C.sub.1-C.sub.6 alkyl group, a C.sub.1-C.sub.4 haloalkyl group, a
--C(O)OR' group or a --C(O)--(CH.sub.2).sub.n--R'' group wherein n
is 0 or 1, R' is a hydrogen atom, a linear or branched
C.sub.1-C.sub.3 alkyl group or a C.sub.1-C.sub.3 haloalkyl group
and R'' is a cyano group, a linear or branched C.sub.1-C.sub.3
alkyl group or a C.sub.1-C.sub.3 haloalkyl group; and when R.sub.8
is a heteroaryl or heterocyclyl group it is unsubstituted or
substituted with one or more substituents selected from Ra, wherein
Ra is as defined above.
[0323] In the compounds of formula (I-c) when R.sub.8 is a
heteroaryl group, it is preferably a 5- to 6-membered heteroaryl
group containing one or two nitrogen atoms. Pyridyl is preferred.
Preferably, when R.sub.8 is a heteroaryl group it is unsubstituted
or substituted with one or more halogen atoms.
[0324] In the compound of formula (I-c) when R.sub.8 is a
heterocyclyl group it is preferably a 5- or 6-membered heterocyclyl
group, e.g. a 6-membered heterocyclyl group, containing one or two
heteroatoms selected from N and O, more preferably containing one
or two nitrogen atoms. Tetrahydropyranyl and piperidinyl groups are
preferred. Piperidinyl is more preferred. Preferably, the
heterocyclyl group is linked to the rest of the molecule via a ring
carbon atom, in other words it is linked to the group
--Z--(CR.sub.6R.sub.7).sub.m-- via a ring carbon atom. Substituents
on a piperidinyl group are typically at least present on the
nitrogen atom and may optionally be present on any other ring
atom.
[0325] Most preferably, in the compound of the invention of formula
(I-c) R.sub.8 represents a linear or branched C.sub.1-C.sub.6 alkyl
group; a C.sub.1-C.sub.4 haloalkyl group; a C.sub.3-C.sub.7
cycloalkyl group, which cycloalkyl group is unsubstituted or
substituted by one or more substituents selected from halogen atoms
and hydroxyl groups; a phenyl group, which phenyl group is
unsubstituted or substituted by one or more halogen atoms; a
--(CH.sub.2).sub.n--OR group wherein n is 0 or 1 and R represents a
linear or branched C.sub.1-C.sub.3 alkyl group; a pyridyl group,
which pyridyl group is unsubstituted or substituted by one or more
substituents selected from halogen atoms and hydroxyl groups; a
tetrahydropyranyl group, which tetrahydropyranyl group is
unsubstituted or substituted by one or more substituents selected
from halogen atoms and hydroxyl groups; or a piperidinyl group,
which piperidinyl group is unsubstituted or substituted by one or
more substituents selected from [0326] a linear or branched
C.sub.1-C.sub.3 alkyl group; [0327] a halogen atom; [0328] a
pyridyl group, which pyridyl group is unsubstituted or substituted
by one or more cyano groups; [0329] a 1,2,4-triazolyl group; and
[0330] a --C(O)--(CH.sub.2).sub.n--R'' group, wherein n is 0 or 1
and R'' is a cyano group, a linear or branched C.sub.1-C.sub.6
alkyl group, a C.sub.1-C.sub.4 haloalkyl group or a C.sub.3-C.sub.7
cycloalkyl group.
[0331] In another embodiment, in the compound of the invention of
formula (I-c) R.sub.8 represents a linear or branched
C.sub.1-C.sub.6 alkyl group, a C.sub.1-C.sub.4 haloalkyl group, a
C.sub.3-C.sub.7 cycloalkyl group, a phenyl group, a 5- to
6-membered monocyclic heteroaryl group containing 1, 2 or 3
heteroatoms selected from N, O and S, a 5- to 7-membered
heterocyclyl group containing 1, 2 or 3 heteroatoms selected from
N, O and S, or a --(CH.sub.2).sub.nOR group wherein n is 0 or 1 and
R represents a linear or branched C.sub.1-C.sub.6 alkyl group or a
C.sub.1-C.sub.4 haloalkyl group; [0332] wherein the haloalkyl,
cycloalkyl, phenyl, and heterocyclyl groups are unsubstituted or
substituted by one or more substituents selected from Ra; and the
alkyl group is unsubstituted or substituted by one or more
substituents selected from Rb, wherein Ra and Rb, are as defined
above.
[0333] Alternatively, R.sub.8 may represent a linear or branched
C.sub.1-C.sub.6 alkyl group; a C.sub.1-C.sub.4 haloalkyl group; a
C.sub.3-C.sub.7 cycloalkyl group, which cycloalkyl group is
unsubstituted or substituted by one or more substituents selected
from halogen atoms and hydroxyl groups; a --(CH.sub.2).sub.n--OR
group wherein n is 0 or 1 and R represents a linear or branched
C.sub.1-C.sub.3 alkyl group; a tetrahydropyranyl group, which
tetrahydropyranyl group is unsubstituted or substituted by one or
more substituents selected from halogen atoms and hydroxyl groups;
or a piperidinyl group, which piperidinyl group is unsubstituted or
substituted by one or more substituents selected from [0334] a
linear or branched C.sub.1-C.sub.3 alkyl group; [0335] a halogen
atom; [0336] a pyridyl group, which pyridyl group is unsubstituted
or substituted by one or more cyano groups; [0337] a
1,2,4-triazolyl group; and [0338] a --C(O)--(CH.sub.2).sub.n--R''
group, wherein n is 0 or 1 and R'' is a cyano group, a linear or
branched C.sub.1-C.sub.6 alkyl group, a C.sub.1-C.sub.4 haloalkyl
group or a C.sub.3-C.sub.7 cycloalkyl group.
[0339] Particularly preferred substituents on the ring nitrogen of
the piperidinyl group at R.sub.8 in the compound of the invention
of formula (I-c) are substituents selected from [0340] a pyridyl
group, which pyridyl group is unsubstituted or substituted by one
or more cyano groups; [0341] a 1,2,4-triazolyl group; and [0342] a
--C(O)--(CH.sub.2).sub.n--R'' group, wherein n is 0 or 1 and R'' is
a cyano group or a linear or branched C.sub.1-C.sub.3 alkyl
group.
[0343] In one embodiment R.sub.8 represents a 6-membered
heterocyclyl group, e.g. a tetrahydropyranyl group or a piperidinyl
group, e.g. a piperidinyl group. Preferred substituents on these
groups are defined above.
[0344] In one embodiment, when R.sub.8 of formula (Ic) represents a
5- to 7-membered heterocyclyl group containing one nitrogen atom,
said heterocyclyl group is substituted by one or more substituents,
wherein said substitution is at least on the ring nitrogen atom of
the heterocyclyl group, and wherein this substituent is other than
a tert-butoxycarbonyl group. Preferably, said heterocyclyl group is
a piperidinyl group which is substituted by one or more
substituents, wherein said substitution is at least on the ring
nitrogen of the piperidinyl group, the substituents being selected
from [0345] a linear or branched C.sub.1-C.sub.3 alkyl group;
[0346] a halogen atom; [0347] a pyridyl group, which pyridyl group
is unsubstituted or substituted by one or more cyano groups; [0348]
a 1,2,4-triazolyl group; and [0349] a --C(O)--(CH.sub.2).sub.n--R''
group, wherein n is 0 or 1 and R'' is a cyano group, a linear or
branched C.sub.1-C.sub.6 alkyl group, a C.sub.1-C.sub.4 haloalkyl
group or a C.sub.3-C.sub.7 cycloalkyl group.
[0350] Preferred substituents are selected from: [0351] a pyridyl
group, which pyridyl group is unsubstituted or substituted by one
or more cyano groups; [0352] a 1,2,4-triazolyl group; and [0353] a
--C(O)--(CH.sub.2).sub.n--R'' group, wherein n is 0 or 1 and R'' is
a cyano group or a linear or branched C.sub.1-C.sub.3 alkyl
group.
[0354] Typically, in the compound of the invention of formula (I-c)
R.sub.9 represents a hydrogen atom, a halogen atom, a hydroxyl
group, a cyano group, a linear or branched C.sub.1-C.sub.6 alkyl
group or a --NR'R'' group, wherein R' and R'' are the same or
different and each represents a hydrogen atom, a linear or branched
C.sub.1-C.sub.6 alkyl group or a C.sub.1-C.sub.4 haloalkyl group;
preferably R.sub.9 represents a hydrogen atom, a halogen atom, a
linear or branched C.sub.1-C.sub.3 alkyl group or a --NH.sub.2
group.
[0355] Typically, in the compound of formula (I-c), m is 0, 1 or 2,
preferably 0 or 1.
[0356] In a further particular preferred embodiment, in the
compound of formula (I-c):
m is 0, 1 or 2; W represents a nitrogen atom or a --CR.sub.3 group,
preferably a --CR.sub.3 group; X and Y independently represent a
nitrogen atom or a --CR.sub.9 group, wherein at least one of X and
Y represents a nitrogen atom, and the other represents a --CR.sub.9
group; R.sub.1 represents a hydrogen atom or a --NH.sub.2 group;
R.sub.2 represents a hydrogen atom or a linear or branched
C.sub.1-C.sub.3 alkyl group; R.sub.3 represents a hydrogen atom, a
cyano group or a linear or branched C.sub.1-C.sub.3 alkyl group;
R.sub.4 represents a hydrogen atom or a linear or branched
C.sub.1-C.sub.3 alkyl group; R.sub.5 represents a hydrogen atom or
a linear or branched C.sub.1-C.sub.3 alkyl group; R.sub.6 and
R.sub.7 independently represent a hydrogen atom or a linear or
branched C.sub.1-C.sub.3 alkyl group, R.sub.8 represents a linear
or branched C.sub.1-C.sub.6 alkyl group; a C.sub.1-C.sub.4
haloalkyl group; a C.sub.3-C.sub.7 cycloalkyl group, which
cycloalkyl group is unsubstituted or substituted by one or more
substituents selected from halogen atoms and hydroxyl groups; a
phenyl group, which phenyl group is unsubstituted or substituted by
one or more halogen atoms; a --(CH.sub.2).sub.n--OR group wherein n
is 0 or 1 and R represents a linear or branched C.sub.1-C.sub.3
alkyl group; a pyridyl group, which pyridyl group is unsubstituted
or substituted by one or more substituents selected from halogen
atoms and hydroxyl groups; a tetrahydropyranyl group, which
tetrahydropyranyl group is unsubstituted or substituted by one or
more substituents selected from halogen atoms and hydroxyl groups;
and a piperidinyl group, which piperidinyl group is unsubstituted
or substituted by one or more substituents selected from [0357] a
linear or branched C.sub.1-C.sub.3 alkyl group; [0358] a halogen
atom; [0359] a pyridyl group, which pyridyl group is unsubstituted
or substituted by one or more cyano groups; and [0360] a
--C(O)--(CH.sub.2).sub.n--R'' group, wherein n is 0 or 1 and R'' is
a cyano group, a linear or branched C.sub.1-C.sub.6 alkyl group, a
C.sub.1-C.sub.4 haloalkyl group or a C.sub.3-C.sub.7 cycloalkyl
group; and R.sub.9 represents a hydrogen atom, a halogen atom, a
linear or branched C.sub.1-C.sub.3 alkyl group or a --NH.sub.2
group.
[0361] In another preferred embodiment, in the compound of formula
(I-c):
m is 0, 1 or 2; W represents a nitrogen atom or a --CR.sub.3 group,
preferably a --CR.sub.3 group; Z represents a NR.sub.5 group; X and
Y independently represent a nitrogen atom or a --CR.sub.9 group,
wherein at least one of X and Y represents a nitrogen atom, and the
other represents a --CR.sub.9 group; R.sub.1 represents a hydrogen
atom or a --NH.sub.2 group; R.sub.2 represents a hydrogen atom or a
linear or branched C.sub.1-C.sub.3 alkyl group; R.sub.3 represents
a hydrogen atom, a cyano group or a linear or branched
C.sub.1-C.sub.3 alkyl group; R.sub.4 represents a hydrogen atom or
a linear or branched C.sub.1-C.sub.3 alkyl group; R.sub.5
represents a hydrogen atom or a linear or branched C.sub.1-C.sub.3
alkyl group; R.sub.6 and R.sub.7 independently represent a hydrogen
atom or a linear or branched C.sub.1-C.sub.3 alkyl group, R.sub.8
represents a linear or branched C.sub.1-C.sub.6 alkyl group; a
C.sub.1-C.sub.4 haloalkyl group; a C.sub.3-C.sub.7 cycloalkyl
group, which cycloalkyl group is unsubstituted or substituted by
one or more substituents selected from halogen atoms and hydroxyl
groups; a phenyl group, which phenyl group is unsubstituted or
substituted by one or more halogen atoms; a --(CH.sub.2).sub.n--OR
group wherein n is 0 or 1 and R represents a linear or branched
C.sub.1-C.sub.3 alkyl group; a pyridyl group, which pyridyl group
is unsubstituted or substituted by one or more substituents
selected from halogen atoms and hydroxyl groups; a
tetrahydropyranyl group, which tetrahydropyranyl group is
unsubstituted or substituted by one or more substituents selected
from halogen atoms and hydroxyl groups; and a piperidinyl group,
which piperidinyl group is unsubstituted or substituted by one or
more substituents selected from [0362] a linear or branched
C.sub.1-C.sub.3 alkyl group; [0363] a halogen atom; [0364] a
pyridyl group, which pyridyl group is unsubstituted or substituted
by one or more cyano groups; [0365] a 1,2,4-triazolyl group; and
[0366] a --C(O)--(CH.sub.2).sub.n--R'' group, wherein n is 0 or 1
and R'' is a cyano group, a linear or branched C.sub.1-C.sub.6
alkyl group, a C.sub.1-C.sub.4 haloalkyl group or a C.sub.3-C.sub.7
cycloalkyl group; and R.sub.9 represents a hydrogen atom, a halogen
atom, a linear or branched C.sub.1-C.sub.3 alkyl group or a
--NH.sub.2 group.
[0367] Typically, when R.sub.8 is a piperidinyl group, it is
substituted by one or more substituents, wherein said substitution
is at least on the ring nitrogen of the piperidinyl group, the
substituents being selected from [0368] a linear or branched
C.sub.1-C.sub.3 alkyl group; [0369] a halogen atom; [0370] a
pyridyl group, which pyridyl group is unsubstituted or substituted
by one or more cyano groups; [0371] a 1,2,4-triazolyl group; and
[0372] a --C(O)--(CH.sub.2).sub.n--R'' group, wherein n is 0 or 1
and R'' is a cyano group, a linear or branched C.sub.1-C.sub.6
alkyl group, a C.sub.1-C.sub.4 haloalkyl group or a C.sub.3-C.sub.7
cycloalkyl group
[0373] More typically, said substituents are selected from [0374] a
linear or branched C.sub.1-C.sub.3 alkyl group; [0375] a halogen
atom; [0376] a pyridyl group, which pyridyl group is unsubstituted
or substituted by one or more cyano groups; and [0377] a
--C(O)--(CH.sub.2).sub.n--R'' group, wherein n is 0 or 1 and R'' is
a cyano group, a linear or branched C.sub.1-C.sub.6 alkyl group, a
C.sub.1-C.sub.4 haloalkyl group or a C.sub.3-C.sub.7 cycloalkyl
group.
[0378] In a particularly preferred embodiment, in the compound of
formula (I)
m is 0, 1 or 2; W represents a nitrogen atom or a --CR.sub.3 group,
preferably a --CR.sub.3 group; Z represents a NR.sub.5 group; X and
Y independently represent a nitrogen atom or a --CR.sub.9 group,
wherein when one of X and Y represents a nitrogen atom, the other
represents a --CR.sub.9 group; T represents a --CR.sub.9 group;
R.sub.1 represents a hydrogen atom or a --NH.sub.2 group; R.sub.2
represents a hydrogen atom or a linear or branched C.sub.1-C.sub.3
alkyl group; R.sub.3 represents a hydrogen atom, a cyano group or a
linear or branched C.sub.1-C.sub.3 alkyl group; R.sub.4 represents
a hydrogen atom or a linear or branched C.sub.1-C.sub.3 alkyl
group; R.sub.5 represents a hydrogen atom or a linear or branched
C.sub.1-C.sub.3 alkyl group; R.sub.6 and R.sub.7 independently
represent a hydrogen atom or a linear or branched C.sub.1-C.sub.3
alkyl group, R.sub.8 represents a linear or branched
C.sub.1-C.sub.6 alkyl group; a C.sub.1-C.sub.4 haloalkyl group; a
C.sub.3-C.sub.7 cycloalkyl group, which cycloalkyl group is
unsubstituted or substituted by one or more hydroxyl groups; a
phenyl group, which phenyl group is unsubstituted or substituted by
one or more halogen atoms; a --(CH.sub.2).sub.n--OR group wherein n
is 0 or 1 and R represents a linear or branched C.sub.1-C.sub.3
alkyl group; and a piperidinyl group, which piperidinyl group is
unsubstituted or substituted by one or more substituents selected
from [0379] a pyridyl group, which pyridyl group is unsubstituted
or substituted by one or more cyano groups; and [0380] a
--C(O)--(CH.sub.2).sub.n--R'' group, wherein n is 0 or 1 and R'' is
a cyano group, a linear or branched C.sub.1-C.sub.6 alkyl group, a
C.sub.1-C.sub.4 haloalkyl group or a C.sub.3-C.sub.7 cycloalkyl
group; and R.sub.9 represents a hydrogen atom, a halogen atom or a
linear or branched C.sub.1-C.sub.3 alkyl group.
[0381] In a further particularly preferred embodiment, the compound
is of formula (I-a)
##STR00005##
wherein m is 0, 1 or 2; W represents a nitrogen atom or a
--CR.sub.3 group, preferably a --CR.sub.3 group; X represents a
nitrogen atom or a --CR.sub.9 group; R.sub.1 represents a hydrogen
atom or a --NH.sub.2 group; R.sub.2 represents a hydrogen atom or a
linear or branched C.sub.1-C.sub.3 alkyl group; R.sub.3 represents
a hydrogen atom, a cyano group or a linear or branched
C.sub.1-C.sub.3 alkyl group; R.sub.4 represents a hydrogen atom or
a linear or branched C.sub.1-C.sub.3 alkyl group; R.sub.5
represents a hydrogen atom or a linear or branched C.sub.1-C.sub.3
alkyl group; R.sub.6 and R.sub.7 independently represent a hydrogen
atom or a linear or branched C.sub.1-C.sub.3 alkyl group, R.sub.8
represents a linear or branched C.sub.1-C.sub.6 alkyl group; a
C.sub.1-C.sub.4 haloalkyl group; a C.sub.3-C.sub.7 cycloalkyl
group, which cycloalkyl group is unsubstituted or substituted by
one or more hydroxyl groups; a phenyl group, which phenyl group is
unsubstituted or substituted by one or more halogen atoms; a
(CH.sub.2).sub.n--OR group wherein n is 0 or 1 and R represents a
linear or branched C.sub.1-C.sub.3 alkyl group; and a piperidinyl
group, which piperidinyl group is unsubstituted or substituted by
one or more substituents selected from [0382] a pyridyl group,
which pyridyl group is unsubstituted or substituted by one or more
cyano groups; and [0383] a --C(O)--(CH.sub.2).sub.n--R'' group,
wherein n is 0 or 1 and R'' is a cyano group, a linear or branched
C.sub.1-C.sub.6 alkyl group, a C.sub.1-C.sub.4 haloalkyl group or a
C.sub.3-C.sub.7 cycloalkyl group; and R.sub.9 represents a hydrogen
atom, a halogen atom or a linear or branched C.sub.1-C.sub.3 alkyl
group.
[0384] In a further particular preferred embodiment, in the
compound of formula (I-a):
m is 0 or 1; W represents a nitrogen atom or a --CR.sub.3 group,
preferably a --CR.sub.3 group; X represents a nitrogen atom or a
--CR.sub.9 group; R.sub.1 represents a hydrogen atom; R.sub.2
represents a hydrogen atom; R.sub.3 represents a hydrogen atom or a
cyano group; R.sub.4 represents a hydrogen atom; R.sub.5 represents
a hydrogen atom or a linear or branched C.sub.1-C.sub.3 alkyl
group; R.sub.6 and R.sub.7 independently represent a hydrogen atom
or a linear or branched C.sub.1-C.sub.3 alkyl group; R.sub.8
represents a linear or branched C.sub.1-C.sub.6 alkyl group; a
C.sub.1-C.sub.4 haloalkyl group; a C.sub.3-C.sub.7 cycloalkyl
group, which cycloalkyl group is unsubstituted or substituted by
one or more hydroxyl groups; a phenyl group, which phenyl group is
unsubstituted or substituted by one or more halogen atoms; a
(CH.sub.2).sub.n--OR group wherein n is 0 or 1 and R represents a
linear or branched C.sub.1-C.sub.3 alkyl group; and a piperidinyl
group, which piperidinyl group is unsubstituted or substituted by
one or more substituents selected from [0385] a pyridyl group,
which pyridyl group is unsubstituted or substituted by one or more
cyano groups; and [0386] a --C(O)--(CH.sub.2).sub.n--R'' group,
wherein n is 0 or 1 and R'' is a cyano group, a linear or branched
C.sub.1-C.sub.3 alkyl group, or a C.sub.1-C.sub.4 haloalkyl group;
and R.sub.9 represents a hydrogen atom, a halogen atom or a linear
or branched C.sub.1-C.sub.3 alkyl group.
[0387] In an alternative particularly preferred embodiment, the
compound is of formula (I-b):
##STR00006##
wherein m is 0, 1 or 2; X represents a nitrogen atom or a
--CR.sub.9 group; R.sub.1 represents a hydrogen atom or a
--NH.sub.2 group; R.sub.2 represents a hydrogen atom or a linear or
branched C.sub.1-C.sub.3 alkyl group; R.sub.4 represents a hydrogen
atom or a linear or branched C.sub.1-C.sub.3 alkyl group; R.sub.5
represents a hydrogen atom or a linear or branched C.sub.1-C.sub.3
alkyl group; R.sub.6 and R.sub.7 independently represent a hydrogen
atom or a linear or branched C.sub.1-C.sub.3 alkyl group, R.sub.8
represents a linear or branched C.sub.1-C.sub.6 alkyl group; a
C.sub.1-C.sub.4 haloalkyl group; a C.sub.3-C.sub.7 cycloalkyl
group, which cycloalkyl group is unsubstituted or substituted by
one or more hydroxyl groups; a phenyl group, which phenyl group is
unsubstituted or substituted by one or more halogen atoms; a
(CH.sub.2).sub.n--OR group wherein n is 0 or 1 and R represents a
linear or branched C.sub.1-C.sub.3 alkyl group; and a piperidinyl
group, which piperidinyl group is unsubstituted or substituted by
one or more substituents selected from [0388] a pyridyl group,
which pyridyl group is unsubstituted or substituted by one or more
cyano groups; and [0389] a --C(O)--(CH.sub.2).sub.n--R'' group,
wherein n is 0 or 1 and R'' is a cyano group, a linear or branched
C.sub.1-C.sub.6 alkyl group, a C.sub.1-C.sub.4 haloalkyl group or a
C.sub.3-C.sub.7, cycloalkyl group; and
[0390] R.sub.9 represents a hydrogen atom, a halogen atom or a
linear or branched C.sub.1-C.sub.3 alkyl group.
[0391] In a further particular preferred embodiment, in the
compound of formula (I-b):
m is 0 or 1; X represents a nitrogen atom; R.sub.1 represents a
hydrogen atom; R.sub.2 represents a hydrogen atom; R.sub.4
represents a hydrogen atom or a linear or branched C.sub.1-C.sub.3
alkyl group; R.sub.5 represents a hydrogen atom or a linear or
branched C.sub.1-C.sub.3 alkyl group; R.sub.6 and R.sub.7
independently represent a hydrogen atom or a linear or branched
C.sub.1-C.sub.3 alkyl group, R.sub.8 represents a linear or
branched C.sub.1-C.sub.6 alkyl group; a C.sub.3-C.sub.7 cycloalkyl
group, which cycloalkyl group is unsubstituted or substituted by
one or more hydroxyl groups; a phenyl group, which phenyl group is
unsubstituted or substituted by one or more halogen atoms; and a
piperidinyl group, which piperidinyl group is unsubstituted or
substituted by one or more substituents selected from [0392] a
pyridyl group, which pyridyl group is unsubstituted or substituted
by one or more cyano groups; and [0393] a
--C(O)--(CH.sub.2).sub.n--R'' group, wherein n is 0 or 1 and R'' is
a cyano group, a linear or branched C.sub.1-C.sub.3 alkyl group or
a C.sub.1-C.sub.3 haloalkyl group; and R.sub.9 represents a
hydrogen atom, a halogen atom or a linear or branched
C.sub.1-C.sub.3 alkyl group.
[0394] Particular individual compounds of the invention include:
[0395]
3-(4-{[(1S)-1-Phenylethyl]amino}pyrimidin-2-yl)pyrazolo[1,5-a]pyridine-5--
carbonitrile; [0396]
3-{4-[(Cyclohexylmethyl)amino]pyrimidin-2-yl}pyrazolo[1,5-a]pyridine-5-ca-
rbonitrile; [0397]
3-[4-(Benzylamino)pyrimidin-2-yl]pyrazolo[1,5-a]pyridine-5-carbonitrile;
[0398]
3-{4-[(2,2-Dimethylpropyl)amino]pyrimidin-2-yl}pyrazolo[1,5-a]pyri-
dine-5-carbonitrile; [0399]
3-(4-{[(1S)-2-Methoxy-1-methylethyl]amino}pyrimidin-2-yl)pyrazolo[1,5-a]p-
yridine-5-carbonitrile; [0400]
3-{4-[(Cyclopropylmethyl)amino]pyrimidin-2-yl}pyrazolo[1,5-a]pyridine-5-c-
arbonitrile; [0401]
3-{4-[(2,2,2-Trifluoroethyl)amino]pyrimidin-2-yl}pyrazolo[1,5-a]pyridine--
5-carbonitrile; [0402]
N-(1-Phenylethyl)-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-amine;
[0403]
3-{6-[(Cyclohexylmethyl)amino]pyridin-2-yl}pyrazolo[1,5-a]pyridine-5-carb-
onitrile; [0404]
3-{6-[(2,2-Dimethylpropyl)amino]pyridin-2-yl}pyrazolo[1,5-a]pyridine-5-ca-
rbonitrile; [0405]
3-{6-[(3-Fluorobenzyl)amino]pyridin-2-yl}pyrazolo[1,5-a]pyridine-5-carbon-
itrile; [0406]
3-[6-(Benzylamino)pyridin-2-yl]pyrazolo[1,5-a]pyridine-5-carbonitrile;
[0407]
3-(6-{[(1S)-1-Phenylethyl]amino}pyridin-2-yl)pyrazolo[1,5-a]pyridi-
ne-5-carbonitrile; [0408]
3-(4-{[(3R)-1-(Cyanoacetyl)piperidin-3-yl]amino}pyrimidin-2-yl)pyrazolo[1-
,5-a]pyridine-5-carbonitrile; [0409]
3-(4-{[(3R)-1-Acetylpiperidin-3-yl]amino}pyrimidin-2-yl)pyrazolo[1,5-a]py-
ridine-5-carbonitrile; [0410]
3-(4-{[(3R)-1-(5-Cyanopyridin-2-yl)piperidin-3-yl]amino}pyrimidin-2-yl)py-
razolo[1,5-a]pyridine-5-carbonitrile; [0411]
3-(4-{[(3R)-1-(3,3,3-Trifluoropropanoyl)piperidin-3-yl]amino}pyrimidin-2--
yl)pyrazolo[1,5-a]pyridine-5-carbonitrile; [0412]
3-{4-[[(3R)-1-(Cyanocarbonyl)piperidin-3-yl](methyl)amino]pyrimidin-2-yl}-
pyrazolo[1,5-a]pyridine-5-carbonitrile; [0413]
3-(4-((Trans)-4-Hydroxycyclohexylamino)pyrimidin-2-yl)pyrazolo[1,5-a]pyri-
dine-5-carbonitrile; [0414]
N-(Cyclohexylmethyl)-2-pyrazolo[1,5-a]pyrazin-3-ylpyrimidin-4-amine;
[0415]
(S)--N-(1-phenylethyl)-2-(pyrazolo[1,5-a]pyrazin-3-yl)pyrimidin-4--
amine; [0416]
N-Benzyl-2-pyrazolo[1,5-a]pyrazin-3-ylpyrimidin-4-amine; [0417]
N-(2,2-Dimethylpropyl)-2-pyrazolo[1,5-a]pyrazin-3-ylpyrimidin-4-am-
ine; [0418]
3-Oxo-3-{(3R)-3-[(2-pyrazolo[1,5-a]pyrazin-3-ylpyrimidin-4-yl)amino]piper-
idin-1-yl}propanenitrile; [0419]
6-{(3R)-3-[(2-Pyrazolo[1,5-a]pyrazin-3-ylpyrimidin-4-yl)amino]piperidin-1-
-yl}nicotinonitrile; [0420]
2-Pyrazolo[1,5-a]pyrazin-3-yl-N-[(3R)-1-(3,3,3-trifluoropropanoyl)piperid-
in-3-yl]pyrimidin-4-amine; [0421]
3-{(3R)-3-[Methyl(2-pyrazolo[1,5-a]pyrazin-3-ylpyrimidin-4-yl)amino]piper-
idin-1-yl}-3-oxopropanenitrile; [0422]
3-{(3R)-3-[(5-Chloro-2-pyrazolo[1,5-a]pyrazin-3-ylpyrimidin-4-yl)amino]pi-
peridin-1-yl}-3-oxopropanenitrile; [0423]
3-{(3R)-3-[(5-Fluoro-2-pyrazolo[1,5-a]pyrazin-3-ylpyrimidin-4-yl)amino]pi-
peridin-1-yl}-3-oxopropanenitrile; [0424]
5-Fluoro-2-pyrazolo[1,5-a]pyrazin-3-yl-N-[(3R)-1-(3,3,3-trifluoropropanoy-
l)piperidin-3-yl]pyrimidin-4-amine; [0425]
3-{(3R)-3-[(5-Methyl-2-pyrazolo[1,5-a]pyrazin-3-ylpyrimidin-4-yl)amino]pi-
peridin-1-yl}-3-oxopropanenitrile; [0426]
(S)--N-(1-(5-fluoropyridin-2-yl)ethyl)-2-(pyrazolo[1,5-a]pyrazin-3-yl)pyr-
imidin-4-amine; [0427]
N-((5-fluoropyridin-2-yl)methyl)-2-(pyrazolo[1,5-a]pyrazin-3-yl)pyrimidin-
-4-amine; [0428]
5-chloro-N-((5-fluoropyridin-2-yl)methyl)-2-(pyrazolo[1,5-a]pyrazin-3-yl)-
pyrimidin-4-amine; [0429]
N.sup.4-(4,4-difluorocyclohexyl)-2-(pyrazolo[1,5-a]pyrazin-3-yl)pyrimidin-
e-4,5-diamine; [0430]
(S)-5-chloro-N-(1-(5-fluoropyridin-2-yl)ethyl)-2-(pyrazolo[1,5-a]pyrazin--
3-yl)pyrimidin-4-amine; [0431]
2-(pyrazolo[1,5-a]pyrazin-3-yl)-N.sup.4-(tetrahydro-2H-pyran-4-yl)pyrimid-
ine-4,5-diamine; [0432]
(R)-3-oxo-3-(3-(6-(pyrazolo[1,5-a]pyrazin-3-yl)pyrazin-2-ylamino)piperidi-
n-1-yl)propanenitrile; [0433]
(R)-3-oxo-3-(3-(6-(pyrazolo[1,5-a]pyridin-3-yl)pyrazin-2-ylamino)piperidi-
n-1-yl)propanenitrile; [0434]
(R)-3-oxo-3-(3-(2-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-4-ylamino)piperi-
din-1-yl)propanenitrile; [0435]
3-(3-(5-fluoro-2-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-4-ylamino)piperid-
in-1-yl)-3-oxopropanenitrile; [0436]
3-(3-(5-chloro-2-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-4-ylamino)piperid-
in-1-yl)-3-oxopropanenitrile; [0437]
3-(4-fluoro-3-(6-(pyrazolo[1,5-a]pyridin-3-yl)pyrazin-2-ylamino)piperidin-
-1-yl)-3-oxopropanenitrile; [0438]
3-(4-methyl-3-(6-(pyrazolo[1,5-a]pyridin-3-yl)pyrazin-2-ylamino)piperidin-
-1-yl)-3-oxopropanenitrile; [0439]
N-(1-(4H-1,2,4-Triazol-3-yl)piperidin-3-yl)-6-(pyrazolo[1,5-a]pyridin-3-y-
l)pyrazin-2-amine; [0440]
N-(1-(4H-1,2,4-Triazol-3-yl)piperidin-3-yl)-2-(pyrazolo[1,5-a]pyridin-3-y-
l)pyrimidin-4-amine; and pharmaceutically acceptable salts,
solvates, N-oxides or deuterated derivatives thereof.
[0441] Examples of the preferred compounds are [0442]
3-(4-{[(1S)-1-Phenylethyl]amino}pyrimidin-2-yl)pyrazolo[1,5-a]pyridine-5--
carbonitrile; [0443]
3-{4-[(Cyclohexylmethyl)amino]pyrimidin-2-yl}pyrazolo[1,5-a]pyridine-5-ca-
rbonitrile; [0444]
3-[4-(Benzylamino)pyrimidin-2-yl]pyrazolo[1,5-a]pyridine-5-carbonitrile;
[0445]
3-{4-[(2,2-Dimethylpropyl)amino]pyrimidin-2-yl}pyrazolo[1,5-a]pyri-
dine-5-carbonitrile; [0446]
3-(4-{[(1S)-2-Methoxy-1-methylethyl]amino}pyrimidin-2-yl)pyrazolo[1,5-a]p-
yridine-5-carbonitrile; [0447]
3-{4-[(Cyclopropylmethyl)amino)]pyrimidin-2-yl}pyrazolo[1,5-a]pyridine-5--
carbonitrile; [0448]
3-{4-[(2,2,2-Trifluoroethyl)amino]pyrimidin-2-yl}pyrazolo[1,5-a]pyridine--
5-carbonitrile; [0449]
N-(1-Phenylethyl)-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-amine;
[0450]
3-{6-[(Cyclohexylmethyl)amino]pyridin-2-yl}pyrazolo[1,5-a]pyridine-5-carb-
onitrile; [0451]
3-{6-[(2,2-Dimethylpropyl)amino]pyridin-2-yl}pyrazolo[1,5-a]pyridine-5-ca-
rbonitrile; [0452]
3-{6-[(3-Fluorobenzyl)amino]pyridin-2-yl}pyrazolo[1,5-a]pyridine-5-carbon-
itrile; [0453]
3-[6-(Benzylamino)pyridin-2-yl]pyrazolo[1,5-a]pyridine-5-carbonitrile;
[0454]
3-(6-{[(1S)-1-Phenylethyl]amino}pyridin-2-yl)pyrazolo[1,5-a]pyridi-
ne-5-carbonitrile; [0455]
3-(4-{[(3R)-1-(Cyanoacetyl)piperidin-3-yl]amino}pyrimidin-2-yl)pyrazolo[1-
,5-a]pyridine-5-carbonitrile; [0456]
3-(4-{[(3R)-1-Acetylpiperidin-3-yl]amino}pyrimidin-2-yl)pyrazolo[1,5-a]py-
ridine-5-carbonitrile; [0457]
3-(4-{[(3R)-1-(5-Cyanopyridin-2-yl)piperidin-3-yl]amino}pyrimidin-2-yl)py-
razolo[1,5-a]pyridine-5-carbonitrile; [0458]
3-(4-{[(3R)-1-(3,3,3-Trifluoropropanoyl)piperidin-3-yl]amino}pyrimidin-2--
yl)pyrazolo[1,5-a]pyridine-5-carbonitrile; [0459]
3-{4-[[(3R)-1-(Cyanocarbonyl)piperidin-3-yl](methyl)amino]pyrimidin-2-yl}-
pyrazolo[1,5-a]pyridine-5-carbonitrile; [0460]
3-(4-((Trans)-4-Hydroxycyclohexylamino)pyrimidin-2-yl)pyrazolo[1,5-a]pyri-
dine-5-carbonitrile; [0461]
N-(Cyclohexylmethyl)-2-pyrazolo[1,5-a]pyrazin-3-ylpyrimidin-4-amine;
[0462]
(S)--N-(1-phenylethyl)-2-(pyrazolo[1,5-a]pyrazin-3-yl)pyrimidin-4--
amine; [0463]
N-Benzyl-2-pyrazolo[1,5-a]pyrazin-3-ylpyrimidin-4-amine; [0464]
N-(2,2-Dimethylpropyl)-2-pyrazolo[1,5-a]pyrazin-3-ylpyrimidin-4-am-
ine; [0465]
3-Oxo-3-{(3R)-3-[(2-pyrazolo[1,5-a]pyrazin-3-ylpyrimidin-4-yl)amino]piper-
idin-1-yl}propanenitrile; [0466]
6-{(3R)-3-[(2-Pyrazolo[1,5-a]pyrazin-3-ylpyrimidin-4-yl)amino]piperidin-1-
-yl}nicotinonitrile; [0467]
2-Pyrazolo[1,5-a]pyrazin-3-yl-N-[(3R)-1-(3,3,3-trifluoropropanoyl)piperid-
in-3-yl]pyrimidin-4-amine; [0468]
3-{(3R)-3-[Methyl(2-pyrazolo[1,5-a]pyrazin-3-ylpyrimidin-4-yl)amino]piper-
idin-1-yl}-3-oxopropanenitrile; [0469]
3-{(3R)-3-[(5-Chloro-2-pyrazolo[1,5-a]pyrazin-3-ylpyrimidin-4-yl)amino]pi-
peridin-1-yl}-3-oxopropanenitrile; [0470]
3-{(3R)-3-[(5-Fluoro-2-pyrazolo[1,5-a]pyrazin-3-ylpyrimidin-4-yl)amino]pi-
peridin-1-yl}-3-oxopropanenitrile; [0471]
5-Fluoro-2-pyrazolo[1,5-a]pyrazin-3-yl-N-[(3R)-1-(3,3,3-trifluoropropanoy-
l)piperidin-3-yl]pyrimidin-4-amine; [0472]
3-{(3R)-3-[(5-Methyl-2-pyrazolo[1,5-a]pyrazin-3-ylpyrimidin-4-yl)amino]pi-
peridin-1-yl}-3-oxopropanenitrile; and pharmaceutically acceptable
salts, solvates, N-oxides or deuterated derivatives thereof.
[0473] Of outstanding interest are: [0474]
3-(4-{[(1S)-1-Phenylethyl]amino}pyrimidin-2-yl)pyrazolo[1,5-a]pyridine-5--
carbonitrile; [0475]
3-{4-[(2,2-Dimethylpropyl)amino]pyrimidin-2-yl}pyrazolo[1,5-a]pyridine-5--
carbonitrile; [0476]
3-(4-{[(1S)-2-Methoxy-1-methylethyl]amino}pyrimidin-2-yl)pyrazolo[1,5-a]p-
yridine-5-carbonitrile; [0477]
N-(1-Phenylethyl)-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-amine;
[0478]
3-(4-{[(3R)-1-(Cyanoacetyl)piperidin-3-yl]amino}pyrimidin-2-yl)pyrazolo[1-
,5-a]pyridine-5-carbonitrile; [0479]
3-(4-{[(3R)-1-(3,3,3-Trifluoropropanoyl)piperidin-3-yl]amino}pyrimidin-2--
yl)pyrazolo[1,5-a]pyridine-5-carbonitrile; [0480]
3-{4-[[(3R)-1-(Cyanocarbonyl)piperidin-3-yl](methyl)amino]pyrimidin-2-yl}-
pyrazolo[1,5-a]pyridine-5-carbonitrile; [0481]
3-(4-((Trans)-4-Hydroxycyclohexylamino)pyrimidin-2-yl)pyrazolo[1,5-a]pyri-
dine-5-carbonitrile; [0482]
(S)--N-(1-phenylethyl)-2-(pyrazolo[1,5-a]pyrazin-3-yl)pyrimidin-4-amine;
[0483] N-Benzyl-2-pyrazolo[1,5-a]pyrazin-3-ylpyrimidin-4-amine;
[0484]
N-(2,2-Dimethylpropyl)-2-pyrazolo[1,5-a]pyrazin-3-ylpyrimidin-4-amine;
[0485]
3-Oxo-3-{(3R)-3-[(2-pyrazolo[1,5-a]pyrazin-3-ylpyrimidin-4-yl)amin-
o]piperidin-1-yl}propanenitrile; [0486]
6-{(3R)-3-[(2-Pyrazolo[1,5-a]pyrazin-3-ylpyrimidin-4-yl)amino]piperidin-1-
-yl}nicotinonitrile; [0487]
3-{(3R)-3-[Methyl(2-pyrazolo[1,5-a]pyrazin-3-ylpyrimidin-4-yl)amino]piper-
idin-1-yl}-3-oxopropanenitrile; [0488]
3-{(3R)-3-[(5-Chloro-2-pyrazolo[1,5-a]pyrazin-3-ylpyrimidin-4-yl)amino]pi-
peridin-1-yl}-3-oxopropanenitrile; [0489]
3-{(3R)-3-[(5-Fluoro-2-pyrazolo[1,5-a]pyrazin-3-ylpyrimidin-4-yl)amino]pi-
peridin-1-yl}-3-oxopropanenitrile; [0490]
5-Fluoro-2-pyrazolo[1,5-a]pyrazin-3-yl-N-[(3R)-1-(3,3,3-trifluoropropanoy-
l)piperidin-3-yl]pyrimidin-4-amine; [0491]
3-{(3R)-3-[(5-Methyl-2-pyrazolo[1,5-a]pyrazin-3-ylpyrimidin-4-yl)amino]pi-
peridin-1-yl}-3-oxopropanenitrile; [0492]
(S)--N-(1-(5-fluoropyridin-2-yl)ethyl)-2-(pyrazolo[1,5-a]pyrazin-3-yl)pyr-
imidin-4-amine; [0493]
N-((5-fluoropyridin-2-yl)methyl)-2-(pyrazolo[1,5-a]pyrazin-3-yl)pyrimidin-
-4-amine; [0494]
5-chloro-N-((5-fluoropyridin-2-yl)methyl)-2-(pyrazolo[1,5-a]pyrazin-3-yl)-
pyrimidin-4-amine; [0495]
N.sup.4-(4,4-difluorocyclohexyl)-2-(pyrazolo[1,5-a]pyrazin-3-yl)pyrimidin-
e-4,5-diamine; [0496]
(S)-5-chloro-N-(1-(5-fluoropyridin-2-yl)ethyl)-2-(pyrazolo[1,5-a]pyrazin--
3-yl)pyrimidin-4-amine; [0497]
2-(pyrazolo[1,5-a]pyrazin-3-yl)-N.sup.4-(tetrahydro-2H-pyran-4-yl)pyrimid-
ine-4,5-diamine; [0498]
(R)-3-oxo-3-(3-(6-(pyrazolo[1,5-a]pyrazin-3-yl)pyrazin-2-ylamino)piperidi-
n-1-yl)propanenitrile; [0499]
(R)-3-oxo-3-(3-(6-(pyrazolo[1,5-a]pyridin-3-yl)pyrazin-2-ylamino)piperidi-
n-1-yl)propanenitrile; [0500]
(R)-3-oxo-3-(3-(2-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-4-ylamino)piperi-
din-1-yl)propanenitrile; [0501]
3-(3-(5-fluoro-2-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-4-ylamino)piperid-
in-1-yl)-3-oxopropanenitrile; [0502]
3-(3-(5-chloro-2-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-4-ylamino)piperid-
in-1-yl)-3-oxopropanenitrile; [0503]
3-(4-fluoro-3-(6-(pyrazolo[1,5-a]pyridin-3-yl)pyrazin-2-ylamino)piperidin-
-1-yl)-3-oxopropanenitrile; [0504]
3-(4-methyl-3-(6-(pyrazolo[1,5-a]pyridin-3-yl)pyrazin-2-ylamino)piperidin-
-1-yl)-3-oxopropanenitrile; [0505]
N-(1-(4H-1,2,4-Triazol-3-yl)piperidin-3-yl)-6-(pyrazolo[1,5-a]pyridin-3-y-
l)pyrazin-2-amine; [0506]
N-(1-(4H-1,2,4-Triazol-3-yl)piperidin-3-yl)-2-(pyrazolo[1,5-a]pyridin-3-y-
l)pyrimidin-4-amine; and pharmaceutically acceptable salts,
solvates, N-oxides or deuterated derivatives thereof.
[0507] Preferred individual compounds of the invention include:
[0508]
3-(4-{[(1S)-1-Phenylethyl]amino}pyrimidin-2-yl)pyrazolo[1,5-a]pyridine-5--
carbonitrile; [0509]
3-{4-[(2,2-Dimethylpropyl)amino]pyrimidin-2-yl}pyrazolo[1,5-a]pyridine-5--
carbonitrile; [0510]
3-(4-{[(1S)-2-Methoxy-1-methylethyl]amino}pyrimidin-2-yl)pyrazolo[1,5-a]p-
yridine-5-carbonitrile; [0511]
N-(1-Phenylethyl)-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-amine;
[0512]
3-(4-{[(3R)-1-(Cyanoacetyl)piperidin-3-yl]amino}pyrimidin-2-yl)pyrazolo[1-
,5-a]pyridine-5-carbonitrile; [0513]
3-(4-{[(3R)-1-(3,3,3-Trifluoropropanoyl)piperidin-3-yl]amino}pyrimidin-2--
yl)pyrazolo[1,5-a]pyridine-5-carbonitrile; [0514]
3-{4-[[(3R)-1-(Cyanocarbonyl)piperidin-3-yl](methyl)amino]pyrimidin-2-yl}-
pyrazolo[1,5-a]pyridine-5-carbonitrile; [0515]
3-(4-((Trans)-4-Hydroxycyclohexylamino)pyrimidin-2-yl)pyrazolo[1,5-a]pyri-
dine-5-carbonitrile; [0516]
(S)--N-(1-phenylethyl)-2-(pyrazolo[1,5-a]pyrazin-3-yl)pyrimidin-4-amine;
[0517] N-Benzyl-2-pyrazolo[1,5-a]pyrazin-3-ylpyrimidin-4-amine;
[0518]
N-(2,2-Dimethylpropyl)-2-pyrazolo[1,5-a]pyrazin-3-ylpyrimidin-4-amine;
[0519]
3-Oxo-3-{(3R)-3-[(2-pyrazolo[1,5-a]pyrazin-3-ylpyrimidin-4-yl)amin-
o]piperidin-1-yl}propanenitrile; [0520]
6-{(3R)-3-[(2-Pyrazolo[1,5-a]pyrazin-3-ylpyrimidin-4-yl)amino]piperidin-1-
-yl}nicotinonitrile; [0521]
3-{(3R)-3-[Methyl(2-pyrazolo[1,5-a]pyrazin-3-ylpyrimidin-4-yl)amino]piper-
idin-1-yl}-3-oxopropanenitrile; [0522]
3-{(3R)-3-[(5-Chloro-2-pyrazolo[1,5-a]pyrazin-3-ylpyrimidin-4-yl)amino]pi-
peridin-1-yl}-3-oxopropanenitrile; [0523]
3-{(3R)-3-[(5-Fluoro-2-pyrazolo[1,5-a]pyrazin-3-ylpyrimidin-4-yl)amino]pi-
peridin-1-yl}-3-oxopropanenitrile; [0524]
5-Fluoro-2-pyrazolo[1,5-a]pyrazin-3-yl-N-[(3R)-1-(3,3,3-trifluoropropanoy-
l)piperidin-3-yl]pyrimidin-4-amine; [0525]
3-{(3R)-3-[(5-Methyl-2-pyrazolo[1,5-a]pyrazin-3-ylpyrimidin-4-yl)amino]pi-
peridin-1-yl}-3-oxopropanenitrile; [0526]
(S)--N-(1-(5-fluoropyridin-2-yl)ethyl)-2-(pyrazolo[1,5-a]pyrazin-3-yl)pyr-
imidin-4-amine; [0527]
N-((5-fluoropyridin-2-yl)methyl)-2-(pyrazolo[1,5-a]pyrazin-3-yl)pyrimidin-
-4-amine; [0528]
5-chloro-N-((5-fluoropyridin-2-yl)methyl)-2-(pyrazolo[1,5-a]pyrazin-3-yl)-
pyrimidin-4-amine; [0529]
N.sup.4-(4,4-difluorocyclohexyl)-2-(pyrazolo[1,5-a]pyrazin-3-yl)pyrimidin-
e-4,5-diamine; [0530]
(S)-5-chloro-N-(1-(5-fluoropyridin-2-yl)ethyl)-2-(pyrazolo[1,5-a]pyrazin--
3-yl)pyrimidin-4-amine; [0531]
2-(pyrazolo[1,5-a]pyrazin-3-yl)-N.sup.4-(tetrahydro-2H-pyran-4-yl)pyrimid-
ine-4,5-diamine; [0532]
(R)-3-oxo-3-(3-(6-(pyrazolo[1,5-a]pyrazin-3-yl)pyrazin-2-ylamino)piperidi-
n-1-yl)propanenitrile; [0533]
(R)-3-oxo-3-(3-(6-(pyrazolo[1,5-a]pyridin-3-yl)pyrazin-2-ylamino)piperidi-
n-1-yl)propanenitrile; [0534]
(R)-3-oxo-3-(3-(2-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-4-ylamino)piperi-
din-1-yl)propanenitrile; [0535]
3-(3-(5-fluoro-2-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-4-ylamino)piperid-
in-1-yl)-3-oxopropanenitrile; [0536]
3-(3-(5-chloro-2-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-4-ylamino)piperid-
in-1-yl)-3-oxopropanenitrile; [0537]
3-(4-fluoro-3-(6-(pyrazolo[1,5-a]pyridin-3-yl)pyrazin-2-ylamino)piperidin-
-1-yl)-3-oxopropanenitrile; [0538]
3-(4-methyl-3-(6-(pyrazolo[1,5-a]pyridin-3-yl)pyrazin-2-ylamino)piperidin-
-1-yl)-3-oxopropanenitrile; [0539]
N-(1-(4H-1,2,4-Triazol-3-yl)piperidin-3-yl)-6-(pyrazolo[1,5-a]pyridin-3-y-
l)pyrazin-2-amine; [0540]
N-(1-(4H-1,2,4-Triazol-3-yl)piperidin-3-yl)-2-(pyrazolo[1,5-a]pyridin-3-y-
l)pyrimidin-4-amine; and pharmaceutically acceptable salts,
solvates, N-oxides or deuterated derivatives thereof.
[0541] According to one embodiment of the present invention,
compounds of general formula (I-d), a subformula of claimed
compounds of general formula (I) where the central heteroaryl
moiety is a pyrimidine ring, may be prepared by the following
synthetic route as illustrated in Scheme 1:
##STR00007##
[0542] Compounds of formula (I-d) may be obtained from
chlorine-containing heteroaromatic compounds of formula (III) by
reaction with an appropriate nucleophile of formula (IV), such as
an amine or an alcohol, in the presence of a base such as
N,N'-diisopropylethylamine or triethylamine in a solvent such as
N,N'-dimethylformamide, dimethylsulfoxide, tetrahydrofuran or
ethanol at temperatures ranging from ambient temperature to
150.degree. C. with or without the use of microwave irradiation.
Compounds of formula (III) may be prepared by treatment of
pyrimidones of formula (II) with a suitable chlorinating agent, for
example phosphorous (V) oxychloride or phosphorous (V) chloride, at
temperatures ranging from 25.degree. C. to reflux. In the
particular case where Z.dbd.NR.sub.5, compounds of formula (I-d)
may be obtained directly from compounds of formula (II) by
treatment with an appropriate activating agent such as
benzotriazolyloxy-tris-(dimethylamino) phosphonium
hexafluorophosphate in the presence of a suitable base such as
1,8-diazabiciclo[5.4.0]undec-7-ene at temperatures ranging from 25
to 80.degree. C. in a suitable solvent such as
N,N'-dimethylformamide in the presence of a nucleophile of type
(IV) following the protocol as described in the literature (J. Org.
Chem., 2007, 72 (26), 10194-10210).
[0543] Compounds of general formula (II-a), a subformula of
intermediates of formula (II) in which R.sub.1 is an hydrogen atom,
may be obtained as shown in Scheme 2:
##STR00008##
[0544] Amidines of formula (V) may be reacted with unsaturated
esters of formula (VI) (where LG is --OH, --OMe, --OEt or
--NMe.sub.2) to give pyrimidones of formula (II-a). Such reactions
may be carried out in the presence of a suitable base such as
triethylamine in a solvent such as ethanol at temperatures ranging
from ambient temperature to reflux.
[0545] Intermediate amidines of general formula (V) may be prepared
by the following synthetic route as illustrated in Scheme 3:
##STR00009##
[0546] Reaction of ethyl propiolate with N-aminopyridinium (in the
particular case where W.dbd.CR.sub.3) or N-aminopyrazinium salts
(in the particular case where W.dbd.N) of formula (VIII) in the
presence of a base, for example potassium carbonate, in a solvent
such as N,N' dimethylformamide at temperatures ranging from
0.degree. C. to ambient temperature, furnishes esters of formula
(IX). N-aminopyridinium and N-aminopyrazinium salts of formula
(VIII) may be commercially available or may be prepared by reaction
of the corresponding pyridines (in the particular case where
W.dbd.CR.sub.3) or pyrazines (in the particular case where W.dbd.N)
of formula (VII) with O-(mesitylsulfonyl)hydroxylamine in a
suitable solvent such as dichloromethane at temperatures ranging
from 0.degree. C. to ambient temperature. Carboxylic acids of
formula (X) may be prepared by treatment of esters of formula (IX)
with a suitable base such as sodium hydroxide in a solvent such as
ethanol at temperatures ranging from ambient temperature to reflux.
Treatment of compounds of formula (X) with a suitable chlorinating
reagent such as thionyl chloride at temperatures ranging from
ambient temperature to reflux furnishes intermediate acid chlorides
which when treated with an ammonia source, such as aqueous ammonium
hydroxide, gives rise to amides of formula (XI). Reaction of amides
of formula (XI) with a suitable dehydrating reagent such as
phosphoryl trichloride at temperatures ranging from ambient
temperature to reflux furnishes nitriles of formula (XII).
Treatment of nitriles of formula (XII) with catalytic sodium
methoxide in methanol at ambient temperature followed by treatment
of the corresponding imidate intermediates with ammonium chloride
in methanol at refluxing temperatures furnishes amidine
intermediates of formula (V).
[0547] In another synthetic pathway, compounds of general formula
(II-a) may be prepared by the following synthetic route as
described in Scheme 4:
##STR00010##
[0548] Reaction of 2-chloropyrimidines of formula (XIII) with
ethynyltrimethylsilane under palladium and copper-catalyzed
coupling conditions with suitable catalysts such as
bis(triphenylphosphine)palladium (II) dichloride and copper(I)
iodide in the presence of a base, for example triethylamine, in a
solvent such as tetrahydrofuran at temperatures ranging from room
temperature to reflux, with or without the use of microwave
irradiation, furnishes alkynes of formula (XVI). Treatment of
compounds of formula (XVI) with a suitable reagent such as
tetrabutylammonium fluoride in the presence of a catalytic amount
of acetic acid in a suitable solvent such as tetrahydrofuran at
ambient temperature, gives rise to desired terminal alkynes of
formula (XVII). Reaction of alkynes of formula (XVII) with
N-aminopyridinium (in the particular case where W.dbd.CR.sub.3) or
N-aminopyrazinium salts (in the particular case where W.dbd.N) of
formula (VIII) in the presence of a base, for example potassium
carbonate, in a solvent such as N,N' dimethylformamide at
temperatures ranging from 0.degree. C. to room temperature,
furnishes compounds of formula (XV). Alternatively, compounds of
formula (XV) may be prepared directly from 2-chloropyrimidines of
formula (XIII) by reaction with boronic esters of formula (XIV)
under Suzuki-Miyaura reaction conditions (Miyaura, N.; Suzuki, A.
Chem. Rev. 1995, 95, 2457). Such reactions may be catalyzed by a
suitable palladium catalyst such as
tris(dibencylidenoacetone)dipalladium (0), in the presence of a
ligand such as tricyclohexylphosphine, in a solvent such as
N,N'-dimethylformamide, in the presence of a base such as potassium
phosphate, at temperatures ranging from 80-120.degree. C. with or
without the use of microwave irradiation. Treatment of compounds of
formula (XV) with suitable reagents such as
trimethylsilylchloride/sodium iodide in a suitable solvent such as
acetonitrile at reflux, with potassium hydroxide in a mixture of
ethanol and water under microwave heating at 130.degree. C. or with
an aqueous hydrogen chloride or hydrogen bromide solution at
100.degree. C., gives rise to desired pyrimidones of formula
(II-a).
[0549] Intermediate boronic esters of general formula (XIV) may be
prepared as shown in Scheme 5:
##STR00011##
[0550] Carboxylic acids of formula (X) may be transformed into
bromo derivatives of formula (XVIII) by treatment with a
brominating reagent such as N-bromosuccinimide in the presence of a
base, such as sodium hydrogen carbonate, in a solvent such as
N,N'-dimethylformamide at ambient temperature. Treatment of bromo
derivatives of formula (XVIII) with an appropriate boron reagent
such as bis(pinacolato)diboron with a palladium catalyst such as
palladium (II) acetate, in the presence of a ligand such as
tricyclohexylphosphine, in a solvent such as diglyme or water, in
the presence of a base such as potassium carbonate, at temperatures
ranging from 80-120.degree. C. with or without the use of microwave
irradiation provides boronic esters of formula (XIV).
[0551] Compounds of general formula (I-e), a subformula of claimed
compounds of general formula (I) where the central heteroaryl
moiety is a pyridine ring and R.sub.1 is an hydrogen atom, may be
prepared by the following synthetic route as illustrated in Scheme
6:
##STR00012##
[0552] Alkynes of formula (XX) may be prepared by reaction of
dichloropyridines of formula (XIX) with ethynyltrimethylsilane
under palladium and copper-catalyzed coupling conditions with
suitable catalysts such as bis(triphenylphosphine)palladium (II)
dichloride and copper (I) iodide in the presence of a base, for
example triethylamine, in a solvent such as tetrahydrofuran at
temperatures ranging from ambient temperature to reflux with or
without the use of microwave irradiation. Treatment of compounds of
formula (XX) with a suitable reagent such as tetrabutylammonium
fluoride in the presence of a catalytic amount of acetic acid in a
suitable solvent such as tetrahydrofuran at room temperature, gives
rise to desired terminal alkynes of formula (XXI). Reaction of
alkynes of formula (XXI) with N-aminopyridinium (in the particular
case where W.dbd.CR.sub.3) or N-aminopyrazinium salts (in the
particular case where W.dbd.N) of formula (VIII) in the presence of
a base, for example potassium carbonate, in a solvent such as
N,N'-dimethylformamide at temperatures ranging from 0.degree. C. to
ambient temperature, furnishes compounds of formula (XXII).
Treatment of chloropyridines of formula (XXII) with nucleophiles of
formula (IV) such as an amine or an alcohol, in the presence of a
base, such as N,N'-diisopropylethylamine or triethylamine, in an
aprotic solvent such as N,N'-dimethylformamide or dimethylsulfoxide
at temperatures ranging from ambient temperature to 140.degree. C.
gives rises to compounds of formula (I-e). In the particular case
where Z.dbd.NR.sub.5, compounds of formula (I-e) may be prepared by
reaction of compounds of formula (XXII) with nitrogen nucleophiles
of formula (IV) using a suitable catalyst such as palladium (II)
acetate in the presence of a ligand such as
1,1'-binaphthalene-2,2'-diylbis(diphenylphosphine) and a base, for
example cesium carbonate, in a solvent such as toluene at a
temperature ranging from 80-120.degree. C. with or without the use
of microwave irradiation.
[0553] Compounds of general formula (I-f), a subformula of claimed
compounds of general formula (I) where the central heteroaryl
moiety is a pyrazine ring and R.sub.1 is an hydrogen atom, may be
prepared by the following synthetic route as described in Scheme
7:
##STR00013##
[0554] Boronic esters of formula (XIV) may be reacted with
2,6-dichloropyrazines of formula (XXIII) under Suzuki-Miyaura
reaction conditions (Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95,
2457) to give compounds of formula (XXIV). Such reactions may be
catalyzed by a suitable palladium catalyst such as
tris(dibencylidenoacetone) dipalladium (0), in the presence of a
ligand such as tricyclohexylphosphine, in a solvent such as
N,N'-dimethylformamide, in the presence of a base such as potassium
phosphate, at temperatures ranging from 80-120.degree. C. with or
without the use of microwave irradiation. Treatment of
chloropyrazines of formula (XXIV) with nucleophiles of formula (IV)
in the presence of a base, such as cesium fluoride, in an aprotic
solvent such as dimethylsulfoxide at temperatures ranging from
ambient temperature to 140.degree. C. gives rises to compounds of
formula (I-f). In the particular case where Z.dbd.NR.sub.5,
compounds of formula (I-f) may be prepared by reaction of compounds
of formula (XXIV) with nitrogen nucleophiles of formula (IV) using
a suitable catalyst such as tris(dibencylidenoacetone)dipalladium
(0), in the presence of a ligand such as
9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene and a base, for
example cesium carbonate, in a solvent such as
N,N'-dimethylformamide at a temperature ranging from 80-120.degree.
C. with or without the use of microwave irradiation.
[0555] In another particular case, compounds of formula (I-d),
(I-e) or (I-f) where Z is NR.sub.5 and R.sub.5 is an hydrogen atom,
may undergo further reaction with a suitable base such as sodium
hydride in a solvent such as N,N'-dimethylformamide followed by the
addition of an alkylating agent, such as methyl iodide at
temperatures ranging from 0.degree. C. to reflux, to furnish
compounds of formula (I-d), (I-e) or (I-f) where R.sub.5 is now an
alkyl group.
[0556] In yet another particular case, compounds of formula (I-d),
(I-e) or (I-f) in which the residue at R.sub.9 is a nitro group,
may undergo further reaction with hydrogen gas at atmospheric
pressure using a suitable catalyst such as palladium or platinum on
carbon in a solvent such as ethanol or methanol at ambient
temperature to furnish compounds of formula (I-d), (I-e) or (I-f)
where R.sub.9 is now an amino group.
[0557] In yet another particular case, compounds of formula (I-d),
(I-e) or (I-f) in which the residue at R.sub.6, R.sub.7 or R.sub.8
contains, in part, an amine moiety functionalized with an
appropriate protecting group such as tert-butoxycarbonyl (BOC) or
benzyloxycarbonyl (CBZ), may be deprotected at the amine moiety
under standard conditions (Greene's Protective Groups in Organic
Synthesis, ISBN: 0471697540). The corresponding free amine may then
be further functionalized under standard conditions to give the
corresponding amides, sulphonamides, ureas, and N-alkylated and
N-arylated amines. The syntheses of the compounds of the invention
and of the intermediates for use therein are illustrated by the
following Examples (1-47) (including Preparation Examples
(Preparations 1-41)) and are given in order to provide a person
skilled in the art with a sufficiently clear and complete
explanation of the present invention, but should not be considered
as limiting of the essential aspects of its subject, as set out in
the preceding portions of this description.
Preparation 1
2-Ethynyl-4-methoxypyrimidine
##STR00014##
[0558] a) 4-Methoxy-2-[(trimethylsilyl)ethynyl]pyrimidine
[0559] An oven-dried resealable Schlenk tube was charged with
2-chloro-4-methoxypyrimidine (2.60 g, 17.99 mmol),
ethynyltrimethylsilane (3.05 mL, 21.58 mmol), tetrahydrofuran (24
mL) and triethylamine (12.53 mL, 89.90 mmol). The Schlenk tube was
subjected to three cycles of evacuation-backfilling with argon and
then copper(I) iodide (0.14 g, 0.72 mmol) and
bis(triphenylphosphine)palladium(II) dichloride (0.51 g, 0.72 mmol)
were added. After three further cycles of evacuation-backfilling
with argon, the Schlenk tube was sealed and the mixture was stirred
and heated in an oil bath at 90.degree. C. After 16 hours, the
mixture was filtered and the solvent was removed under reduced
pressure. The residue was taken up in a mixture of ethyl acetate
and water and the organic layer was separated, washed with 4%
aqueous sodium hydrogencarbonate solution, dried (MgSO.sub.4) and
evaporated. Purification of the residue by flash chromatography
(9:1 hexane/ethyl acetate) gave the title compound (2.85 g, 77%) as
an oil.
[0560] LRMS (m/z): 207 (M+1).sup.+.
[0561] .sup.1H-NMR .delta. (300 MHz, CDCl.sub.3): 0.0 (s, 9H), 3.7
(s, 3H), 6.4 (d, 1H), 8.1 (d, 1H).
b) 2-Ethynyl-4-methoxypyrimidine
[0562] Tetrabutylammonium fluoride (0.97 mL of a 1M solution in
tetrahydrofuran, 0.97 mmol) was added to a stirred solution of
4-methoxy-2-[(trimethylsilyl)ethynyl]pyrimidine (Preparation 1a,
0.20 g, 0.97 mmol) in tetrahydrofuran (1.4 mL) and acetic acid (56
.mu.L) at room temperature. After 5 minutes, 10% aqueous potassium
carbonate solution was added to the reaction mixture and the
mixture was extracted with dichloromethane. The organic layer was
separated, dried (MgSO.sub.4) and evaporated. Purification of the
residue by flash chromatography (dichloromethane) gave the title
compound (0.11 g, 85%) as a pale orange solid.
[0563] LRMS (m/z): 135 (M+1).sup.+.
[0564] .sup.1H-NMR .delta. (300 MHz, CDCl.sub.3): 3.1 (s, 1H), 4.0
(s, 3H), 6.7 (d, 1H), 8.4 (d, 1H).
Preparation 2
1-Amino-4-cyanopyridinium 2,4,6-trimethylbenzenesulfonate
##STR00015##
[0566] A solution of O-(mesitylsulfonyl)hydroxylamine (prepared as
described in Synthesis, 1977, 1; 2.17 g, 10.1 mmol) in anhydrous
dichloromethane (21 mL) was added dropwise to a stirred solution of
isonicotinonitrile (1.05 g, 10.1 mmol) in anhydrous dichloromethane
(10 mL) at 0.degree. C. and the mixture was stirred at ambient
temperature for 1 hour and 30 minutes. Diethyl ether was then added
to the mixture and the precipitate that formed was collected by
filtration, washed with diethyl ether and dried in vacuo to give
the title compound (3.03 g, 94%) as a white solid.
[0567] LRMS (m/z): 120 (M+1).sup.+, 199 (M-1).sup.-.
[0568] .sup.1H-NMR .delta. (300 MHz, CD.sub.3OD): 2.2 (s, 3H), 2.6
(s, 6H), 6.9 (bs, 2H), 8.3 (d, 1H), 8.9 (d, 1H).
Preparation 3
3-(4-Hydroxypyrimidin-2-yl)pyrazolo[1,5-a]pyridine-5-carbonitrile
##STR00016##
[0569] a)
3-(4-Methoxypyrimidin-2-yl)pyrazolo[1,5-a]pyridine-5-carbonitril-
e
[0570] 1-Amino-4-cyanopyridinium 2,4,6-trimethylbenzenesulfonate
(Preparation 2, 12.10 g, 37.88 mmol) was added in portions over 6
hours to a stirred suspension of 2-ethynyl-4-methoxypyrimidine
(Preparation 1b, 2.54 g, 18.94 mmol) and potassium carbonate (3.93
g, 28.43 mmol) in anhydrous N,N'-dimethylformamide (47 mL) at
0.degree. C. and the resulting mixture was stirred at ambient
temperature for 48 hours. The solvent was evaporated and
dichloromethane was added to the residue. The solid formed was
filtered and the filtrate evaporated to dryness. The crude product
was purified by flash chromatography (4:1 hexanes/ethyl acetate) to
give the title compound (3.51 g, 74%) as a solid.
[0571] LRMS (m/z): 252 (M+1).sup.+.
[0572] .sup.1H-NMR .delta. (300 MHz, CDCl.sub.3): 4.1 (s, 3H), 6.6
(d, 1H), 7.0 (d, 1H), 8.5 (d, 1H), 8.6 (d, 1H), 8.8 (s, 1H), 9.1
(s, 1H).
b)
3-(4-Hydroxypyrimidin-2-yl)pyrazolo[1,5-a]pyridine-5-carbonitrile
[0573] Chlorotrimethylsilane (0.61 mL, 4.83 mmol) and sodium iodide
(0.72 g, 4.83 mmol) were added to a stirred suspension of
3-(4-methoxypyrimidin-2-yl)pyrazolo[1,5-a]pyridine-5-carbonitrile
(Preparation 3a, 0.14 g, 0.54 mmol) in acetonitrile (11 mL) and the
mixture was heated at 70.degree. C. in a sealed tube and left
overnight. The mixture was then cooled and the solvent evaporated.
Water (4 mL) and 10% aqueous sodium thiosulfate solution (5 mL)
were added to the residue and the suspension was stirred for 20
minutes. The suspension was filtered and the precipitate was dried
in vacuo to give the title compound in quantitative yield which was
used in the next synthetic step without further purification.
[0574] LRMS (m/z): 238 (M+1).sup.+.
[0575] .sup.1H-NMR .delta. (300 MHz, DMSO-d.sub.6): 6.3 (d, 1H),
7.5 (d, 1H), 8.1 (d, 1H), 9.0 (s, 1H), 9.1 (s, 1H), 9.1 (d,
1H).
Preparation 4
2-Pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-ol
##STR00017##
[0576] a) 3-(4-Methoxypyrimidin-2-yl)pyrazolo[1,5-a]pyridine
[0577] Obtained as a solid (49%) from 2-ethynyl-4-methoxypyrimidine
(Preparation 1b) and 1-aminopyridinium iodide following the
experimental procedure as described in Preparation 3a followed by
purification by flash chromatography (4:1 hexane/ethyl
acetate).
[0578] LRMS (m/z): 227 (M+1).sup.+.
[0579] .sup.1H-NMR .delta. (300 MHz, CDCl.sub.3): 4.1 (s, 3H), 6.5
(dd, 1H), 6.9 (t, 1H), 7.4 (dd, 1H), 8.5 (dd, 1H), 8.6 (dd, 1H),
8.6 (d, 1H), 8.7 (s, 1H).
b) 2-Pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-ol
[0580] 48% Aqueous hydrogen bromide (19.50 mL) was added to
3-(4-methoxypyrimidin-2-yl)pyrazolo[1,5-a]pyridine (Preparation 4a,
0.30 g, 1.32 mmol) and the resulting mixture was heated to
100.degree. C. with stirring. After 3 hours, the mixture was cooled
and the resultant precipitate was filtered and dried in vacuo to
give the title compound (0.28 g, 99%) as the hydrobromide salt.
[0581] LRMS (m/z): 213 (M+1).sup.+.
Preparation 5
2-Chloro-6-ethynylpyridine
##STR00018##
[0582] a) 2-Chloro-6-[(trimethylsilyl)ethynyl]pyridine
[0583] Obtained as an oil (38%) from 2,6-dichloropyridine and
ethynyltrimethylsilane following the experimental procedure as
described in Preparation 1a followed by purification by flash
chromatography (hexane to 30:1 hexane/ethyl acetate).
[0584] LRMS (m/z): 210 (M+1).sup.+.
b) 2-Chloro-6-ethynylpyridine
[0585] Obtained as an oil (29%) from
2-chloro-6-[(trimethylsilyl)ethynyl]pyridine (Preparation 5a)
following the experimental procedure as described in Preparation 1b
followed by purification by flash chromatography (hexane to 10:1
hexane/ethyl acetate).
[0586] .sup.1H-NMR .delta. (300 MHz, CDCl.sub.3): 3.2 (s, 1H), 7.3
(d, 1H), 7.4 (d, 1H), 7.6 (t, 1H).
Preparation 6
3-(6-Chloropyridin-2-yl)pyrazolo[1,5-a]pyridine-5-carbonitrile
##STR00019##
[0588] Obtained as a solid (30%) from 2-chloro-6-ethynylpyridine
(Preparation 5b) and 1-amino-4-cyanopyridinium
2,4,6-trimethylbenzenesulfonate (Preparation 2) following the
experimental procedure as described in Preparation 3a followed by
purification by flash chromatography (99:1
dichloromethane/methanol).
[0589] LRMS (m/z): 255 (M+1).sup.+.
[0590] .sup.1H-NMR .delta. (300 MHz, CDCl.sub.3): 6.9-7.1 (m, 1H),
7.2-7.3 (m, 1H), 7.5-7.8 (m, 2H), 8.4-8.7 (m, 2H), 9.0-9.1 (m,
1H).
Preparation 7
3-{4-[(3R)-Piperidin-3-ylamino]pyrimidin-2-yl}pyrazolo[1,5-a]pyridine-5-ca-
rbonitrile
##STR00020##
[0591] a) Tert-butyl
(3R)-3-{[2-(5-cyanopyrazolo[1,5-a]pyridin-3-yl)pyrimidin-4-yl]amino}piper-
idine-1-carboxylate
[0592] Tert-butyl (3R)-3-aminopiperidine-1-carboxylate (1.49 g,
7.46 mmol) was added to a stirred solution of
3-(4-hydroxypyrimidin-2-yl)pyrazolo[1,5-a]pyridine-5-carbonitrile
(Preparation 3b, 0.70 g, 2.98 mmol),
(benzotriazol-1-yloxy)tris(dimethylamino) phosphonium
hexafluorophosphate (1.71 g, 3.88 mmol) and
1,8-diazabicyclo[5.4.0]undec-7-ene (0.67 mL g, 4.48 mmol) in
N,N'-dimethylformamide (15 mL) and the resulting mixture was
stirred at room temperature for 16 hours. Then the solvent was
removed under reduced pressure and the residue was taken up in a
mixture of dichloromethane and 4% aqueous sodium hydrogencarbonate
solution. The organic layer was separated, dried (MgSO.sub.4) and
evaporated in vacuo. The crude product was purified by flash
chromatography (99:1 dichloromethane/methanol) to give a residue
that was repurified by reverse phase chromatography (C-18 silica
from Waters, water/acetonitrile/methanol as eluents [0.1% v/v
formic acid buffered] 0% to 100%) to give the title compound (0.83
g, 66%) and
3-(4-(1H-benzo[d][1,2,3]triazol-1-yloxy)pyrimidin-2-yl)pyrazolo[1,5-a]pyr-
idine-5-carbonitrile (0.10 g) as the main reaction byproduct.
[0593] LRMS (m/z): 420 (M+1).sup.+, 418 (M-1).sup.-.
[0594] .sup.1H-NMR .delta. (300 MHz, CDCl.sub.3): 0.7-0.9 (m, 4H),
1.5 (s, 9H), 1.6-1.7 (m, 2H), 1.7-1.9 (m, 2H), 2.0-2.1 (m, 1H), 5.0
(bs, 1H), 6.3 (d, 1H), 7.0 (dd, 1H), 8.3 (d, 1H), 8.6 (d, 1H), 8.8
(s, 1H), 9.1 (t, 1H).
b)
3-{4-[(3R)-Piperidin-3-ylamino]pyrimidin-2-yl}pyrazolo[1,5-a]pyridine-5-
-carbonitrile
[0595] Trifluoroacetic acid (0.61 mL, 7.97 mmol) was added to a
stirred solution of (R)-tert-butyl
3-(2-(5-cyanopyrazolo[1,5-a]pyridin-3-yl)pyrimidin-4-ylamino)piperidine-1-
-carboxylate (Preparation 7a, 0.12 g, 0.27 mmol) in dichloromethane
(4 mL) and the mixture was stirred at room temperature for 4 hours.
4% Aqueous sodium hydrogencarbonate solution and solid sodium
hydrogencarbonate were then added until the pH was basic and the
mixture was further extracted with more dichloromethane. The
organic layer was separated, dried (MgSO.sub.4) and evaporated to
give the title compound (0.06 g, 62%) as a pale yellow solid which
was used in the next synthetic step without further
purification.
[0596] LRMS (m/z): 320 (M+1).sup.+, 318 (M-1).sup.-.
[0597] .sup.1H-NMR .delta. (300 MHz, CDCl.sub.3): 0.8-0.9 (m, 4H),
1.5 (s, 9H), 1.8-2.3 (m, 5H), 5.7 (bs, 1H), 6.3 (d, 1H), 7.0 (dd,
1H), 8.2 (d, 1H), 8.6 (d, 1H), 8.7 (s, 1H), 9.1 (bs, 1H).
Preparation 8
(R)-3-(4-(Methyl(piperidin-3-yl)amino)pyrimidin-2-yl)pyrazolo[1,5-a]pyridi-
ne-5-carbonitrile
##STR00021##
[0598] a) (R)-Tert-butyl
3-((2-(5-cyanopyrazolo[1,5-a]pyridin-3-yl)pyrimidin-4-yl)(methyl)amino)pi-
peridine-1-carboxylate
[0599] Sodium hydride (60% dispersion in mineral oil, 102 mg, 2.55
mmol) was added to a cooled (0.degree. C.) solution of tert-butyl
(3R)-3-{[2-(5-cyanopyrazolo[1,5-a]pyridin-3-yl)pyrimidin-4-yl]amino}piper-
idine-1-carboxylate (Preparation 7a, 0.83 g, 1.98 mmol) in
NIP-dimethylformamide (5 mL) and the reaction mixture was stirred
at the same temperature for 30 minutes. Methyl iodide (0.135 mL,
2.17 mmol) was then added and the reaction mixture was stirred at
room temperature for 2 hours. The solvent was concentrated in vacuo
and the residue was partitioned between water and ethyl acetate.
The organic layer was separated, washed with water and brine, dried
(MgSO.sub.4) and the solvent was evaporated to give the title
compound (0.39 g, 80%) as a beige solid.
[0600] LRMS (m/z): 434 (M+1).sup.+.
b)
(R)-3-(4-(Methyl(piperidin-3-yl)amino)pyrimidin-2-yl)pyrazolo[1,5-a]pyr-
idine-5-carbonitrile
[0601] Obtained as a pale orange solid (77%) from (R)-tert-butyl
3-((2-(5-cyanopyrazolo[1,5-a]pyridin-3-yl)pyrimidin-4-yl)(methyl)amino)pi-
peridine-1-carboxylate (Preparation 8a) following the experimental
procedure as described in Preparation 7b.
[0602] LRMS (m/z): 334 (M+1).sup.+.
[0603] .sup.1H-NMR .delta. (400 MHz, DMSO-d.sub.6): 1.5-1.9 (m,
5H), 2.3-2.5 (m, 2H), 2.7 (t, 1H), 2.8-3.1 (m, 5H), 6.6 (bs, 1H),
7.3 (dd, 1H), 8.3 (d, 1H), 8.8 (s, 1H), 8.9-9.0 (m, 2H).
Preparation 9
1-Aminopyrazin-1-ium 2,4,6-trimethylbenzenesulfonate
##STR00022##
[0605] Obtained as a white solid (75%) from pyrazine and
O-(mesitylsulfonyl)hydroxylamine (prepared as described in
Synthesis, 1977, 1) following the experimental procedure as
described in Preparation 2.
[0606] .sup.1H-NMR .delta. (400 MHz, DMSO-d.sub.6): 2.2 (s, 3H),
2.5 (s, 6H), 6.8 (s, 2H), 8.7 (d, 2H), 9.2 (d, 2H), 9.6 (s,
2H).
Preparation 10
2-(Pyrazolo[1,5-a]pyrazin-3-yl)pyrimidin-4-ol
##STR00023##
[0607] a) 3-(4-Methoxypyrimidin-2-yl)pyrazolo[1,5-a]pyrazine
[0608] Obtained as a solid (43%) from 2-ethynyl-4-methoxypyrimidine
(Preparation 1b) and 1-aminopyrazin-1-ium
2,4,6-trimethylbenzenesulfonate (Preparation 9) following the
experimental procedure as described in Preparation 3a.
[0609] LRMS (m/z): 228 (M+1).sup.+.
[0610] .sup.1H-NMR .delta. (400 MHz, CDCl.sub.3): 4.1 (s, 3H), 6.6
(d, 1H), 8.0 (d, 1H), 8.4 (dd, 1H), 8.5 (d, 1H), 8.8 (s, 1H), 10.0
(s, 1H).
b) 2-(Pyrazolo[1,5-a]pyrazin-3-yl)pyrimidin-4-ol
[0611] Obtained (83%) from
3-(4-methoxypyrimidin-2-yl)pyrazolo[1,5-a]pyrazine (Preparation
10a) following the experimental procedure as described in
Preparation 4b.
[0612] LRMS (m/z): 214 (M+1).sup.+, 212 (M-1).sup.-.
[0613] .sup.1H-NMR .delta. (300 MHz, DMSO-d.sub.6): 6.4 (d, 1H),
8.2 (d, 1H), 8.2 (s, 1H), 9.0 (dd, 1H), 9.0 (s, 1H), 9.9 (d,
1H).
Preparation 11
(R)--N-(Piperidin-3-yl)-2-(pyrazolo[1,5-a]pyrazin-3-yl)pyrimidin-4-amine
##STR00024##
[0614] a) (R)-Tert-butyl
3-(2-(pyrazolo[1,5-a]pyrazin-3-yl)pyrimidin-4-ylamino)piperidine-1-carbox-
ylate
[0615] Obtained (50%) from
2-(pyrazolo[1,5-a]pyrazin-3-yl)pyrimidin-4-ol (Preparation 10b) and
tert-butyl (3R)-3-aminopiperidine-1-carboxylate following the
experimental procedure as described in Preparation 7a followed by
purification by flash chromatography (dichloromethane to 97:3
dichloromethane/methanol).
[0616] LRMS (m/z): 396 (M+1).sup.+.
b)
(R)--N-(Piperidin-3-yl)-2-(pyrazolo[1,5-a]pyrazin-3-yl)pyrimidin-4-amin-
e
[0617] Obtained (91%) from (R)-tert-butyl
3-(2-(pyrazolo[1,5-a]pyrazin-3-yl)pyrimidin-4-ylamino)piperidine-1-carbox-
ylate (Preparation 11a) and trifluoroacetic acid following the
experimental procedure as described in Preparation 7b.
[0618] LRMS (m/z): 296 (M+1).sup.+.
[0619] .sup.1H-NMR .delta. (400 MHz, CDCl.sub.3): 1.6-1.7 (m, 2H),
1.7-1.9 (m, 3H), 2.7-3.0 (m, 4H), 3.2-3.3 (m, 1H), 5.5 (bs, 1H),
6.2 (d, 1H), 8.0 (d, 1H), 8.2 (d, 1H), 8.4 (dd, 1H), 8.7 (s, 1H),
10.0 (s, 1H).
Preparation 12
N-Methyl-N-[(3R)-piperidin-3-yl]-2-pyrazolo[1,5-a]pyrazin-3-ylpyrimidin-4--
amine
##STR00025##
[0620] a) Tert-butyl
(3R)-3-[methyl(2-pyrazolo[1,5-a]pyrazin-3-ylpyrimidin-4-yl)amino]piperidi-
ne-1-carboxylate
[0621] Obtained (9%) from (R)-tert-butyl
3-(2-(pyrazolo[1,5-a]pyrazin-3-yl)pyrimidin-4-ylamino)
piperidine-1-carboxylate (Preparation 11a) and methyl iodide
following the experimental procedure as described in Preparation 8a
followed by purification by reverse phase chromatography (C-18
silica from Waters, water/acetonitrile/methanol as eluents [0.1%
v/v formic acid buffered] 5% to 50%).
[0622] LRMS (m/z): 410 (M+1).sup.+.
b)
N-Methyl-N-[(3R)-piperidin-3-yl]-2-pyrazolo[1,5-a]pyrazin-3-ylpyrimidin-
-4-amine
[0623] Obtained (94%) from tert-butyl
(3R)-3-[methyl(2-pyrazolo[1,5-a]pyrazin-3-ylpyrimidin-4-yl)amino]piperidi-
ne-1-carboxylate (Preparation 12a) and trifluoroacetic acid
following the experimental procedure as described in Preparation
7b.
[0624] LRMS (m/z): 310 (M+1).sup.+.
Preparation 13
5-Chloro-2-ethynyl-4-methoxypyrimidine
##STR00026##
[0625] a)
5-Chloro-4-methoxy-2-[(trimethylsilyl)ethynyl]pyrimidine
[0626] Obtained (44%) from 2,5-dichloro-4-methoxypyrimidine
(prepared as described in Tetrahedron Lett. 2006, 47, 4415) and
ethynyltrimethylsilane following the experimental procedure as
described in Preparation 1a followed by purification by flash
chromatography (dichloromethane to 4:6 dichloromethane/hexane).
[0627] LRMS (m/z): 241 (M+1).sup.+.
[0628] .sup.1H-NMR .delta. (300 MHz, CDCl.sub.3): 0.1 (bs, 9H), 3.8
(bs, 3H), 8.1 (s, 1H).
b) 5-Chloro-2-ethynyl-4-methoxypyrimidine
[0629] Obtained as a grey solid (78%) from
5-chloro-4-methoxy-2-((trimethylsilyl)ethynyl)pyrimidine
(Preparation 13a) following the experimental procedure as described
in Preparation 1b followed by purification by flash chromatography
(9:1 hexane/ethyl acetate).
[0630] LRMS (m/z): 169 (M+1).sup.+.
[0631] .sup.1H-NMR .delta. (300 MHz, CDCl.sub.3): 3.1 (s, 1H), 4.1
(s, 3H), 8.4 (s, 1H).
Preparation 14
5-Chloro-2-pyrazolo[1,5-a]pyrazin-3-ylpyrimidin-4-ol
##STR00027##
[0632] a)
3-(5-Chloro-4-methoxypyrimidin-2-yl)pyrazolo[1,5-a]pyrazine
[0633] Obtained as an orange solid (84%) from
5-chloro-2-ethynyl-4-methoxypyrimidine (Preparation 13b) and
1-aminopyrazin-1-ium trimethylbenzene sulfonate (Preparation 9)
following the experimental procedure as described in preparation 3a
followed by purification by flash chromatography (dichloromethane
to 7:3 dichloromethane/methanol).
[0634] LRMS (m/z): 262 (M+1).sup.+.
[0635] .sup.1H-NMR .delta. (300 MHz, CDCl.sub.3): 4.2 (s, 3H), 8.0
(d, 1H), 8.5 (d, 1H), 8.5 (s, 1H), 8.7 (s, 1H), 10.0 (s, 1H).
b) 5-Chloro-2-pyrazolo[1,5-a]pyrazin-3-ylpyrimidin-4-ol
[0636] Obtained as a green solid (62%) from
3-(5-chloro-4-methoxypyrimidin-2-yl)pyrazolo[1,5-a]pyrazine
(Preparation 14a) following the experimental procedure as described
in Preparation 4b.
Preparation 15
5-Chloro-N-[(3R)-piperidin-3-yl]-2-pyrazolo[1,5-a]pyrazin-3-ylpyrimidin-4--
amine
##STR00028##
[0637] a) Tert-butyl
(3R)-3-[(5-chloro-2-pyrazolo[1,5-a]pyrazin-3-ylpyrimidin-4-yl)amino]piper-
idine-1-carboxylate
[0638] Obtained as a yellow solid (40%) from
5-chloro-2-(pyrazolo[1,5-a]pyrazin-3-yl)pyrimidin-4-ol (Preparation
14b) and (R)-tert-butyl 3-aminopiperidine 1-carboxylate following
the experimental procedure as described in Preparation 7a followed
by purification by flash chromatography (hexane to 6:4 hexane/ethyl
acetate).
[0639] LRMS (m/z): 430 (M+1).sup.+.
[0640] .sup.1H-NMR .delta. (300 MHz, CDCl.sub.3): 1.4 (bs, 9H), 1.7
(bs, 3H), 1.9-2.1 (m, 2H), 3.4 (bs, 1H), 3.7 (bs, 2H), 4.3 (bs,
1H), 5.6 (bs, 1H), 8.0 (d, 1H), 8.3 (s, 1H), 8.4 (d, 1H), 8.7 (s,
1H), 9.9 (s, 1H).
b)
5-Chloro-N-[(3R)-piperidin-3-yl]-2-pyrazolo[1,5-a]pyrazin-3-ylpyrimidin-
-4-amine
[0641] Obtained as a yellow solid (87%) from tert-butyl
3-(5-chloro-2-(pyrazolo[1,5-a]pyrazin-3-yl)pyrimidin-4-ylamino)piperidine-
-1-carboxylate (Preparation 15a) and trifluoroacetic acid following
the experimental procedure as described in Preparation 7b.
[0642] LRMS (m/z): 330 (M+1).sup.+.
[0643] .sup.1H-NMR .delta. (300 MHz, CDCl.sub.3): 1.3 (bs, 2H), 1.9
(bs, 3H), 2.9 (bs, 3H), 3.2-3.3 (m, 1H), 4.4 (bs, 1H), 5.9 (bs,
1H), 8.0 (d, 1H), 8.2 (s, 1H), 8.4 (d, 1H), 8.7 (s, 1H), 9.9 (s,
1H).
Preparation 16
2-Ethynyl-5-fluoro-4-methoxypyrimidine
##STR00029##
[0644] a) 2-Chloro-5-fluoro-4-methoxypyrimidine
[0645] To a mixture of sodium (450 mg, 19 mmol) in methanol (20 mL)
was added a solution of 2,4-dichloro-5-fluoropyrimidine (3.25 g, 19
mmol) in methanol (10 mL). The reaction mixture was stirred at room
temperature overnight before being partitioned between water and
diethyl ether. The organic phase was separated, washed with brine
and evaporated to dryness to give the title compound as an orange
oil (80%), which was used in the next step without further
purification.
[0646] .sup.1H-NMR .delta. (400 MHz, CDCl.sub.3): 4.1 (s, 3H), 8.2
(s, 1H).
b) 5-Fluoro-4-methoxy-2-[(trimethylsilyl)ethynyl]pyrimidine
[0647] Obtained (17%) from 2-chloro-5-fluoro-4-methoxypyrimidine
(Preparation 16a) and ethynyltrimethylsilane following the
experimental procedure as described in Preparation 1a followed by
purification by flash chromatography (2:8 hexane/dichloromethane to
100% dichloromethane).
[0648] LRMS (m/z): 225 (M+1).sup.+.
[0649] .sup.1H-NMR .delta. (400 MHz, CDCl.sub.3): 0.1 (s, 9H), 3.8
(s, 3H), 8.0 (d, 1H).
c) 2-Ethynyl-5-fluoro-4-methoxypyrimidine
[0650] Obtained (82%) from
5-fluoro-4-methoxy-2-((trimethylsilyl)ethynyl)pyrimidine
(Preparation 16b) following the experimental procedure as described
in Preparation 1b followed by purification by flash chromatography
(99:1 dichloromethane/methanol).
[0651] .sup.1H-NMR .delta. (400 MHz, CDCl.sub.3): 3.1 (d, 1H), 4.1
(s, 3H), 8.3 (d, 1H).
Preparation 17
5-Fluoro-2-pyrazolo[1,5-a]pyrazin-3-ylpyrimidin-4-ol
##STR00030##
[0652] a)
3-(5-Fluoro-4-methoxypyrimidin-2-yl)pyrazolo[1,5-a]pyrazine
[0653] Obtained (72%) from 2-ethynyl-5-fluoro-4-methoxypyrimidine
(Preparation 16c) and 1-aminopyrazin-1-ium
2,4,6-trimethylbenzenesulfonate (Preparation 9) following the
experimental procedure as described in Preparation 3a followed by
purification by flash chromatography (dichloromethane to 97:3
dichloromethane/methanol).
[0654] LRMS (m/z): 246 (M+1).sup.+.
[0655] .sup.1H-NMR .delta. (400 MHz, CDCl.sub.3): 4.2 (s, 3H), 8.0
(d, 1H), 8.4 (d, 1H), 8.4 (dd, 1H), 8.7 (s, 1H), 10.0 (d, 1H).
b) 5-Fluoro-2-pyrazolo[1,5-a]pyrazin-3-ylpyrimidin-4-ol
[0656] Aqueous hydrogen chloride (13 mL of a 6N solution, 78 mmol)
was added to
3-(5-fluoro-4-methoxypyrimidin-2-yl)pyrazolo[1,5-a]pyrazine
(Preparation 17a, 0.38 g, 1 mmol) in a microwave vessel. The
resulting mixture was subjected to microwave irradiation for 1 hour
at 120.degree. C. After cooling to room temperature, 8N aqueous
sodium hydroxide solution was added until a basic pH was reached.
The solid formed was filtered and dried to yield the title compound
(72%), which was used in the next step without further
purification.
[0657] LRMS (m/z): 232 (M+1).sup.+.
[0658] .sup.1H-NMR .delta. (400 MHz, DMSO-d.sub.6): 8.1-8.2 (m,
3H), 9.0 (bs, 1H), 9.8 (bs, 1H).
Preparation 18
5-Fluoro-N-[(3R)-piperidin-3-yl]-2-pyrazolo[1,5-a]pyrazin-3-ylpyrimidin-4--
amine
##STR00031##
[0659] a) Tert-butyl
(3R)-3-[(5-fluoro-2-pyrazolo[1,5-a]pyrazin-3-ylpyrimidin-4-yl)amino]piper-
idine-1-carboxylate
[0660] Obtained as a white solid (50%) from
5-fluoro-2-(pyrazolo[1,5-a]pyrazin-3-yl)pyrimidin-4-ol (Preparation
17b) and tert-butyl (3R)-3-aminopiperidine-1-carboxylate following
the experimental procedure as described in Preparation 7a followed
by purification by flash chromatography (dichloromethane to 95:5
dichloromethane/methanol).
[0661] LRMS (m/z): 414 (M+1).sup.+.
[0662] .sup.1H-NMR .delta. (400 MHz, CDCl.sub.3): 1.4-1.5 (m, 2H),
1.7 (s, 9H), 1.8 (m, 1H), 1.9-2.0 (m, 1H), 2.0-2.1, (m, 1H), 3.4
(bs, 1H), 3.6 (bs, 1H), 3.7 (bs, 1H), 4.3-4.4 (m, 1H), 8.0 (d, 1H),
8.1 (d, 1H), 8.4 (dd, 1H), 8.7 (s, 1H), 9.9 (d, 1H).
b)
5-Fluoro-N-[(3R)-piperidin-3-yl]-2-pyrazolo[1,5-a]pyrazin-3-ylpyrimidin-
-4-amine
[0663] Obtained as a solid (94%) from (R)-tert-butyl
3-(5-fluoro-2-(pyrazolo[1,5-a]pyrazin-3-yl)pyrimidin-4-ylamino)piperidine-
-1-carboxylate (Preparation 18a) and trifluoroacetic acid following
the experimental procedure as described in Preparation 7b followed
by purification by flash chromatography (dichloromethane to 92:8
dichloromethane/methanol).
[0664] LRMS (m/z): 314 (M+1).sup.+.
[0665] .sup.1H-NMR .delta. (400 MHz, CDCl.sub.3): 1.6 (m, 1H),
1.7-1.9 (m, 2H), 2.0 (m, 1H), 2.1 (bs, 1H), 2.8-2.9 (m, 2H), 3.3
(bs, 1H), 4.3-4.4 (m, 1H), 5.7 (d, 1H), 8.0 (d, 1H), 8.1 (d, 1H),
8.4 (dd, 1H), 8.6 (s, 1H), 9.9 (d, 1H).
Preparation 19
2-Ethynyl-4-methoxy-5-methylpyrimidine
##STR00032##
[0666] a) 2-Chloro-4-methoxy-5-methylpyrimidine
[0667] Obtained as a white solid (85%) from
2,4-dichloro-5-methylpyrimidine following the experimental
procedure as described in Preparation 16a followed by purification
by flash chromatography (hexane to 95:5 hexane/ethyl acetate).
[0668] LRMS (m/z): 159 (M+1).sup.+.
[0669] .sup.1H-NMR .delta. (400 MHz, CDCl.sub.3): 2.1 (d, 3H), 4.0
(s, 3H), 8.1 (d, 1H).
b) 4-Methoxy-5-methyl-2-[(trimethylsilyl)ethynyl]pyrimidine
[0670] Obtained as a yellow solid (19%) from
2-chloro-4-methoxy-5-methylpyrimidine (Preparation 19a) and
ethynyltrimethylsilane following the experimental procedure as
described in Preparation 1a followed by purification by flash
chromatography (hexane to 93:7 hexane/diethyl ether).
[0671] LRMS (m/z): 221 (M+1).sup.+.
[0672] .sup.1H-NMR .delta. (400 MHz, CDCl.sub.3): 0.1 (s, 9H), 1.9
(d, 3H), 3.7 (s, 3H), 7.9 (s, 1H).
c) 2-Ethynyl-4-methoxy-5-methylpyrimidine
[0673] Obtained as a white solid (55%) from
4-methoxy-5-methyl-2-((trimethylsilyl)ethynyl)pyrimidine
(Preparation 19b) following the experimental procedure as described
in Preparation 1b followed by purification by flash chromatography
(dichloromethane).
[0674] LRMS (m/z): 149 (M+1).sup.+.
[0675] .sup.1H-NMR .delta. (400 MHz, CDCl.sub.3): 2.2 (s, 3H), 3.0
(s, 1H), 4.0 (s, 3H), 8.2 (s, 1H).
Preparation 20
3-(4-Methoxy-5-methylpyrimidin-2-yl)pyrazolo[1,5-a]pyrazine
##STR00033##
[0676] a)
3-(4-Methoxy-5-methylpyrimidin-2-yl)pyrazolo[1,5-a]pyrazine
[0677] Obtained as a yellow solid (99%) from
2-ethynyl-4-methoxy-5-methylpyrimidine (Preparation 19c) and
1-aminopyrazin-1-ium 2,4,6-trimethylbenzene sulfonate (Preparation
9) following the experimental procedure as described in Preparation
3a followed by purification by flash chromatography
(dichloromethane to 95:5 dichloromethane/methanol).
[0678] LRMS (m/z): 242 (M+1).sup.+.
[0679] .sup.1H-NMR .delta. (400 MHz, CDCl.sub.3): 3.0 (s, 3H), 4.2
(s, 3H), 8.0 (d, 1H), 8.3 (d, 1H), 8.4 (dd, 1H), 8.7 (s, 1H), 10.0
(d, 1H).
b) 3-(4-Methoxy-5-methylpyrimidin-2-yl)pyrazolo[1,5-a]pyrazine
[0680] 35% Aqueous potassium hydroxide solution (5 mL) was added to
a solution of
3-(4-methoxy-5-methylpyrimidin-2-yl)pyrazolo[1,5-a]pyrazine
(Preparation 20a, 0.70 g, 2.89 mmol) in ethanol (10 mL). The
mixture was placed in a microwave vessel and was subjected to
microwave irradiation for 1 hour at 130.degree. C. After cooling to
room temperature, the organic solvent was removed under reduced
pressure and the residue was acidified with 5N aqueous hydrogen
chloride solution. The solid formed was filtered, washed with water
and dried to give the title compound (64%) as a brown solid.
[0681] LRMS (m/z): 228 (M+1).sup.+.
[0682] .sup.1H-NMR .delta. (400 MHz, DMSO-d.sub.6): 3.3 (bs, 3H),
8.0 (bs, 1H), 8.1 (bs, 1H), 9.0 (bs, 2H), 9.8 (bs, 1H).
Preparation 21
5-Methyl-N-[(3R)-piperidin-3-yl]-2-pyrazolo[1,5-a]pyrazin-3-ylpyrimidin-4--
amine
##STR00034##
[0683] a) Tert-butyl
(3R)-3-[(5-methyl-2-pyrazolo[1,5-a]pyrazin-3-ylpyrimidin-4-yl)amino]piper-
idine-1-carboxylate
[0684] Obtained as a yellow oil (58%) from
5-methyl-2-(pyrazolo[1,5-a]pyrazin-3-yl)pyrimidin-4-ol (Preparation
20b) and tert-butyl (3R)-3-aminopiperidine-1-carboxylate following
the experimental procedure as described in Preparation 7a followed
by purification by flash chromatography (hexane to 30:70
hexane/ethyl acetate).
[0685] LRMS (m/z): 410 (M+1).sup.+.
[0686] .sup.1H-NMR .delta. (400 MHz, DMSO-d.sub.6) .delta. 1.2 (bs,
1H), 1.4 (bs, 1H), 1.7 (bs, 1H), 1.8 (bs, 1H), 2.1 (s, 6H), 2.0 (s,
3H), 2.8-2.9 (m, 1H), 3.4 (s, 3H), 3.9 (bs, 2H), 4.0 (q, 1H), 4.1
(bs, 1H), 8.0 (d, 1H), 8.1 (s, 1H), 8.9 (bs, 2H), 9.8 (s, 1H).
b)
5-Methyl-N-[(3R)-piperidin-3-yl]-2-pyrazolo[1,5-a]pyrazin-3-ylpyrimidin-
-4-amine
[0687] Obtained as a yellow oil (85%) from (R)-tert-butyl
3-(5-methyl-2-(pyrazolo[1,5-a]pyrazin-3-yl)pyrimidin-4-ylamino)piperidine-
-1-carboxylate (Preparation 21a) and trifluoroacetic acid following
the experimental procedure as described in Preparation 7b.
[0688] LRMS (m/z): 310 (M+1).sup.+.
[0689] .sup.1H-NMR .delta. (400 MHz, CDCl.sub.3): 1.6 (bs, 2H), 1.8
(bs, 2H), 2.1 (s, 3H), 2.7-2.9 (m, 1H), 3.2-3.3 (m, 2H), 4.4 (bs,
2H), 7.9 (d, 1H), 8.0 (s, 1H), 8.4 (d, 1H), 8.7 (s, 1H), 10.0 (s,
1H).
Preparation 22
3-Bromopyrazolo[1,5-a]pyridine
##STR00035##
[0690] a) Ethyl pyrazolo[1,5-a]pyridine-3-carboxylate
[0691] Ethyl propionate (50.2 mL, 49.54 mmol) and 1-aminopyridinium
iodide (10.0 g, 45 mmol) were added to a suspension of potassium
carbonate (8.71 g, 63.02 mmol) in N,N'-dimethylformamide (100 mL)
and the resulting mixture was stirred at room temperature for 2 h
before being poured into 100 mL of water. Ethyl acetate was then
added and the aqueous layer was separated and washed with ethyl
acetate (.times.2). The combined organic layers were dried over
magnesium sulphate, filtered and evaporated. The crude product was
purified by flash chromatography (hexanes to 4:1 hexanes/ethyl
acetate) to give the title compound (4.30 g, 50%) as an orange
solid.
[0692] LRMS (m/z): 191 (M+1).sup.+.
[0693] .sup.1H-NMR .delta. (250 MHz, CDCl.sub.3): 1.4 (t, 3H), 4.3
(q, 2H), 6.9 (t, 1H), 7.4 (t, 1H), 8.1 (s, 1H), 8.4 (s, 1H), 8.5
(d, 1H).
b) Pyrazolo[1,5-a]pyridine-3-carboxylic acid
[0694] A 2.5 N aqueous solution of sodium hydroxide (36 mL) was
added to a solution of ethyl pyrazolo[1,5-a]pyridine-3-carboxylate
(Preparation 22a, 4.3 g, 22.6 mmol) in ethanol (70 mL) and the
resulting reaction mixture was heated to reflux for 1 h. After
evaporation of the ethanol, the reaction mixture was acidified with
15% aqueous hydrochloric acid solution. The solid formed was
filtered, washed with water and diethyl ether and dried to give the
title compound (2.81 g, 77%) as a pale pink solid.
[0695] LRMS (m/z): 163 (M+1).sup.+.
[0696] .sup.1H-NMR .delta. (250 MHz, DMSO-d.sub.6): 7.1 (t, 1H),
7.6 (t, 1H), 8.1 (dd, 1H), 8.4 (s, 1H), 8.9 (d, 1H), 12.5 (s,
1H).
c) 3-Bromopyrazolo[1,5-a]pyridine
[0697] N-Bromosuccinimide (3.06 g, 17.22 mmol) and sodium hydrogen
carbonate (4.34 g, 51.66 mmol) were added to a solution of
pyrazolo[1,5-a]pyridine-3-carboxylic acid (Preparation 22b, 2.81 g,
17.22 mmol) in N,N-dimethylformamide (40 mL) and the resulting
mixture was stirred at room temperature for 4 h before being poured
over 100 mL of water. The resulting suspension was extracted twice
with ethyl acetate and the combined organic layers were dried over
magnesium sulphate, filtered and the solvent was evaporated. The
crude product was purified by flash chromatography (8:2
hexane/ethyl acetate) to yield the title compound (2.58 g,
76%).
[0698] LRMS (m/z): 197 (M+1).sup.+.
[0699] .sup.1H-NMR .delta. (250 MHz, CDCl.sub.3): 6.8 (t, 1H), 7.2
(t, 1H), 7.5 (d, 1H), 7.9 (s, 1H), 8.4 (d, 1H).
Preparation 23
3-Bromopyrazolo[1,5-a]pyrazine
##STR00036##
[0700] a) Ethyl pyrazolo[1,5-a]pyrazine-3-carboxylate
[0701] Obtained as an orange solid (28%) from 1-aminopyrazin-1-ium
2,4,6-trimethyl benzenesulfonate (Preparation 9) and ethyl
propionate following the experimental procedure as described in
Preparation 22a followed by purification by flash chromatography
(hexane to 4:6 hexane/ethyl acetate).
[0702] LRMS (m/z): 192 (M+1).sup.+.
b) Pyrazolo[1,5-a]pyrazine-3-carboxylic acid
[0703] Obtained as a white solid (99%) from ethyl
pyrazolo[1,5-a]pyrazine-3-carboxylate (Preparation 23a) following
the experimental procedure as described in Preparation 22b.
[0704] LRMS (m/z): 164 (M+1).sup.+.
c) 3-Bromopyrazolo[1,5-a]pyrazine
[0705] Obtained as a yellowish solid (69%) from
pyrazolo[1,5-a]pyrazine-3-carboxylic acid (Preparation 23b)
according to the experimental procedure as described in Preparation
22c followed by purification by flash chromatography (2:8 to 6:4
ethyl acetatehexane).
[0706] LRMS (m/z): 198 (M+1).sup.+.
Preparation 24
3-(4-Chloro-5-nitropyrimidin-2-yl)pyrazolo[1,5-a]pyrazine
##STR00037##
[0707] a) Pyrazolo[1,5-a]pyrazine-3-carboxamide
[0708] A suspension of pyrazolo[1,5-a]pyrazine-3-carboxylic acid
(Preparation 23b, 6.70 g, 41.1 mmol) in thionyl chloride (50 mL)
was heated to reflux for 7 hours. After cooling, the reaction
mixture was concentrated in vacuo and the residue was azeotroped
with toluene (2.times.30 mL). The resultant solid was suspended in
25% aqueous ammonium hydroxide solution (80 mL) and the mixture was
stirred for 16 hours at ambient temperature. The mixture was
concentrated to dryness to give the crude title compound (10.0 g,
>100%) as a beige solid which was used in the next synthetic
step without further purification.
[0709] LRMS (m/z): 163 (M+1).sup.+.
[0710] .sup.1H NMR .delta. (300 MHz, DMSO-d.sub.6): 8.1 (d, 1H),
8.7 (s, 1H), 8.9 (d, 1H), 9.6 (s, 1H).
b) Pyrazolo[1,5-a]pyrazine-3-carbonitrile
[0711] A suspension of crude pyrazolo[1,5-a]pyrazine-3-carboxamide
(Preparation 24a, 6.66 g) in phosphoryl trichloride (80 mL) was
heated to reflux for 2.5 hours. The reaction mixture was then
poured onto a saturated aqueous sodium hydrogen carbonate solution
(200 mL) and then the pH was adjusted to 7-8 by addition of a 10%
aqueous sodium hydroxide solution. The mixture was extracted with
ethyl acetate, the organic layer was dried (MgSO.sub.4) and
evaporated and the resulting residue was purified by flash
chromatography (1:1 hexanes/ethyl acetate) to give the title
compound (3.10 g, 52%) as a yellow solid.
[0712] LRMS (m/z): 145 (M+1).sup.+.
[0713] .sup.1H NMR .delta. (300 MHz, DMSO-d.sub.6): 8.3 (d, 1H),
8.8 (s, 1H), 9.1 (d, 1H), 9.5 (s, 1H).
c) Pyrazolo[1,5-a]pyrazine-3-carboximidamide hydrochloride
[0714] Freshly prepared sodium methoxide (0.44 g, 8.1 mmol) was
added to a suspension of pyrazolo[1,5-a]pyrazine-3-carbonitrile
(Preparation 24b, 6.09 g, 42.3 mmol) in anhydrous methanol (350 mL)
and the mixture was stirred at ambient temperature. After 20 hours,
further sodium methoxide (0.44 g, 8.1 mmol) was added and the
reaction mixture was stirred for a further 48 hours. Ammonium
chloride (3.91 g, 73.1 mmol) was added and the mixture was stirred
and heated to 70.degree. C. in a sealed tube. After 3 days, the
mixture was concentrated to dryness to give a solid which was
suspended in ethyl acetate and stirred overnight. The precipitate
was filtered and dried in vacuo to give the crude title compound
(8.50 g, >100%) as a white solid which was used in the next
synthetic step without further purification.
[0715] LRMS (m/z): 162 (M+1).sup.+.
[0716] .sup.1H NMR .delta. (300 MHz, DMSO-d.sub.6): 8.2 (d, 1H),
8.8 (s, 1H), 9.0 (d, 1H), 9.5 (s, 1H).
d) 5-Nitro-2-(pyrazolo[1,5-a]pyrazin-3-yl)pyrimidin-4-ol
[0717] A mixture of crude pyrazolo[1,5-a]pyrazine-3-carboximidamide
hydrochloride (Preparation 24c, 4.88 g), (Z)-ethyl
3-(dimethylamino)-2-nitroacrylate (8.04 g, 42.7 mmol) and
triethylamine (6.25 mL, 44.8 mmol) in ethanol (165 mL) was stirred
and heated to 90.degree. C. in a sealed tube. After 22 hours, the
reaction mixture was cooled and the precipitate was filtered,
washed with ethanol and diethyl ether and dried to give the title
compound (3.12 g, 66%) as a yellow solid.
[0718] LRMS (m/z): 257 (M-1).sup.+.
[0719] NMR .delta. (300 MHz, DMSO-d.sub.6): 8.1 (d, 1H), 8.7 (s,
1H), 8.8 (s, 1H), 8.9 (d, 1H), 9.9 (s, 1H).
e) 3-(4-Chloro-5-nitropyrimidin-2-yl)pyrazolo[1,5-a]pyrazine
[0720] A suspension of
5-nitro-2-(pyrazolo[1,5-a]pyrazin-3-yl)pyrimidin-4-ol (Preparation
24d, 1.50 g, 5.8 mmol) in phosphoryl trichloride (12 mL) was
stirred and heated to 90.degree. C. in a sealed tube. After 2
hours, the mixture was concentrated in vacuo and the residue was
azeotroped with toluene. The resultant solid was treated with
saturated aqueous sodium hydrogen carbonate solution and, upon
scratching, a solid formed which was filtered, washed with water
(40 mL) and dried to give the title compound (1.38 g, 86%) as a
yellow solid.
[0721] LRMS (m/z): 277 (M+1).sup.+.
[0722] .sup.1H NMR .delta. (300 MHz, DMSO-d.sub.6): 8.3 (d, 1H),
9.0 (s, 1H), 9.1 (d, 1H), 9.6 (s, 1H), 9.9 (s, 1H).
Preparation 25
5-Nitro-2-(pyrazolo[1,5-a]pyrazin-3-yl)-N-(tetrahydro-2H-pyran-4-yl)pyrimi-
din-4-amine
##STR00038##
[0724] Diisopropylethylamine (2.30 mL, 13.20 mmol) and
tetrahydro-2H-pyran-4-amine acetate (526 mg, 3.28 mmol) were added
to a stirred suspension of
3-(4-chloro-5-nitropyrimidin-2-yl)pyrazolo[1,5-a]pyrazine
(Preparation 24e, 0.91 g, 3.29 mmol) in tetrahydrofuran (15 mL) and
the mixture was stirred at room temperature for 3 hours. The
solvent was evaporated and water was added. The mixture was
filtered to give the title compound (0.785 g, 70%) as a yellow
solid.
[0725] LRMS (m/z): 342 (M+1).sup.+.
Preparation 26
N-(4,4-Difluorocyclohexyl)-5-nitro-2-(pyrazolo[1,5-a]pyrazin-3-yl)pyrimidi-
n-4-amine
##STR00039##
[0727] Obtained as a yellow solid (86%) from
3-(4-chloro-5-nitropyrimidin-2-yl)pyrazolo[1,5-a]pyrazine
(Preparation 24e) and 4,4-difluorocyclohexanamine following the
experimental procedure as described in Preparation 25.
[0728] LRMS (m/z): 376 (M+1).sup.+.
[0729] .sup.1H NMR .delta. (300 MHz, DMSO-d.sub.6): 1.9-2.2 (m,
8H), 4.6 (m, 1H), 8.2 (d, 1H), 8.5 (d, 1H), 8.9 (s, 1H), 9.0 (d,
1H), 9.2 (s, 1H), 9.9 (s, 1H).
Preparation 27
3-(6-Chloropyrazin-2-yl)pyrazolo[1,5-a]pyridine
##STR00040##
[0730] a)
3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]py-
ridine
[0731] 4,4,4',4',5,5,5',5'-Octamethyl-2,2'-bi(1,3,2-dioxaborolane)
(1.27 g, 5.0 mmol), palladium (II) acetate (0.050 g, 0.228 mmol),
tricyclohexylphosphine (0.127 g, 0.46 mmol), potassium carbonate
(0.945 g, 6.84 mmol) and water (0.05 mL) were added to a solution
of 3-bromopyrazolo[1,5-a]pyridine (Preparation 22c, 0.90 g, 4.56
mmol)) in diglyme (10 mL) and the resulting mixture was heated at
100.degree. C. for 2 h. After cooling, the reaction mixture was
filtered through Celite.RTM., eluting with methanol. The filtrate
was evaporated and the crude product was used with no further
purification in the next synthetic step.
[0732] LRMS (m/z): 245 (M+1).sup.+.
b) 3-(6-Chloropyrazin-2-yl)pyrazolo[1,5-a]pyridine
[0733] 2,6-Dichloropyrazine (0.316 g, 2.12 mmol),
tris(dibenzylideneacetone) dipalladium (0), (0.097 g, 0.106 mmol),
tricyclohexylphosphine (0.06 g, 0.212 mmol) and potassium phosphate
(1.35 g, 6.36 mmol) were added to a suspension of
3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine
(Preparation 27a, 0.518 g, 2.12 mmol)) in N,N'-dimethylformamide
(10 mL). This mixture was subjected to microwave irradiation at
100.degree. C. for 40 min. The reaction mixture was filtered
through Celite.RTM., eluting with methanol, and the filtrate was
evaporated. The resulting residue was purified by flash
chromatography (2:8 to 3:7 ethyl acetatehexane) to yield the title
compound (0.162 g, 33%, two steps) as a pale yellow solid.
[0734] LRMS (m/z): 231 (M+1).sup.+.
[0735] .sup.1H-NMR .delta. (250 MHz, CDCl.sub.3): 7.0 (t, 1H), 7.4
(t, 1H), 8.3 (s, 1H), 8.5 (s, 1H), 8.5 (m, 2H), 8.8 (s, 1H).
Preparation 28
[0736]
(R)--N-(Piperidin-3-yl)-6-(pyrazolo[1,5-a]pyridin-3-yl)pyrazin-2-am-
ine
##STR00041##
a) (R)-tert-Butyl
3-(6-(pyrazolo[1,5-a]pyridin-3-yl)pyrazin-2-ylamino)piperidine-1-carboxyl-
ate
[0737] Tert-Butyl (3R)-3-aminopiperidine-1-carboxylate (0.51 g,
2.54 mmol) and cesium fluoride (0.83 g, 5.46 mmol) were added to a
stirred solution of 3-(6-chloropyrazin-2-yl)pyrazolo[1,5-a]pyridine
(Preparation 27b, 0.42 g, 1.82 mmol) in dimethylsulfoxide (20 mL).
The resulting mixture was stirred at 100.degree. C. for 22 h before
being poured onto 50 mL of water. The resultant suspension was
extracted with ethyl acetate (.times.2) and the combined organic
layers were dried over magnesium sulphate, filtered and evaporated
to dryness. The crude product was purified by flash chromatography
(3:7 to 7:3 ethyl acetatehexane) to give the title compound (0.244
g, 34%) as a yellowish foam.
[0738] LRMS (m/z): 395 (M+1).sup.+.
b)
(R)--N-(Piperidin-3-yl)-6-(pyrazolo[1,5-a]pyridin-3-yl)pyrazin-2-amine
[0739] Trifluoroacetic acid (0.35 mL, 4.56 mmol) was added to a
solution of (R)-tert-butyl
3-(6-(pyrazolo[1,5-a]pyridin-3-yl)pyrazin-2-ylamino)piperidine-1-carboxyl-
ate (Preparation 28a, 0.30 g, 0.76 mmol) in methylene chloride (10
mL) and the resulting solution was stirred at ambient temperature
overnight and then at 50.degree. C. for additional 24 h. The
solvent was then evaporated and the residue was redissolved in
methylene chloride and washed with a 10% aqueous sodium hydroxide
solution. The organic phase was dried over magnesium sulphate,
filtered and the solvent was evaporated. The crude product was
purified by flash chromatography (10-15%
MeOH/CH.sub.2Cl.sub.2NH.sub.3) to yield the title compound (0.125
g, 56%) as an oil.
[0740] LRMS (m/z): 295 (M+1).sup.+.
Preparation 29
3-(6-Chloropyrazin-2-yl)pyrazolo[1,5-a]pyrazine
##STR00042##
[0741] a)
3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]py-
razine
[0742] Obtained from 3-bromopyrazolo[1,5-a]pyrazine (Preparation
23c) following the experimental procedure as described in
Preparation 27a, irradiating the reaction mixture at 100.degree. C.
for 1 h. The crude product was used without further purification in
the next synthetic step.
[0743] LRMS (m/z): 246 (M+1).sup.+.
b) 3-(6-Chloropyrazin-2-yl)pyrazolo[1,5-a]pyrazine
[0744] Obtained as a yellow solid (28% yield, two steps) from
3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyrazine
(Preparation 29a) according to the experimental procedure as
described in Preparation 27b followed by purification by flash
chromatography (2:8 ethyl acetatehexane).
[0745] LRMS (m/z): 232 (M+1).sup.+.
Preparation 30
[0746]
(R)--N-(Piperidin-3-yl)-6-(pyrazolo[1,5-a]pyrazin-3-yl)pyrazin-2-am-
ine
##STR00043##
a) (R)-tert-Butyl
3-(6-(pyrazolo[1,5-a]pyrazin-3-yl)pyrazin-2-ylamino)piperidine-1-carboxyl-
ate
[0747] Tert-butyl (3R)-3-aminopiperidine-1-carboxylate (0.41 g,
2.05 mmol), tris(dibencylideno acetone)dipalladium(0) (0.034 g,
0.037 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino) xanthene
(0.043 g, 0.074 mmol) and cesium carbonate (0.848 g, 2.6 mmol) were
added to a suspension of
3-(6-chloropyrazin-2-yl)pyrazolo[1,5-a]pyrazine (Preparation 29b,
0.43 g, 1.86 mmol)) in N,N'-dimethylformamide (10 mL) and the
resulting mixture was purged with argon before being heated to
100.degree. C. for 7 h. After cooling to ambient temperature, the
reaction mixture was filtered though Celite.RTM., eluting with
methanol. The filtrate was evaporated and the residue was purified
by flash chromatography (7:3 ethyl acetatehexane to 100% ethyl
acetate) to yield the title compound (0.320 g, 44%) as a greenish
solid.
[0748] LRMS (m/z): 396 (M+1).sup.+.
[0749] .sup.1H-NMR .delta. (250 MHz, CDCl.sub.3): 1.4 (s, 9H), 1.8
(m, 2H), 2.0 (m, 2H), 3.5 (m, 3H), 3.7 (m, 1H), 4.1 (m, 1H), 4.8
(m, 1H), 7.8 (s, 1H), 8.0 (d, 1H), 8.3 (s, 1H), 8.4 (dd, 1H), 8.5
(s, 1H), 9.8 (d, 1H).
b)
(R)--N-(Piperidin-3-yl)-6-(pyrazolo[1,5-a]pyrazin-3-yl)pyrazin-2-amine
[0750] Obtained as a yellow foam (99%) from (R)-tert-butyl
3-(6-(pyrazolo[1,5-a]pyrazin-3-yl)pyrazin-2-ylamino)piperidine-1-carboxyl-
ate (Preparation 30a) and trifluoroacetic acid following the
experimental procedure as described in Preparation 28b. The crude
product was used in the next synthetic step without further
purification.
[0751] LRMS (m/z): 296 (M+1).sup.+.
Preparation 31
3-(4-Chloropyrimidin-2-yl)pyrazolo[1,5-a]pyrazine
##STR00044##
[0753] A solution of 2-(pyrazolo[1,5-a]pyrazin-3-yl)pyrimidin-4-ol
(Preparation 10b, 150 mg, 0.7 mmol) in phosphorous oxychloride
(1.42 mL, 15.51 mmol) was heated overnight at 110.degree. C. After
cooling to ambient temperature, the reaction mixture was poured
with caution onto water and basified by addition of a 2N aqueous
sodium hydroxide solution. Ethyl acetate was then added and the
organic phase was separated, washed with water and brine, dried
(MgSO.sub.4), filtered and evaporated under reduced pressure to
yield the title compound (170 mg, 87%) as a solid which was used in
the next synthetic step without further purification.
[0754] LRMS (m/z): 232 (M+1).sup.+
[0755] .sup.1H NMR .delta. (300 MHz, CDCl.sub.3): 7.0 (t, 1H), 7.1
(d, 1H), 7.4 (d, 1H), 8.6 (dd, 2H), 8.8 (s, 1H).
Preparation 32
3-(4,5-Dichloropyrimidin-2-yl)pyrazolo[1,5-a]pyrazine
##STR00045##
[0757] Obtained as a solid (57%) from
5-chloro-2-(pyrazolo[1,5-a]pyrazin-3-yl)pyrimidin-4-ol (Preparation
14b) and phosphorous oxychloride following the experimental
procedure as described in Preparation 31.
[0758] LRMS (m/z): 267 (M+1).sup.+
Preparation 33
3-(4-Chloropyrimidin-2-yl)pyrazolo[1,5-a]pyridine
##STR00046##
[0760] Obtained as a yellowish solid (99%) from
2-(pyrazolo[1,5-a]pyrazin-3-yl)pyrimidin-4-ol (Preparation 4b) and
phosphorous oxychloride following the experimental procedure as
described in Preparation 31.
[0761] LRMS (m/z): 231 (M+1).sup.+
[0762] .sup.1H NMR .delta. (300 MHz, CDCl.sub.3): 7.0 (t, 1H), 7.1
(d, 1H), 7.4 (d, 1H), 8.6 (dd, 3H), 8.8 (s, 1H).
Preparation 34
[0763]
(R)--N-(Piperidin-3-yl)-2-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-4--
amine
##STR00047##
a) (R)-Tert-Butyl
3-(2-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-4-ylamino)piperidine-1-carbox-
ylate
[0764] A solution of
3-(4-chloropyrimidin-2-yl)pyrazolo[1,5-a]pyridine (Preparation 33,
130 mg, 0.56 mmol) and (R)-tert-butyl
3-aminopiperidine-1-carboxylate (326 mg, 1.63 mmol) in ethanol (5
mL) was heated overnight at 100.degree. C. After cooling to ambient
temperature, the solvent was evaporated under reduced pressure and
the residue was taken up in a mixture of chloroform and water. The
aqueous layer was separated and washed with chloroform (.times.2).
The combined organic extracts were dried (MgSO.sub.4) and
evaporated in vacuo. The crude product was purified by flash
chromatography (dichloromethane to 95:5 dichloromethane/methanol)
to give the title compound (150 mg, 68%).
[0765] LRMS (m/z): 395 (M+1).sup.+
[0766] .sup.1H NMR .delta. (300 MHz, CDCl.sub.3): 1.5 (s, 9H), 2.1
(m, 2H), 3.0-4.2 (m, 7H), 5.0-5.1 (m, 1H), 6.2 (d, 1H), 6.9 (t,
1H), 7.3 (d, 1H), 8.2 (d, 1H), 8.5 (d, 1H), 8.6 (d, 1H), 8.7 (s,
1H).
b)
(R)--N-(Piperidin-3-yl)-2-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-4-amin-
e
[0767] Obtained as a pale yellow solid (89%) from (R)-tert-butyl
3-(2-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-4-ylamino)piperidine-1-carbox-
ylate (Preparation 34a) and trifluoroacetic acid following the
experimental procedure as described in Preparation 7b.
[0768] LRMS (m/z): 295 (M+1).sup.+, 293 (M-1).sup.-.
[0769] .sup.1H NMR .delta. (300 MHz, CDCl.sub.3): 1.5-1.9 (m, 4H),
2.0 (td, 2H), 2.3 (bs, 1H), 2.6-3.0 (m, 2H), 3.2 (dd, 1H), 5.4 (bs,
1H), 6.2 (d, 1H), 6.9 (t, 1H), 7.3 (d, 1H), 8.2 (d, 1H), 8.5 (d,
1H), 8.6 (d, 1H), 8.7 (s, 1H).
Preparation 35
5-Chloro-2-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-4-ol
##STR00048##
[0770] a)
3-(5-Chloro-4-methoxypyrimidin-2-yl)pyrazolo[1,5-a]pyridine
[0771] Obtained as a yellowish solid (69%) from
5-chloro-2-ethynyl-4-methoxypyrimidine (Preparation 13b) and
1-aminopyridinium iodide following the experimental procedure as
described in Preparation 3a. After usual work up, the crude
material was triturated with ethyl ether and the insoluble solid
was isolated by filtration to yield the title compound which was
used in the next synthetic step without further purification.
[0772] LRMS (m/z): 262 (M+1)+
b) 5-Chloro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-ol
[0773] Obtained as a dark solid (61%) from
3-(5-chloro-4-methoxypyrimidin-2-yl)pyrazolo[1,5-a]pyridine
(Preparation 35a) following the experimental procedure as described
in Preparation 4b.
[0774] LRMS (m/z): 247 (M+1).sup.+.
Preparation 36
3-(4,5-Dichloropyrimidin-2-yl)pyrazolo[1,5-a]pyridine
##STR00049##
[0776] Obtained as a yellowish solid (84%) from
5-chloro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-ol (Preparation
35b) and phosphorous oxychloride following the experimental
procedure as described in Preparation 31.
[0777] LRMS (m/z): 266 (M+1).sup.+
[0778] .sup.1H NMR .delta. (300 MHz, CDCl.sub.3): 6.9-7.0 (m, 1H),
7.4-7.5 (m, 1H), 8.6 (ddt, 2H), 8.6 (d, 1H), 8.7 (s, 1H).
Preparation 37
(R)-5-Chloro-N-(piperidin-3-yl)-2-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-4-
-amine
##STR00050##
[0779] a) (R)-Tert-butyl
3-(5-chloro-2-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-4-ylamino)
piperidine-1-carboxylate
[0780] Obtained as an oil (100%) from
3-(4,5-dichloropyrimidin-2-yl)pyrazolo[1,5-a]pyridine (Preparation
36) and (R)-tert-butyl 3-aminopiperidine-1-carboxylate following
the experimental procedure as described in Preparation 34a.
[0781] LRMS (m/z): 429 (M+1).sup.+
[0782] .sup.1H NMR .delta. (300 MHz, CDCl.sub.3): 1.8 (s, 9H), 2.1
(s, 2H), 3.0 (s, 4H), 4.0 (s, 2H), 4.3 (s, 1H), 5.4 (bs, 1H), 6.9
(t, 1H), 7.3-7.4 (m, 1H), 8.2 (s, 1H), 8.5 (t, 2H), 8.7 (s, H).
b)
(R)-5-Chloro-N-(piperidin-3-yl)-2-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidi-
n-4-amine
[0783] Obtained as an oil (100%) from (R)-tert-butyl
3-(5-chloro-2-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-4-ylamino)piperidine-
-1-carboxylate (Preparation 37a) and trifluoroacetic acid following
the experimental procedure as described in Preparation 7b.
[0784] LRMS (m/z): 329 (M+1).sup.+
Preparation 38
Tert-Butyl
(2-oxo-2-{(3R)-3-[(6-pyrazolo[1,5-a]pyridin-3-ylpyrazin-2-yl)am-
ino]piperidin-1-yl}ethyl)carbamate
##STR00051##
[0786] [(Tert-Butoxycarbonyl)amino]acetic acid (65 mg, 0.37 mmol),
O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate (142 mg, 0.37 mmol) and diisopropylethylamine
(65 mL, 0.37 mmol) were added to a solution of
(R)--N-(piperidin-3-yl)-6-(pyrazolo[1,5-a]pyridin-3-yl)pyrazin-2-amine
(Preparation 28b, 100 mg, 0.34 mmol) in N,N'-dimethylformamide (2
mL) and the resulting mixture was stirred at ambient temperature
overnight. The reaction mixture was then partitioned between ethyl
acetate and water and the organic layer was separated, washed with
brine, dried (MgSO.sub.4) and evaporated. The residue was purified
by reverse phase chromatography (C-18 silica from Waters, water/1:1
acetonitrile-methanol as eluents [0.1% v/v formic acid buffered] 0%
to 100%) to yield the title compound (88 mg, 57%).
[0787] LRMS (m/z): 452 (M+1)+.
[0788] .sup.1H NMR .delta. (400 MHz, CDCl.sub.3): 1.5 (s, 9H),
1.6-2.2 (m, 5H), 3.2-4.2 (m, 7H), 4.8 (m, 1H), 5.6 (s, 1H), 6.9 (t,
1H), 7.3 (m, 1H), 7.7 (s, 1H), 8.2 (m, 1H), 8.4 (m, 1H), 8.4 (m,
1H).
Preparation 39
5-Fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-ol
##STR00052##
[0789] a)
3-(5-Fluoro-4-methoxypyrimidin-2-yl)pyrazolo[1,5-a]pyridine
[0790] Obtained as a solid (23%) from
3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine
(Preparation 27a) and 2-chloro-5-fluoro-4-methoxypyrimidine
(Preparation 16a) following the experimental procedure as described
in Preparation 27b.
[0791] LRMS (m/z): 245 (M+1)+.
[0792] .sup.1H NMR .delta. (400 MHz, CDCl.sub.3): 4.2 (s, 3H),
6.9-7.0 (m, 1H), 7.3-7.4 (m, 1H), 8.3 (d, 1H), 8.5-8.6 (m, 2H), 8.7
(bs, 1H).
b) 5-Fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-ol
[0793] Obtained as a solid (74%) from
3-(5-fluoro-4-methoxypyrimidin-2-yl)pyrazolo[1,5-a]pyridine
(Preparation 39a) and 48% aqueous hydrogen bromide following the
experimental procedure as described in Preparation 4b.
[0794] LRMS (m/z): 231 (M+1)+
Preparation 40
5-Fluoro-N-[(3R)-piperidin-3-yl]-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4--
amine
##STR00053##
[0795] a) Tert-Butyl
(3R)-3-[(5-fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl)amino]piper-
idine-1-carboxylate
[0796] Obtained as an oil (88%) from
5-fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-ol (Preparation
39b) and tert-butyl (3R)-3-aminopiperidine-1-carboxylate following
the experimental procedure as described in Preparation 7a.
[0797] LRMS (m/z): 413 (M+1)+
b)
5-Fluoro-N-[(3R)-piperidin-3-yl]-2-pyrazolo-[1,5-a]pyridin-3-ylpyrimidi-
n-4-amine
[0798] Obtained as an oil (98%) from tert-butyl
(3R)-3-[(5-fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl)amino]piper-
idine-1-carboxylate (Preparation 40a) and trifluoroacetic acid
following the experimental procedure as described in Preparation
7b.
[0799] LRMS (m/z): 313 (M+1)+.
Preparation 41
N-[(3s,4r)-4-fluoropiperidin-3-yl]-6-pyrazolo[1,5-a]pyridin-3-ylpyrazin-2--
amine
##STR00054##
[0800] a) Benzyl
(3s,4r)-4-fluoro-3-[(6-pyrazolo[1,5-a]pyridin-3-ylpyrazin-2-yl)amino]pipe-
ridine-1-carboxylate
[0801] Obtained as a solid (39%) from
3-(6-chloropyrazin-2-yl)pyrazolo[1,5-a]pyridine (Preparation 27b)
and benzyl (3s,4r)-3-amino-4-fluoropiperidine-1-carboxylate
(prepared as described in WO2010/016005) following the experimental
procedure as described in Preparation 28a.
[0802] LRMS (m/z): 447 (M+1)+.
b)
N-[(3s,4r)-4-fluoropiperidin-3-yl]-6-pyrazolo[1,5-a]pyridin-3-ylpyrazin-
-2-amine
[0803] Benzyl
(3s,4r)-4-fluoro-3-[(6-pyrazolo[1,5-a]pyridin-3-ylpyrazin-2-yl)amino]pipe-
ridine-1-carboxylate (Preparation 41a, 229 mg, 0.51 mmol) was added
to a 3N hydrochloric acid solution in methanol (45 mL) and the
resulting mixture was heated overnight at 100.degree. C. in a
sealed tube. A 37% aqueous hydrochloric acid solution (10 mL) was
then added and the reaction mixture was stirred at 100.degree. C.
for four additional hours. After cooling to ambient temperature,
water was added and the organic solvent was evaporated under
reduced pressure. The resulting aqueous phase was washed with
methylene chloride, basified by addition of an aqueous 2N sodium
hydroxide solution until a basic pH was reached and washed again
with methylene chloride (.times.3). The combined organic phases
were washed with brine, dried (MgSO.sub.4) and the solvent was
evaporated in vacuo to yield the title compound (153 mg, 95%) as an
oil.
[0804] LRMS (m/z): 313 (M+1)+.
[0805] .sup.1H NMR .delta. (400 MHz, CDCl.sub.3): 2.0-2.3 (m, 2H),
2.9-3.8 (m, 5H), 4.3-5.2 (m, 1H), 4.9-5.2 (m, 2H), 6.9 (m, 1H), 7.4
(m, 1H), 7.8 (s, 1H), 8.3 (s, 1H), 8.4 (s, 1H), 8.5 (m, 1H).
EXAMPLE 1
3-(4-{[(1S)-1-Phenylethyl]amino}pyrimidin-2-yl)pyrazolo[1,5-a]pyridine-5-c-
arbonitrile
##STR00055##
[0807] Obtained as monoformate salt (15%) from
3-(4-hydroxypyrimidin-2-yl)pyrazolo[1,5-a]pyridine-5-carbonitrile
(Preparation 3b) and (S)-1-phenylethanamine following the
experimental procedure as described in Preparation 7a followed by
purification by flash chromatography (99:1
dichloromethane/methanol) to give a residue that was repurified by
reverse phase chromatography (C-18 silica from Waters,
water/acetonitrile/methanol as eluents [0.1% v/v formic acid
buffered] 0% to 100%).
[0808] LRMS (m/z): 341 (M).sup.+.
[0809] .sup.1H-NMR .delta. (300 MHz, CD.sub.3OD): 1.6 (d, 3H), 5.3
(bs, 1H), 5.5 (bs, 1H), 7.1 (d, 1H), 7.2 (t, 1H), 7.4 (t, 2H), 7.5
(d, 2H), 8.1 (d, 1H), 8.5 (bs, 1H), 8.6 (s, 1H), 8.7 (d, 1H).
EXAMPLE 2
3-{4-[(Cyclohexylmethyl)amino]pyrimidin-2-yl}pyrazolo[1,5-a]pyridine-5-car-
bonitrile
##STR00056##
[0811] Obtained as monoformate salt (22%) from
3-(4-hydroxypyrimidin-2-yl)pyrazolo[1,5-a]pyridine-5-carbonitrile
(Preparation 3b) and cyclohexylmethanamine following the
experimental procedure as described in Preparation 7a followed by
purification by reverse phase chromatography (C-18 silica from
Waters, water/acetonitrile/methanol as eluents [0.1% v/v formic
acid buffered] 5% to 50%).
[0812] LRMS (m/z): 333 (M).sup.+.
[0813] .sup.1H-NMR .delta. (300 MHz, CD.sub.3OD): 1.1-1.3 (m, 4H),
1.7-1.8 (m, 5H), 1.9-1.9 (m, 2H), 3.3-3.4 (m, 2H), 6.3 (d, 1H), 7.2
(d, 1H), 8.0 (bs, 1H), 8.5 (s, 2H), 8.7 (s, 1H), 8.8 (d, 1H), 9.1
(bs, 1H).
EXAMPLE 3
3-[4-(Benzylamino)pyrimidin-2-yl]pyrazolo[1,5-a]pyridine-5-carbonitrile
##STR00057##
[0815] Obtained as monoformate salt (8%) from
3-(4-hydroxypyrimidin-2-yl)pyrazolo[1,5-a]pyridine-5-carbonitrile
(Preparation 3b) and phenylmethanamine following the experimental
procedure as described in Preparation 7a followed by purification
by reverse phase chromatography (C-18 silica from Waters,
water/acetonitrile/methanol as eluents [0.1% v/v formic acid
buffered] 5% to 50%).
[0816] LRMS (m/z): 327 (M+1).sup.+, 325 (M-1).sup.-.
[0817] .sup.1H-NMR .delta. (300 MHz, CDCl.sub.3): 4.7 (bs, 2H), 6.3
(d, 1H), 6.9 (d, 1H), 7.3-7.4 (m, 1H), 7.4 (d, 4H), 8.3 (d, 1H),
8.6 (d, 1H), 8.8 (s, 1H), 9.0 (bs, 1H).
EXAMPLE 4
3-{4-[(2,2-Dimethylpropyl)amino]pyrimidin-2-yl}pyrazolo[1,5-a]pyridine-5-c-
arbonitrile
##STR00058##
[0819] Obtained as a yellow solid (11%) from
3-(4-hydroxypyrimidin-2-yl)pyrazolo[1,5-a]pyridine-5-carbonitrile
(Preparation 3b) and (2,2-dimethylpropyl)amine following the
experimental procedure as described in Preparation 7a followed by
purification by flash chromatography (10:1 hexane/ethyl acetate to
100% ethyl acetate).
[0820] LRMS (m/z): 307 (M+1).sup.+, 305 (M-1).sup.-.
[0821] .sup.1H-NMR .delta. (300 MHz, CDCl.sub.3): 1.1 (s, 9H), 3.3
(s, 2H) 5.2 (bs, 1H), 6.3 (d, 1H), 7.0 (d, 1H), 8.3 (d, 1H), 8.6
(d, 1H), 8.8 (s, 1H), 9.2 (bs, 1H).
EXAMPLE 5
3-(4-{[(1S)-2-Methoxy-1-methylethyl]amino}pyrimidin-2-yl)pyrazolo[1,5-a]py-
ridine-5-carbonitrile
##STR00059##
[0823] Obtained as a yellow solid (10%) from
3-(4-hydroxypyrimidin-2-yl)pyrazolo[1,5-a]pyridine-5-carbonitrile
(Preparation 3b) and [(1S)-2-methoxy-1-methylethyl]amine following
the experimental procedure as described in Preparation 7a followed
by purification by flash chromatography (10:1 hexane/ethyl acetate
to 100% ethyl acetate).
[0824] LRMS (m/z): 309 (M+1).sup.+, 307 (M-1).sup.-.
[0825] .sup.1H-NMR .delta. (300 MHz, CDCl.sub.3): 1.4 (d, 3H), 3.4
(s, 3H), 3.5 (d, 2H), 4.2 (m, 1H), 5.1 (bs, 1H), 6.2 (d, 1H), 7.0
(dd, 1H), 8.2 (d, 1H), 8.6 (d, 1H), 8.8 (s, 1H), 9.1 (s, 1H).
EXAMPLE 6
3-{4-[(Cyclopropylmethyl)amino]pyrimidin-2-yl}pyrazolo[1,5-a]pyridine-5-ca-
rbonitrile
##STR00060##
[0827] Obtained as a pale yellow solid (15%) from
3-(4-hydroxypyrimidin-2-yl)pyrazolo[1,5-a]pyridine-5-carbonitrile
(Preparation 3b) and (cyclopropylmethyl)amine following the
experimental procedure as described in Preparation 7a followed by
purification by flash chromatography (10:1 hexane/ethyl acetate to
100% ethyl acetate).
[0828] LRMS (m/z): 291 (M+1).sup.+, 289 (M-1).sup.-.
[0829] .sup.1H-NMR .delta. (300 MHz, CDCl.sub.3): 0.4 (m, 2H), 0.7
(m, 2H), 1.2 (m, 1H), 3.3 (bs, 2H), 5.1 (bs, 1H), 6.2 (d, 1H), 7.0
(dd, 1H), 8.3 (d, 1H), 8.6 (d, 1H), 8.8 (s, 1H), 9.1 (s, 1H).
EXAMPLE 7
3-{4-[(2,2,2-Trifluoroethyl)amino]pyrimidin-2-yl}pyrazolo[1,5-a]pyridine-5-
-carbonitrile
##STR00061##
[0831] Obtained as a pale yellow solid (10%) from
3-(4-hydroxypyrimidin-2-yl)pyrazolo[1,5-a]pyridine-5-carbonitrile
(Preparation 3b) and (2,2,2-trifluoroethyl)amine following the
experimental procedure as described in Preparation 7a followed by
purification by flash chromatography (10:1 to 1:1 hexane/ethyl
acetate).
[0832] LRMS (m/z): 319 (M+1).sup.+, 317 (M-1).sup.-.
[0833] .sup.1H-NMR .delta. (300 MHz, CDCl.sub.3): 4.2 (m, 2H), 5.1
(bs, 1H), 6.3 (d, 1H), 7.0 (dd, 1H), 8.3 (d, 1H), 8.6 (d, 1H), 8.8
(s, 1H), 9.0 (s, 1H).
EXAMPLE 8
N-(1-Phenylethyl)-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-amine
##STR00062##
[0835] Obtained as a solid (5%) from
2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-ol (Preparation 4b) and
1-phenylethanamine following the experimental procedure as
described in Preparation 7a.
[0836] LRMS (m/z): 316 (M+1).sup.+.
[0837] .sup.1H-NMR .delta. (300 MHz, CD.sub.3OD): 1.6 (d, 3H), 4.6
(bs, 1H), 6.4 (bs, 1H), 7.0 (t, 1H), 7.2-7.3 (m, 2H), 7.3 (t, 2H),
7.4 (d, 2H), 8.0 (d, 2H), 8.5 (s, 1H), 8.5 (d, 1H).
EXAMPLE 9
3-{6-[(Cyclohexylmethyl)amino]pyridin-2-yl}pyrazolo[1,5-a]pyridine-5-carbo-
nitrile
##STR00063##
[0839] A mixture of
3-(6-chloropyridin-2-yl)pyrazolo[1,5-a]pyridine-5-carbonitrile
(Preparation 6, 30 mg, 0.12 mmol), cyclohexylmethanamine (46 .mu.L,
0.35 mmol) and triethylamine (50 .mu.L, 0.36 mmol) in
dimethylsulfoxide (0.5 mL) was heated at 140.degree. C. for 20
hours. The mixture was then cooled, water was added and the
resultant precipitate was filtered and dried in vacuo. Purification
of the solid by flash chromatography (dichloromethane to 150:1
dichloromethane/methanol) gave the title compound (13 mg, 33%) as a
yellow foam.
[0840] LRMS (m/z): 332 (M+1).sup.+.
[0841] .sup.1H-NMR .delta. (300 MHz, CDCl.sub.3): 1.1 (m, 1H),
1.2-1.4 (m, 3H), 1.5-1.8 (m, 5H), 1.9 (m, 2H), 3.2 (m, 2H), 4.7
(bs, 1H), 6.3 (d, 1H), 6.9-7.0 (m, 2H), 7.5 (t, 1H), 8.4 (s, 1H),
8.5 (d, 1H), 9.1 (s, 1H).
EXAMPLE 10
3-{6-[(2,2-Dimethylpropyl)amino]pyridin-2-yl}pyrazolo[1,5-a]pyridine-5-car-
bonitrile
##STR00064##
[0843] An oven dried resealable Schlenk tube was charged with
3-(6-chloropyridin-2-yl)pyrazolo[1,5-a]pyridine-5-carbonitrile
(Preparation 6, 30 mg, 0.12 mmol), (2,2-dimethylpropyl)amine (14
.mu.L, 0.12 mmol), cesium carbonate (77 mg, 0.24 mmol),
1,1-binaphthalene-2,2'-diylbis(diphenylphosphine) (3 mg) and
toluene (1.5 mL). The Schlenk tube was subjected to three cycles of
evacuation-backfilling with argon and palladium (II) acetate (5 mg)
was added. After three further cycles of evacuation-backfilling
with argon, the Schlenk tube was capped and placed in an oil bath
at 120.degree. C. and stirred for 16 h. The mixture was then cooled
and ethyl acetate was added. The organic layer was washed with
water, dried (MgSO.sub.4) and the solvents were evaporated.
Purification of the residue by flash chromatography
(dichloromethane to 150:1 dichloromethane/methanol) gave the title
compound (13 mg, 34%) as a yellow solid.
[0844] LRMS (m/z): 306 (M+1).sup.+.
[0845] .sup.1H-NMR .delta. (300 MHz, CDCl.sub.3): 1.0 (s, 9H), 3.2
(d, 2H), 4.7 (bs, 1H), 6.3 (d, 1H), 6.9-7.0 (m, 2H), 7.5 (t, 1H),
8.4 (bs, 1H), 8.5 (d, 1H), 9.1 (bs, 1H).
EXAMPLE 11
3-{6-[(3-Fluorobenzyl)amino]pyridin-2-yl}pyrazolo[1,5-a]pyridine-5-carboni-
trile
##STR00065##
[0847] Obtained as a yellow solid (57%) from
3-(6-chloropyridin-2-yl)pyrazolo[1,5-a]pyridine-5-carbonitrile
(Preparation 6) and (3-fluorobenzyl)amine following the
experimental procedure as described in Example 10 followed by
purification by flash chromatography (dichloromethane to 250:1
dichloromethane/methanol).
[0848] LRMS (m/z): 344 (M+1).sup.+.
[0849] .sup.1H-NMR .delta. (300 MHz, CDCl.sub.3): 4.7 (bs, 2H), 5.1
(bs, 1H), 6.3 (d, 1H), 6.9 (d, 1H), 7.0 (t, 2H), 7.0-7.3 (m, 2H),
7.3-7.4 (m, 1H), 7.4-7.5 (m, 1H), 8.4 (s, 1H), 8.5 (d, 1H), 8.8
(bs, 1H).
EXAMPLE 12
3-[6-(Benzylamino)pyridin-2-yl]pyrazolo[1,5-a]pyridine-5-carbonitrile
##STR00066##
[0851] Obtained as a yellow solid (33%) from
3-(6-chloropyridin-2-yl)pyrazolo[1,5-a]pyridine-5-carbonitrile
(Preparation 6) and benzylamine following the experimental
procedure as described in Example 10 followed by purification by
flash chromatography (100% dichloromethane to 300:1
dichloromethane/methanol).
[0852] LRMS (m/z): 326 (M+1).sup.+.
[0853] .sup.1H-NMR .delta. (300 MHz, CDCl.sub.3): 4.6 (d, 2H), 5.0
(bs, 1H), 6.3 (d, 1H), 6.9 (dd, 1H), 7.0 (d, 1H), 7.2-7.3 (m, 1H),
7.3-7.5 (m, 5H), 8.4 (s, 1H), 8.5 (d, 1H), 8.9 (bs, 1H).
EXAMPLE 13
3-(6-{[(1S)-1-Phenylethyl]amino}pyridin-2-yl)pyrazolo[1,5-a]pyridine-5-car-
bonitrile
##STR00067##
[0855] Obtained as a yellow solid (39%) from
3-(6-chloropyridin-2-yl)pyrazolo[1,5-a]pyridine-5-carbonitrile
(Preparation 6) and (S)-1-phenylethanamine following the
experimental procedure as described in Example 10 followed by
purification by flash chromatography (dichloromethane to 350:1
dichloromethane/methanol).
[0856] LRMS (m/z): 340 (M+1).sup.+.
[0857] .sup.1H-NMR .delta. (300 MHz, CDCl.sub.3): 1.7 (d, 3H),
4.9-5.0 (m, 1H), 5.0 (bs, 1H), 6.2 (d, 1H), 6.9 (dd, 1H), 7.0 (d,
1H), 7.2-7.3 (m, 2H), 7.3-7.5 (m, 4H), 8.4 (s, 1H), 8.5 (d, 1H),
8.9 (s, 1H).
EXAMPLE 14
3-(4-{[(3R)-1-(Cyanoacetyl)piperidin-3-yl]amino}pyrimidin-2-yl)pyrazolo[1,-
5-a]pyridine-5-carbonitrile
##STR00068##
[0859] 3-[(2,5-Dioxopyrrolidin-1-yl)oxy]-3-oxopropanenitrile
(prepared as described in BE875054(A1), 40 mg, 0.20 mmol) was added
to a stirred solution of
3-{4-[(3R)-piperidin-3-ylamino]pyrimidin-2-yl}pyrazolo[1,5-a]pyridine-5-c-
arbonitrile (Preparation 7b, 60 mg, 0.16 mmol) in ethanol (1.2 mL)
and the mixture was stirred at ambient temperature for 20 hours.
The solvent was then removed under reduced pressure and the residue
was taken-up in a mixture of dichloromethane and 4% aqueous sodium
hydrogen carbonate solution. The organic layer was separated, dried
(MgSO.sub.4) and the solvent evaporated in vacuo. The crude product
was purified by flash chromatography (chloroform to 40:1
chloroform/methanol) to give the title compound (20 mg, 27%) as a
solid.
[0860] LRMS (m/z): 388 (M+1).sup.+, 386 (M-1).sup.-.
[0861] .sup.1H-NMR .delta. (300 MHz, CDCl.sub.3, 2:1 mixture of
rotamers): 1.7-1.9 (m, 4H), 2.0-2.1 (m, 1H), 2.2-2.3 (m, 1H),
2.9-3.0 (m, 1H), 3.3-3.4 (m, 1H), 3.5 (d, 1H), 3.5-3.6 (m, 1H), 4.1
(bs, 1H), 4.6 (d, 1H), 6.3 (d, 1H), 6.4 (d, 1H, minor rotamer), 7.0
(d, 1H), 7.1 (d, 1H, minor rotamer), 8.2 (d, 1H), 8.3 (d, 1H, minor
rotamer), 8.5 (d, 1H), 8.6 (d, 1H, minor rotamer), 8.7 (s, 1H,
minor rotamer), 8.8 (s, 1H), 9.0 (s, 1H).
EXAMPLE 15
3-(4-{[(3R)-1-Acetylpiperidin-3-yl]amino}pyrimidin-2-yl)pyrazolo[1,5-a]pyr-
idine-5-carbonitrile
##STR00069##
[0863] Triethylamine (44 .mu.L, 0.32 mmol), acetic anhydride (8.2
.mu.L, 0.09 mmol) and N,N-dimethylpyridin-4-amine (1.2 mg, 0.01
mmol) were added to a stirred solution of
3-{4-[(3R)-piperidin-3-ylamino]pyrimidin-2-yl}pyrazolo[1,5-a]pyridine-5-c-
arbonitrile (Preparation 7b, 40 mg, 0.06 mmol) in dichloromethane
(1.5 mL) and the mixture was stirred at ambient temperature for 20
hours before being partitioned between dichloromethane and 4%
aqueous sodium hydrogen carbonate solution. The organic layer was
separated, washed with water and brine, dried (MgSO.sub.4) and the
solvent was evaporated in vacuo. The crude product was purified by
flash chromatography (100:1 to 20:1 chloroform/methanol) to give
the title compound (10 mg, 44%) as a solid.
[0864] LRMS (m/z): 363 (M+1).sup.+, 361 (M-1).sup.-.
[0865] .sup.1H-NMR .delta. (300 MHz, CDCl.sub.3): 0.7-0.9 (m, 2H),
1.9 (d, 2H), 2.1 (d, 1H), 2.2 (s, 3H), 3.2-3.5 (m, 1H), 3.6 (bs,
1H), 3.8 (bs, 1H), 4.3-4.5 (m, 1H), 5.0 (bs, 1H), 6.2-6.3 (m, 1H),
7.0 (t, 1H), 8.3 (dd, 1H), 8.6 (t, 1H), 8.8 (d, 1H), 9.1 (d,
1H).
EXAMPLE 16
3-(4-{[(3R)-1-(5-Cyanopyridin-2-yl)piperidin-3-yl]amino}pyrimidin-2-yl)pyr-
azolo[1,5-a]pyridine-5-carbonitrile
##STR00070##
[0867] 6-Chloronicotinonitrile (0.04 g, 0.29 mmol) and
triethylamine (0.15 mL, 1.08 mmol) were added to a stirred solution
of
3-{4-[(3R)-piperidin-3-ylamino]pyrimidin-2-yl}pyrazolo[1,5-a]pyridine-5-c-
arbonitrile (Preparation 7b, 0.11 g, 0.24 mmol) in dichloromethane
(3.3 mL) and the resulting mixture was stirred at 50.degree. C. for
20 hours. The reaction mixture was then cooled to ambient
temperature and dichloromethane and 4% aqueous sodium
hydrogencarbonate solution were added. The organic layer was
separated, washed with water and brine, dried (MgSO.sub.4) and
evaporated in vacuo. The crude product was purified by flash
chromatography (200:1 to 60:1 chloroform/methanol) to give the
title compound (0.07 g, 71%) as a pale yellow solid.
[0868] LRMS (m/z): 422 (M+1).sup.+, 420 (M-1).sup.-.
[0869] .sup.1H-NMR .delta. (300 MHz, CDCl.sub.3): 1.3-1.4 (m, 1H),
1.8 (m, 2H), 1.9-2.0 (m, 1H), 2.2-2.3 (m, 1H), 3.2-3.5 (m, 2H),
4.0-4.1 (m, 1H), 4.5-4.6 (m, 1H), 5.0 (bs, 1H), 6.3 (bs, 1H), 6.7
(d, 1H), 7.0 (dd, 1H), 7.6 (dd, 1H), 8.3 (d, 1H), 8.4 (bs, 1H), 8.6
(d, 1H), 8.8 (s, 1H), 9.0 (s, 1H).
EXAMPLE 17
3-(4-{[(3R)-1-(3,3,3-Trifluoropropanoyl)piperidin-3-yl]amino}pyrimidin-2-y-
l)pyrazolo[1,5-a]pyridine-5-carbonitrile
##STR00071##
[0871] 3,3,3-Trifluoropropanoic acid (0.03 mL, 0.29 mmol),
N-[(dimethylamino)(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methylene]-N--
methylmethanaminium hexafluorophosphate (0.12 g, 0.30 mmol) and
diisopropylethylamine (0.21 mL, 1.21 mmol) were added to a stirred
solution of
3-{4-[(3R)-piperidin-3-ylamino]pyrimidin-2-yl}pyrazolo[1,5-a]pyridine-5-c-
arbonitrile (Preparation 7b, 0.11 g, 0.24 mmol) in
N,N'-dimethylformamide (3 mL) and the mixture was stirred at room
temperature for 20 hours. The reaction mixture was then partitioned
between dichloromethane and 4% aqueous sodium hydrogen carbonate
solution. The organic layer was separated, washed with 4% aqueous
sodium hydrogen carbonate solution, dried (MgSO.sub.4) and the
solvents were evaporated in vacuo. The crude product was purified
by flash chromatography (200:1 to 10:1 chloroform/methanol) to give
a residue that was repurified by flash chromatography (1:1
hexane/ethyl acetate to 100% ethyl acetate) to give the title
compound (0.02 g, 19%) as a pale yellow solid.
[0872] LRMS (m/z): 430 (M+1).sup.+, 428 (M-1).sup.-.
[0873] .sup.1H-NMR .delta. (300 MHz, CDCl.sub.3): 1.9-2.0 (m, 1H),
3.0-3.2 (m, 2H), 3.3-3.5 (m, 4H), 3.6-3.8 (m, 1H), 3.9 (d, 1H),
4.1-4.3 (m, 1H), 4.5 (d, 1H), 5.0 (bs, 1H), 6.3 (dd, 1H), 6.9-7.0
(m, 1H), 8.2-8.3 (m, 1H), 8.6 (t, 1H), 8.7 (d, 1H), 9.1 (bs,
1H).
EXAMPLE 18
3-{4-[[(3R)-1-(Cyanocarbonyl)piperidin-3-yl]methyl)amino]pyrimidin-2-yl}py-
razolo[1,5-a]pyridine-5-carbonitrile
##STR00072##
[0875] Obtained as a yellow solid (52%) from
(R)-3-(4-(methyl(piperidin-3-yl)amino)pyrimidin-2-yl)pyrazolo[1,5-a]pyrid-
ine-5-carbonitrile (Preparation 8b) and
3-[(2,5-dioxopyrrolidin-1-yl)oxy]-3-oxopropanenitrile (prepared as
described in BE875054(A1)) following the experimental procedure as
described in Example 14 followed by purification by flash
chromatography (dichloromethane to 9:1
dichloromethane/methanol).
[0876] LRMS (m/z): 401 (M+1).sup.+.
[0877] .sup.1H-NMR .delta. (300 MHz, CDCl.sub.3, 2:1 mixture of
rotamers): 1.7-1.9 (m, 4H), 2.1-2.2 (m, 1H), 2.3-2.5 (m, 1H),
2.9-3.0 (m, 1H), 3.1 (s, 3H, minor rotamer), 3.2 (s, 3H, major
rotamer), 3.3-3.4 (m, 1H), 3.5 (d, 1H), 3.6-3.7 (m, 1H), 4.2 (bs,
1H), 4.5 (d, 1H), 6.2 (d, 1H), 6.5 (d, 1H, minor rotamer), 7.1 (d,
1H), 7.2 (d, 1H, minor rotamer), 8.2 (d, 1H), 8.3 (d, 1H, minor
rotamer), 8.5 (d, 1H), 8.7 (d, 1H, minor rotamer), 8.7 (s, 1H,
minor rotamer), 8.8 (s, 1H), 9.0 (s, 1H).
EXAMPLE 19
3-(4-((Trans)-4-Hydroxycyclohexylamino)pyrimidin-2-yl)pyrazolo[1,5-a]pyrid-
ine-5-carbonitrile
##STR00073##
[0879] Trans-4-aminocyclohexanol (85 mg, 0.74 mmol) was added to a
solution of
3-(4-(1H-benzo[d][1,2,3]triazol-1-yloxy)pyrimidin-2-yl)pyrazolo[1,5-a]pyr-
idine-5-carbonitrile (byproduct of Preparation 7a, 105 mg, 0.30
mmol) in N,N'-dimethylformamide (3 mL) and the mixture was stirred
at ambient temperature overnight. The solvent was then evaporated
and the residue was partitioned between water and ethyl acetate.
The organic layer was separated, washed with water and brine, dried
(MgSO.sub.4) and the solvent evaporated. The crude product was
purified by flash chromatography (dichloromethane to 9:1
dichloromethane/methanol) to give the title compound (66 mg, 67%)
as a yellow solid.
[0880] LRMS (m/z): 335 (M+1).sup.+.
[0881] .sup.1H-NMR .delta. (400 MHz, DMSO-d.sub.6): 0.4-0.6 (m,
3H), 1.0-1.1 (m, 3H), 1.2-1.3 (m, 2H), 2.3 (d, 1H), 2.7 (bs, 1H),
3.0 (bs, 1H), 5.5 (bs, 1H), 6.5 (d, 1H), 6.6 (d, 1H), 7.2 (bs, 1H),
7.9 (s, 1H), 8.1 (bs, 1H), 8.2 (d, 1H).
EXAMPLE 20
N-(Cyclohexylmethyl)-2-pyrazolo[1,5-a]pyrazin-3-ylpyrimidin-4-amine
##STR00074##
[0883] Obtained as monoformate salt (16%) from
2-(pyrazolo[1,5-a]pyrazin-3-yl)pyrimidin-4-ol (Preparation 10b) and
cyclohexylmethanamine following the experimental procedure as
described in Preparation 7a followed by purification by reverse
phase chromatography (C-18 silica from Waters,
water/acetonitrile/methanol as eluents [0.1% v/v formic acid
buffered] 5% to 50%).
[0884] LRMS (m/z): 309 (M+1).sup.+.
[0885] .sup.1H-NMR .delta. (300 MHz, CD.sub.3OD): 0.8-1.0 (m, 1H),
1.0-1.2 (m, 2H), 1.2-1.4 (m, 4H), 1.7-1.8 (m, 4H), 1.9 (d, 2H), 6.4
(bs, 1H), 7.8-8.1 (m, 2H), 8.4-8.6 (m, 1H), 8.7 (bs, 2H), 10.0 (bs,
1H).
EXAMPLE 21
(S)--N-(1-phenylethyl)-2-(pyrazolo[1,5-a]pyrazin-3-yl)pyrimidin-4-amine
##STR00075##
[0887] Obtained as a solid (38%) from
2-(pyrazolo[1,5-a]pyrazin-3-yl)pyrimidin-4-ol (Preparation 10b) and
(S)-1-phenylethanamine following the experimental procedure as
described in Preparation 7a followed by purification by flash
chromatography (dichloromethane to 99:1
dichloromethane/methanol).
[0888] LRMS (m/z): 317 (M+1).sup.+.
[0889] .sup.1H-NMR .delta. (300 MHz, CD.sub.3OD): 1.1-1.2 (m, 1H),
1.6 (d, 3H), 5.3 (bs, 1H), 7.1-7.2 (m, 1H), 7.3-7.4 (m, 2H), 7.4
(d, 2H), 7.9 (bs, 1H), 8.1 (d, 1H), 8.6 (d, 2H), 9.6 (bs, 1H).
EXAMPLE 22
N-Benzyl-2-pyrazolo[1,5-a]pyrazin-3-ylpyrimidin-4-amine
##STR00076##
[0891] Obtained as monoformate salt (48%) from
2-(pyrazolo[1,5-a]pyrazin-3-yl)pyrimidin-4-ol (Preparation 10b) and
benzylamine following the experimental procedure as described in
Preparation 7a followed by purification by reverse phase
chromatography (C-18 silica from Waters,
water/acetonitrile/methanol as eluents [0.1% v/v formic acid
buffered] 5% to 50%).
[0892] LRMS (m/z): 303 (M+1).sup.+.
[0893] .sup.1H-NMR .delta. (300 MHz, CD.sub.3OD): 4.7 (s, 2H), 6.4
(bs, 1H), 7.2-7.3 (m, 1H), 7.3-7.5 (m, 4H), 8.0 (bs, 1H), 8.1 (bs,
1H), 8.5 (bs, 1H), 8.6 (bs, 2H), 9.7 (bs, 1H).
EXAMPLE 23
N-(2,2-Dimethylpropyl)-2-pyrazolo[1,5-a]pyrazin-3-ylpyrimidin-4-amine
##STR00077##
[0895] Obtained (43%) from
2-(pyrazolo[1,5-a]pyrazin-3-yl)pyrimidin-4-ol (Preparation 10b) and
2,2-dimethylpropan-1-amine following the experimental procedure as
described in Preparation 7a followed by purification by flash
chromatography (98:2 to 95:5 dichloromethane/methanol).
[0896] LRMS (m/z): 283 (M+1).sup.+.
[0897] .sup.1H-NMR .delta. (300 MHz, CDCl.sub.3): 1.0 (s, 9H), 3.2
(bs, 2H), 5.1 (bs, 1H), 6.3 (d, 1H), 8.0 (d, 1H), 8.3 (d, 1H), 8.4
(d, 1H), 8.7-8.8 (m, 1H), 10.0 (bs, 1H).
EXAMPLE 24
3-Oxo-{(3R)-3-[(2-pyrazolo[1,5-a]pyrazin-3-ylpyrimidin-4-yl)amino]piperidi-
n-1-yl}propanenitrile
##STR00078##
[0899] Obtained as a solid (55%) from
(R)--N-(piperidin-3-yl)-2-(pyrazolo[1,5-a]pyrazin-3-yl)pyrimidin-4-amine
(Preparation 11b) and 3-[(2,5-dioxopyrrolidin-1-yl)oxy]-3-oxo
propanenitrile (prepared as described in BE875054(A1)) following
the experimental procedure as described in Example 14 followed by
purification by flash chromatography (dichloromethane to 9:1
dichloromethane/methanol).
[0900] LRMS (m/z): 363 (M+1).sup.+.
[0901] .sup.1H-NMR .delta. (400 MHz, CDCl.sub.3, 1:1 mixture of
rotamers): 1.7-2.0 (m, 6H), 2.1-2.2 (m, 2H), 3.4 (s, 2H, rotamer
1), 3.6 (s, 2H, rotamer 2), 4.2-4.4 (m, 1H), 5.0 (bs, 1H), 6.3 (d,
1H, rotamer 1), 6.3 (d, 1H, rotamer 2), 8.0 (d, 1H, rotamer 1), 8.0
(d, 1H, rotamer 2), 8.3 (d, 1H, rotamer 1), 8.3 (d, 1H, rotamer 2),
8.4 (dd, 1H, rotamer 1), 8.5 (dd, 1H, rotamer 2), 8.7 (s, 1H,
rotamer 1), 8.7 (s, 1H, rotamer 2), 10.0 (s, 1H).
EXAMPLE 25
6-{(3R)-3-[(2-Pyrazolo[1,5-a]pyrazin-3-ylpyrimidin-4-yl)amino]piperidin-1--
yl}nicotinonitrile
##STR00079##
[0903] Obtained as a solid (23%) from
(R)--N-(piperidin-3-yl)-2-(pyrazolo[1,5-a]pyrazin-3-yl)pyrimidin-4-amine
(Preparation 11b) and 6-chloronicotinonitrile following the
experimental procedure as described in Example 16 followed by
purification by flash chromatography (dichloromethane to 85:15
dichloromethane/methanol).
[0904] LRMS (m/z): 398 (M+1).sup.+.
[0905] .sup.1H-NMR .delta. (200 MHz, CDCl.sub.3): 1.8 (m, 4H),
3.3-3.6 (m, 2H), 3.8-4.3 (m, 2H), 4.4 (m, 1H), 5.0 (bs, 1H), 6.3
(d, 1H), 6.7 (d, 1H), 7.6 (dd, 1H), 8.0 (d, 1H), 8.3 (d, 1H),
8.3-8.5 (m, 2H), 8.7 (s, 1H), 10.0 (s, 1H).
EXAMPLE 26
2-Pyrazolo[1,5-a]pyrazin-3-yl-N-[(3R)-1-(3,3,3-trifluoropropanoyl)piperidi-
n-3-yl]pyrimidin-4-amine
##STR00080##
[0907] Obtained as a solid (12%) from
(R)--N-(piperidin-3-yl)-2-(pyrazolo[1,5-a]pyrazin-3-yl)pyrimidin-4-amine
(Preparation 11b) and 3,3,3-trifluoropropanoic acid following the
experimental procedure as described in Example 17 followed by
purification by flash chromatography (dichloromethane to 9:1
dichloromethane/methanol).
[0908] LRMS (m/z): 406 (M+1).sup.+.
[0909] .sup.1H-NMR .delta. (400 MHz, CDCl.sub.3, 4:3 mixture of
rotamers): 1.7-1.8 (m, 1H), 1.8-2.0 (m, 2H), 2.0-2.2, (m, 2H), 2.6
(s, 2H, major rotamer), 2.7 (s, 2H, minor rotamer), 3.1-3.2 (m,
1H), 3.3-3.4 (m, 1H), 3.8-3.9 (m, 1H), 4.3 (bs, 1H), 4.9 (bs, 1H,
minor rotamer), 5.0 (bs, 1H, major rotamer), 6.3 (d, 1H, minor
rotamer), 6.3 (d, 1H, major rotamer), 8.0 (d, 1H), major rotamer),
8.0 (d, 1H, minor rotamer), 8.3 (d, 1H, major rotamer), 8.3 (d, 1H,
minor rotamer), 8.4 (d, 1H, major rotamer), 8.4 (d, 1H, minor
rotamer), 8.7 (s, 1H, minor rotamer), 8.7 (s, 1H, major rotamer),
10.0 (s, 1H).
EXAMPLE 27
3-{(3R)-3-[Methyl(2-pyrazolo[1,5-a]pyrazin-3-ylpyrimidin-4-yl)amino]piperi-
din-1-yl}-3-oxopropanenitrile
##STR00081##
[0911] Obtained (76%) from
N-methyl-N-[(3R)-piperidin-3-yl]-2-pyrazolo[1,5-a]pyrazin-3-yl)pyrimidin--
4-amine (Preparation 12b) and
3-[(2,5-dioxopyrrolidin-1-yl)oxy]-3-oxopropane nitrile (prepared as
described in BE875054(A1)) following the experimental procedure as
described in Example 14.
[0912] LRMS (m/z): 377 (M+1).sup.+.
[0913] .sup.1H-NMR .delta. (400 MHz, CDCl.sub.3, 2:1 mixture of
rotamers): 1.2-1.4 (m, 2H) 1.7-2.2 (m, 4H), 3.1 (s, 2H, major
rotamer), 3.1 (s, 2H, minor rotamer), 3.1-3.3 (m, 1H) 3.5 (s, 3H,
minor rotamer), 3.6 (s, 3H, major rotamer), 3.7-3.9 (m, 2H), 6.4
(d, 1H), 6.4 (d, 1H), 8.0 (d, 1H), 8.0 (d, 1H), 8.3 (d, 1H), 8.3
(d, 1H), 8.4 (dd, 1H), 8.4 (dd, 1H), 8.7 (s, 1H), 8.7 (s, 1H), 9.9
(s, 1H), 9.9 (s, 1H).
EXAMPLE 28
3-{(3R)-3-[(5-Chloro-2-pyrazolo[1,5-a]pyrazin-3-ylpyrimidin-4-yl)amino]pip-
eridin-1-yl}-3-oxopropanenitrile
##STR00082##
[0915] Obtained as a white solid (61%) from
5-chloro-N-(piperidin-3-yl)-2-(pyrazolo[1,5-a]pyrazin-3-yl)pyrimidin-4-am-
ine (Preparation 15b) and
3-[(2,5-dioxopyrrolidin-1-yl)oxy]-3-oxopropanenitrile (prepared as
described in BE875054(A1)) following the experimental procedure as
described in Example 14 followed by purification by flash
chromatography (dichloromethane to 9:1
dichloromethane/methanol).
[0916] LRMS (m/z): 397 (M+1).sup.+.
[0917] .sup.1H-NMR .delta. (300 MHz, CDCl.sub.3): 1.7-2.0 (m, 2H),
2.2 (bs, 2H), 3.3-3.5 (m, 2H), 3.6 (s, 2H), 3.8 (bs, 1H), 4.4 (bs,
2H), 5.4 (bs, 1H), 8.0 (bs, 1H), 8.3 (s, 1H), 8.4 (bs, 1H), 8.8 (s,
1H), 9.9 (s, 1H).
EXAMPLE 29
3-{(3R)-3-[(5-Fluoro-2-pyrazolo[1,5-a]pyrazin-3-ylpyrimidin-4-yl)amino]pip-
eridin-1-yl}-3-oxopropanenitrile
##STR00083##
[0919] Obtained as a white solid (62%) from
(R)-5-fluoro-N-(piperidin-3-yl)-2-(pyrazolo[1,5-a]pyrazin-3-yl)pyrimidin--
4-amine (Preparation 18b) and
3-[(2,5-dioxopyrrolidin-1-yl)oxy]-3-oxopropanenitrile (prepared as
described in BE875054(A1)) following the experimental procedure as
described in Example 14 followed by purification by flash
chromatography (dichloromethane to 8:2
dichloromethane/methanol).
[0920] LRMS (m/z): 381 (M+1).sup.+.
[0921] .sup.1H-NMR .delta. (400 MHz, CDCl.sub.3, 1:1 mixture of
rotamers): 1.7-2.0 (m, 4H), 2.1-2.25 (m, 1H), 3.3-3.4 (m, 1H),
3.4-3.6 (m, 1H), 3.6 (s, 2H), 3.8-3.9 (m, 1H), 4.3-4.4 (m, 1H), 5.1
(t, 1H), 8.0 (d, 1H, rotamer 2), 8.0 (d, 1H, rotamer 1), 8.1 (d,
1H, rotamer 2), 8.2 (d, 1H, rotamer 1), 8.4 (d, 1H, rotamer 2), 8.4
(d, 1H, rotamer 1), 8.6 (s, 1H, rotamer 2), 8.7 (s, 1H, rotamer 1),
9.9 (s, 1H).
EXAMPLE 30
5-Fluoro-2-pyrazolo[1,5-a]pyrazin-3-yl-N-[(3R)-1-(3,3,3-trifluoropropanoyl-
)piperidin-3-yl]pyrimidin-4-amine
##STR00084##
[0923] Obtained as a white solid (42%) from
(R)-5-fluoro-N-(piperidin-3-yl)-2-(pyrazolo[1,5-a]pyrazin-3-yl)pyrimidin--
4-amine (Preparation 18b) and 3,3,3-trifluoropropanoic acid
following the experimental procedure as described in Example 17
followed by purification by flash chromatography (dichloromethane
to 92:8 dichloromethane/methanol).
[0924] LRMS (m/z): 424 (M+1).sup.+.
[0925] .sup.1H-NMR .delta. (400 MHz, CDCl.sub.3, 1:1 mixture of
rotamers): 1.7-1.8 (m, 2H), 1.8-2.0 (m, 4H), 2.1-2.2 (m, 1H),
3.3-3.4 (m, 1H, rotamer 1), 3.4-3.5 (m, 1H, rotamer 2), 3.6 (d, 1H,
rotamer 1), 3.9 (d, 1H, rotamer 2), 4.2 (d, 1H, rotamer 1), 4.4
(bs, 1H, rotamer 2), 5.1 (d, 1H, rotamer 1), 5.2 (d, 1H, rotamer
2), 8.0 (d, 1H, rotamer 1), 8.0 (d, 1H, rotamer 2), 8.1 (d, 1H,
rotamer 1), 8.2 (d, 1H, rotamer 2), 8.4 (d, 1H, rotamer 1), 8.4 (d,
1H, rotamer 2), 8.6 (s, 1H, rotamer 1), 8.7 (s, 1H, rotamer 2), 9.9
(s, 1H, rotamer 1), 9.9 (bs, 1H, rotamer 2).
EXAMPLE 31
3-{(3R)-3-[(5-Methyl-2-pyrazolo[1,5-a]pyrazin-3-ylpyrimidin-4-yl)amino]pip-
eridin-1-yl}-3-oxopropanenitrile
##STR00085##
[0927] Obtained as a white solid (45%) from
5-methyl-N-[(3R)-piperidin-3-yl]-2-pyrazolo[1,5-a]pyrazin-3-ylpyrimidin-4-
-amine (Preparation 21b) and
3-[(2,5-dioxopyrrolidin-1-yl)oxy]-3-oxopropanenitrile (prepared as
described in BE875054(A1)) following the experimental procedure as
described in Example 14 followed by purification by
recrystallization from ethanol.
[0928] LRMS (m/z): 377 (M+1).sup.+.
[0929] .sup.1H-NMR .delta. (400 MHz, DMSO-d.sub.6, 1:1 mixture of
rotamers): 1.6-1.7 (m, 2H), 1.8 (bs, 2H), 2.1 (s, 3H), 2.1-2.2 (m,
1H, rotamer 2), 2.6-2.8 (m, 1H, rotamer 1), 3.0-3.2 (m, 1H), 3.4
(s, 2H), 3.7 (d, 1H, rotamer 2), 3.8 (d, 1H, rotamer 1), 3.9-4.2
(m, 1H, rotamer 2), 4.3 (bs, 1H, rotamer 1), 6.6 (d, 1H, rotamer
2), 6.7 (d, 1H, rotamer 1) 8.0 (bs, 1H, rotamer 2), 8.1 (bs, 1H,
rotamer 1), 8.8 (s, 1H, rotamer 2), 8.8 (s, 1H, rotamer 1), 8.9
(bs, 1H), 9.8 (s, 1H, rotamer 2), 9.8 (s, 1H, rotamer 1).
EXAMPLE 32
(S)--N-(1-(5-Fluoropyridin-2-yl)ethyl)-2-(pyrazolo[1,5-a]pyrazin-3-yl)pyri-
midin-4-amine
##STR00086##
[0931] A solution of
3-(4-chloropyrimidin-2-yl)pyrazolo[1,5-a]pyrazine (Preparation 31,
170 mg, 0.61 mmol), (S)-1-(5-fluoropyridin-2-yl)ethanamine (85 mg,
0.61 mmol, prepared as described in WO2006/82392A1) and
diisopropylethylamine (122 .mu.L, 0.70 mmol) in
N,N'-dimethylformamide (5 mL) was heated to 150.degree. C. in a
microwave oven for 75 min. The solvent was then removed under
reduced pressure and the residue was partitioned between 4% aqueous
sodium hydrogen carbonate solution and ethyl acetate. The organic
phase was separated, washed with brine, dried (MgSO.sub.4) and
concentrated to give a crude which was purified by reverse phase
chromatography (C-18 silica from Waters,
water/acetonitrile/methanol as eluents [0.1% v/v formic acid
buffered] 5% to 50%) to give the title compound (9 mg, 4%) as an
oil. The corresponding fumarate salt was prepared by adding a
solution of fumaric acid (3.1 mg, 0.027 mmol) in ethanol (0.5 mL)
to a solution of the title compound (as free base, 9 mg, 0.027
mmol) in ethanol (2 mL) followed by evaporation of the solvent. The
resulting solid was dried in an oven under vacuum to give 11 mg of
the desired fumarate salt.
[0932] LRMS (m/z): 336 (M+1).sup.+
[0933] .sup.1H NMR .delta. (400 MHz, CDCl.sub.3, fumarate salt):
1.6 (d, 3H), 5.9-6.1 (m, 1H), 6.2-6.4 (m, 1H), 7.4 (dd, 2H), 8.0
(d, 1H), 8.2 (d, 1H), 8.4 (dd, 2H), 8.7 (s, 1H), 10.0 (s, 1H).
EXAMPLE 33
N-((5-Fluoropyridin-2-yl)methyl)-2-(pyrazolo[1,5-a]pyrazin-3-yl)pyrimidin--
4-amine
##STR00087##
[0935] Obtained as a solid (5%) from
2-(pyrazolo[1,5-a]pyrazin-3-yl)pyrimidin-4-ol (Preparation 10b) and
(5-fluoropyridin-2-I)methanamine following the experimental
procedure as described in Preparation 7a followed by purification
by reverse phase chromatography (C-18 silica from Waters.COPYRGT.,
water/acetonitrile/methanol as eluents [0.1% v/v formic acid
buffered] 0% to 100%).
[0936] LRMS (m/z): 322 (M+1).sup.+, 320 (M-1).sup.-.
[0937] .sup.1H NMR .delta. (400 MHz, CDCl.sub.3): 4.7-5.0 (m, 2H),
6.3-6.4 (m, 1H), 7.4 (d, 2H), 8.0 (d, 1H), 8.3 (d, 1H), 8.4 (dd,
2H), 8.7 (s, 1H), 10.00 (d, 1H).
EXAMPLE 34
5-Chloro-N-((5-fluoropyridin-2-yl)methyl)-2-(pyrazolo[1,5-a]pyrazin-3-yl)p-
yrimidin-4-amine
##STR00088##
[0939] A mixture of
3-(4,5-dichloropyrimidin-2-yl)pyrazolo[1,5-a]pyrazine (Preparation
32, 75 mg, 0.26 mmol), (5-fluoropyridin-2-yl)methanamine (33 mg,
0.26 mmol) and diisopropylethylamine (52 .mu.L, 30 mmol) in
tetrahydrofuran (3 mL) was heated to reflux for 72 h. The solvent
was then evaporated under reduced pressure and the crude product
was purified by reverse phase chromatography (C-18 silica from
Waters.COPYRGT., water/acetonitrile/methanol as eluents [0.1% v/v
formic acid buffered] 0% to 100%) to give the title compound (37
mg, 39%).
[0940] LRMS (m/z): 356 (M+1).sup.+
[0941] .sup.1H NMR .delta. (300 MHz, CDCl.sub.3): 4.8-5.0 (m, 2H),
6.7 (bs, 1H), 7.4 (d, 2H), 8.0 (d, 1H), 8.3 (s, 1H), 8.4 (dd, 1H),
8.6 (s, 1H), 8.7 (s, 1H), 9.8 (s, 1H).
EXAMPLE 35
2-(Pyrazolo[1,5-a]pyrazin-3-yl)-N.sup.4-(tetrahydro-2H-pyran-4-yl)pyrimidi-
ne-4,5-diamine
##STR00089##
[0943] 10% Palladium on carbon (0.392 g, 0.37 mmol) was added to a
suspension of
5-nitro-2-(pyrazolo[1,5-a]pyrazin-3-yl)-N-(tetrahydro-2H-pyran-4-yl)pyrim-
idin-4-amine (Preparation 25, 0.785 g, 2.31 mmol) in ethanol (50
mL) and the mixture was stirred under an hydrogen atmosphere at
ambient temperature. After 4 hours, the mixture was filtered
through Celite.RTM. and the filter cake was washed with ethanol.
The combined filtrate and washings were evaporated to give the
title compound (0.670 g, 94%) as a pale green solid.
[0944] LRMS (m/z): 312 (M+1).sup.+.
[0945] .sup.1H NMR .delta. (300 MHz, DMSO-d.sub.6): 1.6 (ddd, 2H),
2.1 (d, 2H), 3.5 (t, 2H), 4.0 (d, 2H), 4.2-4.3 (m, 1H), 5.0 (s,
2H), 6.4 (d, 1H), 7.7 (s, 1H), 7.9 (d, 1H), 8.5 (s, 1H), 8.8 (dd,
1H), 9.8 (d, 1H).
EXAMPLE 36
N.sup.4-(4,4-Difluorocyclohexyl)-2-(pyrazolo[1,5-a]pyrazin-3-yl)pyrimidine-
-4,5-diamine
##STR00090##
[0947] Obtained as an off white solid (87%) from
N-(4,4-difluorocyclohexyl)-5-nitro-2-(pyrazolo[1,5-a]pyrazin-3-yl)pyrimid-
in-4-amine (Preparation 26) following the experimental procedure as
described in Example 35.
[0948] LRMS (m/z): 346 (M+1).sup.+.
[0949] .sup.1H NMR .delta. (300 MHz, DMSO-d.sub.6): 1.7 (m, 2H),
2.0-2.2 (m, 6H), 4.3 (m, 1H), 5.0 (s, 2H), 6.4 (d, 1H), 7.7 (s,
1H), 8.0 (d, 1H), 8.6 (s, 1H), 8.8 (d, 1H), 9.8 (s, 1H).
EXAMPLE 37
(S)-5-Chloro-N-(1-(5-fluoropyridin-2-yl)ethyl)-2-(pyrazolo[1,5-a]pyrazin-3-
-yl)pyrimidin-4-amine
##STR00091##
[0951] Obtained as a solid (57%) from
3-(4,5-dichloropyrimidin-2-yl)pyrazolo[1,5-a]pyrazine (Preparation
32) and (S)-1-(5-fluoropyridin-2-yl)ethanamine (prepared as
described in WO2006/82392) following the experimental procedure as
described in Example 34.
[0952] LRMS (m/z): 370 (M+1).sup.+
[0953] .sup.1H NMR .delta. (300 MHz, CDCl.sub.3): 1.7 (d, 3H),
5.4-5.6 (m, 1H), 6.6-6.8 (m, 1H), 7.3-7.5 (m, 2H), 7.9-8.1 (m, 1H),
8.3 (s, 1H), 8.3-8.5 (m, 1H), 8.5-8.6 (m, 1H), 8.7 (s, 1H), 9.9 (s,
1H).
EXAMPLE 38
(R)-3-Oxo-3-(3-(6-(pyrazolo[1,5-a]pyrazin-3-yl)pyrazin-2-ylamino)piperidin-
-1-yl)propanenitrile
##STR00092##
[0955] A solution of
(R)--N-(piperidin-3-yl)-6-(pyrazolo[1,5-a]pyrazin-3-yl)pyrazin-2-amine
(Preparation 30b, 0.23 g, 0.78 mmol),
3-[(2,5-dioxopyrrolidin-1-yl)oxy]-3-oxopropane nitrile (prepared as
described in BE875054(A1), 0.17 g, 0.94 mmol)) and triethylamine
(0.13 mL, 0.94 mmol) in methylene chloride (10 mL) was stirred
overnight at ambient temperature. After evaporation of the solvent,
the crude mixture was purified by flash chromatography (95:5 to
93:7 methylene chloride/methanol) to yield the title compound
(0.158 g, 38%) as a pale yellow solid.
[0956] LRMS (m/z): 363 (M+1).sup.+.
[0957] .sup.1H-NMR .delta. (400 MHz, DMSO-d.sub.6): 1.7 (m, 2H),
1.8 (m, 1H), 2.1 (m, 1H), 3.2 (m, 2H), 4.3-3.5 (m, 5H), 6.9 (s,
1H), 7.9 (s, 1H), 8.0 (d, 1H), 8.3 (s, 1H), 8.8 (m, 2H), 9.8 (s,
1H).
EXAMPLE 39
(R)-3-oxo-3-(3-(6-(pyrazolo[1,5-a]pyridin-3-yl)pyrazin-2-ylamino)piperidin-
-1-yl)propanenitrile
##STR00093##
[0959] Obtained as a pale green solid (50%) from
(R)--N-(piperidin-3-yl)-6-(pyrazolo[1,5-a]pyridin-3-yl)pyrazin-2-amine
(Preparation 28b) and
3-[(2,5-dioxopyrrolidin-1-yl)oxy]-3-oxopropanenitrile (prepared as
described in BE875054(A1) following the experimental procedure as
described in Example 38 followed by purification by flash
chromatography (95:5 methylene chloride/methanol).
[0960] LRMS (m/z): 362 (M+1).sup.+.
[0961] .sup.1H-NMR .delta. (400 MHz, DMSO-d.sub.6): 1.6 (m, 2H),
1.8 (m, 1H), 2.1 (m, 1H), 3.2 (m, 1H), 4.4-3.6 (m, 5H), 4.5 (s,
1H), 6.9 (m, 1H), 7.0 (t, 1H), 7.4 (t, 1H), 7.8 (m, 1H), 8.3 (s,
1H), 8.4 (m, 1H), 8.6 (s, 1H), 8.7 (d, 1H).
EXAMPLE 40
(R)-3-oxo-3-(3-(2-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-4-ylamino)piperid-
in-1-yl)propanenitrile
##STR00094##
[0963] Obtained as solid (41%) from
((R)--N-(piperidin-3-yl)-2-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-4-amine
(Preparation 34) and 3-[(2,5-dioxopyrrolidin-1-yl)oxy]-3-oxopropane
nitrile (prepared as described in BE875054(A1) following the
experimental procedure as described in Example 38 followed by
purification by recristalization from acetonitrile.
[0964] LRMS (m/z): 362 (M+1).sup.+.
[0965] .sup.1H NMR .delta. (300 MHz, CDCl.sub.3): 1.5-2.1 (m, 4H),
2.1 (d, 2H), 3.3-3.6 (m, 2H), 3.8 (d, 1H), 4.0-4.3 (m, 1H), 4.4-4.5
(m, 1H), 4.9-5.2 (m, 1H) 6.2 (t, 1H), 6.9 (d, 1H), 7.3 (t, 1H), 8.3
(d, 1H), 8.5 (d, 2H), 8.7 (d, 1H).
EXAMPLE 41
(R)-3-(3-(5-Chloro-2-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-4-ylamino)pipe-
ridin-1-yl)-3-oxopropanenitrile
##STR00095##
[0967] Obtained as a white solid (41%) from
(R)-5-chloro-N-(piperidin-3-yl)-2-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin--
4-amine (Preparation 37b) and
3-[(2,5-dioxopyrrolidin-1-yl)oxy]-3-oxopropanenitrile (prepared as
described in BE875054(A1)) following the experimental procedure as
described in Example 38 followed by purification by reverse phase
chromatography (C-18 silica from Waters.COPYRGT.,
water/acetonitrile/methanol as eluents [0.1% v/v formic acid
buffered] 0% to 100%).
[0968] LRMS (m/z): 396 (M+1).sup.+
[0969] .sup.1H NMR .delta. (300 MHz, DMSO-d.sub.6): 1.5-1.9 (m,
3H), 2.0 (s, 1H), 2.7 (dd, 1H), 2.9-3.2 (m, 1H), 3.7 (dd, 1H),
3.9-4.2 (m, 2H), 4.3 (d, 1H), 4.7 (d, 1H), 7.0-7.2 (m, 2H), 7.5
(dd, 1H), 8.3 (d, 1H), 8.4 (d, 1H), 8.7 (d, 1H), 8.8 (t, 1H).
EXAMPLE 42
(R)--N-(1-(4H-1,2,4-Triazol-3-yl)piperidin-3-yl)-2-(pyrazolo[1,5-a]pyridin-
-3-yl)pyrimidin-4-amine
##STR00096##
[0971] A mixture of
(R)--N-(piperidin-3-yl)-2-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-4-amine
(Preparation 34, 298 mg, 1.01 mmol) and 3-bromo-1H-1,2,4-triazole
(75 mg, 0.51 mmol, prepared as described in Journal of Medicinal
Chemistry, 2004, 47 (19), 4645-4648) was heated at 150.degree. C.
overnight. The crude mixture was purified by reverse phase
chromatography (C-18 silica from Waters.COPYRGT.,
water/acetonitrile/methanol as eluents [0.1% v/v formic acid
buffered] 0% to 100%) to give the title compound (96 mg, 52%) as a
white solid.
[0972] LRMS (m/z): 362 (M+1).sup.+.
[0973] .sup.1H NMR .delta. (300 MHz, DMSO-d.sub.6): 1.5 (d, 1H),
1.7 (ms, 1H), 1.8 (m, 1H), 2.0 (m, 1H), 2.8 (m, 1H), 3.0 (m, 1H),
3.4 (m, 1H), 3.7 (m, 1H), 4.2 (m, 2H), 6.3 (bs, 1H), 7.0 (t, 1H),
7.3 (m, 1H), 7.4 (m, 1H), 8.1 (m, 1H), 8.2 (s, 1H), 8.5 (m, 1H),
8.6 (s, 1H), 8.8 (d, 1H).
EXAMPLE 43
N-[(3R)-1-(Aminoacetyl)piperidin-3-yl]-6-pyrazolo[1,5-a]pyridin-3-ylpyrazi-
n-2-amine
##STR00097##
[0975] A solution of hydrochloric acid in dioxane (4M, 10 mL) was
added to a solution of tert-butyl
(2-oxo-2-{(3R)-3-[(6-pyrazolo[1,5-a]pyridin-3-ylpyrazin-2-yl)amino]piperi-
din-1-yl}ethyl)carbamate (Preparation 38, 88 mg, 0.23 mmol) in
methanol (3 mL) and the resulting mixture was stirred at ambient
temperature for one hour. The solvents were then evaporated to half
of their volume and the yellow solid that precipitated was
filtered, washed with diethyl ether and dried to give the title
compound (76 mg, 95%).
[0976] LRMS (m/z): 352 (M+1).sup.+.
EXAMPLE 44
(R)-3-(3-(5-Fluoro-2-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-4-ylamino)pipe-
ridin-1-yl)-3-oxopropanenitrile
##STR00098##
[0978] Obtained as a solid (68%) from
5-fluoro-N-[(3R)-piperidin-3-yl]-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-
-amine (Preparation 40) and 3-[(2,5-dioxopyrrolidin-1-yl)oxy]-3-oxo
propanenitrile (prepared as described in BE875054(A1)) following
the experimental procedure as described in Example 38 followed by
purification by flash chromatography (dichloromethane to 9:1
dichloromethane/methanol).
[0979] LRMS (m/z): 380 (M+1).sup.+.
[0980] .sup.1H NMR .delta. (400 MHz, DMSO-d.sub.6): 1.5-1.7 (m,
1H), 1.8 (bs, 1H), 2.1 (d, 1H), 2.6-2.7 (m, 1H), 2.7-2.9 (m, 1H),
3.1 (td, 1H), 3.6 (bs, 1H), 3.8 (bs, 1H), 3.9-4.0 (m, 1H), 4.1 (q,
2H), 4.7 (d, 1H), 7.0 (t, 1H), 7.4-7.5 (m, 1H), 7.5-7.6 (m, 1H),
8.2 (d, 1H), 8.4 (d, 1H), 8.8 (t, 1H).
EXAMPLE 45
3-((3s,4r)-4-Fluoro-3-(6-(pyrazolo[1,5-a]pyridin-3-yl)pyrazin-2-ylamino)pi-
peridin-1-yl)-3-oxopropanenitrile
##STR00099##
[0982] Obtained as a green solid (47%) from
N-[(3s,4r)-4-fluoropiperidin-3-yl]-6-pyrazolo[1,5-a]pyridin-3-ylpyrazin-2-
-amine (Preparation 41) and
3-[(2,5-dioxopyrrolidin-1-yl)oxy]-3-oxopropanenitrile (prepared as
described in BE875054(A1)) following the experimental procedure as
described in Example 38 followed by purification by flash
chromatography (dichloromethane to 93:7
dichloromethane/methanol).
[0983] LRMS (m/z): 381 (M+1)+.
[0984] .sup.1H NMR .delta. (400 MHz, CDCl.sub.3, 1:1 mixture of
rotamers): 1.9-2.3 (m, 2H), 2.9-3.8 (m, 5H), 4.3-5.2 (m, 4H), 6.9
(m, 1H), 7.4 (m, 1H), 7.8 (s, 1H, rotamer A), 7.9 (s, 1H, rotamer
B), 8.2 (d, 1H, rotamer A), 8.3 (s, 1H, rotamer A), 8.3 (s, 1H,
rotamer B), 8.4 (d, 1H, rotamer B), 8.4 (s, 1H), 8.5 (d, 1H,
rotamer A), 8.6 (d, 1H, rotamer B).
EXAMPLE 46
3-((3r,4r)-4-Methyl-3-(6-(pyrazolo[1,5-a]pyridin-3-yl)pyrazin-2-ylamino)pi-
peridin-1-yl)-3-oxopropanenitrile
##STR00100##
[0985] EXAMPLE 47
(R)--N-(1-(4H-1,2,4-Triazol-3-yl)piperidin-3-yl)-6-(pyrazolo[1,5-a]pyridin-
-3-yl)pyrazin-2-amine
##STR00101##
[0986] Pharmacological Activity
In Vitro JAK Kinase Assays
[0987] Compounds were screened for their ability to inhibit JAK1,
JAK2 and JAK3 using the assays as indicated below.
[0988] The catalytic domains of human JAK1 (aa 850-1154), JAK2 (aa
826-1132), JAK3 (aa 795-1124) and Tyk2 (aa 871-1187) were expressed
as N-terminal GST-fusion proteins using a baculovirus expression
system and were purchased from Carna Biosciences. The enzymatic
activity was assayed using as substrate a biotinylated peptide,
poly (GT)-Biotin (CisBio). The peptide concentration in the
reactions was 60 nM for JAK1, 20 nM for JAK2, 140 nM for JAK3 and
50 nM for Tyk2. The degree of phosphorylation was detected by
TR-FRET (time-resolved fluorescence energy transfer).
[0989] IC.sub.50s of compounds were measured for each kinase in a
reaction mixture containing the enzyme, ATP and the peptide in 8 mM
MOPS (pH 7.0), 10 mM MgCl.sub.2, 0.05% .beta.-mercaptoethanol, 0.45
mg/ml BSA. The ATP concentration in the reactions was 3 .mu.M for
JAK1, 0.2 .mu.M for JAK2, 0.6 .mu.M for JAK3 and 1.8 .mu.M for
Tyk2. The enzymatic reactions took place for 30 minutes at room
temperature. Then, the reactions were stopped with 20 .mu.L of
quench detection buffer (50 mM HEPES, 0.5 M KF, EDTA 0.25 M, 0.1%
(w/v) BSA, pH 7.5) containing 0.115 .mu.g/mL of anti-phosphoTyr
(PT66)-Cryptate (CisBio) and a variable concentration of SA-XL665
(CisBio) to keep the SA-B ratio constant. Incubate for 3 h and read
on Victor 2V spectrofluorometer (PerkinElmer) set to read
fluorescence resonance energy transfer.
[0990] Some of the acronyms used above have the following
meaning:
AA: aminoacids GST: glutathione-S-transferase MOPS:
3-(N-morpholino)propane sulfonic acid BSA: bovine serum albumin
ATP: adenosine tri-phosphate EDTA: ethylenediaminetetraacetic acid
HEPES: 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid
[0991] Table 1 depicts IC.sub.50 values for certain exemplary
compounds described in the invention. In Table 1, "A" represents an
IC.sub.50 value of less than 0.1 .mu.M (100 nM), "B" represents an
IC.sub.50 value in the range of 0.1 .mu.M (100 nM) to 1 .mu.M, and
C represents an IC.sub.50 value higher than 1 .mu.M.
TABLE-US-00001 TABLE 1 IC.sub.50 JAK3 IC.sub.50 JAK2 IC.sub.50 JAK1
Example No. (.mu.M) (.mu.M) (.mu.M) 5 A A B 7 B A C 14 A A B 19 A A
B 21 A A A 25 A A B 27 A A B 30 A A B 35 B A B 37 A A A
[0992] It can be seen from Table 1 that the compounds of formula
(I) are potent inhibitors of JAK1, JAK2 and JAK3 kinases. Preferred
heteroaryl imidazolone derivatives of the invention possess an
IC.sub.50 value for the inhibition of JAK1, JAK2 and JAK3 kinases
(determined as defined above) of less than 1 .mu.M, preferably less
than 0.5 .mu.M for each JAK kinase.
Combinations
[0993] The pyrazole derivatives defined herein may also be combined
with other active compounds in the treatment of a pathological
condition or disease susceptible to amelioration by inhibition of
Janus Kinases.
[0994] The combinations of the invention can optionally comprise
one or more additional active substances which are known to be
useful in the treatment of myeloproliferative disorders (such as
polycythemia vera, essential thrombocythemia or myelofibrosis),
leukemia, lymphoid malignancies and solid tumors; bone marrow and
organ transplant rejection; and immune-mediated diseases, more in
particular wherein the pathological condition or disease is
selected from rheumatoid arthritis, multiple sclerosis,
inflammatory bowel disease, dry eye, uveitis, allergic
conjunctivitis, allergic rhinitis, asthma, chronic obstructive
pulmonary disease (COPD), atopic dermatitis and psoriasis, such as
(a) Dyhydrofolate reductase inhibitors, such as Methotrexate or
CH-1504; (b) DHODH inhibitors such as leflunomide, teriflunomide,
or the compounds described in the International Patent Application
Nos. WO2008/077639 and WO2009021696; (c) Immunomodulators such as
Glatiramer acetate (Copaxone), Laquinimod or Imiquimod; (d)
Inhibitors of DNA synthesis and repair, such as Mitoxantrone or
Cladribine; (e) Anti-alpha 4 integrin antibodies, such as
Natalizumab (Tysabri); (f) Alpha 4 integrin antagonists such as
R-1295, TBC-4746, CDP-323, ELND-002, Firategrast or TMC-2003; (g)
Corticoids and glucocorticoids such as prednisone or
methylprednisolone, fluticasone, mometasone, or beta-metasone; (h)
Fumaric acid esters, such as BG-12; (i) Anti-TNF alpha antibodies,
such as Infliximab, Adalimumab, or Certolizumab pegol; (j) Soluble
TNF alpha receptors such as Ethanercept; (k) Anti-CD20 monoclonal
antibodies such as Rituximab, Ocrelizumab Ofatumumab or TRU-015;
(l) Anti-CD52 such as alemtuzumab; (m) Anti-CD25 such as
daclizumab; (n) Anti-CD88, such as eculizumab or pexilizumab; (o)
Anti-IL12R/IL23R, such as ustekinumab; (p) Calcineurin inhibitors
such as cyclosporine A or tacrolimus; (q) IMPDH inhibitors, such as
mycophenolate mophetyl; (r) Cannabinoid receptor agonists such as
Sativex; (s) Chemokine CCR1 antagonists such as MLN-3897 or
PS-031291; (t) Chemokine CCR2 antagonists such as INCB-8696; (u)
NF-kappaB activation inhibitors such as MLN-0415; (v) S1P receptor
agonists such as fingolimod, BAF-312, ACT128800 or the compounds
described in the International Patent Application Nos.
PCT/EP2009/007348 and PCT/EP2009/008968; (w) S1P liase inhibitors
such as LX2931; (x) Syk inhibitors, such as R-112; (y) PKC
inhibitors, such as NVP-AEB071; (z) M3 antagonists such as
tiotropium or aclidinium; (aa) Long-acting beta adrenergic agonists
such as salmeterol, formoterol or indacaterol; (bb) Vitamin D
derivatives like calcipotriol (Daivonex); (cc) Phosphosdiesterase
IV inhibitors such as roflumilast or GRC-4039; (dd) p38 Inhibitors
such as ARRY-797; (ee) MEK inhibitors, such as ARRY-142886 or
ARRY-438162; (ff) PI3K.delta..gamma. inhibitors; (gg) Interferons
comprising Interferon beta 1a such as Avonex from Biogen Idec,
CinnoVex from CinnaGen and Rebif from EMD Serono, and Interferon
beta 1b such as Betaferon from Schering and Betaseron from Berlex;
and (hh) Interferon alpha such as Sumiferon MP.
[0995] Typically, the additional active substance is not
methotrexate. Preferably, the additional active substance is
selected from (b) DHODH inhibitors such as leflunomide,
teriflunomide, or the compounds described in the International
Patent Application Nos. WO2008/077639 and WO2009021696; (c)
Immunomodulators such as Glatiramer acetate (Copaxone), Laquinimod
or Imiquimod; (e) Anti-alpha 4 integrin antibodies, such as
Natalizumab (Tysabri); (f) Alpha 4 integrin antagonists such as
R-1295, TBC-4746, CDP-323, ELND-002, Firategrast or TMC-2003; (g)
Corticoids and glucocorticoids such as prednisone or
methylprednisolone, fluticasone, mometasone, or beta-metasone; (h)
Fumaric acid esters, such as BG-12; (i) Anti-TNF alpha antibodies,
such as Infliximab, Adalimumab, or Certolizumab pegol; (j) Soluble
TNF alpha receptors such as Ethanercept; (k) Anti-CD20 monoclonal
antibodies such as Rituximab, Ocrelizumab Ofatumumab or TRU-015;
(n) Anti-CD88, such as eculizumab or pexilizumab; (o) Anti-IL12R
IL23R, such as ustekinumab; (p) Calcineurin inhibitors such as
cyclosporine A or tacrolimus; (q) IMPDH inhibitors, such as
mycophenolate mophetyl; (r) Cannabinoid receptor agonists such as
Sativex; (s) Chemokine CCR1 antagonists such as MLN-3897 or
PS-031291; (t) Chemokine CCR2 antagonists such as INCB-8696; (u)
NF-kappaB activation inhibitors such as MLN-0415; (v) S1P receptor
agonists such as fingolimod, BAF-312, ACT128800 or the compounds
described in the International Patent Application Nos.
PCT/EP2009/007348 and PCT/EP2009/008968; (w) S1P liase inhibitors
such as LX2931; (x) Syk inhibitors, such as R-112; (y) PKC
inhibitors, such as NVP-AEB071; (z) M3 antagonists such as
tiotropium or aclidinium; (aa) Long-acting beta adrenergic agonists
such as salmeterol, formoterol or indacaterol; (bb) Vitamin D
derivatives like calcipotriol (Daivonex); (cc) Phosphosdiesterase
IV inhibitors such as roflumilast or GRC-4039; (dd) p38 Inhibitors
such as ARRY-797; (ee) ARRY-438162; (ff) PI3K.delta..gamma.
inhibitors; (gg) Interferon beta 1a such as Avonex from Biogen
Idec, CinnoVex from CinnaGen and Rebif from EMD Serono; and
Interferon beta 1b such as Betaferon from Schering and Betaseron
from Berlex.
[0996] More preferably, the additional active substance is selected
from (b) DHODH inhibitors such as leflunomide, teriflunomide, or
the compounds described in the International Patent Application
Nos. WO2008/077639 and WO2009021696; (c) Immunomodulators such as
Glatiramer acetate (Copaxone), Laquinimod or Imiquimod; (e)
Anti-alpha 4 integrin antibodies, such as Natalizumab (Tysabri);
(f) Alpha 4 integrin antagonists such as R-1295, TBC-4746, CDP-323,
ELND-002, Firategrast or TMC-2003; (g) Corticoids and
glucocorticoids such as prednisone or methylprednisolone,
fluticasone, mometasone, or beta-metasone; (h) Fumaric acid esters,
such as BG-12; (i) Anti-TNF alpha antibodies, such as Infliximab,
Adalimumab, or Certolizumab pegol; (j) Soluble TNF alpha receptors
such as Ethanercept; (k) Anti-CD20 monoclonal antibodies such as
Rituximab, Ocrelizumab Ofatumumab or TRU-015; (n) Anti-CD88, such
as eculizumab or pexilizumab; (o) Anti-IL12R IL23R, such as
ustekinumab; (p) Calcineurin inhibitors such as cyclosporine A or
tacrolimus; (q) IMPDH inhibitors, such as mycophenolate mophetyl;
(r) Cannabinoid receptor agonists such as Sativex; (s) Chemokine
CCR1 antagonists such as MLN-3897 or PS-031291; (t) Chemokine CCR2
antagonists such as INCB-8696; (u) NF-kappaB activation inhibitors
such as MLN-0415; (v) S1P receptor agonists such as fingolimod,
BAF-312, ACT128800 or the compounds described in the International
Patent Application Nos. PCT/EP2009/007348 and PCT/EP2009/008968;
(w) S1P liase inhibitors such as LX2931; (x) Syk inhibitors, such
as R-112; (y) PKC inhibitors, such as NVP-AEB071; (z) M3
antagonists such as tiotropium or aclidinium; (aa) Long-acting beta
adrenergic agonists such as salmeterol, formoterol or indacaterol;
(bb) Vitamin D derivatives like calcipotriol (Daivonex); (cc)
Phosphosdiesterase IV inhibitors such as roflumilast or GRC-4039;
(dd) p38 Inhibitors such as ARRY-797; (ff) PI3K.delta..gamma.
inhibitors; (gg) Interferon beta 1a such as Avonex from Biogen
Idec, CinnoVex from CinnaGen and Rebif from EMD Serono; and
Interferon beta 1b such as Betaferon from Schering and Betaseron
from Berlex.
[0997] Specific examples of suitable corticoids and glucocorticoids
that can be combined with the JAK inhibitors of the present
invention are prednisolone, methylprednisolone, dexamethasone,
dexamethasone cipecilate, naflocort, deflazacort, halopredone
acetate, budesonide, beclomethasone dipropionate, hydrocortisone,
triamcinolone acetonide, fluocinolone acetonide, fluocinonide,
clocortolone pivalate, methylprednisolone aceponate, dexamethasone
palmitoate, tipredane, hydrocortisone aceponate, prednicarbate,
alclometasone dipropionate, halometasone, methylprednisolone
suleptanate, mometasone furoate, rimexolone, prednisolone
farnesylate, ciclesonide, butixocort propionate, RPR-106541,
deprodone propionate, fluticasone propionate, fluticasone furoate,
halobetasol propionate, loteprednol etabonate, betamethasone
butyrate propionate, flunisolide, prednisone, dexamethasone sodium
phosphate, triamcinolone, betamethasone 17-valerate, betamethasone,
betamethasone dipropionate, hydrocortisone acetate, hydrocortisone
sodium succinate, prednisolone sodium phosphate and hydrocortisone
probutate.
[0998] Specific examples of suitable Syk kinase inhibitors that can
be combined with the JAK inhibitors of the present invention are
fosfamatinib (from Rigel), R-348 (from Rigel), R-343 (from Rigel),
R-112 (from Rigel), piceatannol,
2-(2-Aminoethylamino)-4-[3-(trifluoromethyl)phenylamino]pyrimidine-5-carb-
oxamide, R-091 (from Rigel),
6-[5-Fluoro-2-(3,4,5-trimethoxyphenylamino)pyrimidin-4-ylamino]-2,2-dimet-
hyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-3-one benzenesulfonate
(R-406 from Rigel),
1-(2,4,6-Trihydrayphenyl)-2-(4-methoxyphenyl)ethan-1-one,
N-[4-[6-(Cyclobutylamino)-9H-purin-2-ylamino]phenyl]-N-methylacetamide
(QAB-205 from Novartis),
2-[7-(3,4-Dimethoxyphenyl)imidazo[1,2-c]pyrimidin-5-ylamino]pyridine-3-ca-
rboxamide dihydrochloride (BAY-61-3606 from Bayer) and AVE-0950
(from Sanofi-Aventis).
[0999] Specific examples of suitable M3 antagonists
(anticholinergics) that can be combined with the JAK inhibitors of
the present invention are tiotropium salts, oxitropium salts,
flutropium salts, ipratropium salts, glycopyrronium salts, trospium
salts, revatropate, espatropate,
3-[2-Hydroxy-2,2-bis(2-thienyl)acetoxy]-1-(3-phenoxypropyl)-1-azoniabicyc-
lo[2.2.2]octane salts (in particular aclidinium salts, more
preferably aclidinium bromide),
1-(2-Phenylethyl)-3-(9H-xanthen-9-ylcarbonyloxy)-1-azoniabicyclo[2.2.2]oc-
tane salts, 2-oxo-1,2,3,4-tetrahydroquinazoline-3-carboxylic acid
endo-8-methyl-8-azabicyclo[3.2.1]oct-3-yl ester salts (DAU-5884),
3-(4-Benzylpiperazin-1-yl)-1-cyclobutyl-1-hydroxy-1-phenylpropan-2-one
(NPC-14695),
N-[1-(6-Aminopyridin-2-ylmethyl)piperidin-4-yl]-2(R)-[3,3-difluoro-1(R)-c-
yclopentyl]-2-hydroxy-2-phenylacetamide (J-104135),
2(R)-Cyclopentyl-2-hydroxy-N-[1-[4(S)-methylhexyl]piperidin-4-yl]-2-pheny-
lacetamide (J-106366),
2(R)-Cyclopentyl-2-hydroxy-N-[1-(4-methyl-3-pentenyl)-4-piperidinyl]-2-ph-
enylacetamide (J-104129),
1-[4-(2-Aminoethyl)piperidin-1-yl]-2(R)-[3,3-difluorocyclopent-1(R)-yl]-2-
-hydroxy-2-phenylethan-1-one (Banyu-280634),
N--[N-[2-[N-[1-(Cyclohexylmethyl)piperidin-3(R)-ylmethyl]carbamoyl]ethyl]-
carbamoylmethyl]-3,3,3-triphenylpropionamide (Banyu CPTP),
2(R)-Cyclopentyl-2-hydroxy-2-phenylacetic acid
4-(3-azabicyclo[3.1.0]hex-3-yl)-2-butynyl ester (Ranbaxy 364057),
UCB-101333, Merck's OrM3,
7-endo-(2-hydroxy-2,2-diphenylacetoxy)-9,9-dimethyl-3-oxa-9-azoniatricycl-
o[3.3.1.0(2,4)]nonane salts,
7-(2,2-diphenylpropionyloxy)-7,9,9-trimethyl-3-oxa-9-azoniatricyclo[3.3.1-
.0*2,4*]nonane salts,
7-hydroxy-7,9,9-trimethyl-3-oxa-9-azoniatricyclo[3.3.1.0*2,4*]nonane
9-methyl-9H-fluorene-9-carboxylic acid ester salts, all of them
optionally in the form of their racemates, their enantiomers, their
diastereomers and mixtures thereof, and optionally in the form of
their pharmacologically-compatible acid addition salts. Among the
salts chlorides, bromides, iodides and methanesulphonates are
preferred.
[1000] Specific examples of suitable long-acting beta adrenergic
agonists (.beta.2-agonists) that can be combined with the JAK
inhibitors of the present invention are terbutaline sulphate,
eformoterol fumarate, formoterol fumarate, bambuterol, procaterol
hydrochloride, sibenadet hydrochloride, mabuterol hydrochloride,
albuterol sulphate, salbutamol sulphate, salmeterol xinafoate,
carmoterol hydrochloride, (R)-albuterol hydrochloride, Levalbuterol
hydrochloride; Levosalbutamol hydrochloride; (-)-Salbutamol
hydrochloride, (R,R)-Formoterol tartrate; Arformoterol tartrate,
Bedoradrine sulphate, Indacaterol, Trantinterol hydrochloride,
AZD-3199, GSK-159802; GSK-597901, GSK-678007, GSK-642444;
GSK-961081; AR-C98955AA, Milveterol hydrochloride, BI-1744-CL, and
compounds described in the international Patent Applications Nos.
WO2007/124898, WO2006/122788A1, WO2008/046598 and WO2008095720.
[1001] Specific examples of suitable Phosphosdiesterase IV
inhibitors that can be combined with the JAK inhibitors of the
present invention are benafentrine dimaleate, etazolate,
denbufylline, rolipram, cipamfylline, zardaverine, arofylline,
filaminast, tipelukast, tofimilast, piclamilast, tolafentrine,
mesopram, drotaverine hydrochloride, lirimilast, roflumilast,
cilomilast, oglemilast, apremilast, tetomilast, filaminast,
(R)-(+)-4-[2-(3-Cyclopentyloxy-4-methoxyphenyl)-2-phenylethyl]pyridine
(CDP-840),
N-(3,5-Dichloro-4-pyridinyl)-2-[1-(4-fluorobenzyl)-5-hydroxy-1H-indol-3-y-
l]-2-oxoacetamide (GSK-842470),
9-(2-Fluorobenzyl)-N6-methyl-2-(trifluoromethyl)adenine (NCS-613),
N-(3,5-Dichloro-4-pyridinyl)-8-methoxyquinoline-5-carboxamide
(D-4418),
3-[3-(Cyclopentyloxy)-4-methoxybenzyl]-6-(ethylamino)-8-isopropyl-3H-puri-
ne hydrochloride (V-11294A),
6-[3-(N,N-Dimethylcarbamoyl)phenylsulfonyl]-4-(3-methoxyphenylamino)-8-me-
thylquinoline-3-carboxamide hydrochloride (GSK-256066),
4-[6,7-Diethoxy-2,3-bis(hydroxymethyl)naphthalen-1-yl]-1-(2-methoxyethyl)-
pyridin-2(1H)-one (T-440),
(-)-trans-2-[3'-[3-(N-Cyclopropylcarbamoyl)-4-oxo-1,4-dihydro-1,8-naphthy-
ridin-1-yl]-3-fluorobiphenyl-4-yl]cyclopropanecarboxylic acid
(MK-0873), CDC-801, UK-500001, BLX-914,
2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-difluororomethoxyphenyl)-
cyclohexan1-one, cis
[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-ol,
GRC-4039, CDC-801,
5(S)-[3-(Cyclopentyloxy)-4-methoxyphenyl]-3(S)-(3-methylbenzyl)piperidin--
2-one (IPL-455903), ONO-6126 (Eur Respir J 2003, 22(Suppl. 45):
Abst 2557) and the salts claimed in the International Patent
Applications Nos. WO03/097613, WO2004/058729, WO 2005/049581, WO
2005/123693 and WO 2005/123692.
[1002] Examples of suitable PI3K.delta..gamma. inhibitors that can
be combined with the JAK inhibitors of the present invention are
2-Methyl-2-[4-[3-methyl-2-oxo-8-(3-quinolinyl)-2,3-dihydro-1H-imidazo[4,5-
-c]quinolin-1-yl]phenyl]propanenitrile (BEZ-235 from Novartis),
CAL-101 (from Calistoga Pharmaceuticals) and
N-Ethyl-N'-[3-(3,4,5-trimethoxyphenylamino)pyrido[2,3-b]pyrazin-6-yl]thio-
urea (AEZS-126 from Aeterna Zentaris).
[1003] The compounds of formula (I) and the combinations described
herein may be used in the treatment of myeloproliferative
disorders, leukemia, lymphoid malignancies and solid tumors; bone
marrow and organ transplant rejection; and immune-mediated
diseases, wherein the use of a JAK inhibitor is expected to have a
beneficial effect, for example rheumatoid arthritis, multiple
sclerosis, inflammatory bowel disease (such as ulcerative colitis
or Crohn's disease), dry eye, uveitis, allergic conjunctivitis,
allergic rhinitis, asthma, chronic obstructive pulmonary disease
(COPD), atopic dermatitis and psoriasis. The compounds of formula
(I) and the combinations described herein may also be used in the
treatment of inflammatory diseases.
[1004] In one aspect, the compounds of formula (I) and the
combinations described herein may be used in the treatment of
myeloproliferative disorders, leukemia, lymphoid malignancies and
solid tumors. In this aspect, the treatment is effected by
inhibition of Janus Kinases in the subject. In another aspect, the
compounds of formula (I) and the combinations described herein may
be used in the treatment of bone marrow and organ transplant
rejection; immune-mediated diseases and inflammatory diseases, for
example from bone marrow and organ transplant rejection; and
immune-mediated diseases, e.g. bone marrow and organ transplant
rejection.
[1005] The treatment of these diseases and conditions is typically
effected by inhibiting Janus Kinases (JAK) in the subject. The
compounds of formula (I) and the combinations described herein may
be used in the inhibition of Janus Kinases (JAK).
[1006] The active compounds in the combination may be administered
together in the same pharmaceutical composition or in different
compositions intended for separate, simultaneous, concomitant or
sequential administration by the same or a different route.
[1007] It is contemplated that all active agents would be
administered at the same time, or very close in time.
Alternatively, one or two active agents could be taken in the
morning and the other (s) later in the day. Or in another scenario,
one or two active agents could be taken twice daily and the other
(s) once daily, either at the same time as one of the twice-a-day
dosing occurred, or separately. Preferably at least two, and more
preferably all, of the active agents would be taken together at the
same time. Preferably, at least two, and more preferably all active
agents would be administered as an admixture.
[1008] The invention is also directed to a combination product of
the compounds described herein together with one or more other
therapeutic agents for use in the treatment of a pathological
condition or disease susceptible to amelioration by inhibition of
Janus Kinases (JAK), in particular wherein the pathological
condition or disease is selected from myeloproliferative disorders,
leukemia, lymphoid malignancies and solid tumors; bone marrow and
organ transplant rejection; immune-mediated diseases and
inflammatory diseases, for example myeloproliferative disorders,
leukemia, lymphoid malignancies and solid tumors; bone marrow and
organ transplant rejection; and immune-mediated diseases. More
particularly, the pathological condition or disease is selected
from rheumatoid arthritis, multiple sclerosis, inflammatory bowel
disease, dry eye, uveitis, allergic conjunctivitis, allergic
rhinitis, asthma, chronic obstructive pulmonary disease (COPD),
atopic dermatitis and psoriasis.
[1009] In one aspect, the combination product may be for the
treatment of myeloproliferative disorders, leukemia, lymphoid
malignancies and solid tumors. In this aspect, the treatment is
effected by inhibition of Janus Kinases in the subject. In another
aspect, the combination product may be used in the treatment of
bone marrow and organ transplant rejection; immune-mediated
diseases and inflammatory diseases, for example from bone marrow
and organ transplant rejection; and immune-mediated diseases, e.g.
bone marrow and organ transplant rejection.
[1010] The treatment of these diseases and conditions is typically
effected by inhibiting Janus Kinases (JAK) in the subject. The
combination product may be used in the inhibition of Janus Kinases
(JAK).
[1011] The invention also encompasses the use of a combination of
the compounds of the invention together with one or more other
therapeutic agents for the manufacture of a formulation or
medicament for treating these diseases.
[1012] The invention also provides a method of treatment of a
pathological condition or disease susceptible to amelioration by
inhibition of Janus Kinases (JAK), in particular wherein the
pathological condition or disease is selected from
myeloproliferative disorders, leukemia, lymphoid malignancies and
solid tumors; bone marrow and organ transplant rejection;
immune-mediated diseases and inflammatory diseases, for example
myeloproliferative disorders, leukemia, lymphoid malignancies and
solid tumors; bone marrow and organ transplant rejection; and
immune-mediated diseases. More particularly, the pathological
condition or disease is selected from rheumatoid arthritis,
multiple sclerosis, inflammatory bowel disease, dry eye, uveitis,
allergic conjunctivitis, allergic rhinitis, asthma, chronic
obstructive pulmonary disease (COPD), atopic dermatitis and
psoriasis; comprising administering a therapeutically effective
amount of a combination of the compounds described herein together
with one or more other therapeutic agents. In particular, the
treatment is effected by inhibition of Janus Kinases in the
subject.
[1013] The invention also provides a method of inhibiting Janus
kinases in a subject in need thereof, which comprises administering
to said subject a therapeutically effective amount of a combination
of the compounds described herein together with one or more other
therapeutic agents to a subject in need of such treatment.
[1014] The active compounds in the combinations of the invention
may be administered by any suitable route, depending on the nature
of the disorder to be treated, e.g. orally (as syrups, tablets,
capsules, lozenges, controlled-release preparations,
fast-dissolving preparations, etc); topically (as creams,
ointments, lotions, nasal sprays or aerosols, etc); by injection
(subcutaneous, intradermic, intramuscular, intravenous, etc.) or by
inhalation (as a dry powder, a solution, a dispersion, etc).
[1015] The active compounds in the combination, i.e. the pyrazole
derivatives of the invention, and the other optional active
compounds may be administered together in the same pharmaceutical
composition or in different compositions intended for separate,
simultaneous, concomitant or sequential administration by the same
or a different route.
[1016] One execution of the present invention consists of a kit of
parts comprising a pyrazole derivative as described herein together
with instructions for simultaneous, concurrent, separate or
sequential use in combination with another active compound useful
in the treatment of myeloproliferative disorders, leukemia,
lymphoid malignancies and solid tumors; bone marrow and organ
transplant rejection; immune-mediated diseases and inflammatory
diseases, for example myeloproliferative disorders, leukemia,
lymphoid malignancies and solid tumors; bone marrow and organ
transplant rejection; and immune-mediated diseases, and more
particularly, useful in the treatment of rheumatoid arthritis,
multiple sclerosis, inflammatory bowel disease, dry eye, uveitis,
allergic conjunctivitis, allergic rhinitis, asthma, chronic
obstructive pulmonary disease (COPD), atopic dermatitis and
psoriasis.
[1017] Another execution of the present invention consists of a
package comprising a pyrazole derivative as described herein and
another active compound useful in the treatment of
myeloproliferative disorders, leukemia, lymphoid malignancies and
solid tumors; bone marrow and organ transplant rejection;
immune-mediated diseases and inflammatory diseases, for example
myeloproliferative disorders, leukemia, lymphoid malignancies and
solid tumors; bone marrow and organ transplant rejection; and
immune-mediated diseases, and more particularly, useful in the
treatment of rheumatoid arthritis, multiple sclerosis, inflammatory
bowel disease, dry eye, uveitis, allergic conjunctivitis, allergic
rhinitis, asthma, chronic obstructive pulmonary disease (COPD),
atopic dermatitis and psoriasis.
Pharmaceutical Compositions
[1018] Pharmaceutical compositions according to the present
invention comprise the compounds of the invention in association
with a pharmaceutically acceptable diluent or carrier.
[1019] The invention further provides pharmaceutical compositions
comprising the compounds of the invention in association with a
pharmaceutically acceptable diluent or carrier together with one or
more other therapeutic agents for use in the treatment of a
pathological condition or disease susceptible to amelioration by
inhibition of Janus Kinases (JAK), such as the ones previously
described.
[1020] The invention is also directed to pharmaceutical
compositions for use in the treatment of a pathological condition
or disease susceptible to amelioration by inhibition of Janus
Kinases (JAK), in particular wherein the pathological condition or
disease is selected from myeloproliferative disorders, leukemia,
lymphoid malignancies and solid tumors; bone marrow and organ
transplant rejection; immune-mediated diseases and inflammatory
diseases, for example myeloproliferative disorders, leukemia,
lymphoid malignancies and solid tumors; bone marrow and organ
transplant rejection; and immune-mediated diseases, and more
particularly, wherein the pathological condition or disease is
selected from rheumatoid arthritis, multiple sclerosis,
inflammatory bowel disease, dry eye, uveitis, allergic
conjunctivitis, allergic rhinitis, asthma, chronic obstructive
pulmonary disease (COPD), atopic dermatitis and psoriasis. The
invention also encompasses the use of a pharmaceutical composition
of the invention for the manufacture of a medicament for treating
these diseases.
[1021] In one aspect, the pharmaceutical composition may be for the
treatment of myeloproliferative disorders, leukemia, lymphoid
malignancies and solid tumors. In this aspect, the treatment is
effected by inhibition of Janus Kinases in the subject. In another
aspect, the pharmaceutical composition may be used in the treatment
of bone marrow and organ transplant rejection; immune-mediated
diseases and inflammatory diseases, for example from bone marrow
and organ transplant rejection; and immune-mediated diseases, e.g.
bone marrow and organ transplant rejection.
[1022] The treatment of these diseases and conditions is typically
effected by inhibiting Janus Kinases (JAK) in the subject. The
pharmaceutical composition may be used in the inhibition of Janus
Kinases (JAK).
[1023] The invention also provides a method of treatment of a
pathological condition or disease susceptible to amelioration by
inhibition of Janus Kinases (JAK), in particular wherein the
pathological condition or disease is selected from
myeloproliferative disorders, leukemia, lymphoid malignancies and
solid tumors; bone marrow and organ transplant rejection;
immune-mediated diseases and inflammatory diseases, for example
myeloproliferative disorders, leukemia, lymphoid malignancies and
solid tumors; bone marrow and organ transplant rejection; and
immune-mediated diseases, and more particularly, wherein the
pathological condition or disease is selected from rheumatoid
arthritis, multiple sclerosis, inflammatory bowel disease, dry eye,
uveitis, allergic conjunctivitis, allergic rhinitis, asthma,
chronic obstructive pulmonary disease (COPD), atopic dermatitis and
psoriasis, comprising administering a therapeutically effective
amount of a pharmaceutical composition as defined herein. In
particular, the treatment is effected by inhibition of Janus
Kinases in the subject.
[1024] The invention also provides a method of inhibiting Janus
kinases in a subject in need thereof, which comprises administering
to said subject a therapeutically effective amount of a
pharmaceutical composition as defined herein to a subject in need
of such treatment.
[1025] The present invention also provides pharmaceutical
compositions which comprise, as an active ingredient, at least an
pyrazole of formula (I) or a pharmaceutically acceptable salt
thereof in association with a pharmaceutically acceptable excipient
such as a carrier or diluent. The active ingredient may comprise
0.001% to 99% by weight, preferably 0.01% to 90% by weight, of the
composition depending upon the nature of the formulation and
whether further dilution is to be made prior to application.
Preferably the compositions are made up in a form suitable for
oral, inhalation, topical, nasal, rectal, percutaneous or
injectable administration.
[1026] The pharmaceutically acceptable excipients which are admixed
with the active compound or salts of such compound, to form the
compositions of this invention are well-known per se and the actual
excipients used depend inter alia on the intended method of
administering the compositions.
[1027] Compositions for oral administration may take the form of
tablets, retard tablets, sublingual tablets, capsules, inhalation
aerosols, inhalation solutions, dry powder inhalation, or liquid
preparations, such as mixtures, elixirs, syrups or suspensions, all
containing the compound of the invention; such preparations may be
made by methods well-known in the art.
[1028] The diluents which may be used in the preparation of the
compositions include those liquid and solid diluents which are
compatible with the active ingredient, together with colouring or
flavouring agents, if desired. Tablets or capsules may conveniently
contain between 0.01-3000 mg, more preferably 0.5-1000 mg of active
ingredient or the equivalent amount of a pharmaceutically
acceptable salt thereof.
[1029] The liquid composition adapted for oral use may be in the
form of solutions or suspensions. The solutions may be aqueous
solutions of a soluble salt or other derivative of the active
compound in association with, for example, sucrose to form a syrup.
The suspensions may comprise an insoluble active compound of the
invention or a pharmaceutically acceptable salt thereof in
association with water, together with a suspending agent or
flavouring agent.
[1030] Compositions for parenteral injection may be prepared from
soluble salts, which may or may not be freeze-dried and which may
be dissolved in pyrogen free aqueous media or other appropriate
parenteral injection fluid.
[1031] Compositions for topical administration may take the form of
ointments, creams or lotions, all containing the compound of the
invention; such preparations may be made by methods well-known in
the art.
[1032] Effective doses are normally in the range of 0.01-3000 mg,
more preferably 0.5-1000 mg of active ingredient or the equivalent
amount of a pharmaceutically acceptable salt thereof per day. Daily
dosage may be administered in one or more treatments, preferably
from 1 to 4 treatments, per day.
[1033] The pharmaceutical compositions may conveniently be
presented in unit dosage form and may be prepared by any of the
methods well known in the art of pharmacy.
[1034] The pharmaceutical compositions of the present invention
suitable for oral administration may be presented as discrete units
such as capsules, cachets or tablets each containing a
predetermined amount of the active ingredient; as a powder or
granules; as a solution or a suspension in an aqueous liquid or a
non-aqueous liquid; or as an oil-in-water liquid emulsion or a
water-in-oil liquid emulsion. The active ingredient may also be
presented as a bolus, electuary or paste.
[1035] A syrup formulation will generally consist of a suspension
or solution of the compound or salt in a liquid carrier for
example, ethanol, peanut oil, olive oil, glycerine or water with
flavouring or colouring agent.
[1036] Where the composition is in the form of a tablet, any
pharmaceutical carrier routinely used for preparing solid
formulations may be used. Examples of such carriers include
magnesium stearate, talc, gelatine, acacia, stearic acid, starch,
lactose and sucrose.
[1037] A tablet may be made by compression or moulding, optionally
with one or more accessory ingredients. Compressed tablets may be
prepared by compressing in a suitable machine the active ingredient
in a free-flowing form such as a powder or granules, optionally
mixed with a binder, lubricant, inert diluent, lubricating, surface
active or dispersing agent.
[1038] Moulded tablets may be made by moulding in a suitable
machine a mixture of the powdered compound moistened with an inert
liquid diluent. The tablets may optionally be coated or scored and
may be formulated so as to provide slow or controlled release of
the active ingredient therein.
[1039] Where the composition is in the form of a capsule, any
routine encapsulation is suitable, for example using the
aforementioned carriers in a hard gelatine capsule. Where the
composition is in the form of a soft gelatine capsule any
pharmaceutical carrier routinely used for preparing dispersions or
suspensions may be considered, for example aqueous gums,
celluloses, silicates or oils, and are incorporated in a soft
gelatine capsule.
[1040] Dry powder compositions for topical delivery to the lung by
inhalation may, for example, be presented in capsules and
cartridges of, for example, gelatine or blisters of, for example,
laminated aluminium foil, for use in an inhaler or insufflator.
Formulations generally contain a powder mix for inhalation of the
compound of the invention and a suitable powder base (carrier
substance) such as lactose or starch. Use of lactose is preferred.
Each capsule or cartridge may generally contain between 2 .mu.g and
150 .mu.g of each therapeutically active ingredient. Alternatively,
the active ingredient (s) may be presented without excipients.
[1041] Packaging of the formulation for inhalation may be carried
out by using suitable inhaler devices such as Genuair.RTM.
(formerly Novolizer.RTM. SD2FL) which is described in the following
patent applications: WO97/000703, WO03/000325 and
WO2006/008207.
[1042] Typical compositions for nasal delivery include those
mentioned above for inhalation and further include non-pressurized
compositions in the form of a solution or suspension in an inert
vehicle such as water optionally in combination with conventional
excipients such as buffers, anti-microbials, tonicity modifying
agents and viscosity modifying agents which may be administered by
nasal pump.
[1043] Typical dermal and transdermal formulations comprise a
conventional aqueous or non-aqueous vehicle, for example a cream,
ointment, lotion or paste or are in the form of a medicated
plaster, patch or membrane.
[1044] Preferably the composition is in unit dosage form, for
example a tablet, capsule or metered aerosol dose, so that the
patient may administer a single dose.
[1045] The amount of each active which is required to achieve a
therapeutic effect will, of course, vary with the particular
active, the route of administration, the subject under treatment,
and the particular disorder or disease being treated.
[1046] The following preparations forms are cited as formulation
examples:
COMPOSITION EXAMPLE 1
[1047] 50,000 capsules; each containing 100 mg of
(S)--N-(1-Phenylethyl)-2-pyrazolo[1,5-a]pyrazin-3-ylpyrimidin-4-amine
(active ingredient), were prepared according to the following
formulation:
TABLE-US-00002 Active ingredient 5 Kg Lactose monohydrate 10 Kg
Colloidal silicon dioxide 0.1 Kg Corn starch 1 Kg Magnesium
stearate 0.2 Kg
Procedure
[1048] The above ingredients were sieved through a 60 mesh sieve,
and were loaded into a suitable mixer and filled into 50,000
gelatine capsules.
COMPOSITION EXAMPLE 2
[1049] 50,000 tablets, each containing 50 mg of
N-Benzyl-2-pyrazolo[1,5-a]pyrazin-3-ylpyrimidin-4-amine (active
ingredient), are prepared from the following formulation:
TABLE-US-00003 Active ingredient 2.5 Kg Microcrystalline cellulose
1.95 Kg Spray dried lactose 9.95 Kg Carboxymethyl starch 0.4 Kg
Sodium stearyl fumarate 0.1 Kg Colloidal silicon dioxide 0.1 Kg
Procedure
[1050] All the powders are passed through a screen with an aperture
of 0.6 mm, then mixed in a suitable mixer for 20 minutes and
compressed into 300 mg tablets using 9 mm disc and flat bevelled
punches.
COMPOSITION EXAMPLE 3
[1051] 50,000 tablets, each containing 50 mg of
(S)--N-(1-Phenylethyl)-2-pyrazolo[1,5-a]pyrazin-3-ylpyrimidin-4-amine
(active ingredient), were prepared from the following
formulation:
TABLE-US-00004 Active ingredient 2.5 Kg Microcrystalline cellulose
1.95 Kg Spray dried lactose 9.95 Kg Carboxymethyl starch 0.4 Kg
Sodium stearyl fumarate 0.1 Kg Colloidal silicon dioxide 0.1 Kg
Procedure
[1052] All the powders were passed through a screen with an
aperture of 0.6 mm, then mixed in a suitable mixer for 20 minutes
and compressed into 300 mg tablets using 9 mm disc and flat
bevelled punches. The disintegration time of the tablets was about
3 minutes.
[1053] Modifications, which do not affect, alter, change or modify
the essential aspects of the compounds, combinations or
pharmaceutical compositions described, are included within the
scope of the present invention.
* * * * *