U.S. patent application number 15/867425 was filed with the patent office on 2018-05-10 for pyrazolo [3,4-d] pyrimidine derivatives useful to treat respiratory disorders.
The applicant listed for this patent is Novartis AG. Invention is credited to Graham Charles Bloomfield, Ian Bruce, Brian Cox, Lee Edwards, Judy Fox Hayler, Catherine Howsham.
Application Number | 20180125849 15/867425 |
Document ID | / |
Family ID | 36687588 |
Filed Date | 2018-05-10 |
United States Patent
Application |
20180125849 |
Kind Code |
A1 |
Bloomfield; Graham Charles ;
et al. |
May 10, 2018 |
PYRAZOLO [3,4-D] PYRIMIDINE DERIVATIVES USEFUL TO TREAT RESPIRATORY
DISORDERS
Abstract
The present invention concerns a compound of formula (I)
##STR00001## or a pharmaceutically acceptable salt or solvate
thereof, where R.sup.1-R.sup.3 and Y are defined in the
description, and its use in the treatment of disorders in which pi3
kinase is implicated.
Inventors: |
Bloomfield; Graham Charles;
(Heath, GB) ; Bruce; Ian; (Washington, GB)
; Cox; Brian; (Horsham, GB) ; Edwards; Lee;
(West Sussex, GB) ; Hayler; Judy Fox; (West
Sussex, GB) ; Howsham; Catherine; (Horsham,
GB) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Novartis AG |
Basel |
|
CH |
|
|
Family ID: |
36687588 |
Appl. No.: |
15/867425 |
Filed: |
January 10, 2018 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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15194373 |
Jun 27, 2016 |
|
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15867425 |
|
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14049706 |
Oct 9, 2013 |
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15194373 |
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12227314 |
Nov 12, 2008 |
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PCT/EP2007/004501 |
May 21, 2007 |
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14049706 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D 487/04 20130101;
A61K 31/5377 20130101; A61P 11/06 20180101; A61K 31/519 20130101;
A61P 43/00 20180101; A61P 11/08 20180101; A61P 11/00 20180101 |
International
Class: |
A61K 31/519 20060101
A61K031/519; A61K 31/5377 20060101 A61K031/5377; C07D 487/04
20060101 C07D487/04 |
Foreign Application Data
Date |
Code |
Application Number |
May 23, 2006 |
GB |
0610242.0 |
Claims
1. A method to treat a disorder in which pi3 kinase is implicated,
which comprises administering to a subject in need of such
treatment a compound of formula (I) ##STR00149## or a
pharmaceutically acceptable salt thereof, wherein: R.sup.1 is
C.sub.1-C.sub.3-alkyl; R.sup.2 is phenyl having the substitution
pattern, ##STR00150## wherein the R.sup.2 phenyl is fused at
R.sup.4-R.sup.5, R.sup.5-R.sup.6, R.sup.6-R.sup.7 or
R.sup.7-R.sup.8 by a further phenyl, a 5-6 membered heteroaryl
group selected from pyrazolyl, imidazoyl, oxazolyl, isoxazolyl,
thiazolyl, and isothiazolyl, a C.sub.4-C.sub.6 carbocyclic group or
a 5-6 membered heterocyclyl group, where the fused heteroaryl group
is independently optionally substituted by one or more groups
selected from List X; List X represents hydroxyl, cyano, nitro,
C.sub.1-C.sub.8-alkyl, C.sub.1-C.sub.8-alkenyl,
C.sub.1-C.sub.8-alkynyl, C.sub.1-C.sub.8-alkoxy,
C.sub.1-C.sub.8-alkenyloxy, C.sub.1-C.sub.8-alkynyloxy, phenyl, a
5-6 membered heteroaryl group, a C.sub.4-C.sub.6 carbocyclic group
or a 5-6 membered heterocyclyl group,
--(C.sub.0-C.sub.4-alkylene)-O--(C.sub.1-C.sub.4-alkylene)-R.sup.9,
(C.sub.0-C.sub.4-alkylene)-O--(C.sub.2-C.sub.4-alkylene)-R.sup.10,
(C.sub.0-C.sub.4-alkylene)-N(R.sup.11)--(C.sub.1-C.sub.4-alkylene)-R.sup.-
12,
--(C.sub.0-C.sub.4-alkylene)-N(R.sup.13)--(C.sub.2-C.sub.4-alkylene)-R-
.sup.14, halogen, formyl, C.sub.1-C.sub.8-alkylcarbonyl, carboxy,
C.sub.1-C.sub.8-alkoxycarbonyl,
C.sub.1-C.sub.8-alkylaminooxycarbonyl,
di-C.sub.1-C.sub.8-alkylaminooxycarbonyl, amino,
C.sub.1-C.sub.8-alkylamino, di-C.sub.1-C.sub.8-alkylamino,
C.sub.1-C.sub.8-alkylamidino,
--N(H)C(.dbd.NH)C.sub.1-C.sub.8-alkyl,
--N(C.sub.1-C.sub.8-alkyl)C(.dbd.NH)C.sub.1-C.sub.8-alkyl,
C.sub.1-C.sub.8-alkylaminocarbonyl,
di-C.sub.1-C.sub.8-alkylaminocarbonyl, aminocarbonylamino,
aminocarbonyl(C.sub.1-C.sub.8-alkyl)amino,
C.sub.1-C.sub.8-alkylaminocarbonylamino,
di-C.sub.1-C.sub.8-alkylaminocarbonylamino,
C.sub.1-C.sub.8-alkylaminocarbonyl(C.sub.1-C.sub.8-alkyl)amino,
di-C.sub.1-C.sub.8-alkylaminocarbonyl(C.sub.1-C.sub.8-alkyl)amino,
C.sub.1-C.sub.8-alkylcarbonylamino,
C.sub.1-C.sub.8-alkylcarbonyl(C.sub.1-C.sub.8-alkyl)amino,
C.sub.1-C.sub.8-alkylthiocarbonylamino,
C.sub.1-C.sub.8-alkylthiocarbonyl(C.sub.1-C.sub.8-alkyl)amino,
hydroxysulfonyl, C.sub.1-C.sub.8-alkylsulfonylamino,
C.sub.1-C.sub.8-thioalkyl, C.sub.1-C.sub.8-alkylsulfinyl,
C.sub.1-C.sub.8-alkylsulfonyl, aminosulfonyl,
C.sub.1-C.sub.8-alkylaminosulfonyl or
di-C.sub.1-C.sub.8-alkylaminosulfonyl, where each of the
afore-mentioned hydrocarbon groups may be optionally substituted,
where chemically feasible, by one or more halogen, hydroxyl, amino,
C.sub.1-C.sub.4-alkylamino, di-C.sub.1-C.sub.4-alkylamino or
C.sub.1-C.sub.4-alkoxy groups and where said cyclic groups may be
optionally substituted by one or more hydroxyl, cyano, nitro,
C.sub.1-C.sub.8-alkyl, C.sub.1-C.sub.8-alkenyl,
C.sub.1-C.sub.8-alkynyl, C.sub.1-C.sub.8-alkoxy,
C.sub.1-C.sub.8-alkenyloxy, C.sub.1-C.sub.8-alkynyloxy, halogen,
C.sub.1-C.sub.8-alkylcarbonyl, carboxy,
C.sub.1-C.sub.8-alkoxycarbonyl, amino, C.sub.1-C.sub.8-alkylamino,
di-C.sub.1-C.sub.8-alkylamino, C.sub.1-C.sub.8-alkylaminocarbonyl,
di-C.sub.1-C.sub.8-alkylaminocarbonyl,
C.sub.1-C.sub.8-alkylcarbonylamino,
C.sub.1-C.sub.8-alkylcarbonyl(C.sub.1-C.sub.8-alkyl)amino,
C.sub.1-C.sub.8-alkylsulfonylamino, C.sub.1-C.sub.8-thioalkyl,
C.sub.1-C.sub.8-alkylsulfinyl, C.sub.1-C.sub.8-alkylsulfonyl,
aminosulfonyl, C.sub.1-C.sub.8-alkylaminosulfonyl or
di-C.sub.1-C.sub.8-alkylaminosulfonyl groups; R.sup.9 and R.sup.12
independently represent hydrogen, C.sub.1-C.sub.4-alkenyl,
C.sub.1-C.sub.4-alkynyl, halogen, cyano, nitro,
C.sub.1-C.sub.8-alkylcarbonyl, carboxy,
C.sub.1-C.sub.8-alkoxycarbonyl, C.sub.1-C.sub.8-thioalkyl,
C.sub.1-C.sub.8-alkylsulfinyl, C.sub.1-C.sub.8-alkylsulfonyl,
aminosulfonyl, C.sub.1-C.sub.8-alkylaminosulfonyl,
di-C.sub.1-C.sub.8-alkylaminosulfonyl, phenyl, a C-linked 5-6
membered heteroaryl group, a C.sub.4-C.sub.6 carbocyclic group or a
C-linked 5-6 membered heterocyclyl group, where said phenyl or
cyclic groups may be optionally substituted by one or more
hydroxyl, cyano, nitro, C.sub.1-C.sub.8-alkyl,
C.sub.1-C.sub.8-alkenyl, C.sub.1-C.sub.8-alkynyl,
C.sub.1-C.sub.8-alkoxy, C.sub.1-C.sub.8-alkenyloxy,
C.sub.1-C.sub.8-alkynyloxy, halogen, C.sub.1-C.sub.8-alkylcarbonyl,
carboxy, C.sub.1-C.sub.8-alkoxycarbonyl, amino,
C.sub.1-C.sub.8-alkylamino, di-C.sub.1-C.sub.8-alkylamino,
C.sub.1-C.sub.8-alkylaminocarbonyl,
di-C.sub.1-C.sub.8-alkylaminocarbonyl,
C.sub.1-C.sub.8-alkylcarbonylamino,
C.sub.1-C.sub.8-alkylcarbonyl(C.sub.1-C.sub.8-alkyl)amino,
C.sub.1-C.sub.8-alkylsulfonylamino, C.sub.1-C.sub.8-thioalkyl,
C.sub.1-C.sub.8-alkylsulfinyl, C.sub.1-C.sub.8-alkylsulfonyl,
aminosulfonyl, C.sub.1-C.sub.8-alkylaminosulfonyl or
di-C.sub.1-C.sub.8-alkylaminosulfonyl groups; R.sup.10 and R.sup.14
independently represent hydroxyl, C.sub.1-C.sub.4-alkoxy,
C.sub.1-C.sub.4-alkenyloxy, C.sub.1-C.sub.4-alkynyloxy, amino,
C.sub.1-C.sub.8-alkylamino, di-C.sub.1-C.sub.8-alkylamino,
C.sub.1-C.sub.8-alkylaminocarbonyl,
di-C.sub.1-C.sub.8-alkylaminocarbonyl,
C.sub.1-C.sub.8-alkylcarbonylamino,
C.sub.1-C.sub.8-alkylcarbonyl(C.sub.1-C.sub.8-alkyl)amino,
C.sub.1-C.sub.8-alkylsulfonylamino, an N-linked 5-6 membered
heteroaryl group or an N-linked 5-6 membered heterocyclyl, where
said cyclic groups may be optionally substituted by one or more
hydroxyl, nitro, C.sub.1-C.sub.8-alkyl, C.sub.1-C.sub.8-alkenyl,
C.sub.1-C.sub.8-alkynyl, C.sub.1-C.sub.8-alkoxy,
C.sub.1-C.sub.8-alkenyloxy, C.sub.1-C.sub.8-alkynyloxy, halogen,
C.sub.1-C.sub.8-alkylcarbonyl, carboxy,
C.sub.1-C.sub.8-alkoxycarbonyl, amino, C.sub.1-C.sub.8-alkylamino,
di-C.sub.1-C.sub.8-alkylamino, C.sub.1-C.sub.8-alkylaminocarbonyl,
di-C.sub.1-C.sub.8-alkylaminocarbonyl,
C.sub.1-C.sub.8-alkylcarbonylamino,
C.sub.1-C.sub.8-alkylcarbonyl(C.sub.1-C.sub.8-alkyl)amino,
C.sub.1-C.sub.8-alkylsulfonylamino, C.sub.1-C.sub.8-thioalkyl,
C.sub.1-C.sub.8-alkylsulfinyl, C.sub.1-C.sub.8-alkylsulfonyl,
aminosulfonyl, C.sub.1-C.sub.8-alkylaminosulfonyl or
di-C.sub.1-C.sub.8-alkylaminosulfonyl groups; R.sup.11 and R.sup.13
independently represent hydrogen or C.sub.1-C.sub.6-alkyl; R.sup.3
is hydrogen; Y represents the group --N(R.sup.15)R.sup.16; and
R.sup.15 and R.sup.16 independently represent hydrogen or
C.sub.1-C.sub.4-alkyl.
2. The method according to claim 1, wherein: List X represents
hydroxyl, cyano, nitro, C.sub.1-C.sub.8-alkyl,
C.sub.1-C.sub.8-alkoxy, halogen, formyl, amino,
C.sub.1-C.sub.8-alkylamino, di-C.sub.1-C.sub.8-alkylamino,
C.sub.1-C.sub.8-alkylsulfonyl, aminosulfonyl,
C.sub.1-C.sub.8-alkylaminosulfonyl or
di-C.sub.1-C.sub.8-alkylaminosulfonyl.
3. The method according to claim 1, wherein: R.sup.1 is
C.sub.1-C.sub.3-alkyl; R.sup.2 is phenyl having the substitution
pattern, ##STR00151## wherein the R.sup.2 phenyl is fused at
R.sup.4-R.sup.5, R.sup.5-R.sup.6, R.sup.6-R.sup.7 or
R.sup.7-R.sup.8 by a heteroaryl group selected from pyrazolyl,
imidazoyl, oxazolyl, and isoxazolyl, where the fused heteroaryl
group is independently optionally substituted by one or more groups
selected from List X; List X represents hydroxyl, cyano, nitro,
amino, C.sub.1-C.sub.8-alkylamino, di-C.sub.1-C.sub.8-alkylamino,
or C.sub.1-C.sub.8-alkylamidino; R.sup.3 is hydrogen; Y is
--NH.sub.2.
4. The method of claim 1, wherein the disorder in which pi3 kinase
is implicated is a proliferative disease.
5. The method of claim 1, wherein the disorder in which pi3 kinase
is implicated is a respiratory disorder.
6. The method of claim 5 wherein the respiratory disorder is
selected from asthma, acute lung injury (ALI), adult/acute
respiratory distress syndrome (ARDS), chronic obstructive
pulmonary, airways or lung disease (COPD, COAD or COLD), emphysema,
exacerbation of airways hyperreactivity consequent to other drug
therapy, bronchitis and pneumoconiosis.
7. The method of claim 5 wherein the respiratory disorder is
asthma.
8. The method of claim 5, wherein the respiratory condition is
COPD.
9. The method of claim 3, wherein the disorder in which pi3 kinase
is implicated is a proliferative disease.
10. The method of claim 3, wherein the disorder in which pi3 kinase
is implicated is a respiratory disorder.
11. The method of claim 10 wherein the respiratory disorder is
selected from asthma, acute lung injury (ALI), adult/acute
respiratory distress syndrome (ARDS), chronic obstructive
pulmonary, airways or lung disease (COPD, COAD or COLD), emphysema,
exacerbation of airways hyperreactivity consequent to other drug
therapy, bronchitis and pneumoconiosis.
12. The method of claim 10 wherein the respiratory disorder is
asthma.
13. The method of claim 10, wherein the respiratory condition is
COPD.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation application of U.S. Ser.
No. 15/194,373, filed Jun. 27, 2016, which is a continuation of
U.S. Ser. No. 14/049,706, filed Oct. 9, 2013, which is a
continuation application of U.S. Ser. No. 12/227,314, filed Nov.
12, 2008, which is the National Phase filing of International
Application Serial No. PCT/EP2007/004501, filed May 21, 2007, and
claims priority to United Kingdom Application No. 0610242.0, filed
May 23, 2006, the contents of which are incorporated herein by
reference in their entirety.
FIELD OF THE INVENTION
[0002] The present invention relates to organic compounds, their
preparation and their use as pharmaceuticals.
[0003] International Patent Application Publication No. WO03029209
describes pyrazolo[3,4-d]pyrimidines useful as pharmaceuticals.
[0004] In a first aspect, the present invention provides use of a
compound of formula (I)
##STR00002##
or a salt, suitably a pharmaceutically acceptable salt, or solvate
thereof, wherein: R.sup.1 is C.sub.1-C.sub.3-alkyl, optionally
substituted by one to seven fluoro groups; R.sup.2 is a 5-6
membered hetaroaryl group, or R.sup.2 is phenyl having the
substitution pattern,
##STR00003##
where the 5-6 membered heteroaryl group is optionally fused by
phenyl, a further 5-6 membered heteroaryl group, a C.sub.4-C.sub.6
carbocyclic group or a 5-6 membered heterocyclyl group and where
the R.sup.2 phenyl is optionally fused at R.sup.4-R.sup.5,
R.sup.5-R.sup.6, R.sup.6-R.sup.7 or R.sup.7-R.sup.8 by a further
phenyl, a 5-6 membered heteroaryl group, a C.sub.4-C.sub.6
carbocyclic group or a 5-6 membered heterocyclyl group, where the
5-6 membered heteroaryl or fused 5-6 membered heteroaryl, phenyl or
the fused phenyl group is independently optionally substituted by
one or more groups selected from List X; List X represents
hydroxyl, cyano, nitro, C.sub.1-C.sub.8-alkyl,
C.sub.1-C.sub.8-alkenyl, C.sub.1-C.sub.8-alkynyl,
C.sub.1-C.sub.8-alkoxy, C.sub.1-C.sub.8-alkenyloxy,
C.sub.1-C.sub.8-alkynyloxy, phenyl, a 5-6 membered heteroaryl
group, a C.sub.4-C.sub.6 carbocyclic group or a 5-6 membered
heterocyclyl group,
--(C.sub.0-C.sub.4-alkylene)-O--(C.sub.1-C.sub.4-alkylene)-R.sup.9,
(C.sub.0-C.sub.4-alkylene)-O--(C.sub.2-C.sub.4-alkylene)-R.sup.10,
(C.sub.0-C.sub.4-alkylene)-N(R.sup.11)--(C.sub.1-C.sub.4-alkylene)-R.sup.-
12,
--(C.sub.0-C.sub.4-alkylene)-N(R.sup.13)--(C.sub.2-C.sub.4-alkylene)-R-
.sup.14, halogen, formyl, C.sub.1-C.sub.8-alkylcarbonyl, carboxy,
C.sub.1-C.sub.8-alkoxycarbonyl,
C.sub.1-C.sub.8-alkylaminooxycarbonyl,
di-C.sub.1-C.sub.8-alkylaminooxycarbonyl, amino,
C.sub.1-C.sub.8-alkylamino, di-C.sub.1-C.sub.8-alkylamino,
C.sub.1-C.sub.8-alkylamidino,
--N(H)C(.dbd.NH)C.sub.1-C.sub.8-alkyl,
--N(C.sub.1-C.sub.8-alkyl)C(.dbd.NH)C.sub.1-C.sub.8-alkyl,
C.sub.1-C.sub.8-alkylaminocarbonyl,
di-C.sub.1-C.sub.8-alkylaminocarbonyl, aminocarbonylamino,
aminocarbonyl(C.sub.1-C.sub.8-alkyl)amino,
C.sub.1-C.sub.8-alkylaminocarbonylamino,
di-C.sub.1-C.sub.8-alkylaminocarbonylamino,
C.sub.1-C.sub.8-alkylaminocarbonyl(C.sub.1-C.sub.8-alkyl)amino,
di-C.sub.1-C.sub.8-alkylaminocarbonyl(C.sub.1-C.sub.8-alkyl)amino,
C.sub.1-C.sub.8-alkylcarbonylamino,
C.sub.1-C.sub.8-alkylcarbonyl(C.sub.1-C.sub.8-alkyl)amino,
C.sub.1-C.sub.8-alkylthiocarbonylamino,
C.sub.1-C.sub.8-alkylthiocarbonyl(C.sub.1-C.sub.8-alkyl)amino,
hydroxysulfonyl, C.sub.1-C.sub.8-alkylsulfonylamino,
C.sub.1-C.sub.8-thioalkyl, C.sub.1-C.sub.8-alkylsulfinyl,
C.sub.1-C.sub.8-alkylsulfonyl, aminosulfonyl,
C.sub.1-C.sub.8-alkylaminosulfonyl or
di-C.sub.1-C.sub.8-alkylaminosulfonyl, where each of the
afore-mentioned hydrocarbon groups may be optionally substituted,
where chemically feasible, by one or more halogen, hydroxyl, amino,
C.sub.1-C.sub.4-alkylamino, di-C.sub.1-C.sub.4-alkylamino or
C.sub.1-C.sub.4-alkoxy groups and where said cyclic groups may be
optionally substituted by one or more hydroxyl, cyano, nitro,
C.sub.1-C.sub.8-alkyl, C.sub.1-C.sub.8-alkenyl,
C.sub.1-C.sub.8-alkynyl, C.sub.1-C.sub.8-alkoxy,
C.sub.1-C.sub.8-alkenyloxy, C.sub.1-C.sub.8-alkynyloxy, halogen,
C.sub.1-C.sub.8-alkylcarbonyl, carboxy,
C.sub.1-C.sub.8-alkoxycarbonyl, amino, C.sub.1-C.sub.8-alkylamino,
di-C.sub.1-C.sub.8-alkylamino, C.sub.1-C.sub.8-alkylaminocarbonyl,
di-C.sub.1-C.sub.8-alkylaminocarbonyl,
C.sub.1-C.sub.8-alkylcarbonylamino,
C.sub.1-C.sub.8-alkylcarbonyl(C.sub.1-C.sub.8-alkyl)amino,
C.sub.1-C.sub.8-alkylsulfonylamino, C.sub.1-C.sub.8-thioalkyl,
C.sub.1-C.sub.8-alkylsulfinyl, C.sub.1-C.sub.8-alkylsulfonyl,
aminosulfonyl, C.sub.1-C.sub.8-alkylaminosulfonyl or
di-C.sub.1-C.sub.8-alkylaminosulfonyl groups; R.sup.9 and R.sup.12
independently represent hydrogen, C.sub.1-C.sub.4-alkenyl,
C.sub.1-C.sub.4-alkynyl, halogen, cyano, nitro,
C.sub.1-C.sub.8-alkylcarbonyl, carboxy,
C.sub.1-C.sub.8-alkoxycarbonyl, C.sub.1-C.sub.8-thioalkyl,
C.sub.1-C.sub.8-alkylsulfinyl, C.sub.1-C.sub.8-alkylsulfonyl,
aminosulfonyl, C.sub.1-C.sub.8-alkylaminosulfonyl,
di-C.sub.1-C.sub.8-alkylaminosulfonyl, phenyl, a C-linked 5-6
membered heteroaryl group, a C.sub.4-C.sub.6 carbocyclic group or a
C-linked 5-6 membered heterocyclyl group, where said phenyl or
cyclic groups may be optionally substituted by one or more
hydroxyl, cyano, nitro, C.sub.1-C.sub.8-alkyl,
C.sub.1-C.sub.8-alkenyl, C.sub.1-C.sub.8-alkynyl,
C.sub.1-C.sub.8-alkoxy, C.sub.1-C.sub.8-alkenyloxy,
C.sub.1-C.sub.8-alkynyloxy, halogen, C.sub.1-C.sub.8-alkylcarbonyl,
carboxy, C.sub.1-C.sub.8-alkoxycarbonyl, amino,
C.sub.1-C.sub.8-alkylamino, di-C.sub.1-C.sub.8-alkylamino,
C.sub.1-C.sub.8-alkylaminocarbonyl,
di-C.sub.1-C.sub.8-alkylaminocarbonyl,
C.sub.1-C.sub.8-alkylcarbonylamino,
C.sub.1-C.sub.8-alkylcarbonyl(C.sub.1-C.sub.8-alkyl)amino,
C.sub.1-C.sub.8-alkylsulfonylamino, C.sub.1-C.sub.8-thioalkyl,
C.sub.1-C.sub.8-alkylsulfinyl, C.sub.1-C.sub.8-alkylsulfonyl,
aminosulfonyl, C.sub.1-C.sub.8-alkylaminosulfonyl or
di-C.sub.1-C.sub.8-alkylaminosulfonyl groups; R.sup.10 and R.sup.14
independently represent hydroxyl, C.sub.1-C.sub.4-alkoxy,
C.sub.1-C.sub.4-alkenyloxy, C.sub.1-C.sub.4-alkynyloxy, amino,
C.sub.1-C.sub.8-alkylamino, di-C.sub.1-C.sub.8-alkylamino,
C.sub.1-C.sub.8-alkylaminocarbonyl,
di-C.sub.1-C.sub.8-alkylaminocarbonyl,
C.sub.1-C.sub.8-alkylcarbonylamino,
C.sub.1-C.sub.8-alkylcarbonyl(C.sub.1-C.sub.8-alkyl)amino,
C.sub.1-C.sub.8-alkylsulfonylamino, an N-linked 5-6 membered
heteroaryl group or an N-linked 5-6 membered heterocycly where said
cyclic groups may be optionally substituted by one or more
hydroxyl, nitro, C.sub.1-C.sub.8-alkyl, C.sub.1-C.sub.8-alkenyl,
C.sub.1-C.sub.8-alkynyl, C.sub.1-C.sub.8-alkoxy,
C.sub.1-C.sub.8-alkenyloxy, C.sub.1-C.sub.8-alkynyloxy, halogen,
C.sub.1-C.sub.8-alkylcarbonyl, carboxy,
C.sub.1-C.sub.8-alkoxycarbonyl, amino, C.sub.1-C.sub.8-alkylamino,
di-C.sub.1-C.sub.8-alkylamino, C.sub.1-C.sub.8-alkylaminocarbonyl,
di-C.sub.1-C.sub.8-alkylaminocarbonyl,
C.sub.1-C.sub.8-alkylcarbonylamino,
C.sub.1-C.sub.8-alkylcarbonyl(C.sub.1-C.sub.8-alkyl)amino,
C.sub.1-C.sub.8-alkylsulfonylamino, C.sub.1-C.sub.8-thioalkyl,
C.sub.1-C.sub.8-alkylsulfinyl, C.sub.1-C.sub.8-alkylsulfonyl,
aminosulfonyl, C.sub.1-C.sub.8-alkylaminosulfonyl or
di-C.sub.1-C.sub.8-alkylaminosulfonyl groups; R.sup.11 and R.sup.13
independently represent hydrogen or C.sub.1-C.sub.6-alkyl; R.sup.3
is hydrogen, amino or C.sub.1-C.sub.3-alkylamino; Y represents
hydrogen, C.sub.1-C.sub.8-alkyl, C.sub.1-C.sub.8-alkoxy where each
of the afore-mentioned hydrocarbon groups may be optionally
substituted, where chemically feasible, by one or more halogen,
hydroxyl, amino, C.sub.1-C.sub.8-alkylamino,
di-C.sub.1-C.sub.8-alkylamino or C.sub.1-C.sub.8-alkoxy groups, or
Y represents the group
--(C.sub.0-C.sub.4-alkylene)-N(R.sup.5)R.sup.6; and R.sup.15 and
R.sup.16 independently represent hydrogen or C.sub.1-C.sub.4-alkyl,
or R.sup.15 is hydrogen and R.sup.16 is C.sub.1-C.sub.4-alkyl
substituted by phenyl, a 5-6 membered heteroaryl group, a
C.sub.4-C.sub.6 carbocyclic group or a 5-6 membered heterocyclyl
group, where said rings are optionally substituted by one or more
hydroxyl, nitro, C.sub.1-C.sub.8-alkyl, C.sub.1-C.sub.8-alkenyl,
C.sub.1-C.sub.8-alkynyl, C.sub.1-C.sub.8-alkoxy,
C.sub.1-C.sub.8-alkenyloxy, C.sub.1-C.sub.8-alkynyloxy, halogen,
C.sub.1-C.sub.8-alkylcarbonyl, carboxy,
C.sub.1-C.sub.8-alkoxycarbonyl, amino, C.sub.1-C.sub.8-alkylamino,
di-C.sub.1-C.sub.8-alkylamino, C.sub.1-C.sub.8-alkylaminocarbonyl,
di-C.sub.1-C.sub.8-alkylaminocarbonyl,
C.sub.1-C.sub.8-alkylcarbonylamino,
C.sub.1-C.sub.8-alkylcarbonyl(C.sub.1-C.sub.8-alkyl)amino,
C.sub.1-C.sub.8-alkylsulfonylamino, C.sub.1-C.sub.8-thioalkyl,
C.sub.1-C.sub.8-alkylsulfinyl, C.sub.1-C.sub.8-alkylsulfonyl,
aminosulfonyl, C.sub.1-C.sub.8-alkylaminosulfonyl or
di-C.sub.1-C.sub.8-alkylaminosulfonyl groups, where each of the
afore-mentioned hydrocarbon groups may be optionally substituted,
where chemically feasible by one or more halogen, hydroxyl, amino,
C.sub.1-C.sub.4-alkylamino, di-C.sub.1-C.sub.4-alkylamino or
C.sub.1-C.sub.4-alkoxy groups, or R.sup.15 and R.sup.16 together
with the N to which they are attached form a 5-6-membered
heterocyclic ring; in the treatment of, or in the manufacture of a
medicament for the treatment of, a disorder in which pi3 kinase,
particularly pi3 kinase gamma, is implicated, particularly a
respiratory disorder, such as asthma or COPD.
[0005] As a yet further alternative aspect, there is provided a
method of treating a disorder in which pi3 kinase is implicated in
a patient comprising administering an effective amount of a
compound of formula (I), or a pharmaceutically acceptable salt or
solvate thereof. Suitably, the disorder is selected from a
respiratory disorder, such as asthma or COPD.
[0006] In a further aspect of the present invention, there is
provided a compound of formula (I), or a pharmaceutically
acceptable salt or solvate thereof, with the proviso that the
compounds
N-[4-[6-(ethylamino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]-N'-
-[2-fluoro-5-(trifluoromethyl)phenyl urea and
[4-(6-amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]-1,1-dimethy-
l carbamic acid ester are excluded.
[0007] In a yet further aspect, the present invention provides a
compound of formula (IA):
##STR00004##
or a salt, suitably a pharmaceutically acceptable salt, or solvate
thereof, wherein: R.sup.1a is C.sub.1-C.sub.3-alkyl, optionally
substituted by one to seven fluoro groups; R.sup.2a a 5-6 membered
hetaroaryl group substituted by one or more groups selected from
List Xa, or R.sup.2 is phenyl having the substitution pattern,
##STR00005##
where the phenyl may be fused at R.sup.5a-R.sup.6a,
R.sup.6a-R.sup.7a or R.sup.7a-R.sup.8a by a 5-6 membered heteroaryl
group, a C.sub.4-C.sub.6 carbocyclic group or a 5-6 membered
heterocyclyl group, where the phenyl or the fused phenyl group may
be optionally substituted by one or more groups selected from List
Xa; List Xa represents hydroxyl, cyano, nitro,
C.sub.1-C.sub.8-alkyl, C.sub.1-C.sub.8-alkenyl,
C.sub.1-C.sub.8-alkynyl, C.sub.1-C.sub.8-alkoxy,
C.sub.1-C.sub.8-alkenyloxy, C.sub.1-C.sub.8-alkynyloxy,
--O--(C.sub.1-C.sub.4-alkylene)-R.sup.9a,
--O--(C.sub.2-C.sub.4-alkylene)-R.sup.10a, halogen,
C.sub.1-C.sub.8-alkylcarbonyl, carboxy,
C.sub.1-C.sub.8-alkoxycarbonyl, amino, C.sub.1-C.sub.8-alkylamino,
di-C.sub.1-C.sub.8-alkylamino, C.sub.1-C.sub.8-alkylaminocarbonyl,
di-C.sub.1-C.sub.8-alkylaminocarbonyl,
C.sub.1-C.sub.8-alkylcarbonylamino,
C.sub.1-C.sub.8-alkylcarbonyl(C.sub.1-C.sub.8-alkyl)amino,
C.sub.1-C.sub.8-alkylsulfonylamino, C.sub.1-C.sub.8-thioalkyl,
C.sub.1-C.sub.8-alkylsulfinyl, C.sub.1-C.sub.8-alkylsulfonyl,
aminosulfonyl, C.sub.1-C.sub.8-alkylaminosulfonyl or
di-C.sub.1-C.sub.8-alkylaminosulfonyl, where each of the
afore-mentioned hydrocarbon groups may be optionally substituted by
one or more halogen, hydroxyl or C.sub.1-C.sub.8-alkoxy groups;
R.sup.9a represents C.sub.1-C.sub.4-alkenyl,
C.sub.1-C.sub.4-alkynyl, halogen, cyano, nitro,
C.sub.1-C.sub.8-alkylcarbonyl, carboxy,
C.sub.1-C.sub.8-alkoxycarbonyl, C.sub.1-C.sub.8-thioalkyl,
C.sub.1-C.sub.8-alkylsulfinyl, C.sub.1-C.sub.8-alkylsulfonyl,
aminosulfonyl, C.sub.1-C.sub.8-alkylaminosulfonyl,
di-C.sub.1-C.sub.8-alkylaminosulfonyl, phenyl, a C-linked 5-6
membered heteroaryl group, a C.sub.4-C.sub.6 carbocyclic group or a
C-linked 5-6 membered heterocyclyl group, where said phenyl or
cyclic groups may be optionally substituted by one or more
hydroxyl, cyano, nitro, C.sub.1-C.sub.8-alkyl,
C.sub.1-C.sub.8-alkenyl, C.sub.1-C.sub.8-alkynyl,
C.sub.1-C.sub.8-alkoxy, C.sub.1-C.sub.8-alkenyloxy,
C.sub.1-C.sub.8-alkynyloxy, halogen, C.sub.1-C.sub.8-alkylcarbonyl,
carboxy, C.sub.1-C.sub.8-alkoxycarbonyl, amino,
C.sub.1-C.sub.8-alkylamino, di-C.sub.1-C.sub.8-alkylamino,
C.sub.1-C.sub.8-alkylaminocarbonyl,
di-C.sub.1-C.sub.8-alkylaminocarbonyl,
C.sub.1-C.sub.8-alkylcarbonylamino,
C.sub.1-C.sub.8-alkylcarbonyl(C.sub.1-C.sub.8-alkyl)amino,
C.sub.1-C.sub.8-alkylsulfonylamino, C.sub.1-C.sub.8-thioalkyl,
C.sub.1-C.sub.8-alkylsulfinyl, C.sub.1-C.sub.8-alkylsulfonyl,
aminosulfonyl, C.sub.1-C.sub.8-alkylaminosulfonyl or
di-C.sub.1-C.sub.8-alkylaminosulfonyl groups; R.sup.10a represents
hydroxyl, C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.4-alkenyloxy,
C.sub.1-C.sub.4-alkynyloxy, amino, C.sub.1-C.sub.8-alkylamino,
di-C.sub.1-C.sub.8-alkylamino, C.sub.1-C.sub.8-alkylaminocarbonyl,
di-C.sub.1-C.sub.8-alkylaminocarbonyl,
C.sub.1-C.sub.8-alkylcarbonylamino,
C.sub.1-C.sub.8-alkylcarbonyl(C.sub.1-C.sub.8-alkyl)amino,
C.sub.1-C.sub.8-alkylsulfonylamino, an N-linked 5-6 membered
heteroaryl group or an N-linked 5-6 membered heterocycly where said
cyclic groups may be optionally substituted by one or more
hydroxyl, nitro, C.sub.1-C.sub.8-alkyl, C.sub.1-C.sub.8-alkenyl,
C.sub.1-C.sub.8-alkynyl, C.sub.1-C.sub.8-alkoxy,
C.sub.1-C.sub.8-alkenyloxy, C.sub.1-C.sub.8-alkynyloxy, halogen,
C.sub.1-C.sub.8-alkylcarbonyl, carboxy,
C.sub.1-C.sub.8-alkoxycarbonyl, amino, C.sub.1-C.sub.8-alkylamino,
di-C.sub.1-C.sub.8-alkylamino, C.sub.1-C.sub.8-alkylaminocarbonyl,
di-C.sub.1-C.sub.8-alkylaminocarbonyl,
C.sub.1-C.sub.8-alkylcarbonylamino,
C.sub.1-C.sub.8-alkylcarbonyl(C.sub.1-C.sub.8-alkyl)amino,
C.sub.1-C.sub.8-alkylsulfonylamino, C.sub.1-C.sub.8-thioalkyl,
C.sub.1-C.sub.8-alkylsulfinyl, C.sub.1-C.sub.8-alkylsulfonyl,
aminosulfonyl, C.sub.1-C.sub.8-alkylaminosulfonyl or
di-C.sub.1-C.sub.8-alkylaminosulfonyl groups; and R.sup.3a is
hydrogen, amino or C.sub.1-C.sub.3-alkylamino.
[0008] Alkyl, alkenyl, alkynyl, alkylene, and alkoxy groups,
containing the requisite number of carbon atoms, can be unbranched
or branched. Examples of alkyl include methyl, ethyl, n-propyl,
i-propyl, n-butyl, i-butyl, sec-butyl and t-butyl. Examples of
alkoxy include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy,
i-butoxy, sec-butoxy and t-butoxy. Examples of alkylene include
methylene, 1,1-ethylene, 1,2-ethylene, 1,1-propylene,
1,2-propylene, 1,3-propylene and 2,2-propylene.
[0009] A "hydrocarbon group optionally substituted" refers to
replacement of a C--H bond by the requisite bond. Where the
substituent is a halogen, the group formed is defined as a
C.sub.1-C.sub.8-haloalkyl. For example, where the substituent is
fluoro, common haloalkyl groups are trifluoroalkyl,
2,2,2-trifluoroethyl or 2,2,2,1,1-pentafluoroethyl groups.
[0010] "Carbocyclic group" denotes a hydrocarbon ring having the
requisite number of carbon atoms, for example cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl.
[0011] "Halogen" or "halo" may be fluorine, chlorine, bromine or
iodine.
[0012] A heterocyclyl group refers to a saturated or partially
unsaturated ring comprising one or more O, N or S heteratoms.
Specific examples of heterocyclyl groups include [1,3]dioxolane,
[1,4]dioxane, oxiranyl, aziridinyl, oxetanyl, azetidinyl,
tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl,
morpholino, thiomorpholinyl, piperazinyl, azepinyl, oxapinyl,
oxazepinyl and diazepinyl.
[0013] A heteroaryl group refers to an aromatic ring comprising one
or more O, N or S heteroatoms. Examples of heteroaryl groups
include pyridyl, thienyl, furanyl, pyrrolyl, pyrazolyl, imidazoyl,
oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl,
oxadiazolyl, thiadiazolyl and tetrazolyl, and bicyclic heteroaryl
or phenyl fused by heteroaryl groups include indolyl, quinolinyl,
isoquinolinyl, benzimidazolyl and benzofuranyl.
[0014] Throughout this specification and in the claims that follow,
unless the context requires otherwise, the word "comprise", or
variations such as "comprises" or "comprising", will be understood
to imply the inclusion of a stated integer or step or group of
integers or steps but not the exclusion of any other integer or
step or group of integers or steps.
[0015] The following suitable or preferred features of a compound
of formula (I) may be incorporated into the definition of formula
(I) and combined individually or in any combination. It will be
understood that the compounds of formula (IA) are equivalent to the
compounds of formula (I) though the R groups do not correspond, and
that the suitable and preferred features of compounds of formula
(I) apply equally to compounds of formula (IA).
[0016] According to formula (I), R.sup.1 is suitably methyl or
trifluoromethyl, preferably methyl.
[0017] According to formula (I), the R.sup.2 ring is suitably
substituted.
[0018] According to formula (I), where R.sup.2 is an optionally
substituted heteroaryl, including fused heteroaryl, the heteroaryl
is suitably
(i) pyridyl, e.g. 3-pyridyl or 4-pyridyl, optionally substituted by
halogen, e.g. fluoro, trifluoromethyl, methylsulfonyl or
C.sub.1-C.sub.8-alkoxy, e.g. methoxy, (ii) thienyl, e.g. 2-thienyl,
optionally substituted by C.sub.1-C.sub.8-alkylcarbonyl, e.g.
acetyl, or halo, e.g. chloro, (iii) isoxazolyl, e.g. 4-isoxazolyl,
optionally substituted by one or two C.sub.1-C.sub.8-alkyl, e.g.
3,5-dimethyl, (iv) furanyl, e.g. 2-furanyl, or (v) pyrimidyl, e.g.
5-pyrimidyl, optionally substituted by a 5-6 membered heterocyclyl,
e.g. piperazinyl, e.g. 2-piperazinyl or one or two
C.sub.1-C.sub.8-alkoxy, e.g. 2-methoxy or 2,4 di-methoxy.
[0019] Where the R.sup.2 phenyl ring is fused by a further phenyl
to form a naphthyl group, the ring is suitably fused at
R.sup.7-R.sup.8 to form a 1-naphthyl, and the resulting naphthyl is
optionally substituted, e.g. by C.sub.1-C.sub.8-alkoxy, e.g.
ethoxy, e.g. 2-ethoxy.
[0020] Where the R.sup.2 phenyl ring is fused by a 5-6 membered
heteroaryl, the ring is suitably fused at R.sup.5-R.sup.6,
R.sup.6-R.sup.7, or R.sup.7-R.sup.8, suitably by a pyridine,
pyrrole or furan ring. Where an indole or benzofuran ring is
formed, this is suitably 5- or 6-linked. Where a quinolinyl ring is
formed, this is suitably 8-linked. Said rings are optionally
substituted, e.g. an indole ring may be suitably optionally
substituted, e.g. by one or more C.sub.1-C.sub.8-alkyl, e.g.
2,3-dimethyl.
[0021] Where the R.sup.2 phenyl ring is fused by a 5-6 membered
heterocyclyl, the ring is suitably fused at R.sup.5-R.sup.6, e.g.
to form a benzo 1,3-dioxole or a 2,3-Dihydro-benzo[1,4]dioxine
group.
[0022] Where R.sup.2 is a substituted phenyl, suitable substituents
from List X are one two, three or four substituents, suitably two
or three substituents selected from
(i) hydroxyl, (ii) cyano, (iii) nitro, (iv) C.sub.1-C.sub.8-alkyl,
e.g. methyl or isobutyl, (v) C.sub.1-C.sub.8-haloalkyl, e.g.
trifluoromethyl, (vi) C.sub.1-C.sub.8-alkoxy, e.g. methoxy, ethoxy,
n-propoxy, isopropoxy, (vii) a 5-6 membered heterocyclyl group,
e.g. N-piperazinyl, (viii) --O--(C.sub.1-C.sub.4-alkylene)-R.sup.9,
e.g. --O-methylene-R.sup.9, e.g. carboxymethoxy, cyanomethoxy or
optionally substituted benzyloxy, e.g. benzyloxy or
2-fluorobenzyloxy, (ix) --O--(C.sub.2-C.sub.4-alkylene)-R.sup.10,
e.g. --O-ethylene or propylene-R.sup.10, e.g. N-pyrrolidylethoxy,
N-imidazolylethoxy, N-morpholinoethoxy, methoxyethoxy,
hydroxyethoxy, hydroxypropoxy or N-morpholinopropoxy, (x)
--(C.sub.0-C.sub.4-alkylene)-N(R.sup.13)--(C.sub.2-C.sub.4-alkylene)-R.su-
p.14, where C.sub.0-C.sub.4-alkylene is suitably methylene,
R.sup.13 is suitably hydrogen, C.sub.2-C.sub.4-alkylene is suitably
n-propylene and R.sup.14 is suitably di-C.sub.1-C.sub.8-alkylamino,
e.g. dimethylamino, e.g. to form dimethylaminopropylaminomethyl,
(xi) halogen, e.g. fluoro, chloro or bromo, (xii) formyl, (xiii)
C.sub.1-C.sub.8-alkylcarbonyl, e.g. acetyl, (xiv)
C.sub.1-C.sub.8-alkylaminocarbonyl, e.g. methylaminocarbonyl,
isopropylaminocarbonyl or isobutylaminocarbonyl, (xv)
di-C.sub.1-C.sub.8-alkylaminocarbonyl, e.g. dimethylaminocarbonyl,
(xvi) C.sub.1-C.sub.8-alkylcarbonylamino, e.g. methylcarbonylamino,
(xvii) C.sub.1-C.sub.8-alkylsulfonylamino, e.g.
methylsulfonylamino, (xviii) hydroxysulfonyl, (xix)
C.sub.1-C.sub.8-alkylsulfonyl, e.g. methylsulfonyl, (xx)
C.sub.1-C.sub.8-alkylaminosulfonyl, e.g. methylaminosulfonyl or
isopropylaminosulfonyl, (xxi)
di-C.sub.1-C.sub.8-alkylaminosulfonyl, e.g. dimethylaminosulfonyl,
(xxii) C.sub.1-C.sub.8-alkyl substituted by hydroxy, e.g.
hydroxymethyl, (xxiii) C.sub.1-C.sub.8-alkoxy substituted by one or
more, e.g. three halogens, e.g. fluoro, e.g. trifluoromethoxy, and
(xxiv) amino.
[0023] According to formula (I), R.sup.9 suitably represents
carboxy, cyano or phenyl, optionally substituted, e.g. by halogen,
e.g. fluoro, e.g. 2-fluoro.
[0024] According to formula (I), R.sup.10 suitably represents
hydroxyl, C.sub.1-C.sub.4-alkoxy, an N-linked 5-6 membered
heteroaryl group, e.g. N-imidazolyl or an N-linked 5-6 membered
heterocycly, e.g. N-pyrrolidyl or N-morpholino.
[0025] According to formula (I), R.sup.13 is suitably hydrogen.
[0026] According to formula (I), R.sup.14 is suitably
di-C.sub.1-C.sub.8-alkylamino, e.g. dimethylamino.
[0027] Where R.sup.2 is a substituted phenyl, R.sup.4-R.sup.8 may
be substituted by any combination of selections of the following
suitable substituents, suitably one, two, three or four of
R.sup.4-R.sup.8, more suitably two or three.
[0028] R.sup.4 is suitably selected from hydrogen,
C.sub.1-C.sub.8-alkoxy, e.g. methoxy or n-propoxy and halogen, e.g.
fluoro.
[0029] R.sup.5 is suitably selected from hydrogen, hydroxyl, cyano,
formyl, C.sub.1-C.sub.8-haloalkyl, e.g. trifluoromethyl, carboxy,
C.sub.1-C.sub.8-alkoxy, e.g. methoxy, halogen, e.g. fluoro, chloro
or bromo, C.sub.1-C.sub.8-alkylcarbonyl, e.g. acetyl,
C.sub.1-C.sub.8-alkylaminocarbonyl, e.g. methylaminocarbonyl,
isopropylaminocarbonyl or isobutylcarbonyl,
di-C.sub.1-C.sub.8-alkylaminocarbonyl, e.g. dimethylaminocarbonyl,
C.sub.1-C.sub.8-alkylsulfonylamino, e.g. methylsulfonylamino,
C.sub.1-C.sub.8-thioalkyl, C.sub.1-C.sub.8-alkylsulfinyl,
C.sub.1-C.sub.8-alkylsulfonyl, e.g. methylsulfonyl,
--(C.sub.0-C.sub.4-alkylene)-N(R.sup.13)--(C.sub.2-C.sub.4-alkylene)-R.su-
p.14, e.g. dimethylaminopropylaminomethyl, C.sub.1-C.sub.8-alkyl
substituted by hydroxy, e.g. hydroxymethyl, and
hydroxysulfonyl.
[0030] R.sup.6 is suitably selected from hydrogen, hydroxyl, cyano,
nitro, formyl, carboxy, C.sub.1-C.sub.8-alkyl, e.g. methyl or
isobutyl, C.sub.1-C.sub.8-alkoxy e.g. methoxy, ethoxy or
isopropoxy, --O--(C.sub.1-C.sub.4-alkylene)-R.sup.9, suitably
--O-methylene-R.sup.9, e.g. benzyloxy or cyanomethoxy,
--O--(C.sub.2-C.sub.4-alkylene)-R.sup.10, suitably --O-- ethylene
or propylene-R.sup.10, e.g. N-pyrrolidylethoxy, imidazolylethoxy,
N-morpholinoethoxy, methoxyethoxy, hydroxyethoxy, hydroxypropoxy or
N-morpholinopropoxy, halogen, e.g. fluoro or chloro,
C.sub.1-C.sub.8-alkylcarbonyl, e.g. acetyl, amino,
C.sub.1-C.sub.8-alkylaminocarbonyl, e.g. isopropylaminocarbonyl,
C.sub.1-C.sub.8-alkylsulfonylamino, e.g. methylsulfonylamino,
C.sub.1-C.sub.8-alkylsulfonyl, e.g. methylsulfonyl, and
C.sub.1-C.sub.8-alkoxy substituted by one or more, e.g. three
halogens, e.g. fluoro, e.g. trifluoromethoxy.
[0031] R.sup.7 is suitably selected from hydrogen, hydroxyl,
formyl, C.sub.1-C.sub.8-alkoxy, e.g. methoxy, halogen, e.g. bromo,
chloro or fluoro, --O--(C.sub.1-C.sub.4-alkylene)-R.sup.9, e.g.
carboxymethoxy, C.sub.1-C.sub.8-alkylcarbonylamino, e.g.
methylcarbonylamino, and di-C.sub.1-C.sub.8-alkylaminosulfonyl,
e.g. dimethylaminosulfonyl.
[0032] R.sup.8 is suitably selected from hydrogen, hydroxyl,
C.sub.1-C.sub.8-alkoxy, e.g. methoxy,
--O--(C.sub.2-C.sub.4-alkylene)-R.sup.10, e.g.
--O-ethylene-O--R.sup.10, e.g. hydroxyethoxy, and
--O--(C.sub.1-C.sub.4-alkylene)-R.sup.9, suitably
--O-methylene-R.sup.9, e.g. benzyloxy.
[0033] Preferably, R.sup.4 is selected from hydrogen, methoxy,
n-propoxy and fluoro.
[0034] Preferably, R.sup.5 is selected from hydrogen, hydroxyl,
cyano, formyl, trifluoromethyl, carboxy, methoxy, fluoro, chloro,
bromo, acetyl, methylaminocarbonyl, isopropylaminocarbonyl,
isobutylcarbonyl, dimethylaminocarbonyl, methylsulfonylamino,
methylsulfonyl, dimethylaminopropylaminomethyl hydroxymethyl and
hydroxysulfonyl.
[0035] Preferably, R.sup.6 selected from hydrogen, hydroxyl, cyano,
nitro, formyl, carboxy, methyl, isobutyl, methoxy, ethoxy,
isopropoxy, benzyloxy, cyanomethoxy, N-pyrrolidylethoxy,
imidazolylethoxy, N-morpholinoethoxy, methoxyethoxy, hydroxyethoxy,
hydroxypropoxy, N-morpholinopropoxy, fluoro, chloro, acetyl, amino,
isopropylaminocarbonyl, methylsulfonylamino, methylsulfonyl and
trifluoromethoxy,
[0036] Preferably, R.sup.7 is selected from hydrogen, hydroxyl,
formyl, methoxy, bromo, chloro, fluoro, carboxymethoxy,
methylcarbonylamino and dimethylaminosulfonyl.
[0037] Preferably, R.sup.8 is selected from hydrogen, hydroxyl,
methoxy, hydroxyethoxy and benzyloxy.
[0038] When R.sup.2 is phenyl, a preferred substitution pattern is
where R.sup.2 is substituted by at least a fluoro group at
R.sup.5.
[0039] Most preferably, R.sup.2 is [0040]
3-fluoro-4-methoxy-phenyl, [0041] 3-fluoro-4-hydroxy-phenyl, [0042]
3-fluoro-4-(methylsulfonylamino)-phenyl, [0043]
3-fluoro-4-hydroxy-5-bromo-phenyl, [0044]
3,5-bromo-4-hydroxy-phenyl, [0045]
3-fluoro-4-(hydroxyethoxy)-phenyl, or [0046]
3-fluoro-4-hydroxy-5-methoxy-phenyl.
[0047] According to formula (I), R.sup.3 is suitably hydrogen,
amino or methylamino, preferably amino.
[0048] According to formula (I), Y is suitably Y hydrogen, or Y
represents the group N(R.sup.15)R.sup.16, where R.sup.15 is
suitably hydrogen and R.sup.16 is suitably C.sub.1-C.sub.4-alkyl,
e.g. methyl or ethyl, substituted by an optionally substituted
phenyl or 5-6 membered heterocyclyl group, e.g. N-morpholino,
N-piperidyl, N-piperazinyl, where optional substituents are one,
two or three of hydroxyl, cyano, nitro, C.sub.1-C.sub.8-alkyl,
C.sub.1-C.sub.8-alkoxy, halogen, formyl,
C.sub.1-C.sub.8-alkylcarbonyl, carboxy,
C.sub.1-C.sub.8-alkoxycarbonyl, amino, C.sub.1-C.sub.8-alkylamino,
di-C.sub.1-C.sub.8-alkylamino, C.sub.1-C.sub.8-alkylaminocarbonyl,
di-C.sub.1-C.sub.8-alkylaminocarbonyl,
C.sub.1-C.sub.8-alkylcarbonylamino,
C.sub.1-C.sub.8-alkylcarbonyl(C.sub.1-C.sub.8-alkyl)amino,
C.sub.1-C.sub.8-alkylsulfonylamino, C.sub.1-C.sub.8-thioalkyl,
C.sub.1-C.sub.8-alkylsulfinyl, C.sub.1-C.sub.8-alkylsulfonyl,
aminosulfonyl, C.sub.1-C.sub.8-alkylaminosulfonyl or
di-C.sub.1-C.sub.8-alkylaminosulfonyl.
[0049] More suitably, Y is hydrogen, benzylamino or
morpholin-4-yl-ethylamino, most suitably hydrogen.
[0050] A sub-formula of the present invention is represented by a
compound of formula (IB)
##STR00006##
or a salt, suitably a pharmaceutically acceptable salt, or solvate
thereof, wherein: R.sup.1b is methyl; R.sup.2b is phenyl
substituted by one two, three or four substituents, suitably two or
three substituents selected from hydroxyl, cyano, nitro, halogen,
formyl, amino. C.sub.1-C.sub.8-alkyl, C.sub.1-C.sub.8-haloalkyl,
C.sub.1-C.sub.8-alkoxy, a 5-6 membered heterocyclyl group,
--O--(C.sub.1-C.sub.4-alkylene)-R.sup.9b,
--O--(C.sub.2-C.sub.4-alkylene)-R.sup.10b,
--(C.sub.0-C.sub.4-alkylene)-N(H)--(C.sub.2-C.sub.4-alkylene)-R.sup.14b,
C.sub.1-C.sub.8-alkylcarbonyl, C.sub.1-C.sub.8-alkylaminocarbonyl,
di-C.sub.1-C.sub.8-alkylaminocarbonyl, dimethylaminocarbonyl,
C.sub.1-C.sub.8-alkylcarbonylamino,
C.sub.1-C.sub.8-alkylsulfonylamino, hydroxysulfonyl,
C.sub.1-C.sub.8-alkylsulfonyl, C.sub.1-C.sub.8-alkylaminosulfonyl,
di-C.sub.1-C.sub.8-alkylaminosulfonyl, C.sub.1-C.sub.8-alkyl
substituted by hydroxy, C.sub.1-C.sub.8-alkoxy substituted by one
or more fluoro; where each of the afore-mentioned hydrocarbon
groups may be optionally substituted, where chemically feasible, by
one to five halogen or by hydroxyl, amino,
C.sub.1-C.sub.4-alkylamino, di-C.sub.1-C.sub.4-alkylamino or
C.sub.1-C.sub.4-alkoxy; R.sup.3b is amino; R.sup.9b represents
carboxy, cyano or phenyl, optionally substituted by one, two or
three halogen; R.sup.10b represents hydroxyl,
C.sub.1-C.sub.4-alkoxy, an N-linked 5-6 membered heteroaryl group
or an N-linked 5-6 membered heterocyclyl; and R.sup.14b is
di-C.sub.1-C.sub.8-alkylamino.
[0051] A suitable individual compound of the invention is selected
from: [0052]
3-(3-Fluoro-4-methoxy-phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin
6-ylamine; [0053]
3-(4-Ethoxy-3-fluoro-phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6
ylamine; [0054]
3-(3-Fluoro-4-isopropoxy-phenyl)-1-methyl-1H-pyrazolo[3,4
d]pyrimidin-6-ylamine; [0055]
3-(4-Methoxy-phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine;
[0056]
3-(3-Chloro-4-methoxy-phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin
6-ylamine; [0057]
3-(3-Bromo-4-methoxy-phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin
6-ylamine; [0058]
3-(3-Chloro-4-isopropoxy-phenyl)-1-methyl-1H-pyrazolo[3,4
d]pyrimidin-6-ylamine; [0059]
3-Benzo[1,3]dioxol-5-yl-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6
ylamine; [0060]
3-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-1-methyl-1H-pyrazolo[3,4
d]pyrimidin-6-ylamine; [0061]
1-Methyl-3-(3,4,5-trimethoxy-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamin-
e; [0062]
3-(3-Fluoro-phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylami-
ne; [0063]
3-(3,4-Difluoro-phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6--
ylamine; [0064]
3-(3-Chloro-4-fluoro-phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylami-
ne; [0065]
3-(3,4-Dichloro-phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6--
ylamine; [0066]
3-(3-Bromo-5-fluoro-phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamin-
e; [0067]
3-(5-Fluoro-2-methoxy-phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimid-
in-6-ylamine; [0068]
3-(3,5-Difluoro-2-methoxy-phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6--
ylamine; [0069]
3-(2,3-Dimethyl-1H-indol-5-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yla-
mine; [0070]
3-(7-Fluoro-1H-indol-5-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine-
; [0071]
3-Benzofuran-6-yl-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine;
[0072]
1-Methyl-3-(3-trifluoromethyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin--
6-ylamine; [0073]
1-[3-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-phenyl]-ethanone-
; [0074]
3-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-benzonitril-
e; [0075]
3-(3-Methanesulfonyl-phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidi-
n-6-ylamine; [0076]
N-[3-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-phenyl]-methanes-
ulfonamide; [0077]
1-[4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-phenyl]-ethanone-
; [0078]
4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-benzonitril-
e; [0079]
1-Methyl-3-pyridin-4-yl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine;
[0080]
3-(2-Chloro-pyridin-4-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-y-
lamine; [0081]
3-(2-Methoxy-pyridin-4-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine-
; [0082]
1-Methyl-3-pyridin-3-yl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine;
[0083]
3-(6-Methoxy-pyridin-3-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6--
ylamine; [0084]
3-(5-Fluoro-6-methoxy-pyridin-3-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin--
6-ylamine; [0085]
1-[5-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-thiophen-2-yl]-e-
thanone; [0086]
3-(4-Benzyloxy-3-fluoro-phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl-
amine; [0087]
4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluoro-phenol;
[0088]
2-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-4-fluoro-phe-
nol; [0089]
3-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluoro-phenol;
[0090]
4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-phenol;
[0091]
3-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-phenol;
[0092]
4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-chloro-6-m-
ethoxy-phenol; [0093]
4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-bromo-6-fluoro-ph-
enol; [0094]
4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2,6-dibromo-phenol;
[0095]
3-[3-Bromo-5-fluoro-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-1-methyl--
1H-pyrazolo[3,4-d]pyrimidin-6-ylamine; [0096]
3-[3-Bromo-5-fluoro-4-(2-methoxy-ethoxy)-phenyl]-1-methyl-1H-pyrazolo[3,4-
-d]pyrimidin-6-ylamine; [0097]
2-[4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-bromo-6-fluoro-
-phenoxy]-ethanol; [0098]
3-[3-Bromo-5-fluoro-4-(2-morpholin-4-yl-ethoxy)-phenyl]-1-methyl-1H-pyraz-
olo[3,4-d]pyrimidin-6-ylamine; [0099]
2-[4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluoro-phenoxy-
]-ethanol; [0100]
3-[4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluoro-phenoxy-
]-propan-1-ol; [0101]
3-[3-Fluoro-4-(2-methoxy-ethoxy)-phenyl]-1-methyl-1H-pyrazolo[3,4-d]pyrim-
idin-6-ylamine; [0102]
[4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluoro-phenoxy]--
acetonitrile; [0103]
3-[3-Fluoro-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-1-methyl-1H-pyrazolo
[3,4-d]pyrimidin-6-ylamine; [0104]
3-[3-Fluoro-4-(2-imidazol-1-yl-ethoxy)-phenyl]-1-methyl-1H-pyrazolo[3,
4-d]pyrimidin-6-ylamine; [0105]
3-[3-Fluoro-4-(2-morpholin-4-yl-ethoxy)-phenyl]-1-methyl-1H-pyrazolo[3,4--
d]pyrimidin-6-ylamine; [0106]
3-[3-Fluoro-4-(3-morpholin-4-yl-propoxy)-phenyl]-1-methyl-1H-pyrazolo[3,4-
-d]pyrimidin-6-ylamine; [0107]
3-{3-Fluoro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-1-methyl-1H-p-
yrazolo[3,4-d]pyrimidin-6-ylamine; [0108]
2-[2-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-4-fluoro-phenoxy-
]-ethanol; [0109]
3-(4-Amino-3-fluoro-phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamin-
e; [0110]
N-[4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluor-
o-phenyl]-methanesulfonamide; [0111]
[3-(3-Fluoro-phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-methyl-am-
ine, [0112]
3-(3,5-Difluoro-phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine;
[0113]
1-Methyl-3-(2,3,4-trifluoro-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-6--
ylamine trifluoroacetate; [0114]
3-(5-Chloro-thiophen-2-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine
trifluoroacetate; [0115]
3-(5-Bromo-2-methoxy-phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylami-
ne trifluoroacetate; [0116]
3-(2-Ethoxy-naphthalen-1-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylami-
ne trifluoroacetate; [0117]
3-[3-Bromo-2-(2-fluoro-benzyloxy)-phenyl]-1-methyl-1H-pyrazolo[3,4-d]pyri-
midin-6-ylamine trifluoroacetate; [0118]
1-[3-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluoro-phenyl]-
-ethanone; [0119]
3-(4-Fluoro-2-propoxy-phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylam-
ine; [0120]
3-(3,5-Dimethyl-isoxazol-4-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yla-
mine; [0121]
1-Methyl-3-m-tolyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine; [0122]
3-Furan-2-yl-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine; [0123]
3-(5-Chloro-2-methoxy-phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-
-6-ylamine; [0124]
3-(2,5-Dimethoxy-phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine;
[0125]
1-Methyl-3-(4-methyl-3-nitro-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-6-
-ylamine; [0126]
3-(4-Isobutyl-phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine;
[0127]
3-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-4-methoxy-be-
nzaldehyde; [0128]
1-Methyl-3-(3,4,5-trifluoro-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine-
; 1-Methyl-3-quinolin-8-yl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine;
[0129]
3-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-isopropyl-benzami-
de; [0130]
4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2,6-diflu-
oro-benzaldehyde; [0131]
[3-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluoro-phenoxy]--
acetic acid; [0132]
3-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-methyl-benzamide;
[0133]
1-Methyl-3-(2-piperazin-1-yl-pyrimidin-5-yl)-1H-pyrazolo[3,4-d]pyr-
imidin-6-ylamine; [0134]
3-(2,4-Dimethoxy-pyrimidin-5-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-y-
lamine; [0135]
3-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-benzaldehyde;
[0136]
3-(2-Methoxy-pyrimidin-5-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin--
6-ylamine; [0137]
3-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-isobutyl-benzamid-
e; [0138]
3-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-methyl-b-
enzenesulfonamide; [0139]
3-(2-Methoxy-5-trifluoromethyl-phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimid-
in-6-ylamine; [0140]
3-(2,4-Dimethoxy-phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine;
[0141]
3-(2,6-Dimethoxy-phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl-
amine; [0142]
2-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-4-trifluoromethyl-p-
henol; [0143]
4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-benzene-1,3-diol;
[0144]
2-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-4-chloro-phe-
nol; [0145]
3-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-4-methoxy-benzoic
acid; [0146]
4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2,6-dichloro-phenol-
; [0147]
4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-chloro-6--
fluoro-phenol; [0148]
2-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-6-bromo-4-chloro-ph-
enol; [0149]
3-(3,5-Difluoro-4-methoxy-phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6--
ylamine; [0150]
3-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-isopropyl-4-metho-
xy-benzamide; [0151]
3-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-4-hydroxy-benzaldeh-
yde; [0152]
3-(6-Amino-5-trifluoromethyl-pyridin-3-yl)-1-methyl-1H-pyrazolo[3,4-d]pyr-
imidin-6-ylamine; [0153]
4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2,6-difluoro-benzon-
itrile; [0154]
N-[3-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-4-methoxy-phenyl-
]-N',N'-dimethyl-propane-1,3-diamine; [0155]
[3-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-4-methoxy-phenyl]--
methanol; [0156]
N-[5-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-3-fluoro-2-metho-
xy-phenyl]-acetamide; [0157]
4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2,6-difluoro-benzoi-
c acid; [0158]
5-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-3-fluoro-2-hydroxy--
benzaldehyde; [0159]
4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2,6-difluoro-phenol-
; [0160]
5-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-3-fluoro-2--
hydroxy-benzonitrile; [0161]
3-(4-Fluoro-2-methoxy-phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylam-
ine; [0162]
4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-trifluoromethyl-p-
henol; [0163]
2-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-6-fluoro-phenol;
[0164]
5-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2,4-dimethox-
y-benzenesulfonic acid; [0165]
3-(5-Chloro-2,4-dimethoxy-phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6--
ylamine; [0166]
4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-chloro-6-trifluor-
omethyl-phenol; [0167]
5-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-benzyloxy-3-fluor-
o-N, N-dimethyl-benzamide; [0168]
4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-6-chloro-benzene-1,-
3-diol; [0169]
3-(3-Chloro-2-methoxy-5-trifluoromethyl-phenyl)-1-methyl-1H-pyrazolo[3,4--
d]pyrimidin-6-ylamine; [0170]
4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-bromo-6-chloro-be-
nzene-1,3-diol; [0171]
5-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2,4-dimethoxy-N-met-
hyl-benzenesulfonamide; [0172]
5-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-isopropyl-2,4-dim-
ethoxy-benzenesulfonamide; [0173]
2-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-6-chloro-4-trifluor-
omethyl-phenol; [0174]
3-(2-Methoxy-4-trifluoromethoxy-phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimi-
din-6-ylamine; [0175]
2-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-trifluoromethoxy--
phenol; [0176]
3-(5-Chloro-2-methoxy-4-trifluoromethoxy-phenyl)-1-methyl-1H-pyrazolo[3,4-
-d]pyrimidin-6-ylamine; [0177]
6-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-bromo-4-chloro-3--
trifluoromethoxy-phenol; [0178]
5-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N,N-diethyl-2-hydro-
xy-benzenesulfonamide; [0179]
N-[5-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-chloro-phenyl]-
-methanesulfonamide; [0180]
5-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-chloro-N-methyl-b-
enzenesulfonamide; [0181]
3-(5-Methanesulfonyl-pyridin-3-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-
-ylamine; [0182]
3-(1H-Indol-6-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine;
[0183]
1-Methyl-3-(5-trifluoromethyl-pyridin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-
-ylamine hydrochloride; [0184]
N*4*-Benzyl-3-(3-fluoro-4-methoxy-phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyri-
midine-4,6-diamine; [0185]
4-[6-Amino-1-methyl-4-(2-morpholin-4-yl-ethylamino)-1H-pyrazolo[3,4-d]pyr-
imidin-3-yl]-2,6-dichloro-phenol; [0186] or a salt, suitably a
pharmaceutically acceptable salt, or solvate thereof.
[0187] Many of the compounds represented by formula I are capable
of forming acid addition salts, particularly pharmaceutically
acceptable acid addition salts. Pharmaceutically acceptable acid
addition salts of the compound of formula I include those of
inorganic acids, for example, hydrohalic acids such as hydrofluoric
acid, hydrochloric acid, hydrobromic acid or hydroiodic acid,
nitric acid, sulfuric acid, phosphoric acid; and organic acids, for
example aliphatic monocarboxylic acids such as formic acid, acetic
acid, trifluoroacetic acid, propionic acid and butyric acid,
aliphatic hydroxy acids such as lactic acid, citric acid, tartaric
acid or malic acid, dicarboxylic acids such as maleic acid or
succinic acid, aromatic carboxylic acids such as benzoic acid,
p-chlorobenzoic acid, diphenylacetic acid or triphenylacetic acid,
aromatic hydroxy acids such as o-hydroxybenzoic acid,
p-hydroxybenzoic acid, 1-hydroxynaphthalene-2-carboxylic acid or
3-hydroxynaphthalene-2-carboxylic acid, and sulfonic acids such as
methanesulfonic acid or benzenesulfonic acid. These salts may be
prepared from compounds of formula I by known salt-forming
procedures.
[0188] Compounds of formula I which contain acidic, e.g. carboxyl,
groups, are also capable of forming salts with bases, in particular
pharmaceutically acceptable bases such as those well known in the
art; suitable such salts include metal salts, particularly alkali
metal or alkaline earth metal salts such as sodium, potassium,
magnesium or calcium salts, or salts with ammonia or
pharmaceutically acceptable organic amines or heterocyclic bases
such as ethanolamines, benzylamines or pyridine. These salts may be
prepared from compounds of formula I by known salt-forming
procedures.
[0189] In those compounds where there is an asymmetric carbon atom
the compounds exist in individual optically active isomeric forms
or as mixtures thereof, e.g. as racemic or diastereomeric mixtures.
The present invention embraces both individual optically active R
and S isomers as well as mixtures, e.g. racemic or diastereomeric
mixtures, thereof.
[0190] Specific preferred compounds of formula I are described
hereinafter in the Examples.
[0191] The invention provides, in another aspect, a process (A) for
preparing a compound of formula I, where R.sup.1, R.sup.2 and Y are
as hereinbefore described and R.sup.3 is NH.sub.2 or
C.sub.1-C.sub.3-alkylamino, by reaction of a compound of formula
(II)
##STR00007##
where Y, R.sup.1 and R.sup.3 are as hereinbefore described and X
represents a suitable boronic acid coupling group, e.g. bromo or
chloro, with a compound of R.sup.2--(BOH).sub.2 under suitable
boronic acid coupling conditions, such as Pd(0) tetrakis
triphenylphosphine in 1,4-dioxane-water in the presence of a base
such as sodium carbonate. The reaction may be carried out using
conventional or microwave radiation heating.
[0192] Compounds of formula (II) and R.sup.2--(BOH).sub.2 are known
or can be prepared by methods well-known to those skilled in the
art.
[0193] For example, compounds of formula (II) where X is Br, Y is
hydrogen, R.sup.1=Me and R.sup.3 is amino or
C.sub.1-C.sub.3-alkylamino, may be obtained from reacting known
compound of formula (III)
##STR00008##
where X is Br and R.sup.1 is Me, with ammonia or
C.sub.1-C.sub.3alkylamino in an organic solvent such as
tetrahydrofuran (THF) or 1,4-dioxane, as described in WO2005074603
and WO 2003029209.
[0194] Alternatively, compounds of formula (I), where R.sup.3 is
amino or C.sub.1-C.sub.3-alkylamino, can be prepared by reaction of
a compound of formula (IV) where Y, R.sup.1 and R.sup.2 are as
hereinbefore described, with ammonia or C.sub.1-C.sub.3-alkylamino
in an organic solvent.
##STR00009##
[0195] Compounds of formula (IV) may be prepared from compounds of
formula (V), where Y, R.sup.1 and R.sup.2 are as hereinbefore
described, by oxidation of the sulphide group using standard
procedures for oxidising sulfides to sulfones.
##STR00010##
[0196] Compounds of formula V may be prepared from compounds of
formula (VI), where Y and R.sup.1 are hereinbefore described and X
represents a suitable boronic acid coupling group, e.g. triflate or
the known bromo analogue, according to WO2003029209.
##STR00011##
[0197] Compounds of formula VI where R.sup.1 is Me and X is
triflate may be prepared from the known compound of formula VI
where X is OH according to M. Hauser, E. Peters, H. Tieckelmann, J.
Org. Chem., (1960), 25, p 1570-1573 and WO2003029209. Compounds of
formula (II) where Y is N(R.sup.16)NR.sup.17, may be prepared by
reaction of a compound of formula (VII)
##STR00012##
with a compound of HN(R.sup.16)NR.sup.17 at elevated temperature in
a suitable solvent.
[0198] A compound of formula (VII) may be prepared by reaction of a
compound of formula (VIII)
##STR00013##
with hydrazine and a suitable base, e.g. triethylamine, in a
suitable solvent, such as tetrahydrofuran, followed by bromination
or chlorination of the resulting compound using standard methods,
e.g. n-chloro or bromo succinimide in dichloroethane, followed by
optional alkylation where R.sup.1 is not hydrogen. Compounds of
formula (VIII) are commercially available or may be readily
synthesised by methods well-known in the art.
[0199] Compounds of formula I and their pharmaceutically acceptable
salts are useful as pharmaceuticals. In particular, they exhibit
inhibition of phosphatidylinositol 3-kinase (PI 3-kinase) enzymes,
especially the gamma isoform (p110.gamma.), which are responsible
for generating phosphorylated signalling products. The inhibitory
properties of compounds of formula I may be demonstrated in the
following test procedures:
[0200] Baculovirus expressing different fragments of human PI
3-K.gamma. fused to glutathione S-transferase (GST) have been
previously described by Stoyanova, S., Bulgarelli-Leva, G., Kirsch,
C., Hanck, T., Klinger, R., Wetzker, R., Wymann, M. P. (1997)
Lipid- and protein kinase activities of G protein-coupled PI
3-kinase g: structure-activity analysis and interactions with
wortmannin. Biochem. J., 324:489. Residues 38-1102 of human PI
3-K.gamma. are subcloned into the BamH1 and EcoR1 sites of the
transfer vector pAcG2T (Pharmingen) to create a GST-PI 3-K.gamma.
lacking the first 37 residues of PI 3-K.gamma.. To express the
recombinant protein, Sf9 (Spodoptera frugiperda 9) insect cells are
routinely maintained at densities between 3.times.10.sup.5 and
3.times.10.sup.6 cells/ml in serum containing TNMFH medium (Sigma).
Sf9 cells, at a density of 2.times.10.sup.6 are infected with human
GST-PI 3-K.gamma..DELTA.34 baculovirus at a multiplicity of
infection (m.o.i.) of 1 for 72 hours. The infected cells are
harvested by centrifugation at 1400 g for 4 minutes at 4.degree. C.
and the cell pellets are frozen at -80.degree. C. Both Sf9 and Sf21
cells work equally well. Sf9 cells (1.times.10.sup.9) are
resuspended in 100 ml cold (4.degree. C.) lysis buffer (50 mM
Tris-HCl pH 7.5, 1% Triton X-100, 150 mM NaCl, 1 mM NaF, 2 mM DTT
and protease inhibitors. Cells are incubated on ice for 30 minutes
then centrifuged at 15000 g for 20 minutes at 4.degree. C.
Purification of the supernatant sample is carried out at 4.degree.
C. by affinity chromatography using SEPHAROSE.TM. agarose gel beads
coupled to glutathione (from Amersham Pharmacia Biotech). A cell
lysate/GST resin ratio of 50:1 is used. The GST resin is firstly
pre-rinsed to remove ethanol preservative and then equilibrated
with lysis buffer. Cell lysate (supernatant) is added (usually as
50 ml lysate to 1 ml GST resin in 50 ml tubes) and gently rotated
on a mixer at 4.degree. C. for 2-3 hours. The unbound flow through
sample is collected by centrifugation at 1000 g for 5 minutes at
4.degree. C. using a DENLEY.TM. centrifuge. The 1 ml GST resin
containing bound material is transferred to a 15 ml FALCON.TM.
centrifuge tube for subsequent washing and elution steps. Firstly a
series of 3 cycles of washings (mixing by gentle inversion) is
performed with 15 ml ice cold wash Buffer A (50 mM Tris-HCl pH 7.5,
1% Triton X-100, 2 mM DTT) interspersed with centrifugation at 1000
g for 5 minutes at 4.degree. C. A final single wash step is
performed with 15 ml ice cold wash Buffer B (50 mM Tris-HCl pH 7.5,
2 mM DTT) and then centrifuged at 1000 g for 5 minutes at 4.degree.
C. The washed GST resin is finally eluted with 4 cycles of 1 ml ice
cold elution buffer (50 mM Tris-HCl pH 7.5, 10 mM reduced
glutathione, 2 mM DTT, 150 mM NaCl, 1 mM NaF, 50% ethylene glycol
and protease inhibitors) interspersed with centrifugation at 1000 g
for 5 minutes at 4.degree. C. Samples are aliquoted and stored at
-20.degree. C.
[0201] An in vitro kinase assay was established that measures the
transfer of the terminal phosphate of adenosine triphosphate to
phosphatidylinositol. The kinase reaction is performed in a white
96 well microtitre plate as a Scintillation Proximity Assay. Each
well contains 10 .mu.l test compound in 5% dimethylsulphoxide and
20 .mu.l assay mix (40 mM Tris, 200 mM NaCl, 2 mM
ethyleneglycol-aminoethyl-tetraacetic acid (EGTA), 15 .mu.g/ml
phosphatidylinositol, 12.5 .mu.M adenosine triphosphate (ATP), 25
mM MgCl.sub.2, 0.1 .mu.Ci [.sup.33P]ATP). The reaction is started
by the addition of 20 .mu.l of enzyme mix (40 mM Tris, 200 mM NaCl,
2 mM EGTA containing recombinant GST-p110.gamma.). The plate is
incubated at room temperature for 60 minutes and the reaction
terminated by the adding 150 .mu.l of WGA-bead stop solution (40 mM
Tris, 200 mM NaCl, 2 mM EGTA, 1.3 mM ethylene diamine tetraacetic
acid (EDTA), 2.6 .mu.M ATP and 0.5 mg of Wheat Germ Agglutinin-SPA
beads (Amersham Biosciences) to each well. The plate is sealed,
incubated at room temperature for 60 minutes, centrifuged at 1200
rpm and then counted for 1 minute using a scintillation counter.
Total activity is determined by adding 10 .mu.l of 5%
dimethylsulphoxide (DMSO) and non-specific activity is determined
by adding 10 .mu.l 50 mM EDTA in place of the test compound.
[0202] Compounds of the Examples hereinbelow have IC.sub.50 values
below 2.quadrature..quadrature.M in the aforementioned assay.
[0203] Having regard to their inhibition of phosphatidylinositol
3-kinase enzymes, compounds of formula I in free or
pharmaceutically acceptable salt form, hereinafter alternately
referred to as "agents of the invention", are useful in the
treatment of conditions which are mediated by the activation of the
PI 3-kinase enzymes, particularly inflammatory or allergic
conditions. Treatment in accordance with the invention may be
symptomatic or prophylactic.
[0204] Accordingly, agents of the invention are useful in the
treatment of inflammatory or obstructive airways diseases,
resulting, for example, in reduction of tissue damage, airways
inflammation, bronchial hyperreactivity, remodelling or disease
progression. Inflammatory or obstructive airways diseases to which
the present invention is applicable include asthma of whatever type
or genesis including both intrinsic (non-allergic) asthma and
extrinsic (allergic) asthma, mild asthma, moderate asthma, severe
asthma, bronchitic asthma, exercise-induced asthma, occupational
asthma and asthma induced following bacterial infection. Treatment
of asthma is also to be understood as embracing treatment of
subjects, e.g. of less than 4 or 5 years of age, exhibiting
wheezing symptoms and diagnosed or diagnosable as "wheezy infants",
an established patient category of major medical concern and now
often identified as incipient or early-phase asthmatics. (For
convenience this particular asthmatic condition is referred to as
"wheezy-infant syndrome".)
[0205] Prophylactic efficacy in the treatment of asthma will be
evidenced by reduced frequency or severity of symptomatic attack,
e.g. of acute asthmatic or bronchoconstrictor attack, improvement
in lung function or improved airways hyperreactivity. It may
further be evidenced by reduced requirement for other, symptomatic
therapy, i.e. therapy for or intended to restrict or abort
symptomatic attack when it occurs, for example anti-inflammatory
(e.g. corticosteroid) or bronchodilatory. Prophylactic benefit in
asthma may in particular be apparent in subjects prone to "morning
dipping". "Morning dipping" is a recognised asthmatic syndrome,
common to a substantial percentage of asthmatics and characterised
by asthma attack, e.g. between the hours of about 4 to 6 am, i.e.
at a time normally substantially distant form any previously
administered symptomatic asthma therapy.
[0206] Other inflammatory or obstructive airways diseases and
conditions to which the present invention is applicable include
acute lung injury (ALI), adult/acute respiratory distress syndrome
(ARDS), chronic obstructive pulmonary, airways or lung disease
(COPD, COAD or COLD), including chronic bronchitis or dyspnea
associated therewith, emphysema, as well as exacerbation of airways
hyperreactivity consequent to other drug therapy, in particular
other inhaled drug therapy. The invention is also applicable to the
treatment of bronchitis of whatever type or genesis including,
e.g., acute, arachidic, catarrhal, croupus, chronic or phthinoid
bronchitis. Further inflammatory or obstructive airways diseases to
which the present invention is applicable include pneumoconiosis
(an inflammatory, commonly occupational, disease of the lungs,
frequently accompanied by airways obstruction, whether chronic or
acute, and occasioned by repeated inhalation of dusts) of whatever
type or genesis, including, for example, aluminosis, anthracosis,
asbestosis, chalicosis, ptilosis, siderosis, silicosis, tabacosis
and byssinosis.
[0207] Having regard to their anti-inflammatory activity, in
particular in relation to inhibition of eosinophil activation,
agents of the invention are also useful in the treatment of
eosinophil related disorders, e.g. eosinophilia, in particular
eosinophil related disorders of the airways (e.g. involving morbid
eosinophilic infiltration of pulmonary tissues) including
hypereosinophilia as it effects the airways and/or lungs as well
as, for example, eosinophil-related disorders of the airways
consequential or concomitant to Loffler's syndrome, eosinophilic
pneumonia, parasitic (in particular metazoan) infestation
(including tropical eosinophilia), bronchopulmonary aspergillosis,
polyarteritis nodosa (including Churg-Strauss syndrome),
eosinophilic granuloma and eosinophil-related disorders affecting
the airways occasioned by drug-reaction.
[0208] Agents of the invention are also useful in the treatment of
inflammatory or allergic conditions of the skin, for example
psoriasis, contact dermatitis, atopic dermatitis, alopecia areata,
erythema multiforma, dermatitis herpetiformis, scleroderma,
vitiligo, hypersensitivity angiitis, urticaria, bullous pemphigoid,
lupus erythematosus, pemphisus, epidermolysis bullosa acquisita,
and other inflammatory or allergic conditions of the skin.
[0209] Agents of the invention may also be used for the treatment
of other diseases or conditions, in particular diseases or
conditions having an inflammatory component, for example, treatment
of diseases and conditions of the eye such as conjunctivitis,
keratoconjunctivitis sicca, and vernal conjunctivitis, diseases
affecting the nose including allergic rhinitis, and inflammatory
disease in which autoimmune reactions are implicated or having an
autoimmune component or aetiology, including autoimmune
haematological disorders (e.g. haemolytic anaemia, aplastic
anaemia, pure red cell anaemia and idiopathic thrombocytopenia),
systemic lupus erythematosus, polychondritis, sclerodoma, Wegener
granulamatosis, dermatomyositis, chronic active hepatitis,
myasthenia gravis, Steven-Johnson syndrome, idiopathic sprue,
autoimmune inflammatory bowel disease (e.g. ulcerative colitis and
Crohn's disease), endocrine opthalmopathy, Grave's disease,
sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis,
multiple sclerosis, primary billiary cirrhosis, uveitis (anterior
and posterior), keratoconjunctivitis sicca and vernal
keratoconjunctivitis, interstitial lung fibrosis, psoriatic
arthritis and glomerulonephritis (with and without nephrotic
syndrome, e.g. including idiopathic nephrotic syndrome or minal
change nephropathy).
[0210] Other diseases or conditions which may be treated with
agents of the invention include thrombosis, hypertension, heart
ischaemia and pancreatitis, (Nature review November 2006 Vol 5),
treatment of anaemia including haemolytic anaemia, aplastic anaemia
and pure red cell anaemia (WO 2006/040318), septic shock,
rheumatoid arthritis, osteoarthritis, proliferative diseases such
as cancer, atherosclerosis, allograft rejection following
transplantation, stroke, obesity, restenosis, diabetes, e.g.
diabetes mellitus type I (juvenile diabetes) and diabetes mellitus
type II, diarrheal diseases, ischemia/reperfusion injuries,
retinopathy, such as diabetic retinopathy or hyperbaric
oxygen-induced retinopathy, and conditions characterised by
elevated intraocular pressure or secretion of ocular aqueous humor,
such as glaucoma.
[0211] The effectiveness of an agent of the invention in inhibiting
inflammatory conditions, for example in inflammatory airways
diseases, may be demonstrated in an animal model, e.g. a mouse or
rat model, of airways inflammation or other inflammatory
conditions, for example as described by Szarka et al, J. Immunol.
Methods (1997) 202:49-57; Renzi et al, Am. Rev. Respir. Dis. (1993)
148:932-939; Tsuyuki et al., J. Clin. Invest. (1995) 96:2924-2931;
and Cernadas et al (1999) Am. J. Respir. Cell Mol. Biol. 20:1-8.
The agents of the invention are also useful as co-therapeutic
agents for use in combination with other drug substances such as
anti-inflammatory, bronchodilatory or antihistamine drug
substances, particularly in the treatment of obstructive or
inflammatory airways diseases such as those mentioned hereinbefore,
for example as potentiators of therapeutic activity of such drugs
or as a means of reducing required dosaging or potential side
effects of such drugs. An agent of the invention may be mixed with
the other drug substance in a fixed pharmaceutical composition or
it may be administered separately, before, simultaneously with or
after the other drug substance. Accordingly the invention includes
a combination of an agent of the invention as hereinbefore
described with an anti-inflammatory, bronchodilatory or
antihistamine drug substance, said agent of the invention and said
drug substance being in the same or different pharmaceutical
composition. Such anti-inflammatory drugs include steroids, in
particular glucocorticosteroids such as budesonide, beclamethasone
dipropionate, fluticasone propionate, ciclesonide or mometasone
furoate and compounds described in WO 0200679, WO 0288167, WO
0212266 and WO 02100879, LTB4 antagonists such as those described
in U.S. Pat. No. 5,451,700, LTD4 antagonists such as montelukast
and zafirlukast, dopamine receptor agonists such as cabergoline,
bromocriptine, ropinirole and
4-hydroxy-7-[2-[[2-[[3-(2-phenylethoxy)-propyl]-sulfonyl]ethyl]-amino-
]ethyl]-2(3H)-benzothiazolone and pharmaceutically acceptable salts
thereof (the hydrochloride being Viozan.RTM.--AstraZeneca), and
PDE4 inhibitors such as Ariflo.RTM. (GlaxoSmithKline), Roflumilast
(Byk Gulden), V-11294A (Napp), BAY19-8004 (Bayer), SCH-351591
(Schering-Plough), Arofylline (Almirall Prodesfarma), PD189659
(Parke-Davis), AWD-12-281 (Asta Medica), CDC-801 (Celgene) and
KW-4490 (Kyowa Hakko Kogyo) as well as those described in WO
98/18796 and WO 03/39544. Such bronchodilatory drugs include
anticholinergic or antimuscarinic agents, in particular ipratropium
bromide, oxitropium bromide and tiotropium salts but also those
described in WO 01/04118, WO 02/51841, WO 02/53564, WO 03/00840, WO
03/87094, WO 04/05285, WO 02/00652, WO 03/53966, EP 424021, U.S.
Pat. No. 5,171,744, U.S. Pat. No. 3,714,357 and WO 03/33495, and
beta-2 adrenoceptor agonists such as salbutamol, terbutaline,
salmeterol and, especially, formoterol and pharmaceutically
acceptable salts thereof, and compounds (in free or salt or solvate
form) of formula I of PCT International patent publication No. WO
00/75114, which document is incorporated herein by reference,
preferably compounds of the Examples thereof, especially
5-[(R)-2-(5,6-Diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quin-
olin-2-one, and pharmaceutically acceptable salts thereof.
Co-therapeutic antihistamine drug substances include cetirizine
hydrochloride, acetaminophen, clemastine fumarate, promethazine,
loratidine, desloratidine, diphenhydramine and fexofenadine
hydrochloride. Combinations of agents of the invention and
steroids, beta-2 agonists, PDE4 inhibitors or LTD4 antagonists may
be used, for example, in the treatment of COPD or, particularly,
asthma. Combinations of agents of the invention and anticholinergic
or antimuscarinic agents, PDE4 inhibitors, dopamine receptor
agonists or LTB4 antagonists may be used, for example, in the
treatment
of asthma or, particularly, COPD.
[0212] Other useful combinations of agents of the invention with
anti-inflammatory drugs are those with antagonists of chemokine
receptors, e.g. CCR-1, CCR-2, CCR-3, CCR-4, CCR-5, CCR-6, CCR-7,
CCR-8, CCR-9 and CCR10, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5,
particularly CCR-5 antagonists such as Schering-Plough antagonists
SC-351125, SCH-55700 and SCH-D, Takeda antagonists such as
N-[[4-[[[6,7-dihydro-2-(4-methylphenyl)-5H-benzocyclohepten-8-yl]carbonyl-
]amino]phenyl]-methyl]tetrahydro-N,N-dimethyl-2H-pyran-4-aminium
chloride (TAK-770), and CCR-5 antagonists described in U.S. Pat.
No. 6,166,037 (particularly claims 18 and 19), WO00/66558
(particularly claim 8), and WO00/66559 (particularly claim 9).
[0213] The agents of the invention may be administered by any
appropriate route, e.g. orally, for example in the form of a tablet
or capsule; parenterally, for example intravenously; by inhalation,
for example in the treatment of inflammatory or obstructive airways
disease; intranasally, for example in the treatment of allergic
rhinitis; topically to the skin, for example in the treatment of
atopic dermatitis; or rectally, for example in the treatment of
inflammatory bowel disease.
[0214] The present invention also provides a pharmaceutical
composition comprising a compound of formula I in free form or in
the form of a pharmaceutically acceptable salt, optionally together
with a pharmaceutically acceptable diluent or carrier therefore.
The composition may contain a co-therapeutic agent such as an
anti-inflammatory, bronchodilatory or antihistamine drug as
hereinbefore described. Such compositions may be prepared using
conventional diluents or excipients and techniques known in the
galenic art. Thus oral dosage forms may include tablets and
capsules.
[0215] Formulations for topical administration may take the form of
creams, ointments, gels or transdermal delivery systems, e.g.
patches. Compositions for inhalation may comprise aerosol or other
atomizable formulations or dry powder formulations.
[0216] When the composition comprises an aerosol formulation, it
preferably contains, for example, a hydro-fluoro-alkane (HFA)
propellant such as HFA134a or HFA227 or a mixture of these, and may
contain one or more co-solvents known in the art such as ethanol
(up to 20% by weight), and/or one or more surfactants such as oleic
acid or sorbitan trioleate, and/or one or more bulking agents such
as lactose. When the composition comprises a dry powder
formulation, it preferably contains, for example, the compound of
formula I having a particle diameter up to 10 microns, optionally
together with a diluent or carrier, such as lactose, of the desired
particle size distribution and a compound that helps to protect
against product performance deterioration due to moisture. When the
composition comprises a nebulised formulation, it preferably
contains, for example, the compound of formula I either dissolved,
or suspended, in a vehicle containing water, a co-solvent such as
ethanol or propylene glycol and a stabiliser, which may be a
surfactant.
[0217] Dosages of agents of the invention employed in practising
the present invention will of course vary depending, for example,
on the particular condition to be treated, the effect desired and
the mode of administration. In general, suitable daily dosages for
oral administration are of the order of 0.1 to 10 mg/kg.
EXAMPLES
Preparation of Final Compounds
[0218] Compounds of formula I which are also of formula VII
##STR00014##
are shown in Table 1 below, the method of preparation being
described hereinafter. The table also shows mass spectrometry
data.
TABLE-US-00001 TABLE 1 M/s Ex. R.sup.1 R.sup.2 R.sup.3 [M +
H].sup.+ 1 CH.sub.3 ##STR00015## NH.sub.2 274 2 CH.sub.3
##STR00016## NH.sub.2 288 3 CH.sub.3 ##STR00017## NH.sub.2 302 4
CH.sub.3 ##STR00018## NH.sub.2 256 5 CH.sub.3 ##STR00019## NH.sub.2
-- 6 CH.sub.3 ##STR00020## NH.sub.2 336 7 CH.sub.3 ##STR00021##
NH.sub.2 318 8 CH.sub.3 ##STR00022## NH.sub.2 270 9 CH.sub.3
##STR00023## NH.sub.2 284 10 CH.sub.3 ##STR00024## NH.sub.2 316 11
CH.sub.3 ##STR00025## NH.sub.2 243 12 CH.sub.3 ##STR00026##
NH.sub.2 261 13 CH.sub.3 ##STR00027## NH.sub.2 277 14 CH.sub.3
##STR00028## NH.sub.2 294 15 CH.sub.3 ##STR00029## NH.sub.2 322 16
CH.sub.3 ##STR00030## NH.sub.2 17 CH.sub.3 ##STR00031## NH.sub.2
292 18 CH.sub.3 ##STR00032## NH.sub.2 293 19 CH.sub.3 ##STR00033##
NH.sub.2 283 20 CH.sub.3 ##STR00034## NH.sub.2 265 21 CH.sub.3
##STR00035## NH.sub.2 294 22 CH.sub.3 ##STR00036## NH.sub.2 268 23
CH.sub.3 ##STR00037## NH.sub.2 251 24 CH.sub.3 ##STR00038##
NH.sub.2 304 25 CH.sub.3 ##STR00039## NH.sub.2 318 26 CH.sub.3
##STR00040## NH.sub.2 268 27 CH.sub.3 ##STR00041## NH.sub.2 251 28
CH.sub.3 ##STR00042## NH.sub.2 226 29 CH.sub.3 ##STR00043##
NH.sub.2 260 30 CH.sub.3 ##STR00044## NH.sub.2 256 31 CH.sub.3
##STR00045## NH.sub.2 226 32 CH.sub.3 ##STR00046## NH.sub.2 257 33
CH.sub.3 ##STR00047## NH.sub.2 275 34 CH.sub.3 ##STR00048##
NH.sub.2 274 35 CH.sub.3 ##STR00049## NH.sub.2 350 36 CH.sub.3
##STR00050## NH.sub.2 259 37 CH.sub.3 ##STR00051## NH.sub.2 260 38
CH.sub.3 ##STR00052## NH.sub.2 260 39 CH.sub.3 ##STR00053##
NH.sub.2 242 40 CH.sub.3 ##STR00054## NH.sub.2 242 41 CH.sub.3
##STR00055## NH.sub.2 306 42 CH.sub.3 ##STR00056## NH.sub.2 340 43
CH.sub.3 ##STR00057## NH.sub.2 400 44 CH.sub.3 ##STR00058##
NH.sub.2 435 45 CH.sub.3 ##STR00059## NH.sub.2 396 46 CH.sub.3
##STR00060## NH.sub.2 382 47 CH.sub.3 ##STR00061## NH.sub.2 304 48
CH.sub.3 ##STR00062## NH.sub.2 317 49 CH.sub.3 ##STR00063##
NH.sub.2 318 50 CH.sub.3 ##STR00064## NH.sub.2 299 51 CH.sub.3
##STR00065## NH.sub.2 357 52 CH.sub.3 ##STR00066## NH.sub.2 354 53
CH.sub.3 ##STR00067## NH.sub.2 373 54 CH.sub.3 ##STR00068##
NH.sub.2 387 55 CH.sub.3 ##STR00069## NH.sub.2 400 56 CH.sub.3
##STR00070## NH.sub.2 304 57 CH.sub.3 ##STR00071## NH.sub.2 259 58
CH.sub.3 ##STR00072## NH.sub.2 337 59 CH.sub.3 ##STR00073##
NHCH.sub.3 258 60 CH.sub.3 ##STR00074## NH.sub.2 262 61 CH.sub.3
##STR00075## NH.sub.2 280 62 CH.sub.3 ##STR00076## NH.sub.2 266 63
CH.sub.3 ##STR00077## NH.sub.2 334 & 336 64 CH.sub.3
##STR00078## NH.sub.2 320 65 CH.sub.3 ##STR00079## NH.sub.2 428 66
CH.sub.3 ##STR00080## NH.sub.2 286 67 CH.sub.3 ##STR00081##
NH.sub.2 302 68 CH.sub.3 ##STR00082## NH.sub.2 244 69 CH.sub.3
##STR00083## NH.sub.2 240 70 CH.sub.3 ##STR00084## NH.sub.2 216 71
CH.sub.3 ##STR00085## NH.sub.2 290 72 CH.sub.3 ##STR00086##
NH.sub.2 286 73 CH.sub.3 ##STR00087## NH.sub.2 285 74 CH.sub.3
##STR00088## NH.sub.2 282 75 CH.sub.3 ##STR00089## NH.sub.2 284 76
CH.sub.3 ##STR00090## NH.sub.2 280 77 CH.sub.3 ##STR00091##
NH.sub.2 277 78 CH.sub.3 ##STR00092## NH.sub.2 311 79 CH.sub.3
##STR00093## NH.sub.2 290 80 CH.sub.3 ##STR00094## NH.sub.2 318 81
CH.sub.3 ##STR00095## NH.sub.2 283 82 CH.sub.3 ##STR00096##
NH.sub.2 312 83 CH.sub.3 ##STR00097## NH.sub.2 288 84 CH.sub.3
##STR00098## NH.sub.2 254 85 CH.sub.3 ##STR00099## NH.sub.2 258 86
CH.sub.3 ##STR00100## NH.sub.2 325 87 CH.sub.3 ##STR00101##
NH.sub.2 319 88 CH.sub.3 ##STR00102## NH.sub.2 324 89 CH.sub.3
##STR00103## NH.sub.2 286 90 CH.sub.3 ##STR00104## NH.sub.2 286 91
CH.sub.3 ##STR00105## NH.sub.2 310 92 CH.sub.3 ##STR00106##
NH.sub.2 258 93 CH.sub.3 ##STR00107## NH.sub.2 276 94 CH.sub.3
##STR00108## NH.sub.2 300 95 CH.sub.3 ##STR00109## NH.sub.2 310 96
CH.sub.3 ##STR00110## NH.sub.2 294 97 CH.sub.3 ##STR00111##
NH.sub.2 353 & 356 98 CH.sub.3 ##STR00112## NH.sub.2 99
CH.sub.3 ##STR00113## NH.sub.2 341 100 CH.sub.3 ##STR00114##
NH.sub.2 270 101 CH.sub.3 ##STR00115## NH.sub.2 310 102 CH.sub.3
##STR00116## NH.sub.2 287 103 CH.sub.3 ##STR00117## NH.sub.2 244
104 CH.sub.3 ##STR00118## NH.sub.2 286 105 CH.sub.3 ##STR00119##
NH.sub.2 331 106 CH.sub.3 ##STR00120## NH.sub.2 306 107 CH.sub.3
##STR00121## NH.sub.2 288 108 CH.sub.3 ##STR00122## NH.sub.2 278
109 CH.sub.3 ##STR00123## NH.sub.2 285 110 CH.sub.3 ##STR00124##
NH.sub.2 274 111 CH.sub.3 ##STR00125## NH.sub.2 310 112 CH.sub.3
##STR00126## NH.sub.2 260 113 CH.sub.3 ##STR00127## NH.sub.2 336
114 CH.sub.3 ##STR00128## NH.sub.2 320 115 CH.sub.3 ##STR00129##
NH.sub.2 344 116 CH.sub.3 ##STR00130## NH.sub.2 421 117 CH.sub.3
##STR00131## NH.sub.2 292 118 CH.sub.3 ##STR00132## NH.sub.2 358
119 CH.sub.3 ##STR00133## NH.sub.2 370 & 372 120 CH.sub.3
##STR00134## NH.sub.2 379 121 CH.sub.3 ##STR00135## NH.sub.2 407
122 CH.sub.3 ##STR00136## NH.sub.2 344 & 346
123 CH.sub.3 ##STR00137## NH.sub.2 340 124 CH.sub.3 ##STR00138##
NH.sub.2 326 125 CH.sub.3 ##STR00139## NH.sub.2 374 126 CH.sub.3
##STR00140## NH.sub.2 440 127 CH.sub.3 ##STR00141## NH.sub.2 377
128 CH.sub.3 ##STR00142## NH.sub.2 353 129 CH.sub.3 ##STR00143##
NH.sub.2 353 130 CH.sub.3 ##STR00144## NH.sub.2 304 131 CH.sub.3
##STR00145## NH.sub.2 265 132 CH.sub.3 ##STR00146## NH.sub.2
295
[0219] Further preferred compounds of the present invention are as
shown in Table 2 below.
[0220] The methods of preparation being described thereinafter.
TABLE-US-00002 TABLE 2 M/s Ex. Chemical Structure Compound name [M
+ H].sup.+ 2-1 ##STR00147## N*4*-Benzyl-3-(3-fluoro-4-
methoxy-phenyl)-1-methyl- 1H-pyrazolo[3,4-d] pyrimidine-4,6-diamine
379 2-2 ##STR00148## 4-[6-Amino-1-methyl-4-(2-
morpholin-4-yl-ethylamino)- 1H-pyrazolo[3,4-d]
pyrimidin-3-yl]-2,6-dichloro- phenol 438 & 440
General Conditions:
[0221] Mass spectra are run on an open access Waters 600/ZQ
HPLC/Mass Spectrometer system using electrospray ionization.
[M+H].sup.+ refers to mono-isotopic molecular weights.
[0222] The invention is further illustrated by the following
non-limiting examples, where the following abbreviations are
employed:
[0223] THF is tetrahydrofuran, EtOAc is ethyl acetate, mCPBA is
3-chloroperoxybenzoic acid, DMF is N,N-dimethylformamide, DCM is
dichloromethane, MeCN is acetonitrile, DPPF is
1,1'-bis(diphenylphosphino)ferrocine, DIAD is diisopropyl
azodicarboxylate, Et.sub.3N is triethylamine, MeOH is methanol,
EtOH is ethanol, CHCl.sub.3 is chloroform, AcOH is acetic acid,
PCy.sub.3 is tricyclohexyl phosphine, PPh.sub.3 is
triphenylphosphine, DMSO is dimethyl sulfoxide, HPLC is high
performance liquid chromatography, MgSO.sub.4 is magnesium
sulphate, NMP is 1-Methyl-2-pyrrolidinone, TFA is trifluoroacetic
acid, DME is 1,2-dimethoxyethane, HATU is
[Dimethylamino-([1,2,3]triazolo[4,5-b]pyridin-3-yloxy)-methylene]-dimethy-
l-ammonium; hexafluorophosphate, TMSCl is trimethylchlorosilane,
MP-BH.sub.4 is macroporous polystyrene borohydride, Pd(dppf)C.sub.2
is [1,1'-bis (diphenyl phosphino)-ferrocenedichloro palladium(II),
complex with dichloromethane, Pd.sub.2(dba).sub.3 is
tris(dibenzylileneacetone) di palladium(0),
Pd(PPh.sub.3).sub.2Cl.sub.2 is bis (triphenylphosphine)
palladium(II) dichloride, Pd(PPh.sub.3).sub.4 is
tetrakis(triphenylphosphine)palladium(0) and MeNH.sub.2 is
methylamine.
Example 1
3-(3-Fluoro-4-methoxy-phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylami-
ne
Method A (From Intermediates 1 or 2)
3-(3-Fluoro-4-methoxy-phenyl)-1-methyl-6-methylsulfanyl-1H-pyrazolo[3,4-d]-
pyrimidine
a) From Intermediate 1
[0224]
3-Bromo-1-methyl-6-methylsulfanyl-1H-pyrazolo[3,4-d]pyrimidine
(Intermediate 1) (1.2 g, 3.0 mmol) is dissolved in THF (50 ml),
under an inert atmosphere of argon. To this is added
Pd(PPh.sub.3).sub.2Cl.sub.2 (0.1 g, 0.15 mmol) and PPh.sub.3 (0.023
g, 0.09 mmol) simultaneously. A solution of Na.sub.2CO.sub.3 (0.96
g, 9.1 mmol) dissolved in 5 ml of distilled water is added and the
reaction mixture is stirred for 15 minutes at room temperature.
4-methoxy-3-fluoro boronic acid (0.51 g, 3.0 mmol) is added and
resulting mixture is refluxed at 70.degree. C. for 4 hours. The
reaction mixture is diluted with water and the aqueous layer is
extracted with DCM. The organic portion is washed with brine, dried
over Na.sub.2SO.sub.4, filtered and concentrated in vacuo.
Purification of the crude residue by flash chromatography on silica
eluting with 20% EtOAc:iso-hexanes affords the title compound.
[0225] The chloro analogue of Intermediate 1 can also be used by an
analogous process.
b) From Intermediate 2
[0226] Trifluoro-methanesulfonic acid
1-methyl-6-methylsulfanyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl ester
(Intermediate 2) (1.0 g, 3.0 mmol) is dissolved in THF (50 ml),
under an inert atmosphere of argon. To this is added
Pd(PPh.sub.3).sub.2Cl.sub.2 (0.1 g, 0.15 mmol) and PPh.sub.3 (0.023
g, 0.09 mmol) simultaneously. A solution of Na.sub.2CO.sub.3 (0.96
g, 9.1 mmol) dissolved in 5 ml of distilled water is added and the
reaction mixture is stirred for 15 minutes at room temperature.
4-methoxy-3-fluoro boronic acid (0.51 g, 3.0 mmol) is added and
resulting mixture is refluxed at 70.degree. C. for 4 hours. The
reaction mixture is diluted with water and the aqueous layer is
extracted with DCM. The organic portion is washed with brine, dried
over Na.sub.2SO.sub.4, filtered and concentrated in vacuo.
Purification of the crude residue by flash chromatography on silica
eluting with residue is purified by flash column chromatography 20%
EtOAc:iso-hexanes affords the title compound.
3-(3-Fluoro-4-methoxy-phenyl)-6-methanesulfonyl-1-methyl-1H-pyrazolo[3,4-d-
]pyrimidine
[0227]
3-(3-Fluoro-4-methoxy-phenyl)-1-methyl-6-methylsulfanyl-1H-pyrazolo-
[3,4-d]pyrimidine (0.84 g, 2.7 mmol) is dissolved in dry DCM (30
ml). The reaction mixture is cooled to 0-5.degree. C. (ice-bath)
and mCPBA (1.42 g, 8.2 mmol) is added in small portions. The
reaction mixture is stirred for 1 hour at room temperature, diluted
with DCM (20 ml), washed with saturated NaHCO.sub.3, brine, dried
over Na.sub.2SO.sub.4, filtered and concentrated in vacuo.
Purification of the crude residue by flash chromatography on silica
eluting with 0.8% MeOH:CHCl.sub.3 affords compound as a white
solid.
3-(3-Fluoro-4-methoxy-phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylami-
ne
[0228]
3-(3-Fluoro-4-methoxy-phenyl)-6-methanesulfonyl-1-methyl-1H-pyrazol-
o[3,4-d]pyrimidine (0.8 g, 2.3 mmol) is dissolved in a saturated
solution of ammonia in THF in an autoclave and the reaction mixture
is stirred at room temperature for 2-18 hours. The solvent is
removed in vacuo and the resulting solid is suspended in methanol,
stirred at room temperature for 30 minutes and collected by
filtration to afford the title compound as a white solid.
Method B From Intermediate 3
[0229] 3-Bromo-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine
(Intermediate 3) (1.2 g, 5.2 mmol) is dissolved in THF (40 ml),
under an inert atmosphere of argon. To this is added
Pd(PPh.sub.3).sub.2Cl.sub.2 (0.224 g, 0.32 mmol),
[3-fluoro-4-methoxyphenyl]boronic acid (0.98 g, 5.8 mmol) and a
solution of Na.sub.2CO.sub.3 (1.5 g, 14 mmol) dissolved in
distilled water (4 ml). The reaction mixture is heated to reflux at
70.degree. C. for 24 hours. After cooling to room temperature the
reaction mixture is pre-absorbed onto silica and purification by
flash chromatography on silica eluting with iso-hexanes:EtOAc (2:1)
affords the title compound as a solid.
Examples 2-34
[0230] are prepared from either Intermediate 1 or Intermediate 2
following method A, or from Intermediate 3 following method B using
commercial or synthesized boronic acids/esters. The corresponding
chloro intermediates may be used in place of bromo intermediates.
These compounds namely, [0231]
3-(4-Ethoxy-3-fluoro-phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin--
6-ylamine (Example 2) [0232]
3-(3-Fluoro-4-isopropoxy-phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-y-
lamine (Example 3) [0233]
3-(4-Methoxy-phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine
(Example 4) [0234]
3-(3-Chloro-4-methoxy-phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylam-
ine (Example 5) [0235]
3-(3-Bromo-4-methoxy-phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylami-
ne (Example 6) [0236]
3-(3-Chloro-4-isopropoxy-phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-y-
lamine (Example 7) [0237]
3-Benzo[1,3]dioxol-5-yl-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine
(Example 8) [0238]
3-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidi-
n-6-ylamine (Example 9) [0239]
1-Methyl-3-(3,4,5-trimethoxy-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamin-
e (Example 10) [0240]
3-(3-Fluoro-phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine
(Example 11) [0241]
3-(3,4-Difluoro-phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine
(Example 12) [0242]
3-(3-Chloro-4-fluoro-phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylami-
ne (Example 13) [0243]
3-(3,4-Dichloro-phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine
(Example 14) [0244]
3-(3-Bromo-5-fluoro-phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamin-
e (Example 15) [0245]
3-(5-Fluoro-2-methoxy-phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylam-
ine (Example 16) [0246]
3-(3,5-Difluoro-2-methoxy-phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6--
ylamine (Example 17) [0247]
3-(2,3-Dimethyl-1H-indol-5-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yla-
mine (Example 18) [0248]
3-(7-Fluoro-1H-indol-5-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine
(Example 19) [0249]
3-Benzofuran-6-yl-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine
(Example 20) [0250]
1-Methyl-3-(3-trifluoromethyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylami-
ne (Example 21) [0251]
1-[3-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-phenyl]-ethanone
(Example 22) [0252]
3-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-benzonitrile
(Example 23) [0253]
3-(3-Methanesulfonyl-phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylami-
ne (Example 24) [0254]
N-[3-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-phenyl]methanesu-
lfonamide (Example 25) [0255]
1-[4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-phenyl]-ethanone
(Example 26) [0256]
4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-benzonitrile
(Example 27) [0257]
1-Methyl-3-pyridin-4-yl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine
(Example 28) [0258]
3-(2-Chloro-pyridin-4-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine
(Example 29) [0259]
3-(2-Methoxy-pyridin-4-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine
(Example 30) [0260]
1-Methyl-3-pyridin-3-yl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine
(Example 31) [0261]
3-(6-Methoxy-pyridin-3-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine
(Example 32) [0262]
3-(5-Fluoro-6-methoxy-pyridin-3-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin--
6-ylamine (Example 33) [0263]
1-[5-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-thiophen-2-y]-et-
hanone (Example 34)
Example 35
3-(4-Benzyloxy-3-fluoro-phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yla-
mine
[0264] 3-Bromo-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine
(Intermediate 3) (0.33 g, 1.46 mmol) and 4-benzyloxy-3-fluoro
phenylboronic acid (0.43 g, 1.75 mmol) are suspended in 1,4-dioxane
(5 ml) in a microwave vial flushed with argon. A solution of
Cs.sub.2CO.sub.3 (1.43 g, 4.38 mmol) in water (1.5 ml) is added
followed by Pd(PPh.sub.3).sub.4(0.085 g, 0.073 mmol) and the
reaction mixture is heated using microwave radiation at 150.degree.
C. for 0.5 hours. After cooling to room temperature the reaction
mixture is diluted with EtOAc (100 ml) and washed with saturated
NaHCO.sub.3. The organic portion is dried over MgSO.sub.4,
filtered, concentrated in vacuo and the resulting crude solid is
triturated with EtOAc (.about.20 ml) to afford the title compound
as an off-white solid.
Example 36
4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluoro-phenol
[0265]
3-(4-Benzyloxy-3-fluoro-phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidi-
n-6-ylamine (Example 35) (0.52 g, 1.49 mmol) is suspended in a
mixture of EtOH and AcOH (5:1, 120 ml). The reaction mixture is
degassed with argon before the addition of 10% palladium on
activated charcoal (0.50 g) and 1,4-cyclohexadiene (1.4 ml, 14.88
mmol). The reaction mixture is heated at 80.degree. C. overnight
and filtered hot through Celite.RTM. (filter agent) washing
copiously with MeOH (.about.300 ml). The solvents are removed in
vacuo and the resulting residue is triturated with EtOAc (.about.20
ml) to afford the title compound as a white solid.
Examples 37-40
[0266] These compounds namely, [0267]
2-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-4-fluoro-phenol
(Example 37) [0268]
3-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluoro-phenol
(Example 38) [0269]
4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-phenol
(Example 39) [0270]
3-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-phenol
(Example 40) are prepared either from the phenol boronic
acid/esters using standard Suzuki coupling methodology or from the
benzyl protected phenol boronic acid/esters following a similar
procedure described for Example 36.
Example 41
4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-chloro-6-fluoro-ph-
enol
[0271] 3-Bromo-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine
(Intermediate 3) (0.125 g, 0.55 mmol),
2-Chloro-6-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol
(0.203 g, 0.712 mmol) and tetrakis(triphenylphosphine)palladium
(0.038 g, 0.066 mmol) are added to 1,4-dioxane (3 ml) in a
microwave vial and the mixture is sonicated. A solution of cesium
carbonate (0.55 g, 3.29 mmol) in water (0.3 ml) is added and the
reaction mixture is heated using microwave radiation at 150.degree.
C. for 30 minutes. The reaction mixture is filtered through
Celite.RTM. (filter agent) washing with EtOAc, the filtrate is
diluted with more EtOAc and washed with water and brine. The
organic portion is dried over MgSO.sub.4, filtered, concentrated in
vacuo and purification of the crude residue by preparative HPLC
(water/acetonitrile, 0.1% TFA) affords the title compound.
Example 42
4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-bromo-6-fluoro-phe-
nol
Example 42a: HBr Salt
[0272]
4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluoro-phen-
ol (Example 36) (25 mg, 0.10 mmol) is suspended in glacial acetic
acid (0.5 ml). Bromine (5 .mu.L, 0.10 mmol) is added and the
reaction mixture is stirred at room temperature overnight. The
solvents are removed in vacuo to afford the title compound as the
hydrobromide salt.
Example 42b: HCl Salt
[0273] A solution of crude
4-(6-amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-bromo-6-fluoro-ph-
enol hydrobromide (Example 42a) in methanol is converted to its
free base by the addition of excess triethylamine. The resulting
free base is purified by flash chromatography on silica using a
solvent gradient of iso-hexanes:EtOAc (50% EtOAc to 100% EtOAc).
The appropriate fraction are combined and concentrated in vacuo,
the residue is treated with 4M hydrogen chloride (4M in
1,4-dioxane) and the solvent is removed in vacuo. The resulting
hydrochloride salt is purified by reverse phase column
chromatography (Isolute.TM. C18) eluting with water:acetonitrile to
afford the title compound as the hydrochloride salt.
Example 43
4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2,6-dibromo-phenol
[0274] 4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-phenol
(Example 39) (34 mg, 0.14 mmol) is suspended in glacial acetic acid
(2.0 ml). Bromine (14 .mu.L, 0.28 mmol) is added and the reaction
mixture is then stirred at room temperature overnight. The solvents
are removed in vacuo and purification of the crude residue by flash
chromatography on silica using a solvent gradient of
EtOAc:Et.sub.3N (99:1) to remove non-polar impurities then eluting
the product with EtOAc:MeOH:Et.sub.3N (90:10:1) affords the title
compound as a white solid.
Example 44
3-[3-Bromo-5-fluoro-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-1-methyl-1H-pyraz-
olo[3,4-d]pyrimidin-6-ylamine
[0275]
4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-bromo-6-flu-
oro-phenol hydrochloride (Example 42b) (30 mg, 0.08 mmol) is
dissolved in anhydrous THF (10 ml), K.sub.2CO.sub.3 (12 mg, 0.09
mmol) is added and the reaction mixture is stirred at room
temperature for 10 minutes. Triphenylphosphine (116 mg, 0.44 mmol),
DIAD (0.076 ml, 0.40 mmol) and 1-(2-hydroxyethyl)pyrrolidine (0.048
ml, 0.40 mmol) are added and the reaction mixture is heated to
reflux for 20 hours. After cooling to room temperature the reaction
mixture is diluted with water (.about.15 ml) and extracted with
EtOAc (3.times.50 ml). The combined organic portions are dried over
MgSO.sub.4, filtered and concentrated in vacuo. Purification of the
crude residue by flash chromatography on silica firstly eluting the
non-polar impurities with iso-hexanes:EtOAc (4:1 to 1:4) then
eluting the product with EtOAc:MeOH:Et3N (4:1:0.01) affords the
title compound.
Example 45
3-[3-Bromo-5-fluoro-4-(2-methoxy-ethoxy)-phenyl]-1-methyl-1H-pyrazolo[3,4--
d]pyrimidin-6-ylamine
[0276]
4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-bromo-6-flu-
oro-phenol hydrochloride (Example 42b) (30 mg, 0.08 mmol) is
dissolved in DMF (1 ml) then treated with K.sub.2CO.sub.3 (24 mg,
0.18 mmol) and 2-bromoethyl methyl ether (7.5 .mu.L, 0.08 mmol).
The reaction mixture is heated at 120.degree. C. for 3 hours then
cooled to room temperature, diluted with MeOH and concentrated in
vacuo. The crude residue is dry loaded onto silica and purification
by flash chromatography on silica eluting with iso-hexanes:EtOAc
(50% EtOAc to 100% EtOAc) affords the title compound as an
off-white solid.
Example 46
2-[4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-bromo-6-fluoro--
phenoxy]-ethanol
[0277]
4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-bromo-6-flu-
oro-phenol hydrochloride (42b) (30 mg, 0.08 mmol) is dissolved in
DMF (1 ml) then treated with K.sub.2CO.sub.3 (24 mg, 0.18 mmol) and
2-bromoethanol (5.7 .mu.L, 0.08 mmol). The reaction mixture is
heated at 120.degree. C. for 3 hours then cooled to room
temperature, diluted with MeOH and concentrated onto silica.
Purification by flash column chromatography on silica using
iso-hexanes:EtOAc (50% EtOAc to 100% EtOAc) followed by
recrystallisation from MeOH afforded the title compound as an
off-white solid.
Examples 47-56
[0278] are prepared analogously to Example 46 from the
corresponding phenols and halogenated intermediates.
[0279] These compounds namely, [0280]
2-[4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluoro-phenoxy-
]-ethanol (Example 47) [0281]
3-[4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluoro-phenoxy-
]-propan-1-ol (Example 48) [0282]
3-[3-Fluoro-4-(2-methoxy-ethoxy)-phenyl]-1-methyl-1H-pyrazolo[3,4-d]pyrim-
idin-6-ylamine (Example 49) [0283]
[4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluoro-phenoxy]--
acetonitrile (Example 50) [0284]
3-[3-Fluoro-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-1-methyl-1H-pyrazolo[3,4-
-d]pyrimidin-6-ylamine (Example 51) [0285]
3-[3-Fluoro-4-(2-imidazol-1-yl-ethoxy)-phenyl]-1-methyl-1H-pyrazolo[3,4-d-
]pyrimidin-6-ylamine (Example 52) [0286]
3-[3-Fluoro-4-(2-morpholin-4-yl-ethoxy)-phenyl]-1-methyl-1H-pyrazolo[3,4--
d]pyrimidin-6-ylamine (Example 53) [0287]
3-[3-Fluoro-4-(3-morpholin-4-yl-propoxy)-phenyl]-1-methyl-1H-pyrazolo[3,4-
-d]pyrimidin-6-ylamine (Example 54) [0288]
3-{3-Fluoro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-1-methyl-1H-p-
yrazolo[3,4-d]pyrimidin-6-ylamine (Example 55) [0289]
2-[2-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-4-fluoro-phenoxy-
]-ethanol (Example 56)
Example 57
3-(4-Amino-3-fluoro-phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine
[0290] 3-Chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine
(Intermediate 4) (1.2 g, 5.2 mmol) is dissolved in THF (40 ml)
under an inert atmosphere of argon. To this is added
Pd(PPh.sub.3).sub.2Cl.sub.2 (0.224 g, 0.32 mmol),
[3-fluoro-4-methoxyphenyl]boronic acid (0.98 g, 5.8 mmol) and a
solution of Na.sub.2CO.sub.3 (1,5 g, 14 mmol) dissolved in
distilled water (4 ml). The reaction mixture is heated to reflux at
70.degree. C. for 24 hours. The reaction mixture is absorbed on
silica and purification by flash column chromatography on silica
eluting with 2:1 iso-hexanes:EtOAc affords the title compound.
Example 58
N-[4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluoro-phenyl]m-
ethanesulfonamide
[0291]
3-(4-Amino-3-fluoro-phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6--
ylamine (Example 58) (0.13 g, 0.50 mmol) is dissolved in pyridine
(1.5 ml) under an inert atmosphere af argon. The reaction mixture
is cooled to -10.degree. C. (dry ice/acetone bath) then
methanesulfonyl chloride (0.078 ml, 0.75 mmol) is added drop wise
over a period of 15 minutes. The reaction mixture is stirred at
-10.degree. C. for 30 minutes then allowed to warm to room
temperature and stirred for further 3 hours. The reaction mixture
is diluted with EtOAc (100 ml) and washed with water (3.times.40
ml) and brine (10 ml). The organic portion is dried over
MgSO.sub.4, filtered and concentrated in vacuo. The resulting solid
is triturated with hot EtOAc (plus few drops of MeOH), filtered and
dried under vacuum at 50.degree. C. for 3 hours to afford the title
compound as an off-white solid.
Example 59
[3-(3-Fluoro-4-methoxy-phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl]--
methyl-amine
[0292] This compound is prepared analogously to Example 1, Method A
by replacing ammonia in the final step with methylamine to afford
the title compound.
Example 60
[0293]
3-(3,5-Difluoro-phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylam-
ine 3-Bromo-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine
(Intermediate 3) (0.05 g, 0.22 mmol) is suspended in 1,4-dioxane (1
ml). The reaction mixture is sonicated to give a very fine
suspension and placed in a microwave vial containing 3,5-difluoro
phenylboronic acid (38 mg, 0.24 mmol). To this is added a solution
of tris(dibenzylileneacetone) di palladium(0) (0.002 g, 0.0022
mmol) in 1,4-dioxane (0.5 ml) followed by a solution of
tricyclohexyl phosphine (0.0015 g, 0.0053 mmol) in 1,4-dioxane (0.5
ml) and 1.27M aqueous potassium phosphate solution (0.294 ml, 0.374
mmol). The resulting mixture is flushed with argon and heated using
microwave radiation at 150.degree. C. for 30 minutes. The reaction
mixture is treated with DMSO (2 ml) and filtered through a 2 g
silica cartridge washing with EtOAc:MeOH (10:1, 4 ml). The filtrate
is concentrated in vacuo and the resulting residue is dissolved in
NMP (4 ml) and loaded onto an Isolute.TM. SCX column (silica based
cation exchange sorbent) eluting with MeOH (4 ml) and 1M NH.sub.3
in MeOH (6 ml). The appropriate fractions are combined and
concentrated in vacuo to afford the title compound.
Examples 61-77
[0294] are prepared analogously to Example 60 from the appropriate
commercial boronic acids using standard Suzuki coupling
methodology. Examples 61-65 are further purified by preparative
HPLC (water/acetonitrile, 0.1% TFA) to afford the products as the
trifluoroacetate salts.
[0295] These compounds namely, [0296]
1-Methyl-3-(2,3,4-trifluoro-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine
trifluoroacetate (Example 61) [0297]
3-(5-Chloro-thiophen-2-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine
trifluoroacetate (Example 62) [0298]
3-(5-Bromo-2-methoxy-phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylami-
ne trifluoroacetate (Example 63) [0299]
3-(2-Ethoxy-naphthalen-1-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylami-
ne trifluoroacetate (Example 64) [0300]
3-[3-Bromo-2-(2-fluoro-benzyloxy)-phenyl]-1-methyl-1H-pyrazolo[3,4-d]pyri-
midin-6-ylamine trifluoroacetate (Example 65) [0301]
1-[3-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluoro-phenyl]-
-ethanone (Example 66) [0302]
3-(4-Fluoro-2-propoxy-phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylam-
ine (Example 67) [0303]
3-(3,5-Dimethyl-isoxazol-4-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yla-
mine (Example 68) [0304]
1-Methyl-3-m-tolyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine (Example
69) [0305]
3-Furan-2-yl-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine
(Example 70) [0306]
3-(5-Chloro-2-methoxy-phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylam-
ine (Example 71) [0307]
3-(2,5-Dimethoxy-phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine
(Example 72) [0308]
1-Methyl-3-(4-methyl-3-nitro-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamin-
e (Example 73) [0309]
3-(4-Isobutyl-phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine
(Example 74) [0310]
3-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-4-methoxy-benzaldeh-
yde (Example 75) [0311]
1-Methyl-3-(3,4,5-trifluoro-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine
(Example 76) [0312]
1-Methyl-3-quinolin-8-yl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine
(Example 77)
Example 78
3-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-isopropyl-benzamid-
e
[0313] 3-(N-isopropylaminocarbonyl)benzene boronic acid (0.99 g,
0.48 mmol) and 1.27M aqueous potassium phosphate solution (0.591
ml, 0.75 mmol) are stirred in 1,4-dioxane (1 ml), under an inert
atmosphere of argon for 15 minutes. Separately,
3-Bromo-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine
(Intermediate 3) (0.1 g, 0.44 mmol), PCy.sub.3 (4 mg, 0.012 mmol)
and Pd.sub.2(dba).sub.3 (5 mg, 0.005 mmol) are stirred in
1,4-dioxane (1 ml) before being added to the boronic acid solution.
The reaction mixture is heated to 100.degree. C. for 1.5 hours and
then filtered hot to remove the palladium residues. The filtrate is
diluted with a little MeOH/water and the resulting precipitate is
collected by filtration and dried under vacuum at 45.degree. C. to
afford the title compound.
Example 79-87
[0314] are prepared analogously to Example 78 from commercial or
prepared boronic acids using standard Suzuki coupling methodology.
The compounds are recovered from reaction mixtures and purified
using conventional techniques such as, for example, flash
chromatography, reverse phase chromatography or preparative
HPLC.
[0315] These compounds namely, [0316]
4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2,6-difluoro-benzal-
dehyde (Example 79) [0317]
[3-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluoro-phenoxy]--
acetic acid (Example 80) [0318]
3-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-methyl-benzamide
(Example 81) [0319]
1-Methyl-3-(2-piperazin-1-yl-pyrimidin-5-yl)-1H-pyrazolo[3,4-d]pyrimidin--
6-ylamine (Example 82) [0320]
3-(2,4-Dimethoxy-pyrimidin-5-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-y-
lamine (Example 83) [0321]
3-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-benzaldehyde
(Example 84) [0322]
3-(2-Methoxy-pyrimidin-5-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylami-
ne (Example 85) [0323]
3-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-isobutyl-benzamid-
e (Example 86) [0324]
3-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-methyl-benzenesul-
fonamide (Example 87)
Example 88
3-(2-Methoxy-5-trifluoromethyl-phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidi-
n-6-ylamine
[0325] 3-Bromo-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine
(Intermediate 3) (0.1 g, 0.44 mmol),
2-methoxy-5-trifluoromethylphenylboronic acid (0.116 g, 0.53 mmol),
Pd(dppf)Cl.sub.2 (0.032 g, 0.044 mmol), DME (4 ml) and 2M aqueous
Na.sub.2CO.sub.3, are mixed together and heated using microwave
radiation at 100.degree. C. for 30 minutes. The reaction mixture is
diluted with EtOAc (30 mls), MgSO.sub.4 is added and the resulting
mixture is filtered through Celite.RTM. (filter agent), washing
with EtOAc. The reaction mixture is absorbed onto silica and
purification by flash chromatography on silica eluting with DCM
then MeOH:DCM (5:95) affords the title compound.
Example 89 and 90
[0326] are prepared analogously to Example 88 from commercial
boronic acids using standard Suzuki coupling methodology.
[0327] These compounds namely, [0328]
3-(2,4-Dimethoxy-phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine
(Example 89) [0329]
3-(2,6-Dimethoxy-phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine
(Example 90)
Example 91
2-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-4-trifluoromethyl-ph-
enol
[0330] To a solution of
3-(2-Methoxy-5-trifluoromethyl-phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimid-
in-6-ylamine (Example 88) (0.08 g, 0.25 mmol) in DCM (5 ml) is
added drop wise boron tribromide (1M solution in DCM, 0.99 ml, 0.99
mmol), under an inert atmosphere of argon at 0-5.degree. C.
(ice-bath). The reaction mixture is warmed to room temperature,
stirred for 2 hours and then quenched with water (10 ml). The
resulting solid is collected by filtration and dried under vacuum
to afford the title compound.
Example 92
4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-benzene-1,3-diol
[0331] This compound is prepared analogously to Example 91 by
replacing
3-(2-Methoxy-5-trifluoromethyl-phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimid-
in-6-ylamine phenyl) (Example 88) with
3-(2,4-Dimethoxy-phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine
(Example 89). The addition of water during the aqueous quench
results in a precipitate but on filtration a gum forms, this gum is
therefore triturated with diethyl ether (50 ml) to form a solid,
which is collected by filtration and dried under vacuum to afford
the title compound.
Example 93
2-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-4-chloro-phenol
[0332] This compound is prepared analogously to Example 91 by
replacing
3-(2-Methoxy-5-trifluoromethyl-phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimid-
in-6-ylamine (Example 88) with
3-(5-Chloro-2-methoxy-phenyl)-1-methyl-1H-pyrazolo[3,4d]pyrimidin-6-ylami-
ne (Example 71) to afford the title compound.
Example 94
3-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-4-methoxy-benzoic
acid
[0333]
3-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-4-methoxy-ben-
zaldehyde (Example 75) (0.5 g, 1.77 mmol) is suspended in t-butanol
(12 ml) and 2-methyl-2-butene (0.562 ml, 5.31 mmol). To this is
added a solution of sodium chlorite (0.367 g, 4.06 mmol) and sodium
dihydrogen phosphate (0.848 g, 7.06 mmol) in water (5 ml). The
reaction mixture is stirred at room temperature for 48 hours and
the resulting precipitate is collected by filtration, dissolved in
saturated aqueous NaHCO.sub.3 (100 ml) and washed with EtOAc
(2.times.50 ml). The aqueous portion is acidified to pH1 with 2M
HCl resulting in an off-white solid which is collected by
filtration and dried under vacuum for 72 hours to afford the title
compound.
Example 95
4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2,6-dichloro-phenol
Step 1:
3-(4-Benzyloxy-3,5-dichloro-phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyr-
imidin-6-ylamine
[0334] This compound is prepared analogously to Example 78 by
replacing 3-(N-isopropylaminocarbonyl)benzene boronic acid with
4-(benzyloxy)-3,5 dichlorophenyl boronic acid to afford the title
compound.
Step 2:
4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2,6-dichloro-
-phenol
[0335]
3-(4-Benzyloxy-3,5-dichloro-phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyri-
midin-6-ylamine (0.2 g, 0.500 mmol) is dissolved in 48% HBr in
water (20 ml) and heated to 120.degree. C. for 1 hour. The reaction
mixture is cooled to room temperature and the resulting precipitate
is collected by filtration and re-crystallised from EtOH to afford
the title compound.
Example 96
4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-chloro-6-fluoro-ph-
enol
[0336] This compound is prepared analogously to Example 78 by
replacing 3-(N-isopropylamino carbonyl)benzene boronic acid with
3-Chloro-5-fluoro-4-hydroxyphenyl-boronic acid (Intermediate 8).
The reaction is carried out using microwave radiation at
150.degree. C. for 30 minutes.
Example 97
2-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-6-bromo-4-chloro-phe-
nol
Step 1:
3-(5-Chloro-2-methoxy-phenyl)-1-methyl-4,5-dihydro-1H-pyrazolo[3,4-
-d]pyrimidin-6-ylamine trifluoroacetate
[0337]
3-(5-Chloro-2-methoxy-phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin--
6-ylamine (Example 71) is dissolved in MeOH (3 ml) and THF (5 ml).
To this is added NaBH.sub.4 (0.522 g, 13.8 mmol), and the reaction
mixture is stirred at room temperature until no more gas is given
off. After 30 minutes the reaction mixture is filtered through
Celite.RTM. (filter agent), washing with MeOH. The filtrate is
concentrated in vacuo and the resulting residue is diluted with
EtOAc and washed with water. The organic portion is dried over
MgSO.sub.4, filtered, concentrated in vacuo and purification of the
crude residue by preparative HPLC (water/acetonitrile, 0.1% TFA)
affords the title compound as the trifluoroacetate salt.
Step 2:
2-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-6-bromo-4-ch-
loro-phenol
[0338]
3-(5-Chloro-2-methoxy-phenyl)-1-methyl-4,5-dihydro-1H-pyrazolo[3,4--
d]pyrimidin-6-ylamine trifluoroacetate is dissolved in 48% HBr in
water (10 ml) and heated using microwave radiation at 120.degree.
C. for 2 hours. Purification of the reaction mixture by preparative
HPLC (water/acetonitrile, 0.1% TFA) affords the title compound as
the minor product of the reaction as the trifluoroacetate salt.
Example 98
3-(3,5-Difluoro-4-methoxy-phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-y-
lamine
[0339] This compound is prepared analogously to Example 78 by
replacing 3-(N-isopropylamino carbonyl)benzene boronic acid with
3,5-Difluoro-4-methoxy-phenyl-boronic acid (Intermediate 9) to
afford the title compound.
Example 99
3-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-isopropyl-4-methox-
y-benzamide
[0340]
3-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-4-methoxy-ben-
zoic acid (Example 94) (0.075 g, 0.25 mmol) is dissolved in DMF (5
ml), HATU (0.095 g, 0.25 mmol) is then added followed by
N-Methylmorpholine (0.110 ml, 1.0 mmol) and isopropylamine (0.022
ml, 0.25 mmol) and the reaction mixture is stirred at room
temperature for 15 hours. The solvent is removed in vacuo and the
residue is diluted with water (3 ml) and left to stand for 3 hours.
The resulting solid precipitate is collected by filtration, washed
with a further 5 ml of water and dried under vacuum to afford the
title compound.
Example 100
3-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-4-hydroxy-benzaldehy-
de
[0341] This compound is prepared analogously to Example 91 by
replacing
3-(2-Methoxy-5-trifluoromethyl-phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimid-
in-6-ylamine (Example 88) with
3-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-4-methoxy-benzaldeh-
yde (Example 75) to afford the title compound.
Example 101
3-(6-Amino-5-trifluoromethyl-pyridin-3-yl)-1-methyl-1H-pyrazolo[3,4-d]pyri-
midin-6-ylamine
[0342] 3-Bromo-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine
(Intermediate 3) (0.1 g, 0.438 mmol),
tetrakis(triphenylphosphine)palladium (0.031 g, 0.027 mmol),
5-(4,4,5,5-tetra
methyl-[1,3,2]dioxaborolan-2-yl)-3-trifluoromethyl-pyridin-2-ylamine
(Intermediate 10) (0.135 g, 0.669 mmol), cesium carbonate (0.290 g,
0.892 mmol) and water (1 ml) are suspended in 1,4-dioxane (4 ml)
and heated using microwave radiation at 150.degree. C. for 45
minutes. The reaction mixture is cooled to room temperature,
filtered through Celite.RTM. (filter agent) and washed with EtOAc.
The solvents are removed in vacuo and purification of the crude
residue by flash chromatography on silica eluting with
iso-hexanes:EtOAc (2:1) results in an off white solid. The solid is
further purified by recrystallisation from 1:1 MeOH/EtOAc resulting
in a white solid which is collected by filtration and dried under
vacuum to afford the title compound.
Example 102
4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2,6-difluoro-benzoni-
trile
[0343] This compound is prepared analogously to Example 101 by
replacing
5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-3-trifluoromethyl-pyridi-
n-2-ylamine (Intermediate 10) with
2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzonitril-
e (Intermediate 11). Purification by preparative HPLC
(water/acetonitrile, 0.1% TFA) affords the title compound as the
trifluoroacetate salt.
Example 103
N-[3-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-4-methoxy-phenyl]-
-N',N'-dimethyl-propane-1,3-diamine
[0344]
3-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-4-methoxy-ben-
zaldehyde (Example 75) (0.06 g, 0.212 mmol) is suspended in THF (2
ml) and AcOH (0.2 ml). N,N-dimethyl-propane-1,3-diamine (0.0029 ml,
0.233 mmol) is added and reaction mixture is stirred for 1 hour 30
minutes at room temperature. After this time MP-BH.sub.4 (3.2 mmol
loading, 0.07 g, 0.225 mmol) is added and the mixture is continued
to stir for a further 48 hours. The reaction mixture is filtered,
washing with MeOH and the filtrate is concentrated in vacuo.
Purification of the crude residue by preparative HPLC
(water/acetonitrile, 0.5% TFA) affords the title compound as the
trifluoroacetate salt.
Example 104
[3-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-4-methoxy-phenyl]-m-
ethanol
[0345]
3-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-4-methoxy-ben-
zaldehyde (Example 75) (0.040 g, 0.141 mmol) is suspended in dry
MeOH (2.5 ml) and THF (1 ml). The reaction mixture is cooled to
0-5.degree. C. (ice-bath) and sodium borohydride (0.006 g, 0.1551
mmol) is cautiously added. The reaction mixture is stirred at room
temperature for 24 hours, filtered, washing with MeOH and
concentrated in vacuo. The resulting solid is triturated in MeOH
(minimal) and collected by filtration to afford the title compound
as an off-white solid.
Example 105
N-[5-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-3-fluoro-2-methox-
y-phenyl]-acetamide
[0346] This compound is prepared analogously to Example 78 by
replacing 4-(N-isopropylamino carbonyl)phenylboronic acid with
N-[3-Fluoro-2-methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-ph-
enyl]-acetamide (Intermediate 12) to afford the title compound.
Example 106
4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2,6-difluoro-benzoic
acid
[0347]
4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2,6-difluoro--
benzaldehyde (Example 79) (0.103 g, 0.345 mmol) is suspended in 2M
NaOH (0.431 ml, 0.862 mmol), 35% H.sub.2O.sub.2 in water (17.3 ml,
17.025 mmol) is added and the reaction mixture is stirred at room
temperature for 56 hours. The reaction mixture is filtered through
filter paper, ice is added to the filtrate and the mixture is
quenched with 5M HCl resulting in a white precipitate after 1.5
hours. This solid is collected by filtration, washed with water and
dried under vacuum for 24 hours at 45.degree. C. to afford the
title compound.
Example 107
5-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-3-fluoro-2-hydroxy-b-
enzaldehyde
[0348]
4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluoro-phen-
ol (Example 36) (0.101 g, 0.268 mmol) is suspended in AcOH (2 ml)
and hexamethylenetetriamine (0.267 g, 1.90 mmol) is added. The
reaction mixture is heated to 90.degree. C. (mixture solubilises at
this temperature) for 6 hours, then cooled to room temperature and
left overnight. The reaction mixture is concentrated in vacuo to a
brown residue which is diluted with 5M HCl (2.5 ml), heated to
110.degree. C. for 30 minutes, then poured onto ice/water. The
resulting solid is removed by filtration and washed with water. The
aqueous portion is concentrated in vacuo and purification of the
crude residue by preparative HPLC (water/acetonitrile, 0.1% TFA)
affords the title compound as the trifluoroacetate salt.
Example 108
4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2,6-difluoro-phenol
[0349]
3-(3,5-Difluoro-4-methoxy-phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimi-
din-6-ylamine (Example 98) (0.1 g, 0.342 mmol) is dissolved in 48%
HBr in water (5 ml) and heated using microwave radiation at
120.degree. C. for 30 minutes. Purification of the reaction mixture
by preparative HPLC (water/acetonitrile, 0.1% TFA) affords the
title compound as a white solid.
Example 109
5-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-3-fluoro-2-hydroxy-b-
enzonitrile
[0350]
4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-bromo-6-flu-
oro-phenol hydrobromide (Example 42a) (0.07 g, 0.167 mmol),
Zn(CN).sub.2 (0.020 g, 0.167 mmol), Pd.sub.2(dba).sub.3 (0.076 g,
0.08 mmol) and DPPF (0.092 g, 0.167 mmol) are dissolved in DMF (2.5
ml) and heated to 180.degree. C. for 40 minutes. The reaction
mixture is filtered through Celite.RTM. (filter agent) washing with
MeOH, the filtrate is concentrated in vacuo and purification of the
resulting residue is by preparative HPLC (water/acetonitrile, 0.1%
TFA) affords the title compound as a white solid.
Example 110
3-(4-Fluoro-2-methoxy-phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylami-
ne
[0351] This compound is prepared analogously to Example 88 by
replacing 2-methoxy-5-trifluoromethylphenylboronic acid with
4-Fluoro-2-methoxyphenylboronic acid to afford the title
compound.
Example 111
4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-trifluoromethyl-ph-
enol
Step 1:
3-(4-Methoxy-3-trifluoromethyl-phenyl)-1-methyl-1H-pyrazolo[3,4-d]-
pyrimidin-6-ylamine
[0352] This compound is prepared analogously to Example 88 by
replacing 5-trifluoro methyl-2-methoxybenzene boronic acid with
4-methoxy-3-trifluoromethylphenyl boronic acid to afford the title
compound.
Step 2:
4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-trifluorom-
ethyl-phenol
[0353]
3-(4-Methoxy-3-trifluoromethyl-phenyl)-1-methyl-1H-pyrazolo[3,4-d]p-
yrimidin-6-ylamine (0.05 g, 0.154 mmol) is suspended in DCM (3 ml)
at 0-5.degree. C. (ice-bath), to this mixture is added boron
tribromide (1M solution in DCM, 1.24 ml, 1.24 mmol) resulting in a
yellow solid. The reaction mixture is stirred at 0-5.degree. C. for
15 minutes then overnight at room temperature, the mixture is
quenched with water and stirred for a further 24 hours. The
solvents are removed in vacuo and purification by preparative HPLC
(water/acetonitrile, 0.1% TFA) affords the title compound as the
trifluoroacetate salt.
Example 112
2-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-6-fluoro-phenol
Step 1:
3-(3-Fluoro-2-methoxy-phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-
-6-ylamine
[0354] This compound is prepared analogously to Example 88 by
replacing 2-methoxy-5-trifluoromethylphenylboronic acid with
3-fluoro-2methoxyphenylboronic acid to afford the title
compound.
Step 2:
2-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-6-fluoro-phe-
nol
[0355] This compound is prepared analogously to Example 111 (step
2) by replacing
3-(4-methoxy-3-trifluoromethyl-phenyl)-1-methyl-1H-pyrazolo[3,4-
-d]pyrimidin-6-ylamine with
3-(3-Fluoro-2-methoxy-phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylam-
ine to afford the title compound.
Example 113
5-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2,4-dimethoxy-benzen-
esulfonic acid
[0356]
3-(2,4-Dimethoxy-phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yla-
mine (Example 89) (1 g, 3.50 mmol) is dissolved in concentrated
sulfuric acid (25 ml) to give a blood red solution. The reaction
mixture is stirred at room temperature overnight, poured onto
ice-water (200 ml) and the resulting solid is collected by
filtration, washed with water and dried under vacuum to afford the
title compound.
Example 114
3-(5-Chloro-2,4-dimethoxy-phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-y-
lamine
[0357]
3-(2,4-Dimethoxy-phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yla-
mine (Example 89) is suspended in acetonitrile (10 ml),
trichloroisocyanuric acid (0.021 g, 0.09 mmol) is added and the
reaction mixture is stirred for 1.5 hours at room temperature then
stood overnight. The solvents are removed in vacuo, the residue is
dissolved in EtOAc, washed with water and brine, dried over
MgSO.sub.4, filtered, concentrated in vacuo and dried under vacuum
(45.degree. C.) to afford the title compound.
Example 115
4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-chloro-6-trifluoro-
methyl-phenol
Step 1:
3-(3-Chloro-4-methoxy-5-trifluoromethyl-phenyl)-1-methyl-1H-pyrazo-
lo[3,4-d]pyrimidin-6-ylamine
[0358]
3-(4-Methoxy-3-trifluoromethyl-phenyl)-1-methyl-1H-pyrazolo[3,4-d]p-
yrimidin-6-ylamine (Example 111, step 1) (182 mg, 0.56 mmol) is
dissolved in concentrated sulfuric acid (11 ml) to give a red
solution. Trichloroisocyanuric acid (44 mg, 0.188 mmol) is added
and the reaction mixture is stirred at room temperature overnight
then poured onto ice-water. After stirring for 30 minutes, the
resulting precipitate is collected by filtration, washed with water
and dried under vacuum (450) to afford the title compound as the
sulfate salt.
Step 2:
4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-chloro-6-t-
rifluoro methyl-phenol
[0359] This compound is prepared analogously to Example 108 by
replacing
3-(3,5-Difluoro-4-methoxy-phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6--
ylamine (Example 98) with
3-(3-Chloro-4-methoxy-5-trifluoromethyl-phenyl)-1-methyl-1H-pyrazolo[3,4--
d]pyrimidin-6-ylamine sulfate (product from step 1) to afford the
title compound.
Example 116
5-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-benzyloxy-3-fluoro-
-N,N-dimethyl-benzamide
[0360] This compound is prepared analogously to Example 88 by
replacing 2-methoxy-5-trifluoromethylphenylboronic acid with
2-Benzyloxy-3-fluoro-N,N-dimethylbenzamide-5-boronic acid
(Intermediate 13) to afford the title compound.
Example 117
4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-6-chloro-benzene-1,3-
-diol
[0361] This compound is prepared analogously to Example 91 by
replacing
3-(2-Methoxy-5-trifluoromethyl-phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimid-
in-6-ylamine (Example 88) with
3-(5-Chloro-2,4-dimethoxy-phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6--
ylamine (Example 114). Further purification by preparative HPLC
(water/acetonitrile, 0.1% TFA) affords the title compound as the
trifluoroacetate salt.
Example 118
3-(3-Chloro-2-methoxy-5-trifluoromethyl-phenyl)-1-methyl-1H-pyrazolo[3,4-d-
]pyrimidin-6-ylamine
[0362]
3-(2-Methoxy-5-trifluoromethyl-phenyl)-1-methyl-1H-pyrazolo[3,4-d]p-
yrimidin-6-ylamine (Example 88) (526 mg, 1.62 mmol) is dissolved in
concentrated sulfuric acid (98%, 15 ml) and trichloroisocyanuric
acid (126 mg, 0.54 mmol) is added. The reaction mixture is stirred
at room temperature for 3 days, poured onto ice water (100 ml) and
stirred for 30 minutes. The resulting precipitate is collected by
filtration and dried under vacuum to afford the title compound as
the sulfate salt.
Example 119
4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-bromo-6-chloro-ben-
zene-1,3-diol
[0363] This compound is prepared analogously to Example 97 (step 2)
by replacing
2-(6-Amino-1-methyl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-3-y-
l)-4-chloro-phenol with
3-(5-Chloro-2,4-dimethoxy-phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6--
ylamine (Example 114) to afford the title compound.
Example 120
5-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2,4-dimethoxy-N-meth-
yl-benzenesulfonamide
Step 1:
5-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2,4-dimethox-
y-benzenesulfonyl chloride
[0364]
5-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2,4-dimethoxy-
-benzenesulfonic acid (Example 113) (629 mg, 1.72 mmol) is
suspended in thionyl chloride (25 ml), the reaction mixture is
heated to 120.degree. C. for 5 hours then stood overnight at room
temperature. The resulting precipitate is removed by filtration,
the filtrate is concentrated in vacuo and the resulting residue is
azeotroped with toluene to afford the title compound as a
solid.
Step 2:
5-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2,4-dimethox-
y-N-methyl-benzenesulfonamide
[0365]
5-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2,4-dimethoxy-
-benzenesulfonyl chloride (75 mg, 0.195 mmol) is dissolved in 2M
solution NH.sub.2Me in THF (5 ml) and stirred at room temperature
for 1 hour. The reaction mixture is concentrated in vacuo and
purification by preparative HPLC (water/acetonitrile, 0.1% TFA)
affords the title compound as the trifluoroacetate salt.
Example 121
5-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-isopropyl-2,4-dime-
thoxy-benzenesulfonamide
[0366]
5-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2,4-dimethoxy-
-benzenesulfonyl chloride (Example 120, Step 1) (82 mg, 0.213 mmol)
is suspended in DCM (3 ml), triethylamine (0.323 ml, 0.235 mmol) is
added (resulting in a clear solution) followed by iso-propylamine
(14 mg, 0.235 mmol). The reaction mixture is stirred for 1 hour at
room temperature and then stood overnight. Purification of the
crude material by preparative HPLC (water/acetonitrile, 0.1% TFA)
affords the title compound as the trifluoroacetate salt.
Example 122
2-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-6-chloro-4-trifluoro-
methyl-phenol
[0367] This compound is prepared analogously to Example 91 by
replacing
3-(2-Methoxy-5-trifluoromethyl-phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimid-
in-6-ylamine (Example 88) with
3-(3-Chloro-2-methoxy-5-trifluoromethyl-phenyl)-1-methyl-1H-pyrazolo[3,4--
d]pyrimidin-6-ylamine (Example 118) to afford the title
compound.
Example 123
3-(2-Methoxy-4-trifluoromethoxy-phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimid-
in-6-ylamine
[0368] This compound is prepared analogously to Example 88 by
replacing 2-methoxy-5-trifluoromethylphenylboronic acid with
2-methoxy-4-(trifluoromethoxy)-phenylboronic acid to afford the
title compound.
Example 124
2-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-trifluoromethoxy-p-
henol
[0369] A mixture of
3-(2-Methoxy-4-trifluoromethoxy-phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimi-
din-6-ylamine (Example 123) (50 mg, 0.147 mmol) and 1M BBr.sub.3 in
DCM (3 ml, 2.94 mmol) is stirred at room temperature for 30
minutes. The reaction mixture is quenched with water (5 ml) and
stirred for a further 30 minutes. The resulting precipitate is
collected by filtration, washed with water and dried under vacuum
(50.degree. C.) to afford the title compound as the hydrobromide
salt.
Example 125
3-(5-Chloro-2-methoxy-4-trifluoromethoxy-phenyl)-1-methyl-1H-pyrazolo[3,4--
d]pyrimidin-6-ylamine
[0370] This compound is prepared analogously to Example 118 by
replacing
methoxy-4-trifluoromethyl-phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6--
ylamine (Example 88) with
3-(2-Methoxy-4-trifluoromethoxy-phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimi-
din-6-ylamine (Example 123) to afford the title compound as the
sulphate salt.
Example 126
6-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-bromo-4-chloro-3-t-
rifluoromethoxy-phenol
[0371] This compound is prepared analogously to Example 124 by
replacing
3-(2-Methoxy-4-trifluoromethoxy-phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimi-
din-6-ylamine (Example 123) with
3-(5-Chloro-2-methoxy-4-trifluoromethoxy-phenyl)-1-methyl-1H-pyrazolo[3,4-
-d]pyrimidin-6-ylamine (Example 125). Purification by preparative
HPLC (water/acetonitrile, 0.1% TFA), affords the title compound as
the trifluoroacetate salt.
Example 127
5-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N,N-diethyl-2-hydrox-
y-benzenesulfonamide
Step 1:
5-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N,N-diethyl--
2-methoxy-benzenesulfonamide
[0372] This compound is prepared analogously to Example 88 by
replacing 2-methoxy-5-trifluoromethylphenylboronic acid with
4-methoxy-3-(N,N-diethylsulfonyl)benzeneboronic acid to afford the
title compound.
Step 2:
5-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N,N-diethyl--
2-hydroxy-benzenesulfonamide
[0373] This compound is prepared analogously to Example 124 by
replacing
3-(2-Methoxy-4-trifluoromethoxy-phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimi-
din-6-ylamine (Example 123) with
5-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N,N-diethyl-2-metho-
xy-benzenesulfonamide and by using 20 eq of BBr.sub.3 in DCM to
afford the title as the hydrobromide salt.
Example 128
N-[5-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-chloro-phenyl]--
methanesulfonamide
Step 1:
N-[3-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-phenyl]-m-
ethanesulfonamide
[0374] This compound is prepared analogously to Example 88 by
replacing 2-methoxy-5-trifluoromethylphenylboronic acid with
3-(methylsulfonylamino)phenylboronic acid to afford the title
compound.
Step 2:
N-[5-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-chloro--
phenyl]-methanesulfonamide
[0375] This compound is prepared analogously to Example 118 by
replacing
3-(2-Methoxy-5-trifluoromethyl-phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimid-
in-6-ylamine (Example 88) with
N-[3-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-phenyl]-methanes-
ulfonamide. Purification of the crude residue by preparative HPLC
(water/acetonitrile, 0.1% TFA) affords the title compound as the
trifluoroacetate salt.
Example 129
5-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-chloro-N-methyl-be-
nzenesulfonamide
Step 1:
3-(4-Chloro-phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine
[0376] This compound is made analogously to Example 88 by replacing
2-methoxy-5-trifluoromethylphenylboronic acid with
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)chlorobenzene. The
crude residue is stirred with iso-hexanes:EtOAc, the resulting
solid is filtered, washed with iso-hexanes and dried under vacuum
to afford the title compound.
Step 2:
5-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-chloro-ben-
zenesulfonyl chloride
[0377]
3-(4-Chloro-phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine
(559 mg, 2.15 mmol) is dissolved in chlorosulfonic acid (6.45 ml,
96.84 mmol) and the reaction mixture is heated to 120.degree. C.
for 24 hours. After cooling to room temperature the reaction
mixture is used crude as a solution for the next step.
Step 3:
5-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-chloro-N-m-
ethyl-benzenesulfonamide
[0378] 2M MeNH.sub.2 in THF (30 ml) is cooled to 0-5.degree. C. via
an ice-bath, to this is added drop wise
5-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-chloro-benzenesul-
fonyl chloride (1.625 ml, crude solution from step 2) (exothermic)
and the reaction mixture is stirred for 10 minutes at 0-5.degree.
C. (ice-bath) resulting in a brown precipitate. The reaction
mixture is diluted with water and extracted with EtOAc (2.times.100
ml). The organic portion is washed with saturated ammonium chloride
solution (50 ml), dried over MgSO.sub.4, filtered and concentrated
in vacuo. Purification of the crude residue by preparative HPLC
(water/acetonitrile, 0.1% TFA, affords the title compound as the
trifluoroacetate salt.
Example 130
3-(5-Methanesulfonyl-pyridin-3-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6--
ylamine
[0379] 3-Bromo-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine
(Intermediate 3) (150 mg, 0.66 mmol) and
5-(methylsulfonyl)pyridine-3-boronic acid (200 mg, 0.99 mmol) are
suspended in 1,4-dioxane (4 ml). 2M aqueous Na.sub.2CO.sub.3 (1 ml)
is added and the reaction mixture is degassed by bubbling argon
through for 5 minutes. Pd(dppf)Cl.sub.2 (27 mg, 0.033 mmol) is
added and the reaction mixture is heated using microwave radiation
at 100.degree. C. for 30 minutes. Water (20 ml) and Et.sub.2O (50
ml) are added to the reaction mixture and the resulting grey solid
is collected by filtration washing further with water. The solid is
suspended in MeOH and excess TFA is added until a solution forms.
The organic solvent is reduced in vacuo and the crude residue is
purified by reverse phase column chromatography (Isolute.TM.
C.sub.18, water/acetonitrile, 0.1% TFA), the appropriate fractions
are combined and concentrated in vacuo. The resulting solid is
refluxed in EtOH, cooled to room temperature, filtered and dried
under vacuum to afford the title compound.
Example 131
3-(1H-Indol-6-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine
[0380] This compound is prepared analogously to Example 130 from
the appropriate commercial boronic acid using standard Suzuki
coupling methodology. The resulting product after reverse phase
column chromatography is further purified by hot trituration in
Et.sub.2O to afford the title compound.
Example 132
1-Methyl-3-(5-trifluoromethyl-pyridin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-6--
ylamine hydrochloride
[0381] This compound is prepared analogously to Example 130 by
replacing 5-(methylsulfonyl) pyridine-3-boronic acid with
5-trifluoromethylpyridine-3-boronic acid (Intermediate 17). The
resulting product after reverse phase column chromatography is
suspended in MeOH and 4M HCl in 1,4-dioxane (excess) to form the
HCl salt. Further purification by trituration of the solid in
MeOH/Et.sub.2O affords the title compound.
Example 2-1
N*4*-Benzyl-3-(3-fluoro-4-methoxy-phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrim-
idine-4,6-diamine
[0382] This compound is prepared analogously to Example 88 by
replacing 3-Bromo-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine
(Intermediate 3) with
N*4*-Benzyl-3-bromo-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamin-
e (Intermediate 15) and by replacing
2-methoxy-5-trifluoromethylphenylboronic acid with
3-fluoro-4-methoxyphenylboronic acid to afford the title
compound.
Example 2-2
4-[6-Amino-1-methyl-4-(2-morpholin-4-yl-ethylamino)-1H-pyrazolo[3,4-d]pyri-
midin-3-yl]-2,6-dichloro-phenol
[0383] This compound is prepared analogously to Example 88 by
replacing 3-Bromo-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine
(Intermediate 3) with
3-Bromo-1-methyl-N*4*-(2-morpholin-4-yl-ethyl)-1H-pyrazolo[3,4-d]pyr-
imidine-4,6-diamine (Intermediate 16) and by replacing
2-methoxy-5-trifluoromethylphenylboronic acid with
2,6-dichloro-4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenol to
afford the title compound.
Preparation of Intermediates
Intermediate 1
3-Bromo-1-methyl-6-methylsulfanyl-1H-pyrazolo[3,4-d]pyrimidine
[0384] Prepared as described in WO 2003029209 (page 45).
Intermediate 2
Trifluoro-methanesulfonic acid
1-methyl-6-methylsulfanyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl
ester
[0385] 1-Methyl-6-methylsulfanyl-1H-pyrazolo[3,4-d]pyrimidin-3-ol
(WO 2003029209, page 45) (0.50 g, 2.5 mmol) is dissolved in dry DCM
(30 ml) under an inert atmosphere of argon The reaction mixture is
cooled to 0.degree. C. (ice-bath) and pyridine (0.5 ml, 6.0 mmol)
is added drop wise followed by triflic anhydride (0.71 g, 0.45 ml,
2.5 mmol) at 0.degree. C. The reaction mixture is stirred for 10
minutes at room temperature. The organic layer is washed with 1.5M
HCl (5 ml), saturated NaHCO.sub.3 (5 ml), water and brine, dried
over MgSO.sub.4, filtered and concentrated in vacuo to afford the
title compound.
Intermediate 3
3-Bromo-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine
[0386]
3-Bromo-6-methanesulfonyl-1-methyl-1H-pyrazolo[3,4-d]pyrimidine (WO
2003029209, page 46) (0.215 g, 0.0074 mol) is dissolved in 0.5M
ammonia in 1,4-dioxane (11 ml) and stirred overnight at room
temperature. The reaction mixture is concentrated in vacuo to
afford the title compound.
Intermediate 4
3-Chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine
[0387] This is prepared as described in Hauser, Martin; Peters,
Earl; Tieckelmann, Howard. Pyrazolono[3,4-d]pyrimidines. II.
6-Methylpyrazolono[3,4-d]pyrimidines and some reactions of
pyrazolono[3,4-d]pyrimidines. Journal of Organic Chemistry (1961),
26 451-5.
Intermediate 5
7-Fluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole
[0388] Prepared as described in US 2005043347 (page 90)
Intermediate 6
2-Fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine
[0389] A solution containing 4-bromo-2-fluoroaniline (0.50 g, 2.6
mmol), bis(pinacolato)diboron (0.80 g, 3.2 mmol),
Pd(dppf).sub.2Cl.sub.2 (0.158 g, 0.21 mmol) and potassium acetate
(0.775 g, 7.9 mmol) in dry 1,4-dioxane (20 ml) is degassed for 15
minutes then heated to 85.degree. C. with stirring, under an inert
atmosphere of argon, for 18 hours. After cooling to room
temperature, the reaction mixture is diluted with EtOAc, filtered
through Celite.RTM. (filter agent) and washed with water followed
by brine. The organic portion is dried over MgSO.sub.4, filtered
and the solvent removed in vacuo. Purification of the crude residue
by flash chromatography on silica, eluting with iso-hexanes:EtOAc
(1:1), affords the title compound.
Intermediate 7
3-Bromo-6-methanesulfonyl-1-methyl-1H-pyrazolo[3,4-d]pyrimidine
[0390]
3-(3,5-Difluoro-phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylam-
ine (Intermediate 1) (9.0 g, 34.7 mmol) is dissolved in dry DCM
(250 ml). The reaction mixture is cooled to 0-5.degree. C.
(ice-bath) and mCPBA (17.96, 104.1 mmol) is added in small portions
over a period of 15 minutes. The reaction mixture is stirred for
1.5 hours at room temperature then diluted with DCM (1000 ml) and
washed with saturated NaHCO.sub.3 (250 ml) solution followed by
brine (250 ml). The organic portion is dried over MgSO.sub.4,
filtered and concentrated in vacuo to afford the title compound as
a white solid.
Intermediate 8
3-Chloro-5-fluoro-4-hydroxyphenyl-boronic acid
[0391] 4-Bromo-2-chloro-6-fluoro-phenol (0.500 g, 2.21 mmol) is
dissolved in dry THF, the reaction mixture is cooled to -78.degree.
C. (dry-ice/acetone bath) and 2.5M n-butylithium (1.06 ml, 2.66
mmol) is slowly added drop wise with stirring for 5 minutes. TMSCl
(0.298 ml, 2.33 mmol) is added drop wise maintaining the
temperature below -70.degree. C. and the reaction mixture is
stirred for 30 minutes. Boric acid triethyl ester is then added
(0.385 ml, 2.26 mmol) followed by the second addition of
n-butylitlium (1.06 ml, 2.66 mmol) maintaining the temperature
below -65.degree. C. The reaction mixture is stirred at -70.degree.
C. for 30 minutes then quenched with 5M HCl (5 ml) and allowed to
warm to room temperature with stirring for 30 minutes. The reaction
mixture is diluted with water and EtOAc and the organic portion is
washed with 5M NaOH. The aqueous layer is acidified with 5M HCl and
extracted with EtOAc, this organic portion is washed with brine,
dried over MgSO.sub.4 and concentrated in vacuo to afford the title
compound as an off white solid.
Intermediate 9
3,5-Difluoro-4-methoxy-phenyl-boronic acid
[0392] This compound is prepared analogously to Intermediate 8 by
replacing 4-Bromo-2-chloro-6-fluoro-phenol with
5-Bromo-1,3-difluoro-2-methoxy-benzene to afford the title
compound.
Intermediate 10
5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-3-trifluoromethyl-pyridin-
-2-ylamine
Step 1: 5-Bromo-3-trifluoromethyl-pyridin-2-ylamine
[0393] 2-amino-3-trifluoromethylpyridine (0.980 g, 5.92 mmol) is
dissolved in CHCl.sub.3 (7 ml) and AcOH (5 ml). The reaction
mixture is cooled to 0-10.degree. C. (ice-bath) and bromine (0.424
ml, 8.3 mmol) dissolved in CHCl.sub.3 is slowly added drop wise.
The reaction mixture is stirred at this temperature for 1 hour then
allowed to warm room temperature. The solvents are removed in vacuo
and the residue is dissolved in EtOAc washing with saturated
NaHCO.sub.3. The organic portion is dried over MgSO.sub.4, filtered
and concentrated to afford the title compound.
Step 2:
5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-3-trifluoromethyl-
-pyridin-2-ylamine
[0394] 5-Bromo-3-trifluoromethyl-pyridin-2-ylamine (1.0 g, 4.14
mmol), bis(pinacolato) diboron (1.26 g, 4.98 mmol), Pd(dppf)C.sub.2
(0.90 g, 0.1242 mmol), potassium acetate (1.14 g, 11.6 mmol) and
dry DMF (20 ml) are mixed together under an inert atmosphere of
argon and heated using microwave radiation at 150.degree. C. for 2
hours. The reaction mixture is cooled to room temperature, filtered
through Celite.RTM. (filter agent) and concentrated in vacuo. The
resulting residue is dissolved in EtOAc and loaded onto an
Isolute.TM. SCX column (silica based cation exchange sorbent)
eluting with 200 ml 0.35M NH.sub.3 in methanol. The methanolic
ammonia fractions are combined, concentrated in vacuo and dried
under vacuum to afford the title compound. [M+H].sup.+ 381
Intermediate 11
2,6-Difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzonitrile
[0395] 4-Bromo-2,6-difluoro-benzonitrile (0.278 g, 1.03 mmol),
bis(pinacolato)diboron (0.278 g, 1.03 mmol), Pd(dppf).sub.2Cl.sub.2
(0.02 g, 0.0275 mmol), potassium acetate (251 g, 2.568 mmol) and
dry DMF (4 ml) are mixed together and heated using microwave
radiation at 130.degree. C. for 30 minutes. The reaction mixture is
cooled to room temperature, filtered through Celite.RTM. (filter
agent) washing with EtOAc and the filtrate is concentrated in vacuo
to afford the title compound.
Intermediate 12
N-[3-Fluoro-2-methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phe-
nyl]-acetamide
[0396] This compound is prepared analogously to Intermediate 6 by
replacing 4-bromo-2-fluoroaniline with
N-(5-Bromo-3-fluoro-2-methoxy-phenyl)-acetamide to afford the title
compound [M+H].sup.+ 310.
Intermediate 13
2-Benzyloxy-3-fluoro-N,N-dimethylbenzamide-5-boronic acid
Step 1: 2-Benzyloxy-5-bromo-3-fluoro-benzaldehyde
[0397] To a solution of 5-Bromo-3-fluoro-2-hydroxy-benzaldehyde (5
g, 22.8 mmol) in DMF (100 ml) is added benzyl bromide (5.7 ml, 48
mmol) and cesium carbonate (11.9 g, 37 mmol). The reaction mixture
is stirred at room temperature for 20 hours then diluted with water
(150 ml) and extracted with EtOAc (2.times.150 ml), the organic
portions are combined, washed with brine (50 ml), dried over
MgSO.sub.4 and concentrated in vacuo to give a waxy off-white
solid. The solid is stirred in iso-hexanes (30 ml) for 30 minutes,
filtered and dried under vacuum to afford the title compound.
Step 2: 2-Benzyloxy-5-bromo-3-fluoro-benzoic acid
[0398] This compound is prepared as described in Micklatcher, Mark
L.; Cushman, Mark: An Improved Method for the Synthesis of
3-Fluorosalicylic Acid with Application to the Synthesis of
3-(Trifluoromethyl)salicylic Acid. Synthesis (1999), 11,
1878-1880.
Step 3: 2-Benzyloxy-5-bromo-3-fluoro-N,N-dimethyl-benzamide
[0399] 2-Benzyloxy-5-bromo-3-fluoro-benzoic acid (product from step
2) (0.2 g, 0.615 mmol) is dissolved in THF (10 ml) and treated with
2M dimethylamine in THF (0.308 ml), N-methylmorpholine (0.270 ml,
2.46 mmol) and HATU (0.234 g, 0.615 mmol) and stirred at room
temperature overnight. The reaction mixture is diluted with 2M HCl
and extracted with EtOAc (2.times.), the organic portions are
combined washed with brine, dried over MgSO.sub.4 and concentrated
in vacuo. The resulting crude residue is dry loaded onto silica and
purification by flash chromatography eluting with EtOAc affords the
title compound as a white solid.
Step 4: 2-Benzyloxy-3-fluoro-N,N-dimethylbenzamide-5-boronic
acid
[0400] This compound is prepared analogously to Intermediate 8 by
replacing 4-Bromo-2-chloro-6-fluoro-phenol with
2-Benzyloxy-5-bromo-3-fluoro-N,N-dimethyl-benzamide (product from
step 3) to afford the title compound.
Intermediate 14
3-Bromo-4-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine
Step 1: 4-Chloro-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine
[0401] 2-Amino-4,6-dichloro-pyrimidine-5-carbaldehyde (5 g, 26.04
mmol) is dissolved in THF (125 ml), Et.sub.3N (4.13 ml, 29.6 mmol)
is added followed by hydrazine monohydrate (1.19 g, 26.04 mmol) in
water (15 ml) and the reaction mixture is stirred at room
temperature for 1.5 hours. The organic solvent is removed in vacuo
and a further 30 ml of water is added to the reaction mixture. The
resulting precipitate is collected by filtration and dried under
vacuum to afford the title compound.
Step 2: 3-Bromo-4-chloro-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine
[0402] N-bromosuccinimide (673 mg, 3.8 mmol) is added to a
suspension of 4-Chloro-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine (500
mg, 2.96 mmol) in dichloroethane (30 ml) and heated to reflux
overnight. The reaction mixture is cooled to room temperature and
the solvent is removed in vacuo. The resulting solid is diluted
with water, stirred for 30 minutes at room temperature, then
collected by filtration to afford the title compound.
Step 3:
3-Bromo-4-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine
[0403] 3-Bromo-4-chloro-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine (580
mg, 2.3 mmol) is dissolved in DMF (40 ml), potassium hydroxide (131
mg, 2.3 mmol) is added and the reaction mixture is stirred at room
temperature for 15 minutes. Methyl iodide (0.133 ml, 2.3 mmol) is
then added and the reaction is continued stirring overnight. The
reaction mixture is diluted with water (60 ml) and EtOAc (60 ml),
the layers are separated and the organic portion is washed with
brine, dried over MgSO.sub.4, filtered and concentrated in vacuo to
afford the title compound.
Intermediate 15
N*4*-Benzyl-3-bromo-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine
[0404]
3-Bromo-4-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine
(Intermediate 14) (160 mg, 0.61 mmol), benzylamine (0.2 ml, 1.83
mmol) and DMF (5 ml) are mixed together and heated at 40.degree. C.
overnight. After cooling to room temperature the solvent is removed
in vacuo and the residue is dissolved in methanol (30 ml) and
passed through an Isolute.TM. CBA column (silica based carboxylic
acid sorbent). Silica gel is added to the filtrate, the solvent is
removed in vacuo and the resulting residue is flash chromatographed
eluting with EtOAc:iso-hexanes (4:6) and then increasing to
EtOAc:iso-hexanes (1:1). The appropriate fractions are collected
and concentrated in vacuo to afford the title compound.
Intermediate 16
3-Bromo-1-methyl-N*4*-(2-morpholin-4-yl-ethyl)-1H-pyrazolo[3,4-d]pyrimidin-
e-4,6-diamine
[0405]
3-Bromo-4-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine
(Intermediate 14) (750 mg, 2.8 mmol), 2-(4-morpholinyl)ethylamine
(0.44 ml, 3.3 mmol) and DMF (30 ml) are mixed together and heated
to 50.degree. C. overnight. After cooling to room temperature the
reaction mixture is diluted with DCM (60 ml) and water (40 ml) and
the aqueous portion is extracted with a further 40 ml DCM. The
organic portions are combined, dried over MgSO4, filtered and
concentrated in vacuo. The crude residue is dry loaded onto silica
and purification by flash chromatography eluting with DCM then
MeOH:DCM (5:95) affords the title compound.
Intermediate 17
5-Trifluoromethylpyridine-3-boronic acid
[0406] A cooled (-78.degree. C.) solution of
3-bromo-5-(trifluoromethyl)pyridine (5 g, 22.1 mmol) in dry THF (50
ml), under an inert atmosphere of argon, is treated with triethyl
borate (3.39 g, 23.21 mmol) followed by drop wise addition of 1.46M
n-BuLi in hexanes (15.2 ml, 24.34 mmol). The reaction mixture is
allowed to warm to room temperature overnight and treated with 5M
HCl (100 ml). After stirring for 30 minutes, the THF is removed in
vacuo and the aqueous layer is extracted with EtOAc (4.times.100
ml). The aqueous portion is concentrated in vacuo and dried under
vacuum overnight to afford the title compound as the hydrochloride
salt. [M+H].sup.+ 168.
* * * * *