U.S. patent application number 13/308584 was filed with the patent office on 2012-03-22 for 4-(3-aminopyrazole) pyrimidine derivatives for use as tyrosine kinase inhibitors in the treatment of cancer.
This patent application is currently assigned to ASTRAZENECA R&D. Invention is credited to Xiaomei Feng, Huiping Guan, Stephanos Ioannidis, Ying Kan, Bo Peng, Mei Su, Bin Wang, Tao Wang, Hai-Jun Zhang.
Application Number | 20120071480 13/308584 |
Document ID | / |
Family ID | 37575154 |
Filed Date | 2012-03-22 |
United States Patent
Application |
20120071480 |
Kind Code |
A1 |
Feng; Xiaomei ; et
al. |
March 22, 2012 |
4-(3-AMINOPYRAZOLE) PYRIMIDINE DERIVATIVES FOR USE AS TYROSINE
KINASE INHIBITORS IN THE TREATMENT OF CANCER
Abstract
This invention relates to novel compounds having the formula
(I): ##STR00001## and to their pharmaceutical compositions and to
their methods of use. These novel compounds provide a treatment for
cancer.
Inventors: |
Feng; Xiaomei; (Waltham,
MA) ; Guan; Huiping; (Waltham, MA) ;
Ioannidis; Stephanos; (Waltham, MA) ; Peng; Bo;
(Waltham, MA) ; Su; Mei; (Waltham, MA) ;
Wang; Tao; (Waltham, MA) ; Zhang; Hai-Jun;
(Waltham, MA) ; Kan; Ying; (Shanghai, CN) ;
Wang; Bin; (Longmont, CO) |
Assignee: |
; ASTRAZENECA R&D
Sodertalje
SE
|
Family ID: |
37575154 |
Appl. No.: |
13/308584 |
Filed: |
December 1, 2011 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12713695 |
Feb 26, 2010 |
8088784 |
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13308584 |
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12091382 |
Apr 24, 2008 |
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PCT/GB2006/003978 |
Oct 26, 2006 |
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12713695 |
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60731299 |
Oct 28, 2005 |
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60803061 |
May 24, 2006 |
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Current U.S.
Class: |
514/236.5 ;
514/275; 544/122; 544/296 |
Current CPC
Class: |
A61P 35/00 20180101;
A61P 35/04 20180101; A61P 43/00 20180101; C07D 403/14 20130101;
A61P 35/02 20180101 |
Class at
Publication: |
514/236.5 ;
544/296; 514/275; 544/122 |
International
Class: |
A61K 31/5377 20060101
A61K031/5377; A61P 35/02 20060101 A61P035/02; C07D 413/14 20060101
C07D413/14; A61P 35/00 20060101 A61P035/00; C07D 403/14 20060101
C07D403/14; A61K 31/506 20060101 A61K031/506 |
Claims
1. A compound of formula (I): ##STR00015## wherein: R.sup.1 is
selected from hydrogen, hydroxy, amino, mercapto, C.sub.1-6alkyl,
C.sub.2-6alkenyl, C.sub.2-6alkynyl, C.sub.1-6alkoxy,
C.sub.1-6alkanoyloxy, N--(C.sub.1-6alkyl)amino,
N,N--(C.sub.1-6alkyl).sub.2amino, C.sub.1-6alkanoylamino,
C.sub.1-6alkylsulphonylamino, 3-5-membered carbocyclyl or
3-5-membered heterocyclyl; wherein R.sup.1 may be optionally
substituted on carbon by one or more R.sup.6; and wherein if said
heterocyclyl contains an --NH-- moiety that nitrogen may be
optionally substituted by a group selected from R.sup.7; R.sup.2
and R.sup.3 are independently selected from hydrogen, halo, nitro,
cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl,
C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.1-6alkoxy, C.sub.1-6alkanoyl, C.sub.1-6alkanoyloxy,
N--(C.sub.1-6alkyl)amino, N,N--(C.sub.1-6alkyl).sub.2amino,
C.sub.1-6alkanoylamino, N--(C.sub.1-6alkyl)carbamoyl,
N,N--(C.sub.1-6alkyl).sub.2carbamoyl, C.sub.1-6alkylS(O).sub.a
wherein a is 0 to 2, C.sub.1-6alkoxycarbonyl,
N--(C.sub.1-6alkyl)sulphamoyl,
N,N--(C.sub.1-6alkyl).sub.2sulphamoyl,
(C.sub.1-6alkyl).sub.2N--S(O).sub.2--NH--,
(C.sub.1-6alkyl)NH--S(O).sub.2--NH--, NH.sub.2--S(O).sub.2--NH--,
(C.sub.1-6alkyl).sub.2N--S(O).sub.2--N(C.sub.1-6alkyl)-,
(C.sub.1-6alkyl)NH--S(O).sub.2--N(C.sub.1-6alkyl)-,
NH.sub.2--S(O).sub.2--N(C.sub.1-6alkyl)-,
N--(C.sub.1-6alkyl)-N--(C.sub.1-6alkylsulphonyl)amino,
C.sub.1-6alkylsulphonylamino, carbocyclyl-R.sup.19-- or
heterocyclyl-R.sup.21--; wherein R.sup.2 and R.sup.3 independently
of each other may be optionally substituted on carbon by one or
more R.sup.8; and wherein if said heterocyclyl contains an --NH--
moiety that nitrogen may be optionally substituted by a group
selected from R.sup.9; R.sup.4 is selected from cyano, carboxy,
carbamoyl, C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.1-6alkanoyl, N--(C.sub.1-6alkyl)carbamoyl,
N,N--(C.sub.1-6alkyl).sub.2carbamoyl, C.sub.1-6alkoxycarbonyl,
carbocyclyl or heterocyclyl; wherein R.sup.4 may be optionally
substituted on carbon by one or more R.sup.10; and wherein if said
heterocyclyl contains an --NH-- moiety that nitrogen may be
optionally substituted by a group selected from R.sup.11; R.sup.5
is selected from halo, nitro, cyano, hydroxy, amino, carboxy,
carbamoyl, mercapto, sulphamoyl, C.sub.1-6alkyl, C.sub.2-6alkenyl,
C.sub.2-6alkynyl, C.sub.1-6alkoxy, C.sub.1-6alkanoyl,
C.sub.1-6alkanoyloxy, N--(C.sub.1-6alkyl)amino,
N,N--(C.sub.1-6alkyl).sub.2amino, C.sub.1-6alkanoylamino,
N--(C.sub.1-6alkyl)carbamoyl, N,N--(C.sub.1-6alkyl).sub.2carbamoyl,
C.sub.1-6alkylS(O).sub.a wherein a is 0 to 2,
C.sub.1-6alkoxycarbonyl, N--(C.sub.1-6alkyl)sulphamoyl,
N,N--(C.sub.1-6alkyl).sub.2sulphamoyl,
C.sub.1-6alkylsulphonylamino, carbocyclyl or heterocyclyl; wherein
R.sup.5 may be optionally substituted on carbon by one or more
R.sup.12; and wherein if said heterocyclyl contains an --NH--
moiety that nitrogen may be optionally substituted by a group
selected from R.sup.13; n=0, 1, 2 or 3; wherein the values of
R.sup.5 may be the same or different; R.sup.6, R.sup.8, R.sup.10
and R.sup.12 are independently selected from halo, nitro, cyano,
hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl,
C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.1-6alkoxy, C.sub.1-6alkanoyl, C.sub.1-6alkanoyloxy,
N--(C.sub.1-6alkyl)amino, N,N--(C.sub.1-6alkyl).sub.2amino,
C.sub.1-6alkanoylamino, N--(C.sub.1-6alkyl)carbamoyl,
N,N--(C.sub.1-6alkyl).sub.2carbamoyl, C.sub.1-6alkylS(O).sub.a
wherein a is 0 to 2, C.sub.1-6alkoxycarbonyl,
N--(C.sub.1-6alkyl)sulphamoyl,
N,N--(C.sub.1-6alkyl).sub.2sulphamoyl,
C.sub.1-6alkylsulphonylamino, carbocyclyl or heterocyclyl; wherein
R.sup.6, R.sup.8, R.sup.10 and R.sup.12 independently of each other
may be optionally substituted on carbon by one or more R.sup.14;
and wherein if said heterocyclyl contains an --NH-- moiety that
nitrogen may be optionally substituted by a group selected from
R.sup.15; R.sup.7, R.sup.9, R.sup.1I, R.sup.13 and R.sup.15 are
independently selected from C.sub.1-6alkyl, C.sub.1-6alkanoyl,
C.sub.1-6alkylsulphonyl, C.sub.1-6alkoxycarbonyl, carbamoyl,
N--(C.sub.1-6alkyl)carbamoyl, N,N--(C.sub.1-6alkyl)carbamoyl,
benzyl, benzyloxycarbonyl, benzoyl and phenylsulphonyl; wherein
R.sup.7, R.sup.9, R.sup.11, R.sup.13 and R.sup.15 independently of
each other may be optionally substituted on carbon by on or more
R.sup.16; R.sup.14 and R.sup.16 are independently selected from
halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto,
sulphamoyl, C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.1-6alkoxy, C.sub.1-6alkanoyl, C.sub.1-6alkanoyloxy,
N--(C.sub.1-6alkyl)amino, N,N--(C.sub.1-6alkyl).sub.2amino,
C.sub.1-6alkanoylamino, N--(C.sub.1-6alkyl)carbamoyl,
N,N--(C.sub.1-6alkyl).sub.2carbamoyl, C.sub.1-6alkylS(O).sub.a
wherein a is 0 to 2, C.sub.1-6alkoxycarbonyl,
N--(C.sub.1-6alkyl)sulphamoyl,
N,N--(C.sub.1-6alkyl).sub.2sulphamoyl,
C.sub.1-6alkylsulphonylamino, carbocyclyl or heterocyclyl; wherein
R.sup.14 and R.sup.16 independently of each other may be optionally
substituted on carbon by one or more R.sup.17; and wherein if said
heterocyclyl contains an --NH-- moiety that nitrogen may be
optionally substituted by a group selected from R.sup.18; R.sup.17
is selected from halo, nitro, cyano, hydroxy, trifluoromethoxy,
trifluoromethyl, amino, carboxy, carbamoyl, mercapto, sulphamoyl,
methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino,
ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino,
acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl,
N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl,
N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulphinyl,
ethylsulphinyl, mesyl, ethylsulphonyl, methoxycarbonyl,
ethoxycarbonyl, N-methylsulphamoyl, N-ethylsulphamoyl,
N,N-dimethylsulphamoyl, N,N-diethylsulphamoyl or
N-methyl-N-ethylsulphamoyl; and R.sup.19 and R.sup.21 are
independently selected from a direct bond, --O--, --N(R.sup.22)--,
--C(O)--, --N(R.sup.23)C(O)--, --C(O)N(R.sup.24)--, --S(O).sub.s--,
--SO.sub.2N(R.sup.25)-- or --N(R.sup.26)SO.sub.2--; wherein
R.sup.22, R.sup.23, R.sup.24, R.sup.25 and R.sup.26 are
independently selected from hydrogen or C.sub.1-6alkyl and s is
0-2; and R.sup.18 is selected from C.sub.1-6alkyl,
C.sub.1-6alkanoyl, C.sub.1-6alkylsulphonyl,
C.sub.1-6alkoxycarbonyl, carbamoyl, N--(C.sub.1-6alkyl)carbamoyl,
N,N--(C.sub.1-6alkyl)carbamoyl, benzyl, benzyloxycarbonyl, benzoyl
and phenylsulphonyl; or a pharmaceutically acceptable salt
thereof,
2. A compound of formula (I), or a pharmaceutically acceptable salt
thereof, as claimed in claim 1, wherein R.sup.1 is selected from
the group consisting of C.sub.1-6alkyl, C.sub.1-6alkoxy,
3-5-membered carbocyclyl, and N,N(C.sub.1-6alkyl).sub.2amino,
wherein R.sup.1 may be optionally substituted on carbon by one or
more R.sup.6; and R.sup.6 is selected from halo.
3. A compound of formula (I), or a pharmaceutically acceptable salt
thereof, as claimed in claim 1, wherein R.sup.2 is selected from
the group consisting of hydrogen, halo, nitro, and C.sub.1-6alkyl,
wherein R.sup.2 may be optionally substituted on carbon by one or
more R.sup.8; and R.sup.8 is halo.
4. A compound of formula (I), or a pharmaceutically acceptable salt
thereof, as claimed in claim 1, wherein R.sup.3 is selected from
the group consisting of hydrogen, halo, cyano,
N--(C.sub.1-6alkyl)-N--(C.sub.1-6alkylsulphonyl)amino,
C.sub.1-6alkyl,
(C.sub.1-6alkyl).sub.2N--S(O).sub.2--N(C.sub.1-6alkyl)-, and
heterocyclyl-R.sup.21--, wherein R.sup.3 may be optionally
substituted on carbon by one or more R.sup.8, R.sup.8 is halo; and
R.sup.21 is a bond.
5. A compound of formula (I), or a pharmaceutically acceptable salt
thereof, as claimed in claim 1, wherein R.sup.4 is selected from
the group consisting of C.sub.1-6alkyl.
6. A compound of formula (I), or a pharmaceutically acceptable salt
thereof, as claimed in claim 1, wherein R.sup.5 is halo.
7. A compound of formula (I), or a pharmaceutically acceptable salt
thereof, as claimed in claim 1, wherein n is 1.
8. A compound of formula (I), ##STR00016## or a pharmaceutically
acceptable salt thereof, wherein R.sup.1 is selected from the group
consisting of methyl, methoxy, trifluoroethoxy, isopropoxy,
cyclopropyl, and N,N-dimethylamino; R.sup.2 is selected from the
group consisting of hydrogen, chloro, fluoro, bromo, nitro, and
trifluoromethyl; R.sup.3 is selected from the group consisting of
hydrogen, chloro, cyano, trifluoromethyl,
(CH.sub.3).sub.2N--S(O).sub.2--N(CH.sub.3)--,
N-methyl-N-mesylamino, and morpholino; R.sup.4 is methyl; R.sup.5
is fluoro; and n is 1.
9. A compound of formula (I), as claimed in claim 1, selected from
the group consisting of:
N-{5-fluoro-2-{[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]amino}-6-[(5-methyl--
1H-pyrazol-3-yl)amino]pyrimidin-4-yl}-N-methylmethanesulfonamide;
5-Fluoro-N.sup.2-[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]-N.sup.4-(5-methyl-
-1H-pyrazol-3-yl)pyrimidine-2,4-diamine;
5-Chloro-N.sup.2-[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]-N.sup.4-(5-methox-
y-1H-pyrazol-3-yl)pyrimidine-2,4-diamine;
N.sup.2-[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]-N.sup.4-(5-methoxy-1H-pyra-
zol-3-yl)-6-(trifluoromethyl)pyrimidine-2,4-diamine;
N.sup.2-[(1S)-1-(5-Fluoropyrimidin-2-yl)ethyl]-N.sup.4-(5-methyl-1H-pyraz-
ol-3-yl)-6-morpholin-4-ylpyrimidine-2,4-diamine;
5-Chloro-N.sup.4-(5-cyclopropyl-1H-pyrazol-3-yl)-N.sup.2-[(1S)-1-(5-fluor-
opyrimidin-2-yl)ethyl]pyrimidine-2,4-diamine;
5-Fluoro-N.sup.2-[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]-N.sup.4-(5-methyl-
-1H-pyrazol-3-yl)pyrimidine-2,4-diamine;
5-bromo-N.sup.2-[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]-N.sup.4-(5-methoxy-
-1H-pyrazol-3-yl)pyrimidine-2,4-diamine;
N.sup.4-(5-Cyclopropyl-1H-pyrazol-3-yl)-5-fluoro-N.sup.2-[(1S)-1-(5-fluor-
opyrimidin-2-yl)ethyl]pyrimidine-2,4-diamine;
N.sup.2-[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]-5-methyl-N.sup.4-(5-methyl-
-1H-pyrazol-3-yl)pyrimidine-2,4-diamine;
N-{5-chloro-2-{[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]amino}-6-[(5-methoxy-
-1H-pyrazol-3-yl)amino]pyrimidin-4-yl}-N-methylmethanesulfonamide;
N-{5-chloro-2-{[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]amino}-6-[(5-methyl--
1H-pyrazol-3-yl)amino]pyrimidin-4-yl}-N-methylmethanesulfonamide;
N.sup.2-[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]-N.sup.4-(5-methoxy-1H-pyra-
zol-3-yl)-6-morpholin-4-ylpyrimidine-2,4-diamine;
5-chloro-N.sup.2-[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]-N.sup.4-(5-methox-
y-1H-pyrazol-3-yl)-6-morpholin-4-ylpyrimidine-2,4-diamine;
5-fluoro-N.sup.2-[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]-N.sup.4-(5-methyl-
-1H-pyrazol-3-yl)-6-morpholin-4-ylpyrimidine-2,4-diamine; and
5-fluoro-N.sup.2-[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]-N.sup.4-(5-methox-
y-1H-pyrazol-3-yl)-6-morpholin-4-ylpyrimidine-2,4-diamine; or a
pharmaceutically acceptable salt thereof.
10. A process for preparing a compound of claim 1, or a
pharmaceutically acceptable salt thereof, wherein variable groups
are, unless otherwise specified, as defined in claim 1, said
process comprising: Process a) reaction of a pyrimidine of Formula
(II): ##STR00017## wherein L is a displaceable group; with an
pyrazole amine of Formula (III): ##STR00018## or Process b)
reacting a pyrimidine of Formula (IV): ##STR00019## wherein L is a
displaceable group; with a compound of Formula (V): ##STR00020##
Process c) reacting a compound of Formula (VI): ##STR00021## with a
compound of Formula (VII): ##STR00022## wherein X is an oxygen atom
and q is 1; or X is a nitrogen atom and q is 2; and wherein each
R.sup.20 independently represents a C.sub.1-6alkyl group; or
Process d) reacting a compound of Formula (VIII): ##STR00023## with
hydrazine; or and thereafter if necessary: i) converting a compound
of the formula (I) into another compound of the formula (I); ii)
removing any protecting groups; iii) forming a pharmaceutically
acceptable salt.
11. A pharmaceutical composition comprising: a. a compound of
formula (I), or a pharmaceutically acceptable salt thereof, as
claimed in claim 1; and b. at least one pharmaceutically acceptable
carrier, diluent, or excipient.
12-19. (canceled)
20. A method for producing an anti-proliferative effect in a
warm-blooded animal in need of such treatment, said method
comprising administering to said animal an effective amount of a
compound of formula (I), or a pharmaceutically acceptable salt
thereof, as claimed in claim 1.
21. A method for producing a pro-apoptotic effect in a warm-blooded
animal in need of such treatment, said method comprising
administering to said animal an effective amount of a compound of
formula (I), or a pharmaceutically salt thereof, as claimed in
claim 1.
22. A method of treating myeloproliferative disorders,
myelodysplastic syndrome, and cancer in a warm-blooded animal in
need of such treatment, said method comprising administering to
said animal an effective amount of a compound of formula (I), or a
pharmaceutically acceptable salt thereof, as claimed in claim
1.
23. A method of treating chronic myeloid leukemia, polycythemia
vera, essential thrombocythemia, myeloid metaplasia with
myelofibrosis, idiopathic myelofibrosis, chronic myelomonocytic
leukemia and hypereosinophilic syndrome, myelodysplastic syndromes
and cancers selected from oesophageal cancer, myeloma,
hepatocellular, pancreatic, cervical cancer, Ewings sarcoma,
neuroblastoma, Kaposi's sarcoma, ovarian cancer, breast cancer,
colorectal cancer, prostate cancer, bladder cancer, melanoma, lung
cancer--non small cell lung cancer (NSCLC), and small cell lung
cancer (SCLC), gastric cancer, head and neck cancer, mesothelioma,
renal cancer, lymphoma, and leukaemia in a warm-blooded animal in
need of such treatment, said method comprising administering to
said animal an effective amount of a compound of formula (I), as
claimed in claim 1
24. A method of treating cancer in a warm-blooded animal in need of
such treatment, said method comprising administering to said animal
an effective amount of a compound of formula (I), or a
pharmaceutically acceptable salt thereof, as claimed in claim
1.
25-33. (canceled)
Description
FIELD OF THE INVENTION
[0001] The present invention relates to novel pyrazole derivatives,
their pharmaceutical compositions and methods of use. In addition,
the present invention relates to therapeutic methods for the
treatment and prevention of cancers and to the use of these
pyrazole derivatives in the manufacture of medicaments for use in
the treatment and prevention of cancers.
BACKGROUND OF THE INVENTION
[0002] Receptor tyrosine kinases (RTK's) are a sub-family of
protein kinases that play a critical role in cell signalling and
are involved in a variety of cancer related processes including
cell proliferation, survival, angiogenesis and metastasis.
Currently up to 100 different RTK's including tropomyosin-related
kinases (Trk's) have been identified.
[0003] Trk's are the high affinity receptors activated by a group
of soluble growth factors called neurotrophins (NT). The Trk
receptor family has three members--TrkA, TrkB and TrkC. Among the
NTs there are (i) nerve growth factor (NGF) which activates TrkA,
(ii) brain-derived growth factor (BDNF) and NT-4/5 which activate
TrkB and (iii) NT3 which activates TrkC. Each Trk receptor contains
an extra-cellular domain (ligand binding), a trans-membrane region
and an intra-cellular domain (including kinase domain). Upon
binding of the ligand, the kinase catalyzes auto-phosphorylation
and triggers downstream signal transduction pathways.
[0004] Trk's are widely expressed in neuronal tissue during its
development where Trk's are critical for the maintenance and
survival of these cells. A post-embryonic role for the
Trk/neurotrophin axis (or pathway), however, remains in question.
There are reports showing that Trk's play important role in both
development and function of the nervous system (Patapoutian, A. et
al Current Opinion in Neurobiology, 2001, 11, 272-280).
[0005] In the past decade, a considerable number of literature
documentations linking Trk signalling with cancer have published.
For example, while Trk's are expressed at low levels outside the
nervous system in the adult, Trk expression is increased in late
stage prostate cancers. Both normal prostate tissue and
androgen-dependent prostate tumours express low levels of Trk A and
undetectable levels of Trk B and C. However, all isoforms of Trk
receptors as well as their cognate ligands are up-regulated in late
stage, androgen-independent prostate cancer. There is additional
evidence that these late stage prostate cancer cells become
dependent on the Trk/neurotrophin axis for their survival.
Therefore, Trk inhibitors may yield a class of apoptosis-inducing
agents specific for androgen-independent prostate cancer
(Weeraratna, A. T. et al The Prostate, 2000, 45, 140-148).
[0006] Furthermore, very recent literature also shows that
over-expression, activation, amplification and/or mutation of Trk's
are associated with secretory breast carcinoma (Cancer Cell, 2002,
2, 367-376), colorectal cancer (Bardelli et al Science, 2003, 300,
949-949) and ovarian cancer (Davidson, B. et al Clinical Cancer
Research, 2003, 9, 2248-2259).
[0007] There are a few reports of selective Trk tyrosine kinase
inhibitors. Cephalon described CEP-751, CEP-701 (George, D. et al
Cancer Research, 1999, 59, 2395-2341) and other indolocarbazole
analogues (WO0114380) as Trk inhibitors. It was shown that CEP-701
and/or CEP751, when combined with surgically or chemically induced
androgen ablation, offered better efficacy compared with
mono-therapy alone. GlaxoSmithKline disclosed certain oxindole
compounds as Trk A inhibitors in WO0220479 and WO0220513. Recently,
Japan Tobacco reported pyrazolyl condensed cyclic compounds as Trk
inhibitors (JP2003231687A). Pfizer also recently published certain
isothiazole Trk A inhibitors (Bioorg. Med. Chem. Lett. 2006, 16,
3444-3448).
[0008] In addition to the above, Vertex Pharmaceuticals have
described pyrazole compounds as inhibitors of GSK3, Aurora, etc. in
WO0250065, WO0262789, WO03027111 and WO200437814; and AstraZeneca
have reported pyrazole compounds as inhibitors against IGF-1
receptor kinase (WO0348133). AstraZeneca have also reported Trk
inhibitors in International Applications WO 2005/049033, WO
2005/103010, WO 2006/082392, WO 2006/087530, and WO
2006/087538.
[0009] Another such group is the JAK family. The JAK
(Janus-associated kinase)/STAT (signal transducers and activators
or transcription) signalling pathway is involved in a variety of
hyperproliferative and cancer related processes including
cell-cycle progression, apoptosis, angiogenesis, invasion,
metastasis and evasion of the immune system (Haura et al., Nature
Clinical Practice Oncology, 2005, 2(6), 315-324; Verna et al.,
Cancer and Metastasis Reviews, 2003, 22, 423-434).
[0010] The JAK family consists of four non-receptor tyrosine
kinases Tyk2, JAK1, JAK2, and JAK3, which play a critical role in
cytokine- and growth factor mediated signal transduction. Cytokine
and/or growth factor binding to cell-surface receptor(s), promotes
receptor dimerization and facilitates activation of
receptor-associated JAK by autophosphorylation. Activated JAK
phosphorylates the receptor, creating docking sites for SH2
domain-containing signalling proteins, in particular the STAT
family of proteins (STAT1, 2, 3, 4, 5a, 5b and 6). Receptor-bound
STATs are themselves phosphorylated by JAKs, promoting their
dissociation from the receptor, and subsequent dimerization and
translocation to the nucleus. Once in the nucleus, the STATs bind
DNA and cooperate with other transcription factors to regulate
expression of a number of genes including, but not limited to,
genes encoding apoptosis inhibitors (e.g. Bcl-XL, Mcl-1) and cell
cycle regulators (e.g. Cyclin D1/D2, c-myc) (Haura et al., Nature
Clinical Practice Oncology, 2005, 2(6), 315-324; Verna et al.,
Cancer and Metastasis Reviews, 2003, 22, 423-434).
[0011] Over the past decade, a considerable amount of scientific
literature linking constitutive JAK and/or STAT signalling with
hyperproliferative disorders and cancer has been published.
Constitutive activation of the STAT family, in particular STAT3 and
STATS, has been detected in a wide range of cancers and
hyperproliferative disorders (Haura et al., Nature Clinical
Practice Oncology, 2005, 2(6), 315-324). Furthermore, aberrant
activation of the JAK/STAT pathway provides an important
proliferative and/or anti-apoptotic drive downstream of many
kinases (e.g. Flt3, EGFR) whose constitutive activation have been
implicated as key drivers in a variety of cancers and
hyperproliferative disorders (Tibes et al., Annu Rev Pharmacol
Toxicol 2550, 45, 357-384; Choudhary et al., International Journal
of Hematology 2005, 82(2), 93-99; Sordella et al., Science 2004,
305, 1163-1167). In addition, impairment of negative regulatory
proteins, such as the suppressors of cytokine signalling (SOCS)
proteins, can also influence the activation status of the JAK/STAT
signalling pathway in disease (J C Tan and Rabkin R, Pediatric
Nephrology 2005, 20, 567-575).
[0012] Several mutated forms of JAK2 have been identified in a
variety of disease settings. For example, translocations resulting
in the fusion of the JAK2 kinase domain with an oligomerization
domain, TEL-JAK2, Bcr-JAK2 and PCM1-JAK2, have been implicated in
the pathogenesis of various heamatologic malignancies (S D Turner
and Alesander D R, Leukemia, 2006, 20, 572-582). More recently, a
unique acquired mutation encoding a valine-to-phenylalanine (V617F)
substitution in JAK2 was detected in a significant number of
polycythemia vera, essential thrombocythemia and idiopathic
myelofibrosis patients and to a lesser extent in several other
diseases. The mutant JAK2 protein is able to activate downstream
signalling in the absence of cytokine stimulation, resulting in
autonomous growth and/or hypersensitivity to cytokines and is
believed to play a critical role in driving these diseases (M J
Percy and McMullin M F, Hematological Oncology 2005, 23(3-4),
91-93).
[0013] JAKs (in particular JAK3) play an important biological roles
in the immunosuppressive field and there are reports of using JAK
kinase inhibitors as tools to prevent organ transplant rejections
(Changelian, P. S. et al, Science, 2003, 302, 875-878). Merck
(Thompson, J. E. et al Bioorg. Med. Chem. Lett. 2002, 12,
1219-1223) and Incyte (WO2005/105814) reported imidazole based
JAK2/3 inhibitors with enzyme potency at single nM levels. Recent
Vertex described azaindoles as JAK inhibitors (WO2005/95400).
AstraZeneca have published quinoline-3-carboxamides as JAK3
inhibitors (WO2002/92571).
[0014] In addition to the above, Vertex Pharmaceuticals have
described pyrazole compounds as inhibitors of GSK3, Aurora, etc. in
WO2002/50065, WO2002/62789, WO2003/027111 and WO2004/37814; and
AstraZeneca have reported pyrazole compounds as inhibitors against
IGF-1 receptor kinase--WO2003/48133--and Trk in WO2005/049033 and
WO2005/103010.
SUMMARY OF THE INVENTION
[0015] In accordance with the present invention, the applicants
have hereby discovered novel pyrazole compounds, or
pharmaceutically acceptable salts thereof, which possess Trk kinase
inhibitory activity and are accordingly useful for their
anti-proliferation and/or proapoptotic (such as anti-cancer)
activity and in methods of treatment of the human or animal body.
The invention also relates to processes for the manufacture of said
pyrazole compounds, or pharmaceutically acceptable salts thereof,
to pharmaceutical compositions containing them and to their use in
the manufacture of medicaments for use in the production of an
anti-proliferation and/or proapoptotic effect in warm-blooded
animals such as man.
[0016] Also in accordance with the present invention the applicants
provide methods of using such pyrazole compounds, or
pharmaceutically acceptable salts thereof, in the treatment of
cancer.
[0017] The properties of the compounds claimed in this invention
are expected to be of value in the treatment of disease states
associated with cell proliferation such as cancers (solid tumors
and leukemia), fibroproliferative and differentiative disorders,
psoriasis, rheumatoid arthritis, Kaposi's sarcoma, haemangioma,
acute and chronic nephropathies, atheroma, atherosclerosis,
arterial restenosis, autoimmune diseases, acute and chronic
inflammation, bone diseases and ocular diseases with retinal vessel
proliferation.
[0018] Furthermore, the compounds, or pharmaceutically acceptable
salts thereof, of the invention are expected to be of value in the
treatment or prophylaxis of cancers selected from congenital
fibrosarcoma, mesoblastic nephroma, mesothelioma, acute
myeloblastic leukemia, acute lymphocytic leukemia, multiple
myeloma, melanoma, oesophageal cancer, myeloma, hepatocellular,
pancreatic, cervical cancer, Ewings sarcoma, neuroblastoma, Kaposi
sarcoma, ovarian cancer, breast cancer including secretory breast
cancer, colorectal cancer, prostate cancer including hormone
refractory prostate cancer, bladder cancer, melanoma, lung
cancer--non small cell lung cancer (NSCLC), and small cell lung
cancer (SCLC), gastric cancer, head and neck cancer, renal cancer,
lymphoma, thyroid cancer including papillary thyroid cancer,
mesothelioma and leukaemia; particularly ovarian cancer, breast
cancer, colorectal cancer, prostate cancer and lung cancer--NSCLC
and SCLC; more particularly prostate cancer; and more particularly
hormone refractory prostate cancer.
[0019] In accordance with the present invention, the applicants
have further hereby discovered novel compounds, and
pharmaceutically acceptable salts thereof, which possess JAK kinase
inhibitory activity and are accordingly useful for their
anti-proliferation and/or pro-apoptotic activity and in methods of
treatment of the human or animal body. The invention also relates
to processes for the manufacture of said compound, or
pharmaceutically acceptable salts thereof, to pharmaceutical
compositions containing it and to its use in the manufacture of
medicaments for use in the production of an anti-proliferation
and/or pro-apoptotic effect in warm-blooded animals such as man.
Also in accordance with the present invention the applicants
provide methods of using said compound, or pharmaceutically
acceptable salts thereof, in the treatment of myeloproliferative
disorders, myelodysplastic syndrome and cancer.
[0020] The properties of the compounds claimed in this invention
are expected to be of value in the treatment of myeloproliferative
disorders, myelodysplastic syndrome, and cancer by inhibiting the
tyrosine kinases, particularly the JAK family and more particularly
JAK2. Methods of treatment target tyrosine kinase activity,
particularly the JAK family activity and more particularly JAK2
activity, which is involved in a variety of myeloproliferative
disorders, myelodysplastic syndrome and cancer related processes.
Thus, inhibitors of tyrosine kinase, particularly the JAK family
and more particularly JAK2, are expected to be active against
myeloproliferative disorders such as chronic myeloid leukemia,
polycythemia vera, essential thrombocythemia, myeloid metaplasia
with myelofibrosis, idiopathic myelofibrosis, chronic
myelomonocytic leukemia and hypereosinophilic syndrome,
myelodysplastic syndromes and neoplastic disease such as carcinoma
of the breast, ovary, lung, colon, prostate or other tissues, as
well as leukemias, myelomas and lymphomas, tumours of the central
and peripheral nervous system, and other tumour types such as
melanoma, fibrosarcoma and osteosarcoma. Tyrosine kinase
inhibitors, particularly the JAK family inhibitors and more
particularly JAK2 inhibitors are also expected to be useful for the
treatment other proliferative diseases including but not limited to
autoimmune, inflammatory, neurological, and cardiovascular
diseases.
[0021] Furthermore, the compound, or pharmaceutically acceptable
salts thereof, of the invention is expected to be of value in the
treatment or prophylaxis of against myeloproliferative disorders
selected from chronic myeloid leukemia, polycythemia vera,
essential thrombocythemia, myeloid metaplasia with myelofibrosis,
idiopathic myelofibrosis, chronic myelomonocytic leukemia and
hypereosinophilic syndrome, myelodysplastic syndromes and cancers
selected from oesophageal cancer, myeloma, hepatocellular,
pancreatic, cervical cancer, Ewings sarcoma, neuroblastoma,
Kaposi's sarcoma, ovarian cancer, breast cancer, colorectal cancer,
prostate cancer, bladder cancer, melanoma, lung cancer--non small
cell lung cancer (NSCLC), and small cell lung cancer (SCLC),
gastric cancer, head and neck cancer, mesothelioma, renal cancer,
lymphoma and leukaemia; particularly myeloma, leukemia, ovarian
cancer, breast cancer and prostate cancer.
DETAILED DESCRIPTION OF THE INVENTION
[0022] Accordingly, the present invention provides a compound of
formula (I):
##STR00002##
wherein:
[0023] R.sup.1 is selected from hydrogen, hydroxy, amino, mercapto,
C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.1-6alkoxy, C.sub.1-6alkanoyloxy, N--(C.sub.1-6alkyl)amino,
N,N--(C.sub.1-6alkyl).sub.2amino, C.sub.1-6alkanoylamino,
C.sub.1-6alkylsulphonylamino, 3-5-membered carbocyclyl or
3-5-membered heterocyclyl; wherein R.sup.1 may be optionally
substituted on carbon by one or more R.sup.6; and wherein if said
heterocyclyl contains an --NH-- moiety that nitrogen may be
optionally substituted by a group selected from R.sup.7;
[0024] R.sup.2 and R.sup.3 are independently selected from
hydrogen, halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl,
mercapto, sulphamoyl, C.sub.1-6alkyl, C.sub.2-6alkenyl,
C.sub.2-6alkynyl, C.sub.1-6alkoxy, C.sub.1-6alkanoyl,
C.sub.1-6alkanoyloxy, N--(C.sub.1-6alkyl)amino,
N,N--(C.sub.1-6alkyl).sub.2amino, C.sub.1-6alkanoylamino,
N--(C.sub.1-6alkyl)carbamoyl, N,N--(C.sub.1-6alkyl).sub.2carbamoyl,
C.sub.1-6alkylS(O).sub.a wherein a is 0 to 2,
C.sub.1-6alkoxycarbonyl, N--(C.sub.1-6alkyl)sulphamoyl,
N,N--(C.sub.1-6alkyl).sub.2sulphamoyl,
(C.sub.1-6alkyl).sub.2N--S(O).sub.2--NH--,
(C.sub.1-6alkyl)NH--S(O).sub.2--NH--, NH.sub.2--S(O).sub.2--NH--,
(C.sub.1-6alkyl).sub.2N--S(O).sub.2--N(C.sub.1-6alkyl)-,
(C.sub.1-6alkyl)NH--S(O).sub.2--N(C.sub.1-6alkyl)-,
NH.sub.2--S(O).sub.2--N(C.sub.1-6alkyl)-,
N--(C.sub.1-6alkyl)-N--(C.sub.1-6alkylsulphonyl)amino,
C.sub.1-6alkylsulphonylamino, carbocyclyl-R.sup.19-- or
heterocyclyl-R.sup.21--; wherein R.sup.2 and R.sup.3 independently
of each other may be optionally substituted on carbon by one or
more R.sup.8; and wherein if said heterocyclyl contains an --NH--
moiety that nitrogen may be optionally substituted by a group
selected from R.sup.9;
[0025] R.sup.4 is selected from cyano, carboxy, carbamoyl,
C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.1-6alkanoyl, N--(C.sub.1-6alkyl)carbamoyl,
N,N--(C.sub.1-6alkyl).sub.2carbamoyl, C.sub.1-6alkoxycarbonyl,
carbocyclyl or heterocyclyl; wherein R.sup.4 may be optionally
substituted on carbon by one or more R.sup.10; and wherein if said
heterocyclyl contains an --NH-- moiety that nitrogen may be
optionally substituted by a group selected from R.sup.H;
[0026] R.sup.5 is selected from halo, nitro, cyano, hydroxy, amino,
carboxy, carbamoyl, mercapto, sulphamoyl, C.sub.1-6alkyl,
C.sub.2-6alkenyl, C.sub.2-6alkynyl, C.sub.1-6alkoxy,
C.sub.1-6alkanoyl, C.sub.1-6alkanoyloxy, N--(C.sub.1-6alkyl)amino,
N,N--(C.sub.1-6alkyl).sub.2amino, C.sub.1-6alkanoylamino,
N--(C.sub.1-6alkyl)carbamoyl, N,N--(C.sub.1-6alkyl).sub.2carbamoyl,
C.sub.1-6alkylS(O).sub.a wherein a is 0 to 2,
C.sub.1-6alkoxycarbonyl, N--(C.sub.1-6alkyl)sulphamoyl,
N,N--(C.sub.1-6alkyl).sub.2sulphamoyl,
C.sub.1-6alkylsulphonylamino, carbocyclyl or heterocyclyl; wherein
R.sup.5 may be optionally substituted on carbon by one or more
R.sup.12; and wherein if said heterocyclyl contains an --NH--
moiety that nitrogen may be optionally substituted by a group
selected from R.sup.13;
[0027] n=0, 1, 2 or 3; wherein the values of R.sup.5 may be the
same or different;
[0028] R.sup.6, R.sup.8, R.sup.10 and R.sup.12 are independently
selected from halo, nitro, cyano, hydroxy, amino, carboxy,
carbamoyl, mercapto, sulphamoyl, C.sub.1-6alkyl, C.sub.2-6alkenyl,
C.sub.2-6alkynyl, C.sub.1-6alkoxy, C.sub.1-6alkanoyl,
C.sub.1-6alkanoyloxy, N--(C.sub.1-6alkyl)amino,
N,N--(C.sub.1-6alkyl).sub.2amino, C.sub.1-6alkanoylamino,
N--(C.sub.1-6alkyl)carbamoyl, N,N--(C.sub.1-6alkyl).sub.2carbamoyl,
C.sub.1-6alkylS(O).sub.a wherein a is 0 to 2,
C.sub.1-6alkoxycarbonyl, N--(C.sub.1-6alkyl)sulphamoyl,
N,N--(C.sub.1-6alkyl).sub.2sulphamoyl,
C.sub.1-6alkylsulphonylamino, carbocyclyl or heterocyclyl; wherein
R.sup.6, R.sup.8, R.sup.10 and R.sup.12 independently of each other
may be optionally substituted on carbon by one or more R.sup.14;
and wherein if said heterocyclyl contains an --NH-- moiety that
nitrogen may be optionally substituted by a group selected from
R.sup.15;
[0029] R.sup.7, R.sup.9, R.sup.11, R.sup.13 and R.sup.15 are
independently selected from C.sub.1-6alkyl, C.sub.1-6alkanoyl,
C.sub.1-6alkylsulphonyl, C.sub.1-6alkoxycarbonyl, carbamoyl,
N--(C.sub.1-6alkyl)carbamoyl, N,N--(C.sub.1-6alkyl)carbamoyl,
benzyl, benzyloxycarbonyl, benzoyl and phenylsulphonyl; wherein
R.sup.7, R.sup.9, R.sup.11, R.sup.13 and R.sup.15 independently of
each other may be optionally substituted on carbon by on or more
R.sup.16;
[0030] R.sup.14 and R.sup.16 are independently selected from halo,
nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto,
sulphamoyl, C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.1-6alkoxy, C.sub.1-6alkanoyl, C.sub.1-6alkanoyloxy,
N--(C.sub.1-6alkyl)amino, N,N--(C.sub.1-6alkyl).sub.2amino,
C.sub.1-6alkanoylamino, N--(C.sub.1-6alkyl)carbamoyl,
N,N--(C.sub.1-6alkyl).sub.2carbamoyl, C.sub.1-6alkylS(O).sub.a
wherein a is 0 to 2, C.sub.1-6alkoxycarbonyl,
N--(C.sub.1-6alkyl)sulphamoyl,
N,N--(C.sub.1-6alkyl).sub.2sulphamoyl,
C.sub.1-6alkylsulphonylamino, carbocyclyl or heterocyclyl; wherein
R.sup.14 and R.sup.16 independently of each other may be optionally
substituted on carbon by one or more R.sup.17; and wherein if said
heterocyclyl contains an --NH-- moiety that nitrogen may be
optionally substituted by a group selected from R.sup.18;
[0031] R.sup.17 is selected from halo, nitro, cyano, hydroxy,
trifluoromethoxy, trifluoromethyl, amino, carboxy, carbamoyl,
mercapto, sulphamoyl, methyl, ethyl, methoxy, ethoxy, acetyl,
acetoxy, methylamino, ethylamino, dimethylamino, diethylamino,
N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl,
N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl,
N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulphinyl,
ethylsulphinyl, mesyl, ethylsulphonyl, methoxycarbonyl,
ethoxycarbonyl, N-methylsulphamoyl, N-ethylsulphamoyl,
N,N-dimethylsulphamoyl, N,N-diethylsulphamoyl or
N-methyl-N-ethylsulphamoyl; and
[0032] R.sup.19 and R.sup.21 are independently selected from a
direct bond, --O--, --N(R.sup.22)--, --C(O)--, --N(R.sup.23)C(O)--,
--C(O)N(R.sup.24)--, --S(O).sub.s--, --SO.sub.2N(R.sup.25)-- or
--N(R.sup.26)SO.sub.2--; wherein R.sup.22, R.sup.23, R.sup.24,
R.sup.25 and R.sup.26 are independently selected from hydrogen or
C.sub.1-6alkyl and s is 0-2;
[0033] R.sup.18 is selected from C.sub.1-6alkyl, C.sub.1-6alkanoyl,
C.sub.1-6alkylsulphonyl, C.sub.1-6alkoxycarbonyl, carbamoyl,
N--(C.sub.1-6alkyl)carbamoyl, N,N--(C.sub.1-6alkyl)carbamoyl,
benzyl, benzyloxycarbonyl, benzoyl and phenylsulphonyl;
or a pharmaceutically acceptable salt thereof.
[0034] In another aspect, the invention relates to compounds of
formula (I), wherein: R.sup.1 is selected from hydrogen, hydroxy,
amino, mercapto, C.sub.1-6alkyl, C.sub.2-6alkenyl,
C.sub.2-6alkynyl, C.sub.1-6alkoxy, C.sub.1-6alkanoyloxy,
N--(C.sub.1-6alkyl)amino, N,N--(C.sub.1-6alkyl).sub.2amino,
C.sub.1-6alkanoylamino, C.sub.1-6alkylsulphonylamino, 3-5-membered
carbocyclyl or 3-5-membered heterocyclyl; wherein R.sup.1 may be
optionally substituted on carbon by one or more R.sup.6; and
wherein if said heterocyclyl contains an --NH-- moiety that
nitrogen may be optionally substituted by a group selected from
R.sup.7;
[0035] R.sup.2 and R.sup.3 are independently selected from
hydrogen, halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl,
mercapto, sulphamoyl, C.sub.1-6alkyl, C.sub.2-6alkenyl,
C.sub.2-6alkynyl, C.sub.1-6alkoxy, C.sub.1-6alkanoyl,
C.sub.1-6alkanoyloxy, N--(C.sub.1-6alkyl)amino,
N,N--(C.sub.1-6alkyl).sub.2amino, C.sub.1-6alkanoylamino,
N--(C.sub.1-6alkyl)carbamoyl, N,N--(C.sub.1-6alkyl).sub.2carbamoyl,
C.sub.1-6alkylS(O).sub.a wherein a is 0 to 2,
C.sub.1-6alkoxycarbonyl, N--(C.sub.1-6alkyl)sulphamoyl,
N,N--(C.sub.1-6alkyl).sub.2sulphamoyl,
C.sub.1-6alkylsulphonylamino, carbocyclyl-R.sup.19-- or
heterocyclyl-R.sup.21--; wherein R.sup.2 and R.sup.3 independently
of each other may be optionally substituted on carbon by one or
more R.sup.8; and wherein if said heterocyclyl contains an --NH--
moiety that nitrogen may be optionally substituted by a group
selected from R.sup.9;
[0036] R.sup.4 is selected from cyano, carboxy, carbamoyl,
C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.1-6alkanoyl, N--(C.sub.1-6alkyl)carbamoyl,
N,N--(C.sub.1-6alkyl).sub.2carbamoyl, C.sub.1-6alkoxycarbonyl,
carbocyclyl or heterocyclyl; wherein R.sup.4 may be optionally
substituted on carbon by one or more R.sup.19; and wherein if said
heterocyclyl contains an --NH-- moiety that nitrogen may be
optionally substituted by a group selected from R.sup.H;
[0037] R.sup.5 is selected from halo, nitro, cyano, hydroxy, amino,
carboxy, carbamoyl, mercapto, sulphamoyl, C.sub.1-6alkyl,
C.sub.2-6alkenyl, C.sub.2-6alkynyl, C.sub.1-6alkoxy,
C.sub.1-6alkanoyl, C.sub.1-6alkanoyloxy, N--(C.sub.1-6alkyl)amino,
N,N--(C.sub.1-6alkyl).sub.2amino, C.sub.1-6alkanoylamino,
N--(C.sub.1-6alkyl)carbamoyl, N,N--(C.sub.1-6alkyl).sub.2carbamoyl,
C.sub.1-6alkylS(O).sub.a wherein a is 0 to 2,
C.sub.1-6alkoxycarbonyl, N--(C.sub.1-6alkyl)sulphamoyl,
N,N--(C.sub.1-6alkyl).sub.2sulphamoyl,
C.sub.1-6alkylsulphonylamino, carbocyclyl or heterocyclyl; wherein
R.sup.5 may be optionally substituted on carbon by one or more
R.sup.12; and wherein if said heterocyclyl contains an --NH--
moiety that nitrogen may be optionally substituted by a group
selected from R.sup.13;
[0038] n=0, 1, 2 or 3; wherein the values of R.sup.5 may be the
same or different;
[0039] R.sup.6, R.sup.8, R.sup.10 and R.sup.12 are independently
selected from halo, nitro, cyano, hydroxy, amino, carboxy,
carbamoyl, mercapto, sulphamoyl, C.sub.1-6alkyl, C.sub.2-6alkenyl,
C.sub.2-6alkynyl, C.sub.1-6alkoxy, C.sub.1-6alkanoyl,
C.sub.1-6alkanoyloxy, N--(C.sub.1-6alkyl)amino,
N,N--(C.sub.1-6alkyl).sub.2amino, C.sub.1-6alkanoylamino,
N--(C.sub.1-6alkyl)carbamoyl, N,N--(C.sub.1-6alkyl).sub.2carbamoyl,
C.sub.1-6alkylS(O).sub.a wherein a is 0 to 2,
C.sub.1-6alkoxycarbonyl, N--(C.sub.1-6alkyl)sulphamoyl,
N,N--(C.sub.1-6alkyl).sub.2sulphamoyl,
C.sub.1-6alkylsulphonylamino, carbocyclyl or heterocyclyl; wherein
R.sup.6, R.sup.8, R.sup.10 and R.sup.12 independently of each other
may be optionally substituted on carbon by one or more R.sup.14;
and wherein if said heterocyclyl contains an --NH-- moiety that
nitrogen may be optionally substituted by a group selected from
R.sup.15;
[0040] R.sup.7, R.sup.9, R.sup.11, R.sup.13 and R.sup.15 are
independently selected from C.sub.1-6alkyl, C.sub.1-6alkanoyl,
C.sub.1-6alkylsulphonyl, C.sub.1-6alkoxycarbonyl, carbamoyl,
N--(C.sub.1-6alkyl)carbamoyl, N,N--(C.sub.1-6alkyl)carbamoyl,
benzyl, benzyloxycarbonyl, benzoyl and phenylsulphonyl; wherein
R.sup.7, R.sup.9, R.sup.11, R.sup.13 and R.sup.15 independently of
each other may be optionally substituted on carbon by on or more
R.sup.16;
[0041] R.sup.14 and R.sup.16 are independently selected from halo,
nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto,
sulphamoyl, C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.1-6alkoxy, C.sub.1-6alkanoyl, C.sub.1-6alkanoyloxy,
N--(C.sub.1-6alkyl)amino, N,N--(C.sub.1-6alkyl).sub.2amino,
C.sub.1-6alkanoylamino, N--(C.sub.1-6alkyl)carbamoyl,
N,N--(C.sub.1-6alkyl).sub.2carbamoyl, C.sub.1-6alkyl S(O). wherein
a is 0 to 2, C.sub.1-6alkoxycarbonyl,
N--(C.sub.1-6alkyl)sulphamoyl,
N,N--(C.sub.1-6alkyl).sub.2sulphamoyl,
C.sub.1-6alkylsulphonylamino, carbocyclyl or heterocyclyl; wherein
R.sup.14 and R.sup.16 independently of each other may be optionally
substituted on carbon by one or more R.sup.17; and wherein if said
heterocyclyl contains an --NH-- moiety that nitrogen may be
optionally substituted by a group selected from R.sup.18;
[0042] R.sup.17 is selected from halo, nitro, cyano, hydroxy,
trifluoromethoxy, trifluoromethyl, amino, carboxy, carbamoyl,
mercapto, sulphamoyl, methyl, ethyl, methoxy, ethoxy, acetyl,
acetoxy, methylamino, ethylamino, dimethylamino, diethylamino,
N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl,
N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl,
N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulphinyl,
ethylsulphinyl, mesyl, ethylsulphonyl, methoxycarbonyl,
ethoxycarbonyl, N-methylsulphamoyl, N-ethylsulphamoyl,
N,N-dimethylsulphamoyl, N,N-diethylsulphamoyl or
N-methyl-N-ethylsulphamoyl; and
[0043] R.sup.19 and R.sup.21 are independently selected from --O--,
--N(R.sup.22)--, --C(O)--, --N(R.sup.23)C(O)--,
--C(O)N(R.sup.24)--, --S(O).sub.s--, --SO.sub.2N(R.sup.25)-- or
--N(R.sup.26)SO.sub.2--; wherein R.sup.22, R.sup.23, R.sup.24,
R.sup.25 and R.sup.26 are independently selected from hydrogen or
C.sub.1-6alkyl and s is 0-2;
[0044] R.sup.18 is selected from C.sub.1-6alkyl, C.sub.1-6alkanoyl,
C.sub.1-6alkylsulphonyl, C.sub.1-6alkoxycarbonyl, carbamoyl,
N--(C.sub.1-6alkyl)carbamoyl, N,N--(C.sub.1-6alkyl)carbamoyl,
benzyl, benzyloxycarbonyl, benzoyl and phenylsulphonyl;
or a pharmaceutically acceptable salt thereof.
[0045] In another aspect, the invention relates to compounds of
formula (I), wherein: R.sup.1 is selected from hydrogen, hydroxy,
amino, mercapto, C.sub.1-6alkyl, C.sub.2-6alkenyl,
C.sub.2-6alkynyl, C.sub.1-6alkoxy, C.sub.1-6alkanoyloxy,
N--(C.sub.1-6alkyl)amino, N,N--(C.sub.1-6alkyl).sub.2amino,
C.sub.1-6alkanoylamino, C.sub.1-6alkylsulphonylamino, 3-5-membered
carbocyclyl or 3-5-membered heterocyclyl; wherein R.sup.1 may be
optionally substituted on carbon by one or more R.sup.6; and
wherein if said heterocyclyl contains an --NH-- moiety that
nitrogen may be optionally substituted by a group selected from
R.sup.7;
[0046] R.sup.2 and R.sup.3 are independently selected from
hydrogen, halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl,
mercapto, sulphamoyl, C.sub.1-6alkyl, C.sub.2-6alkenyl,
C.sub.2-6alkynyl, C.sub.1-6alkoxy, C.sub.1-6alkanoyl,
C.sub.1-6alkanoyloxy, N--(C.sub.1-6alkyl)amino,
N,N--(C.sub.1-6alkyl).sub.2amino, C.sub.1-6alkanoylamino,
N--(C.sub.1-6alkyl)carbamoyl, N,N--(C.sub.1-6alkyl).sub.2carbamoyl,
C.sub.1-6alkylS(O).sub.a wherein a is 0 to 2,
C.sub.1-6alkoxycarbonyl, N--(C.sub.1-6alkyl)sulphamoyl,
N,N--(C.sub.1-6alkyl).sub.2sulphamoyl,
N--(C.sub.1-6alkyl)-N--(C.sub.1-6alkylsulphonyl)amino,
C.sub.1-6alkylsulphonylamino, carbocyclyl-R.sup.19-- or
heterocyclyl-R.sup.21--; wherein R.sup.2 and R.sup.3 independently
of each other may be optionally substituted on carbon by one or
more R.sup.8; and wherein if said heterocyclyl contains an --NH--
moiety that nitrogen may be optionally substituted by a group
selected from R.sup.9;
[0047] R.sup.4 is selected from cyano, carboxy, carbamoyl,
C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.1-6alkanoyl, N--(C.sub.1-6alkyl)carbamoyl,
N,N--(C.sub.1-6alkyl).sub.2carbamoyl, C.sub.1-6alkoxycarbonyl,
carbocyclyl or heterocyclyl; wherein R.sup.4 may be optionally
substituted on carbon by one or more R.sup.10; and wherein if said
heterocyclyl contains an --NH-- moiety that nitrogen may be
optionally substituted by a group selected from R.sup.11;
[0048] R.sup.5 is selected from halo, nitro, cyano, hydroxy, amino,
carboxy, carbamoyl, mercapto, sulphamoyl, C.sub.1-6alkyl,
C.sub.2-6alkenyl, C.sub.2-6alkynyl, C.sub.1-6alkoxy,
C.sub.1-6alkanoyl, C.sub.1-6alkanoyloxy, N--(C.sub.1-6alkyl)amino,
N,N--(C.sub.1-6alkyl).sub.2amino, C.sub.1-6alkanoylamino,
N--(C.sub.1-6alkyl)carbamoyl, N,N--(C.sub.1-6alkyl).sub.2carbamoyl,
C.sub.1-6alkylS(O).sub.a wherein a is 0 to 2,
C.sub.1-6alkoxycarbonyl, N--(C.sub.1-6alkyl)sulphamoyl,
N,N--(C.sub.1-6alkyl).sub.2sulphamoyl,
C.sub.1-6alkylsulphonylamino, carbocyclyl or heterocyclyl; wherein
R.sup.5 may be optionally substituted on carbon by one or more
R.sup.12; and wherein if said heterocyclyl contains an --NH--
moiety that nitrogen may be optionally substituted by a group
selected from R.sup.13;
[0049] n=0, 1, 2 or 3; wherein the values of R.sup.5 may be the
same or different;
[0050] R.sup.6, R.sup.8, R.sup.10 and R.sup.12 are independently
selected from halo, nitro, cyano, hydroxy, amino, carboxy,
carbamoyl, mercapto, sulphamoyl, C.sub.1-6alkyl, C.sub.2-6alkenyl,
C.sub.2-6alkynyl, C.sub.1-6alkoxy, C.sub.1-6alkanoyl,
C.sub.1-6alkanoyloxy, N--(C.sub.1-6alkyl)amino,
N,N--(C.sub.1-6alkyl).sub.2amino, C.sub.1-6alkanoylamino,
N--(C.sub.1-6alkyl)carbamoyl, N,N--(C.sub.1-6alkyl).sub.2carbamoyl,
C.sub.1-6alkylS(O).sub.a wherein a is 0 to 2,
C.sub.1-6alkoxycarbonyl, N--(C.sub.1-6alkyl)sulphamoyl,
N,N--(C.sub.1-6alkyl).sub.2sulphamoyl,
C.sub.1-6alkylsulphonylamino, carbocyclyl or heterocyclyl; wherein
R.sup.6, R.sup.8, R.sup.10 and R.sup.12 independently of each other
may be optionally substituted on carbon by one or more R.sup.14;
and wherein if said heterocyclyl contains an --NH-- moiety that
nitrogen may be optionally substituted by a group selected from
R.sup.15;
[0051] R.sup.7, R.sup.9, R.sup.11, R.sup.13 and R.sup.15 are
independently selected from C.sub.1-6alkyl, C.sub.1-6alkanoyl,
C.sub.1-6alkylsulphonyl, C.sub.1-6alkoxycarbonyl, carbamoyl,
N--(C.sub.1-6alkyl)carbamoyl, N,N--(C.sub.1-6alkyl)carbamoyl,
benzyl, benzyloxycarbonyl, benzoyl and phenylsulphonyl; wherein
R.sup.7, R.sup.9, R.sup.11, R.sup.13 and R.sup.15 independently of
each other may be optionally substituted on carbon by on or more
R.sup.16;
[0052] R.sup.14 and R.sup.16 are independently selected from halo,
nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto,
sulphamoyl, C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.1-6alkoxy, C.sub.1-6alkanoyl, C.sub.1-6alkanoyloxy,
N--(C.sub.1-6alkyl)amino, N,N--(C.sub.1-6alkyl).sub.2amino,
C.sub.1-6alkanoylamino, N--(C.sub.1-6alkyl)carbamoyl,
N,N--(C.sub.1-6alkyl).sub.2carbamoyl, C.sub.1-6alkylS(O).sub.a
wherein a is 0 to 2, C.sub.1-6alkoxycarbonyl,
N--(C.sub.1-6alkyl)sulphamoyl,
N,N--(C.sub.1-6alkyl).sub.2sulphamoyl,
C.sub.1-6alkylsulphonylamino, carbocyclyl or heterocyclyl; wherein
R.sup.14 and R.sup.16 independently of each other may be optionally
substituted on carbon by one or more R.sup.17; and wherein if said
heterocyclyl contains an --NH-- moiety that nitrogen may be
optionally substituted by a group selected from R.sup.18;
[0053] R.sup.17 is selected from halo, nitro, cyano, hydroxy,
trifluoromethoxy, trifluoromethyl, amino, carboxy, carbamoyl,
mercapto, sulphamoyl, methyl, ethyl, methoxy, ethoxy, acetyl,
acetoxy, methylamino, ethylamino, dimethylamino, diethylamino,
N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl,
N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl,
N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulphinyl,
ethylsulphinyl, mesyl, ethylsulphonyl, methoxycarbonyl,
ethoxycarbonyl, N-methylsulphamoyl, N-ethylsulphamoyl,
N,N-dimethylsulphamoyl, N,N-diethylsulphamoyl or
N-methyl-N-ethylsulphamoyl; and
[0054] R.sup.19 and R.sup.21 are independently selected from a
direct bond, --O--, --N(R.sup.22)--, --C(O)--, --N(R.sup.23)C(O)--,
--C(O)N(R.sup.24)--, --S(O).sub.s--, --SO.sub.2N(R.sup.25)-- or
--N(R.sup.26)SO.sub.2--; wherein R.sup.22, R.sup.23, R.sup.24,
R.sup.25 and R.sup.26 are independently selected from hydrogen or
C.sub.1-6alkyl and s is 0-2;
[0055] R.sup.18 is selected from C.sub.1-6alkyl, C.sub.1-6alkanoyl,
C.sub.1-6alkylsulphonyl, C.sub.1-6alkoxycarbonyl, carbamoyl,
N--(C.sub.1-6alkyl)carbamoyl, N,N--(C.sub.1-6alkyl)carbamoyl,
benzyl, benzyloxycarbonyl, benzoyl and phenylsulphonyl;
or a pharmaceutically acceptable salt thereof.
[0056] Particular values of the variable groups contained in
formula (I) are as follows. Such values may be used, where
appropriate, with any of the definitions, claims or embodiments
defined hereinbefore or hereinafter.
[0057] R.sup.1 is selected from C.sub.1-6alkyl, C.sub.1-6alkoxy,
3-5-membered carbocyclyl, and N,N--(C.sub.1-6alkyl).sub.2amino,
wherein R.sup.1 may be optionally substituted on carbon by one or
more R.sup.6; and wherein R.sup.6 is halo.
[0058] R.sup.1 is C.sub.1-6alkoxy or 3-5-membered carbocyclyl.
[0059] R.sup.1 is selected from C.sub.1-6alkyl, C.sub.1-6alkoxy or
3-5-membered carbocyclyl.
[0060] R.sup.1 is C.sub.1-6alkyl or C.sub.1-6alkoxy.
[0061] R.sup.1 is 3-5 membered carbocyclyl.
[0062] R.sup.1 is N,N(C.sub.1-6alkyl).sub.2amino.
[0063] R.sup.1 is C.sub.1-6alkyl.
[0064] R.sup.1 is C.sub.1-4alkyl.
[0065] R.sup.1 is C.sub.1-6alkoxy.
[0066] R.sup.1 is selected from methyl, methoxy, trifluoroethoxy,
isopropoxy, cyclopropyl, and N,N-dimethylamino;
[0067] R.sup.1 is isopropoxy or cyclopropyl.
[0068] R.sup.1 is methyl, methoxy, isopropoxy or cyclopropyl.
[0069] R.sup.1 is selected from methyl, methoxy, isopropoxy,
N,N-dimethylamino, and cyclopropyl.
[0070] R.sup.1 is isopropoxy.
[0071] R.sup.1 is methyl.
[0072] R.sup.1 is ethyl.
[0073] R.sup.1 is selected from methyl, ethyl, propyl, and
butyl.
[0074] R.sup.1 is selected from C.sub.1-4alkyl, C.sub.1-4alkoxy,
and cyclopropyl.
[0075] R.sup.1 is methoxy.
[0076] R.sup.1 is cyclopropyl. R.sup.1 is N,N-dimethylamino.
[0077] R.sup.2 is selected from hydrogen, halo, nitro, and
C.sub.1-6alkyl, wherein R.sup.2 may be optionally substituted on
carbon by one or more R.sup.8; and wherein R.sup.8 is halo.
[0078] R.sup.2 is selected from hydrogen, chloro, fluoro, bromo,
nitro, and trifluoromethyl.
[0079] R.sup.2 is halo.
[0080] R.sup.2 is C.sub.1-6alkyl, wherein R.sup.2 may be optionally
substituted on carbon by one or more R.sup.8; and wherein R.sup.8
is halo.
[0081] R.sup.2 and R.sup.3 are independently selected from
hydrogen, halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl,
mercapto, sulphamoyl, C.sub.1-6alkyl, C.sub.2-6alkenyl,
C.sub.2-6alkynyl, C.sub.1-6alkoxy, C.sub.1-6alkanoyl,
C.sub.1-6alkanoyloxy, N--(C.sub.1-6alkyl)amino,
N,N--(C.sub.1-6alkyl).sub.2amino, C.sub.1-6alkanoylamino,
N--(C.sub.1-6alkyl)carbamoyl, N,N--(C.sub.1-6alkyl).sub.2carbamoyl,
C.sub.1-6alkylS(O).sub.a wherein a is 0 to 2,
C.sub.1-6alkoxycarbonyl, N--(C.sub.1-6alkyl)sulphamoyl,
N,N--(C.sub.1-6alkyl).sub.2sulphamoyl,
C.sub.1-6alkylsulphonylamino, carbocyclyl-R.sup.19-- or
heterocyclyl-R.sup.21--; wherein R.sup.2 and R.sup.3 independently
of each other may be optionally substituted on carbon by one or
more R.sup.8; and wherein if said heterocyclyl contains an --NH--
moiety that nitrogen may be optionally substituted by a group
selected from R.sup.9.
[0082] R.sup.2 and R.sup.3 are independently selected from
hydrogen, halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl,
mercapto, sulphamoyl, C.sub.1-6alkyl, C.sub.2-6alkenyl,
C.sub.2-6alkynyl, C.sub.1-6alkoxy, C.sub.1-6alkanoyl,
C.sub.1-6alkanoyloxy, N--(C.sub.1-6alkyl)amino,
N,N--(C.sub.1-6alkyl).sub.2amino, C.sub.1-6alkanoylamino,
N--(C.sub.1-6alkyl)carbamoyl, N,N--(C.sub.1-6alkyl).sub.2carbamoyl,
C.sub.1-6alkylS(O).sub.a wherein a is 0 to 2,
C.sub.1-6alkoxycarbonyl, N--(C.sub.1-6alkyl)sulphamoyl,
N,N--(C.sub.1-6alkyl).sub.2sulphamoyl,
N--(C.sub.1-6alkyl)-N--(C.sub.1-6alkylsulphonyl)amino,
C.sub.1-6alkylsulphonylamino, carbocyclyl-R.sup.19-- or
heterocyclyl-R.sup.21--; wherein R.sup.2 and R.sup.3 independently
of each other may be optionally substituted on carbon by one or
more R.sup.8; and wherein if said heterocyclyl contains an --NH--
moiety that nitrogen may be optionally substituted by a group
selected from R.sup.9.
[0083] R.sup.2 and R.sup.3 are independently selected from
hydrogen, halo,
N--(C.sub.1-6alkyl)-N--(C.sub.1-6alkylsulphonyl)amino, or
heterocyclyl-R.sup.21--; wherein R.sup.21 is a direct bond.
[0084] R.sup.2 and R.sup.3 are independently selected from hydrogen
and halo.
[0085] R.sup.2 and R.sup.3 are independently selected from hydrogen
and chloro.
[0086] R.sup.2 and R.sup.3 are independently selected from
hydrogen, fluoro, chloro, bromo, N-methyl-N-mesylamino and
morpholino.
[0087] R.sup.2 is halo and R.sup.3 is hydrogen.
[0088] R.sup.2 is chloro and R.sup.3 is hydrogen. [0089] R.sup.2 is
chloro or fluoro and R.sup.3 is hydrogen. R.sup.3 is selected from
hydrogen, halo, cyano,
N--(C.sub.1-6alkyl)-N--(C.sub.1-6alkylsulphonyl)amino,
C.sub.1-6alkyl,
(C.sub.1-6alkyl).sub.2N--S(O).sub.2--N(C.sub.1-6alkyl)-, and
heterocyclyl-R.sup.21--, wherein R.sup.3 may be optionally
substituted on carbon by one or more R.sup.8; wherein R.sup.8 is
halo; and wherein R.sup.21 is a bond.
[0090] R.sup.3 is hydrogen.
[0091] R.sup.3 is halo.
[0092] R.sup.3 is selected from
N--(C.sub.1-6alkyl)-N--(C.sub.1-6alkylsulphonyl)amino and
(C.sub.1-6alkyl).sub.2N--S(O).sub.2--N(C.sub.1-6alkyl)-.
[0093] R.sup.3 is selected from heterocyclyl-R.sup.21--, wherein
R.sup.3 may be optionally substituted on carbon by one or more
R.sup.8; wherein R.sup.8 is halo; and wherein R.sup.21 is a
bond.
[0094] R.sup.3 is selected from hydrogen, chloro, cyano,
trifluoromethyl, (CH.sub.3).sub.2N--S(O).sub.2--N(CH.sub.3)--,
N-methyl-N-mesylamino, and morpholino.
[0095] R.sup.3 is (CH.sub.3).sub.2N--S(O).sub.2--N(CH.sub.3)--.
[0096] R.sup.3 is N-methyl-N-mesylamino,
[0097] R.sup.3 is morpholino.
[0098] R.sup.4 is C.sub.1-6alkyl.
[0099] R.sup.4 is methyl.
[0100] R.sup.5 is halo.
[0101] R.sup.5 is fluoro.
[0102] n=1.
[0103] R.sup.19 and R.sup.21 are independently selected from --O--,
--N(R.sup.22)--, --C(O)--, --N(R.sup.23)C(O)--,
--C(O)N(R.sup.24)--, --S(O).sub.s--, --SO.sub.2N(R.sup.25)-- or
--N(R.sup.26)SO.sub.2--; wherein R.sup.22, R.sup.23, R.sup.24,
R.sup.25 and R.sup.26 are independently selected from hydrogen or
C.sub.1-6alkyl and s is 0-2.
[0104] Therefore in a further aspect of the invention there is
provided a compound of formula (I) (as depicted herein above)
wherein:
[0105] R.sup.1 is selected from C.sub.1-6alkyl, C.sub.1-6alkoxy or
3-5-membered carbocyclyl;
[0106] R.sup.2 and R.sup.3 are independently selected from
hydrogen, halo,
N--(C.sub.1-6alkyl)-N--(C.sub.1-6alkylsulphonyl)amino, or
heterocyclyl-R.sup.21--;
[0107] R.sup.4 is C.sub.1-6alkyl;
[0108] R.sup.5 is halo;
[0109] n=1;
[0110] R.sup.21 is a direct bond;
or a pharmaceutically acceptable salt thereof.
[0111] Therefore in a further aspect of the invention there is
provided a compound of formula (I) (as depicted herein above)
wherein:
[0112] R.sup.1 is C.sub.1-6alkoxy;
[0113] R.sup.2 and R.sup.3 are independently selected from hydrogen
and halo;
[0114] R.sup.4 is C.sub.1-6alkyl;
[0115] R.sup.5 is halo;
[0116] n=1;
or a pharmaceutically acceptable salt thereof.
[0117] Therefore in a further aspect of the invention there is
provided a compound of formula (I) (as depicted herein above)
wherein:
[0118] R.sup.1 is methyl, methoxy, isopropoxy or cyclopropyl;
[0119] R.sup.2 and R.sup.3 are independently selected from
hydrogen, fluoro, chloro, bromo, N-methyl-N-mesylamino and
morpholino;
[0120] R.sup.4 is methyl;
[0121] R.sup.5 is fluoro; and
[0122] n=1;
or a pharmaceutically acceptable salt thereof.
[0123] Therefore in a further aspect of the invention there is
provided a compound of formula (I) (as depicted herein above)
wherein:
[0124] R.sup.1 is selected from C.sub.1-6alkyl, C.sub.1-6alkoxy,
3-5-membered carbocyclyl, and N,N--(C.sub.1-6alkyl).sub.2amino,
wherein R.sup.1 may be optionally substituted on carbon by one or
more R.sup.6;
[0125] R.sup.2 is selected from hydrogen, halo, nitro, and
C.sub.1-6alkyl, wherein R.sup.2 may be optionally substituted on
carbon by one or more R.sup.8;
[0126] R.sup.3 is selected from hydrogen, halo, cyano,
N--(C.sub.1-6alkyl)-N--(C.sub.1-6alkylsulphonyl)amino,
C.sub.1-6alkyl,
(C.sub.1-6alkyl).sub.2N--S(O).sub.2--N(C.sub.1-6alkyl)-, and
heterocyclyl-R.sup.21--, wherein R.sup.3 may be optionally
substituted on carbon by one or more R.sup.8;
[0127] R.sup.4 is C.sub.1-6alkyl;
[0128] R.sup.5 is halo;
[0129] R.sup.6 is halo;
[0130] R.sup.8 is halo;
[0131] R.sup.21 is a bond; and
[0132] n=1;
or a pharmaceutically acceptable salt thereof.
[0133] Therefore in a further aspect of the invention there is
provided a compound of formula (I) (as depicted herein above)
wherein:
[0134] R.sup.1 is selected from methyl, methoxy, trifluoroethoxy,
isopropoxy, cyclopropyl, and N,N-dimethylamino;
[0135] R.sup.2 is selected from hydrogen, chloro, fluoro, bromo,
nitro, and trifluoromethyl;
[0136] R.sup.3 is selected from hydrogen, chloro, cyano,
trifluoromethyl, (CH.sub.3).sub.2N--S(O).sub.2--N(CH.sub.3)--,
N-methyl-N-mesylamino, and morpholino;
[0137] R.sup.4 is methyl;
[0138] R.sup.5 is fluoro; and
[0139] n is 1;
or a pharmaceutically acceptable salt thereof.
[0140] Therefore in a further aspect of the invention there is
provided a compound of formula (I) (as depicted herein above)
wherein:
[0141] R.sup.1 is selected from C.sub.1-6alkoxy, wherein R.sup.1
may be optionally substituted on carbon by one or more R.sup.6;
[0142] R.sup.2 is selected from hydrogen and halo;
[0143] R.sup.3 is selected from hydrogen, halo, and
heterocyclyl-R.sup.21--;
[0144] R.sup.4 is C.sub.1-6alkyl;
[0145] R.sup.5 is halo;
[0146] R.sup.6 is halo;
[0147] R.sup.21 is a bond;
[0148] n is 1;
or a pharmaceutically acceptable salt thereof.
[0149] Therefore in a further aspect of the invention there is
provided a compound of formula (I) (as depicted herein above)
wherein:
[0150] R.sup.1 is selected from C.sub.1-4alkyl, C.sub.1-4alkoxy,
and cyclopropyl;
[0151] R.sup.2 is selected from hydrogen, halo, nitro, and
C.sub.1-6alkyl, wherein R.sup.2 may be optionally substituted on
carbon by one or more R.sup.8;
[0152] R.sup.3 is selected from hydrogen, halo, cyano,
N--(C.sub.1-6alkyl)-N--(C.sub.1-6alkylsulphonyl)amino,
C.sub.1-6alkyl,
(C.sub.1-6alkyl).sub.2N--S(O).sub.2--N(C.sub.1-6alkyl)-, and
heterocyclyl-R.sup.21--, wherein R.sup.3 may be optionally
substituted on carbon by one or more R.sup.8;
[0153] R.sup.4 is C.sub.1-6alkyl;
[0154] R.sup.5 is halo;
[0155] R.sup.6 is halo;
[0156] R.sup.8 is halo;
[0157] R.sup.21 is a bond; and
[0158] n=1;
or a pharmaceutically acceptable salt thereof.
[0159] In another aspect of the invention, preferred compounds of
the invention are any one of the Examples or a pharmaceutically
acceptable salt thereof.
[0160] In another aspect of the invention, preferred compounds of
the invention are any one of: [0161]
N-{5-fluoro-2-{[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]amino}-6-[(5-methyl--
1H-pyrazol-3-yl)amino]pyrimidin-4-yl}-N-methylmethanesulfonamide;
[0162]
5-Fluoro-N.sup.2-[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]-N.sup.4-(5-methyl-
-1H-pyrazol-3-yl)pyrimidine-2,4-diamine; [0163]
5-Chloro-N.sup.2-[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]-N.sup.4-(5-methox-
y-1H-pyrazol-3-yl)pyrimidine-2,4-diamine; [0164]
N.sup.2-[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]-N.sup.4-(5-methoxy-1H-pyra-
zol-3-yl)-6-(trifluoromethyl)pyrimidine-2,4-diamine; [0165]
N.sup.2-[(1S)-1-(5-Fluoropyrimidin-2-yl)ethyl]-N.sup.4-(5-methyl-1H-pyraz-
ol-3-yl)-6-morpholin-4-ylpyrimidine-2,4-diamine; [0166]
5-Chloro-N.sup.4-(5-cyclopropyl-1H-pyrazol-3-yl)-N.sup.2-[(1S)-1-(5-fluor-
opyrimidin-2-yl)ethyl]pyrimidine-2,4-diamine; [0167]
5-Fluoro-N.sup.2-[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]-N.sup.4-(5-methyl-
-1H-pyrazol-3-yl)pyrimidine-2,4-diamine; [0168]
5-bromo-N.sup.2-[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]-N.sup.4-(5-methoxy-
-1H-pyrazol-3-yl)pyrimidine-2,4-diamine; [0169]
N.sup.4-(5-Cyclopropyl-1H-pyrazol-3-yl)-5-fluoro-N.sup.2-[(1S)-1-(5-fluor-
opyrimidin-2-yl)ethyl]pyrimidine-2,4-diamine; [0170]
N.sup.2-[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]-5-methyl-N.sup.4-(5-methyl-
-1H-pyrazol-3-yl)pyrimidine-2,4-diamine; [0171]
N-{5-chloro-2-{[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]amino}-6-[(5-methoxy-
-1H-pyrazol-3-yl)amino]pyrimidin-4-yl}-N-methylmethanesulfonamide;
[0172]
N-{5-chloro-2-{[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]amino}-6-[(5-methyl--
1H-pyrazol-3-yl)amino]pyrimidin-4-yl}-N-methylmethanesulfonamide;
[0173]
N.sup.2-[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]-N.sup.4-(5-methoxy-1H-pyra-
zol-3-yl)-6-morpholin-4-ylpyrimidine-2,4-diamine; [0174]
5-chloro-N.sup.2-[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]-N.sup.4-(5-methox-
y-1H-pyrazol-3-yl)-6-morpholin-4-ylpyrimidine-2,4-diamine; [0175]
5-fluoro-N.sup.2-[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]-N.sup.4-(5-methyl-
-1H-pyrazol-3-yl)-6-morpholin-4-ylpyrimidine-2,4-diamine; and
[0176]
5-fluoro-N.sup.2-[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]-N.sup.4-(5-methox-
y-1H-pyrazol-3-yl)-6-morpholin-4-ylpyrimidine-2,4-diamine; or a
pharmaceutically acceptable salt thereof.
[0177] In an additional embodiment the present invention provides a
compound of formula (I), or a pharmaceutically acceptable salt
thereof, for use as a medicament.
[0178] In an additional embodiment the present invention provides a
compound of formula (I), or a pharmaceutically acceptable salt
thereof, for use in the manufacture of a medicament for use in the
inhibition of Trk activity.
[0179] In an additional embodiment the present invention provides a
compound of formula (I), or a pharmaceutically acceptable salt
thereof, for use in the manufacture of a medicament for use in the
treatment or prophylaxis of cancer.
[0180] In an additional embodiment the present invention provides a
compound of the formula (I), or a pharmaceutically acceptable salt
thereof, for use in the manufacture of a medicament for use in the
treatment of cancer in a warm-blooded animal such as man.
[0181] In an additional embodiment the present invention provides a
compound of the formula (I), or a pharmaceutically acceptable salt
thereof, for use in the manufacture of a medicament for use in the
treatment or prophylaxis of cancers (solid tumors and leukemia),
fibroproliferative and differentiative disorders, psoriasis,
rheumatoid arthritis, Kaposi's sarcoma, haemangioma, acute and
chronic nephropathies, atheroma, atherosclerosis, arterial
restenosis, autoimmune diseases, acute and chronic inflammation,
bone diseases and ocular diseases with retinal vessel proliferation
in a warm-blooded animal such as man.
[0182] In an additional embodiment the present invention provides a
compound of formula (I), or a pharmaceutically acceptable salt
thereof, for use in the manufacture of a medicament for use in the
production of an anti-proliferative effect.
[0183] In an additional embodiment, the present invention provides
the use of a compound of formula (I), or a pharmaceutically
acceptable salt thereof, in the manufacture of a medicament for use
in the production of an anti-proliferative effect in a warm-blooded
animal such as man.
[0184] In an additional embodiment, the present invention provides
the use of a compound of formula (I), or a pharmaceutically
acceptable salt thereof, in the manufacture of a medicament for use
in the production of an pro-apoptotic effect in a warm-blooded
animal such as man.
[0185] In an additional embodiment, the present invention provides
the use of a compound of formula (I), or a pharmaceutically
acceptable salt thereof, in the manufacture of a medicament for use
in the treatment of myeloproliferative disorders, myelodysplastic
syndrome, and cancer in a warm-blooded animal such as man.
[0186] In an additional embodiment, the present invention provides
the use of a compound of formula (I), or a pharmaceutically
acceptable salt thereof, in the manufacture of a medicament for use
in the treatment of chronic myeloid leukemia, polycythemia vera,
essential thrombocythemia, myeloid metaplasia with myelofibrosis,
idiopathic myelofibrosis, chronic myelomonocytic leukemia and
hypereosinophilic syndrome, myelodysplastic syndromes and cancers
selected from oesophageal cancer, myeloma, hepatocellular,
pancreatic, cervical cancer, Ewings sarcoma, neuroblastoma,
Kaposi's sarcoma, ovarian cancer, breast cancer, colorectal cancer,
prostate cancer, bladder cancer, melanoma, lung cancer--non small
cell lung cancer (NSCLC), and small cell lung cancer (SCLC),
gastric cancer, head and neck cancer, mesothelioma, renal cancer,
lymphoma and leukaemia.
[0187] In an additional embodiment, the present invention provides
the use of a compound of formula (I), or a pharmaceutically
acceptable salt thereof, in the manufacture of a medicament for use
in the treatment of cancer, wherein said cancer is selected from
oesophageal cancer, myeloma, hepatocellular, pancreatic, cervical
cancer, Ewings sarcoma, neuroblastoma, Kaposi's sarcoma, ovarian
cancer, breast cancer, colorectal cancer, prostate cancer, bladder
cancer, melanoma, lung cancer--non small cell lung cancer (NSCLC),
and small cell lung cancer (SCLC), gastric cancer, head and neck
cancer, mesothelioma, renal cancer, lymphoma and leukaemia.
[0188] In an additional embodiment the present invention provides a
method of inhibiting Trk activity comprising administering to a
host in need of such treatment a therapeutically effective amount
of a compound of formula (I), or a pharmaceutically acceptable salt
thereof.
[0189] In an additional embodiment the present invention provides a
method for the treatment of cancer comprising administering to a
host in need of such treatment a therapeutically effective amount
of a compound of formula (I), or a pharmaceutically acceptable salt
thereof.
[0190] In an additional embodiment the present invention provides a
method for the treatment or prophylaxis of cancer comprising
administering a therapeutically effective amount of a compound of
formula (I) or a pharmaceutically acceptable salt thereof.
[0191] In an additional embodiment the present invention provides a
method for the treatment or prophylaxis of cancers (solid tumors
and leukemia), fibroproliferative and differentiative disorders,
psoriasis, rheumatoid arthritis, Kaposi's sarcoma, haemangioma,
acute and chronic nephropathies, atheroma, atherosclerosis,
arterial restenosis, autoimmune diseases, acute and chronic
inflammation, bone diseases and ocular diseases with retinal vessel
proliferation in a warm-blooded animal such as man comprising
administering a therapeutically effective amount of a compound of
formula (I) or a pharmaceutically acceptable salt thereof.
[0192] In an additional embodiment the present invention provides a
method of producing an anti-proliferative effect in a warm-blooded
animal, such as man, in need of such treatment which comprises
administering to said animal an effective amount of a compound of
formula (I), or a pharmaceutically acceptable salt thereof.
[0193] In an additional embodiment, the present invention provides
a method for producing a pro-apoptotic effect in a warm-blooded
animal, such as man, in need of such treatment, said method
comprising administering to said animal an effective amount of a
compound of formula (I), or a pharmaceutically salt thereof.
[0194] In an additional embodiment, the present invention provides
a method of treating myeloproliferative disorders, myelodysplastic
syndrome, and cancer in a warm-blooded animal, such as man, in need
of such treatment, said method comprising administering to said
animal an effective amount of a compound of formula (I), or a
pharmaceutically acceptable salt thereof.
[0195] In an additional embodiment, the present invention provides
a method of treating chronic myeloid leukemia, polycythemia vera,
essential thrombocythemia, myeloid metaplasia with myelofibrosis,
idiopathic myelofibrosis, chronic myelomonocytic leukemia and
hypereosinophilic syndrome, myelodysplastic syndromes and cancers
selected from oesophageal cancer, myeloma, hepatocellular,
pancreatic, cervical cancer, Ewings sarcoma, neuroblastoma,
Kaposi's sarcoma, ovarian cancer, breast cancer, colorectal cancer,
prostate cancer, bladder cancer, melanoma, lung cancer--non small
cell lung cancer (NSCLC), and small cell lung cancer (SCLC),
gastric cancer, head and neck cancer, mesothelioma, renal cancer,
lymphoma, and leukaemia in a warm-blooded animal, such as man, in
need of such treatment, said method comprising administering to
said animal an effective amount of a compound of formula (I).
[0196] In an additional embodiment, the present invention provides
a method of treating myeloma, leukemia, ovarian cancer, breast
cancer, and prostate cancer in a warm-blooded animal, such as man,
in need of such treatment, said method comprising administering to
said animal an effective amount of a compound of formula (I).
[0197] In an additional embodiment, the present invention provides
a method of treating myeloproliferative disorders, myelodysplastic
syndrome and cancers (solid and heamatologic tumors),
fibroproliferative and differentiative disorders, psoriasis,
rheumatoid arthritis, Kaposi's sarcoma, haemangioma, acute and
chronic nephropathies, atheroma, atherosclerosis, arterial
restenosis, autoimmune diseases, acromegaly, acute and chronic
inflammation, bone diseases and ocular diseases with retinal vessel
proliferation in a warm-blooded animal such as man comprising
administering a therapeutically effective amount of a compound of
formula (I) or a pharmaceutically acceptable salt thereof.
[0198] In an additional embodiment, the present invention provides
a method of treating cancer in a warm-blooded animal, such as man,
in need of such treatment, said method comprising administering to
said animal an effective amount of a compound of formula (I), or a
pharmaceutically acceptable salt thereof, wherein said cancer is
selected from oesophageal cancer, myeloma, hepatocellular,
pancreatic, cervical cancer, Ewings sarcoma, neuroblastoma,
Kaposi's sarcoma, ovarian cancer, breast cancer, colorectal cancer,
prostate cancer, bladder cancer, melanoma, lung cancer--non small
cell lung cancer (NSCLC), and small cell lung cancer (SCLC),
gastric cancer, head and neck cancer, mesothelioma, renal cancer,
lymphoma and leukaemia.
[0199] In an additional embodiment, the present invention provides
a method of producing of a JAK inhibitory effect in a warm-blooded
animal, such as man, in need of such treatment, said method
comprising administering to said animal an effective amount of a
compound of formula (I), or a pharmaceutically acceptable salt
thereof.
[0200] In an additional embodiment the present invention provides a
pharmaceutical composition comprising a compound of formula (I), or
a pharmaceutically acceptable salt thereof, together with at least
one pharmaceutically acceptable carrier, diluent or excipient.
[0201] In an additional embodiment the present invention provides a
pharmaceutical composition comprising a compound of formula (I), or
a pharmaceutically acceptable salt thereof, together with at least
one pharmaceutically acceptable carrier, diluent or excipient for
use in the inhibition of Trk activity.
[0202] In an additional embodiment the present invention provides a
pharmaceutical composition comprising a compound of formula (I), or
a pharmaceutically acceptable salt thereof, together with at least
one pharmaceutically acceptable carrier, diluent or excipient for
use in the treatment of cancer.
[0203] In an additional embodiment the present invention provides a
pharmaceutical composition comprising a compound of formula (I), or
a pharmaceutically acceptable salt thereof, together with at least
one pharmaceutically acceptable carrier, diluent or excipient for
use in the treatment or prophylaxis of cancer.
[0204] In an additional embodiment the present invention provides a
pharmaceutical composition comprising a compound of formula (I), or
a pharmaceutically acceptable salt thereof, together with at least
one pharmaceutically acceptable carrier, diluent or excipient for
use in the treatment or prophylaxis of cancers (solid tumors and
leukemia), fibroproliferative and differentiative disorders,
psoriasis, rheumatoid arthritis, Kaposi's sarcoma, haemangioma,
acute and chronic nephropathies, atheroma, atherosclerosis,
arterial restenosis, autoimmune diseases, acute and chronic
inflammation, bone diseases and ocular diseases with retinal vessel
proliferation.
[0205] In an additional embodiment the present invention provides a
pharmaceutical composition comprising a compound of formula (I), or
a pharmaceutically acceptable salt thereof, together with at least
one pharmaceutically acceptable carrier, diluent or excipient for
use in the production of an anti-proliferative effect in a
warm-blooded animal such as man.
[0206] In an additional embodiment, the present invention provides
a pharmaceutical composition comprising a compound of formula (I),
or a pharmaceutically acceptable salt thereof, and at least one
pharmaceutically-acceptable diluent or carrier, for use in the
production of an pro-apoptotic effect in a warm-blooded animal such
as man. In an additional embodiment, the present invention provides
a pharmaceutical composition comprising a compound of formula (I),
or a pharmaceutically acceptable salt thereof, and at least one
pharmaceutically-acceptable diluent or carrier, for use in the
treatment of myeloproliferative disorders, myelodysplastic
syndrome, and cancer in a warm-blooded animal such as man.
[0207] In an additional embodiment, the present invention provides
a pharmaceutical composition comprising a compound of formula (I),
or a pharmaceutically acceptable salt thereof, and at least one
pharmaceutically-acceptable diluent or carrier, for use in the
treatment of chronic myeloid leukemia, polycythemia vera, essential
thrombocythemia, myeloid metaplasia with myelofibrosis, idiopathic
myelofibrosis, chronic myelomonocytic leukemia and
hypereosinophilic syndrome, myelodysplastic syndromes and cancers
selected from oesophageal cancer, myeloma, hepatocellular,
pancreatic, cervical cancer, Ewings sarcoma, neuroblastoma,
Kaposi's sarcoma, ovarian cancer, breast cancer, colorectal cancer,
prostate cancer, bladder cancer, melanoma, lung cancer--non small
cell lung cancer (NSCLC), and small cell lung cancer (SCLC),
gastric cancer, head and neck cancer, mesothelioma, renal cancer,
lymphoma, and leukaemia in a warm blooded animal such as man.
[0208] In an additional embodiment, the present invention provides
a pharmaceutical composition comprising a compound of formula (I),
or a pharmaceutically acceptable salt thereof, and at least one
pharmaceutically acceptable diluent or carrier, for use in the
treatment of myeloma, leukemia, ovarian cancer, breast cancer, and
prostate cancer in a warm-blooded animal, such as man.
[0209] In an additional embodiment, the present invention provides
a pharmaceutical composition comprising a compound of formula (I),
or a pharmaceutically acceptable salt thereof, and at least one
pharmaceutically-acceptable diluent or carrier, for use in the
treatment of cancer, wherein said cancer is selected from
oesophageal cancer, myeloma, hepatocellular, pancreatic, cervical
cancer, Ewings sarcoma, neuroblastoma, Kaposi's sarcoma, ovarian
cancer, breast cancer, colorectal cancer, prostate cancer, bladder
cancer, melanoma, lung cancer--non small cell lung cancer (NSCLC),
and small cell lung cancer (SCLC), gastric cancer, head and neck
cancer, mesothelioma, renal cancer, lymphoma and leukaemia in a
warm blooded animal such as man.
[0210] In an additional embodiment, the present invention provides
a pharmaceutical composition comprising a compound of formula (I),
or a pharmaceutically acceptable salt thereof, and at least one
pharmaceutically-acceptable diluent or carrier, for use in the
production of a JAK inhibitory effect in a warm blooded animal such
as man.
[0211] In an additional embodiment the present invention provides a
compound of formula (I), or a pharmaceutically acceptable salt
thereof, for use in the inhibition of Trk activity.
[0212] In an additional embodiment the present invention provides a
compound of formula (I), or a pharmaceutically acceptable salt
thereof, for use in the treatment or prophylaxis of cancer.
[0213] In an additional embodiment the present invention provides a
compound of the formula (I), or a pharmaceutically acceptable salt
thereof, for use in the treatment of cancer in a warm-blooded
animal such as man.
[0214] In an additional embodiment the present invention provides a
compound of the formula (I), or a pharmaceutically acceptable salt
thereof, for use in the treatment or prophylaxis of cancers (solid
tumours and leukaemia), fibroproliferative and differentiative
disorders, psoriasis, rheumatoid arthritis, Kaposi's sarcoma,
haemangioma, acute and chronic nephropathies, atheroma,
atherosclerosis, arterial restenosis, autoimmune diseases, acute
and chronic inflammation, bone diseases and ocular diseases with
retinal vessel proliferation in a warm-blooded animal such as
man.
[0215] In an additional embodiment the present invention provides a
compound of formula (I), or a pharmaceutically acceptable salt
thereof, for use in the production of an anti-proliferative
effect.
[0216] In one embodiment where the inhibition of Trk activity is
referred to particularly this refers to the inhibition of Trk A
activity.
[0217] In another embodiment where the inhibition of Trk activity
is referred to particularly this refers to the inhibition of Trk B
activity.
[0218] Where the treatment (or prophylaxis) of cancer is referred
to, particularly it refers to the treatment (or prophylaxis) of
mesoblastic nephroma, mesothelioma, acute myeloblastic leukemia,
acute lymphocytic leukemia, multiple myeloma, oesophageal cancer,
myeloma, hepatocellular, pancreatic, cervical cancer, Ewings
sarcoma, neuroblastoma, Kaposi's sarcoma, ovarian cancer, breast
cancer including secretory breast cancer, colorectal cancer,
prostate cancer including hormone refractory prostate cancer,
bladder cancer, melanoma, lung cancer--non small cell lung cancer
(NSCLC), and small cell lung cancer (SCLC), gastric cancer, head
and neck cancer, renal cancer, lymphoma, thyroid cancer including
papillary thyroid cancer, mesothelioma, leukaemia, tumours of the
central and peripheral nervous system, melanoma, fibrosarcoma
including congenital fibrosarcoma and osteosarcoma. More
particularly it refers to prostate cancer. In addition, more
particularly it refers to SCLC, NSCLC, colorectal cancer, ovarian
cancer and/or breast cancer. In a further aspect it refers to
hormone refractory prostate cancer.
[0219] In a further aspect of the present invention provides a
process for preparing a compound of formula (I) or a
pharmaceutically acceptable salt thereof which process (wherein
variable groups are, unless otherwise specified, as defined in
formula (I)) comprises:
Process a) reaction of a pyrimidine of formula (II):
##STR00003##
wherein L is a displaceable group; with an pyrazole amine of
formula (III):
##STR00004##
or Process b) reacting a pyrimidine of formula (IV):
##STR00005##
wherein L is a displaceable group; with a compound of formula
(V):
##STR00006##
Process c) reacting a compound of formula (VI):
##STR00007##
with a compound of formula (VII):
##STR00008##
wherein X is an oxygen atom and q is 1; or X is a nitrogen atom and
q is 2; and wherein each R.sup.20 independently represents a
C.sub.1-6alkyl group; or Process d) reacting a compound of formula
(VIII):
##STR00009##
with hydrazine; or and thereafter if necessary: i) converting a
compound of the formula (I) into another compound of the formula
(I); ii) removing any protecting groups; iii) forming a
pharmaceutically acceptable salt.
[0220] L is a displaceable group, suitable values for L are for
example, a halo or sulphonyloxy group, for example a chloro, bromo,
methanesulphonyloxy or toluene-4-sulphonyloxy group.
[0221] Specific reaction conditions for the above reactions are as
follows.
Process a) Pyrimidines of formula (II) and pyrazole amine of
formula (III) may be reacted together: a) in the presence of a
suitable solvent for example a ketone such as acetone or an alcohol
such as ethanol or butanol or an aromatic hydrocarbon such as
toluene or N-methyl pyrrolid-2-one, optionally in the presence of a
suitable acid for example an inorganic acid such as hydrochloric
acid or sulphuric acid, or an organic acid such as acetic acid or
formic acid (or a suitable Lewis acid) and at a temperature in the
range from 0.degree. C. to reflux, particularly reflux; or b) under
standard Buchwald conditions (for example see J. Am. Chem. Soc.,
118, 7215; J. Am. Chem. Soc., 119, 8451; J. Org. Chem., 62, 1568
and 6066) for example in the presence of palladium acetate, in a
suitable solvent for example an aromatic solvent such as toluene,
benzene or xylene, with a suitable base for example an inorganic
base such as caesium carbonate or an organic base such as
potassium-t-butoxide, in the presence of a suitable ligand such as
2,2'-bis(diphenylphosphino)-1,1'-binaphthyl and at a temperature in
the range from 25 to 80.degree. C.
[0222] Pyrimidines of the formula (II) may be prepared according to
Scheme 1:
##STR00010##
wherein L is a displaceable group as defined herein above.
[0223] Pyrazole amines of formula (III) and compounds of formula
(IIa) are commercially available compounds, or they are known in
the literature, or they are prepared by standard processes known in
the art.
Process b) Compounds of formula (IV) and formula (V) may be reacted
together under the same conditions as outlined in Process a).
[0224] Compounds of the formula (IV) may be prepared according to
Scheme 2:
##STR00011##
[0225] Compounds of the formula (V) are commercially available
compounds, or they are known in the literature, or they are
prepared by standard processes known in the art.
Process c) may conveniently be carried out in a suitable solvent
such as N-methylpyrrolidinone or butanol at a temperature in the
range from 100-200.degree. C., in particular in the range from
150-170.degree. C. The reaction is preferably conducted in the
presence of a suitable base such as, for example, sodium methoxide
or potassium carbonate.
[0226] Compounds of the formula (VI) may be prepared according to
Scheme 3:
##STR00012##
[0227] Compounds of the formula (VII) may be prepared according to
Scheme 4:
##STR00013##
wherein Pg is a suitable nitrogen protecting group. Suitable values
for Pg are defined below. Compounds of the formula (VIa), (VIb),
(VIIa) and (VIIb) are commercially available compounds, or they are
known in the literature, or they are prepared by standard processes
known in the art. Process d) may be carried out in a suitable
solvent, for example, an alcohol such as ethanol or butanol at a
temperature in the range from 50-120.degree. C., in particular in
the range from 70-100.degree. C.
[0228] Compounds of the formula (VIII) may be prepared according to
Scheme 5:
##STR00014##
[0229] It will be appreciated that certain of the various ring
substituents in the compounds of the present invention may be
introduced by standard aromatic substitution reactions or generated
by conventional functional group modifications either prior to or
immediately following the processes mentioned above, and as such
are included in the process aspect of the invention. Such reactions
and modifications include, for example, introduction of a
substituent by means of an aromatic substitution reaction,
reduction of substituents, alkylation of substituents and oxidation
of substituents. The reagents and reaction conditions for such
procedures are well known in the chemical art. Particular examples
of aromatic substitution reactions include the introduction of a
nitro group using concentrated nitric acid, the introduction of an
acyl group using, for example, an acyl halide and Lewis acid (such
as aluminium trichloride) under Friedel Crafts conditions; the
introduction of an alkyl group using an alkyl halide and Lewis acid
(such as aluminium trichloride) under Friedel Crafts conditions;
and the introduction of a halogeno group. Particular examples of
modifications include the reduction of a nitro group to an amino
group by for example, catalytic hydrogenation with a nickel
catalyst or treatment with iron in the presence of hydrochloric
acid with heating; oxidation of alkylthio to alkylsulphinyl or
alkylsulphonyl.
[0230] It will also be appreciated that in some of the reactions
mentioned herein it may be necessary/desirable to protect any
sensitive groups in the compounds. The instances where protection
is necessary or desirable and suitable methods for protection are
known to those skilled in the art. Conventional protecting groups
may be used in accordance with standard practice (for illustration
see T. W. Green, Protective Groups in Organic Synthesis, John Wiley
and Sons, 1991). Thus, if reactants include groups such as amino,
carboxy or hydroxy it may be desirable to protect the group in some
of the reactions mentioned herein.
[0231] A suitable protecting group for an amino or alkylamino group
is, for example, an acyl group, for example an alkanoyl group such
as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl,
ethoxycarbonyl or t-butoxycarbonyl group, an arylmethoxycarbonyl
group, for example benzyloxycarbonyl, or an aroyl group, for
example benzoyl. The deprotection conditions for the above
protecting groups necessarily vary with the choice of protecting
group. Thus, for example, an acyl group such as an alkanoyl or
alkoxycarbonyl group or an aroyl group may be removed for example,
by hydrolysis with a suitable base such as an alkali metal
hydroxide, for example lithium or sodium hydroxide. Alternatively
an acyl group such as a t-butoxycarbonyl group may be removed, for
example, by treatment with a suitable acid as hydrochloric,
sulphuric or phosphoric acid or trifluoroacetic acid and an
arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be
removed, for example, by hydrogenation over a catalyst such as
palladium-on-carbon, or by treatment with a Lewis acid for example
boron tris(trifluoroacetate). A suitable alternative protecting
group for a primary amino group is, for example, a phthaloyl group
which may be removed by treatment with an alkylamine, for example
dimethylaminopropylamine, or with hydrazine.
[0232] A suitable protecting group for a hydroxy group is, for
example, an acyl group, for example an alkanoyl group such as
acetyl, an aroyl group, for example benzoyl, or an arylmethyl
group, for example benzyl. The deprotection conditions for the
above protecting groups will necessarily vary with the choice of
protecting group. Thus, for example, an acyl group such as an
alkanoyl or an aroyl group may be removed, for example, by
hydrolysis with a suitable base such as an alkali metal hydroxide,
for example lithium or sodium hydroxide. Alternatively an
arylmethyl group such as a benzyl group may be removed, for
example, by hydrogenation over a catalyst such as
palladium-on-carbon.
[0233] A suitable protecting group for a carboxy group is, for
example, an esterifying group, for example a methyl or an ethyl
group which may be removed, for example, by hydrolysis with a base
such as sodium hydroxide, or for example a t-butyl group which may
be removed, for example, by treatment with an acid, for example an
organic acid such as trifluoroacetic acid, or for example a benzyl
group which may be removed, for example, by hydrogenation over a
catalyst such as palladium-on-carbon.
[0234] The protecting groups may be removed at any convenient stage
in the synthesis using conventional techniques well known in the
chemical art.
DEFINITIONS
[0235] In this specification the term "alkyl" includes both
straight and branched chain alkyl groups but references to
individual alkyl groups such as "propyl" are specific for the
straight chain version only. For example, "C.sub.1-6alkyl" and
"C.sub.1-4alkyl" include methyl, ethyl, propyl, isopropyl and
t-butyl. However, references to individual alkyl groups such as
`propyl` are specific for the straight-chained version only and
references to individual branched chain alkyl groups such as
`isopropyl` are specific for the branched-chain version only. A
similar convention applies to other radicals. The term "halo"
refers to fluoro, chloro, bromo and iodo.
[0236] Where optional substituents are chosen from "one or more"
groups it is to be understood that this definition includes all
substituents being chosen from one of the specified groups or the
substituents being chosen from two or more of the specified
groups.
[0237] A "heterocyclyl" is a saturated, partially saturated or
unsaturated, mono or bicyclic ring containing 4-12 atoms of which
at least one atom is chosen from nitrogen, sulphur or oxygen, which
may, unless otherwise specified, be carbon or nitrogen linked,
wherein a --CH.sub.2-- group can optionally be replaced by a
--C(O)--, and a ring sulphur atom may be optionally oxidised to
form the S-oxides. Examples and suitable values of the term
"heterocyclyl" are morpholino, piperidyl, pyridyl, pyranyl,
pyrrolyl, isothiazolyl, indolyl, quinolyl, thienyl,
1,3-benzodioxolyl, thiadiazolyl, piperazinyl, thiazolidinyl,
pyrrolidinyl, thiomorpholino, pyrrolinyl, homopiperazinyl,
3,5-dioxapiperidinyl, tetrahydropyranyl, imidazolyl, pyrimidyl,
pyrazinyl, pyridazinyl, isoxazolyl, N-methylpyrrolyl, 4-pyridone,
1-isoquinolone, 2-pyrrolidone, 4-thiazolidone, pyridine-N-oxide and
quinoline-N-oxide. Further examples and suitable values of the term
"heterocyclyl" are morpholino, piperazinyl and pyrrolidinyl. In one
aspect of the invention a "heterocyclyl" is a saturated, partially
saturated or unsaturated, mono or bicyclic ring containing 5 or 6
atoms of which at least one atom is chosen from nitrogen, sulphur
or oxygen, it may, unless otherwise specified, be carbon or
nitrogen linked, a --CH.sub.2-- group can optionally be replaced by
a --C(O)-- and a ring sulphur atom may be optionally oxidised to
form the S-oxides.
[0238] A "3-5-membered heterocyclyl" is a saturated, partially
saturated or unsaturated, monocyclic ring containing 3, 4 or 5
atoms of which at least one atom is chosen from nitrogen, sulphur
or oxygen, which may, unless otherwise specified, be carbon or
nitrogen linked, wherein a --CH.sub.2-- group can optionally be
replaced by a --C(O)--, and a ring sulphur atom may be optionally
oxidised to form the S-oxides. Examples and suitable values of the
term "3-5-membered heterocyclyl" are pyrrolyl, pyrrolinyl,
imidazolyl, thiazolyl and furanyl.
[0239] A "carbocyclyl" is a saturated, partially saturated or
unsaturated, mono or bicyclic carbon ring that contains 3-12 atoms;
wherein a --CH.sub.2-- group can optionally be replaced by a
--C(O)--. Particularly "carbocyclyl" is a monocyclic ring
containing 5 or 6 atoms or a bicyclic ring containing 9 or 10
atoms. Suitable values for "carbocyclyl" include cyclopropyl,
cyclobutyl, 1-oxocyclopentyl, cyclopentyl, cyclopentenyl,
cyclohexyl, cyclohexenyl, phenyl, naphthyl, tetralinyl, indanyl or
1-oxoindanyl.
[0240] A "3-5-membered carbocyclyl" is a saturated, partially
saturated or unsaturated, monocyclic carbon ring that contains 3, 4
or 5 atoms; wherein a --CH.sub.2-- group can optionally be replaced
by a --C(O)--. Suitable values for "3-5-membered carbocyclyl"
include cyclopropyl, cyclobutyl, 1-oxocyclopentyl, cyclopentyl or
cyclopentenyl.
[0241] The term "C.sub.m-n" or "C.sub.m-n group" used alone or as a
prefix, refers to any group having m to n carbon atoms.
[0242] The term "optionally substituted" refers to either groups,
structures, or molecules that are substituted and those that are
not substituted.
[0243] An example of "C.sub.1-6alkanoyloxy" is acetoxy. Examples of
"C.sub.1-6alkoxycarbonyl" include C.sub.1-4alkoxycarbonyl,
methoxycarbonyl, ethoxycarbonyl, n- and t-butoxycarbonyl. Examples
of "C.sub.1-6alkoxy" include C.sub.1-4alkoxy, C.sub.1-3alkoxy,
methoxy, ethoxy and propoxy. Examples of "C.sub.1-6alkoxyimino"
include C.sub.1-4alkoxyimino, C.sub.1-3alkoxyimino, methoxyimino,
ethoxyimino and propoxyimino. Examples of "C.sub.1-6alkanoylamino"
include formamido, acetamido and propionylamino. Examples of
"C.sub.1-6alkylS(O).sub.a wherein a is 0 to 2" include
C.sub.1-4alkylsulphonyl, methylthio, ethylthio, methylsulphinyl,
ethylsulphinyl, mesyl and ethylsulphonyl. Examples of
"C.sub.1-6alkylthio" include methylthio and ethylthio. Examples of
"C.sub.1-6alkylsulphonylamino" include methylsulphonylamino and
ethylsulphonylamino. Examples of "C.sub.1-6alkanoyl" include
C.sub.1-4alkanoyl, propionyl and acetyl. Examples of
"N--(C.sub.1-6alkyl)amino" include methylamino and ethylamino.
Examples of "N,N--(C.sub.1-6alkyl).sub.2amino" include
di-N-methylamino, di-(N-ethyl)amino and N-ethyl-N-methylamino.
Examples of "C.sub.2-6alkenyl" are vinyl, allyl and 1-propenyl.
Examples of "C.sub.2-6alkynyl" are ethynyl, 1-propynyl and
2-propynyl. Examples of "N--(C.sub.1-6alkyl)sulphamoyl" are
N-(methyl)sulphamoyl and N-(ethyl)sulphamoyl. Examples of
"N--(C.sub.1-6alkyl).sub.2sulphamoyl" are N,N-(dimethyl)sulphamoyl
and N-(methyl)-N-(ethyl)sulphamoyl. Examples of
"N--(C.sub.1-6alkyl)carbamoyl" are N--(C.sub.1-4alkyl)carbamoyl,
methylaminocarbonyl and ethylaminocarbonyl. Examples of
"N,N--(C.sub.1-6alkyl).sub.2carbamoyl" are
N,N--(C.sub.1-4alkyl).sub.2carbamoyl, dimethylaminocarbonyl and
methylethylaminocarbonyl. Examples of
"N--(C.sub.1-6alkyl)-N--(C.sub.1-6alkylsulphonyl)amino" are
N-methyl-N-mesylamino and N-ethyl-N-mesylamino. Examples of
(C.sub.1-6alkyl).sub.2N--S(O).sub.2--NH-include
(CH.sub.3).sub.2N--S(O).sub.2--NH-- and
(CH.sub.3)(C.sub.2H.sub.5)N--S(O).sub.2--NH--. Examples of
(C.sub.1-6alkyl)NH--S(O).sub.2--NH-- include
(CH.sub.3)NH--S(O).sub.2--NH-- and
(C.sub.3H.sub.7)NH--S(O).sub.2--NH--. Examples of
(C.sub.1-6alkyl).sub.2N--S(O).sub.2--N(C.sub.1-6alkyl)- include
(CH.sub.3).sub.2N--S(O).sub.2--N(C.sub.1-6alkyl) and
(CH.sub.3)(C.sub.3H.sub.5)N--S(O).sub.2--N(C.sub.2H.sub.5)--.
Examples of (C.sub.1-6alkyl)NH--S(O).sub.2--N(C.sub.1-6alkyl)-
include (CH.sub.3)NH--S(O).sub.2--N(CH.sub.3)-- and
(CH.sub.3)NH--S(O).sub.2--N(C.sub.2H.sub.5). Examples of
NH.sub.2--S(O).sub.2--N(C.sub.1-6alkyl)- include
NH.sub.2--S(O).sub.2--N(CH.sub.3)-- and
NH.sub.2--S(O).sub.2--N(C.sub.3H.sub.7).
[0244] "RT" or "rt" means room temperature.
[0245] A suitable pharmaceutically acceptable salt of a compound of
the invention is, for example, an acid-addition salt of a compound
of the invention which is sufficiently basic, for example, an
acid-addition salt with, for example, an inorganic or organic acid,
for example hydrochloric, hydrobromic, sulphuric, phosphoric,
trifluoroacetic, citric or maleic acid. In addition a suitable
pharmaceutically acceptable salt of a compound of the invention
which is sufficiently acidic is an alkali metal salt, for example a
sodium or potassium salt, an alkaline earth metal salt, for example
a calcium or magnesium salt, an ammonium salt or a salt with an
organic base which affords a physiologically-acceptable cation, for
example a salt with methylamine, dimethylamine, trimethylamine,
piperidine, morpholine or tris-(2-hydroxyethyl)amine.
[0246] It should be noted that the compounds claimed in this
invention are capable of existing in different resonance structures
and thus the compounds claimed herein include all possible
resonance structures, for example optical isomers, diastereoisomers
and geometric isomers and all tautomeric forms of the compounds of
the formula (I).
[0247] It is also to be understood that certain compounds of the
formula (I) can exist in solvated as well as unsolvated forms such
as, for example, hydrated forms. It is to be understood that the
invention encompasses all such solvated forms.
Formulations
[0248] Compounds of the present invention may be administered
orally, parenteral, buccal, vaginal, rectal, inhalation,
insufflation, sublingually, intramuscularly, subcutaneously,
topically, intranasally, intraperitoneally, intrathoracially,
intravenously, epidurally, intrathecally, intracerebroventricularly
and by injection into the joints.
[0249] The dosage will depend on the route of administration, the
severity of the disease, age and weight of the patient and other
factors normally considered by the attending physician, when
determining the individual regimen and dosage level as the most
appropriate for a particular patient.
[0250] An effective amount of a compound of the present invention
for use in therapy of cancer is an amount sufficient to
symptomatically relieve in a warm-blooded animal, particularly a
human the symptoms of cancer, to slow the progression of cancer, or
to reduce in patients with symptoms of cancer the risk of getting
worse.
[0251] For preparing pharmaceutical compositions from the compounds
of this invention, inert, pharmaceutically acceptable carriers can
be either solid or liquid. Solid form preparations include powders,
tablets, dispersible granules, capsules, cachets, and
suppositories.
[0252] A solid carrier can be one or more substance, which may also
act as diluents, flavoring agents, solubilizers, lubricants,
suspending agents, binders, or tablet disintegrating agents; it can
also be an encapsulating material.
[0253] In powders, the carrier is a finely divided solid, which is
in a mixture with the finely divided active component. In tablets,
the active component is mixed with the carrier having the necessary
binding properties in suitable proportions and compacted in the
shape and size desired.
[0254] For preparing suppository compositions, a low-melting wax
such as a mixture of fatty acid glycerides and cocoa butter is
first melted and the active ingredient is dispersed therein by, for
example, stirring. The molten homogeneous mixture is then poured
into convenient sized molds and allowed to cool and solidify.
[0255] Suitable carriers include magnesium carbonate, magnesium
stearate, talc, lactose, sugar, pectin, dextrin, starch,
tragacanth, methyl cellulose, sodium carboxymethyl cellulose, a
low-melting wax, cocoa butter, and the like.
[0256] Some of the compounds of the present invention are capable
of forming salts with various inorganic and organic acids and bases
and such salts are also within the scope of this invention.
Examples of such acid addition salts include acetate, adipate,
ascorbate, benzoate, benzenesulfonate, bicarbonate, bisulfate,
butyrate, camphorate, camphorsulfonate, choline, citrate,
cyclohexyl sulfamate, diethylenediamine, ethanesulfonate, fumarate,
glutamate, glycolate, hemisulfate, 2-hydroxyethylsulfonate,
heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide,
hydroxymaleate, lactate, malate, maleate, methanesulfonate,
meglumine, 2-naphthalenesulfonate, nitrate, oxalate, pamoate,
persulfate, phenylacetate, phosphate, diphosphate, picrate,
pivalate, propionate, quinate, salicylate, stearate, succinate,
sulfamate, sulfanilate, sulfate, tartrate, tosylate
(p-toluenesulfonate), trifluoroacetate, and undecanoate. Base salts
include ammonium salts, alkali metal salts such as sodium, lithium
and potassium salts, alkaline earth metal salts such as aluminum,
calcium and magnesium salts, salts with organic bases such as
dicyclohexylamine salts, N-methyl-D-glucamine, and salts with amino
acids such as arginine, lysine, ornithine, and so forth. Also,
basic nitrogen-containing groups may be quaternized with such
agents as: lower alkyl halides, such as methyl, ethyl, propyl, and
butyl halides; dialkyl sulfates like dimethyl, diethyl, dibutyl;
diamyl sulfates; long chain halides such as decyl, lauryl, myristyl
and stearyl halides; aralkyl halides like benzyl bromide and
others. Non-toxic physiologically-acceptable salts are preferred,
although other salts are also useful, such as in isolating or
purifying the product.
[0257] The salts may be formed by conventional means, such as by
reacting the free base form of the product with one or more
equivalents of the appropriate acid in a solvent or medium in which
the salt is insoluble, or in a solvent such as water, which is
removed in vacuo or by freeze drying or by exchanging the anions of
an existing salt for another anion on a suitable ion-exchange
resin.
[0258] In order to use a compound of the formula (I) or a
pharmaceutically acceptable salt thereof for the therapeutic
treatment (including prophylactic treatment) of mammals including
humans, it is normally formulated in accordance with standard
pharmaceutical practice as a pharmaceutical composition.
[0259] In addition to the compounds of the present invention, the
pharmaceutical composition of this invention may also contain, or
be co-administered (simultaneously or sequentially) with, one or
more pharmacological agents of value in treating one or more
disease conditions referred to herein.
[0260] The term composition is intended to include the formulation
of the active component or a pharmaceutically acceptable salt with
a pharmaceutically acceptable carrier. For example this invention
may be formulated by means known in the art into the form of, for
example, tablets, capsules, aqueous or oily solutions, suspensions,
emulsions, creams, ointments, gels, nasal sprays, suppositories,
finely divided powders or aerosols or nebulisers for inhalation,
and for parenteral use (including intravenous, intramuscular or
infusion) sterile aqueous or oily solutions or suspensions or
sterile emulsions.
[0261] Liquid form compositions include solutions, suspensions, and
emulsions. Sterile water or water-propylene glycol solutions of the
active compounds may be mentioned as an example of liquid
preparations suitable for parenteral administration. Liquid
compositions can also be formulated in solution in aqueous
polyethylene glycol solution. Aqueous solutions for oral
administration can be prepared by dissolving the active component
in water and adding suitable colorants, flavoring agents,
stabilizers, and thickening agents as desired. Aqueous suspensions
for oral use can be made by dispersing the finely divided active
component in water together with a viscous material such as natural
synthetic gums, resins, methyl cellulose, sodium carboxymethyl
cellulose, and other suspending agents known to the pharmaceutical
formulation art.
[0262] The pharmaceutical compositions can be in unit dosage form.
In such form, the composition is divided into unit doses containing
appropriate quantities of the active component. The unit dosage
form can be a packaged preparation, the package containing discrete
quantities of the preparations, for example, packeted tablets,
capsules, and powders in vials or ampoules. The unit dosage form
can also be a capsule, cachet, or tablet itself, or it can be the
appropriate number of any of these packaged forms.
Combinations
[0263] The anti-cancer treatment defined herein may be applied as a
sole therapy or may involve, in addition to the compound of the
invention, conventional surgery or radiotherapy or chemotherapy.
Such chemotherapy may include one or more of the following
categories of anti-tumour agents:
(i) antiproliferative/antineoplastic drugs and combinations
thereof, as used in medical oncology, such as alkylating agents
(for example cis-platin, carboplatin, cyclophosphamide, nitrogen
mustard, melphalan, chlorambucil, busulphan and nitrosoureas);
antimetabolites (for example antifolates such as fluoropyrimidines
like 5-fluorouracil and tegafur, raltitrexed, methotrexate,
cytosine arabinoside and hydroxyurea); antitumour antibiotics (for
example anthracyclines like adriamycin, bleomycin, doxorubicin,
daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin and
mithramycin); antimitotic agents (for example vinca alkaloids like
vincristine, vinblastine, vindesine and vinorelbine and taxoids
like taxol and taxotere); and topoisomerase inhibitors (for example
epipodophyllotoxins like etoposide and teniposide, amsacrine,
topotecan and camptothecin); and proteosome inhibitors (for example
bortezomib [Velcade]); and the agent anegrilide [Agrylin]; and the
agent alpha-interferon; (ii) cytostatic agents such as
antioestrogens (for example tamoxifen, toremifene, raloxifene,
droloxifene and iodoxyfene), oestrogen receptor down regulators
(for example fulvestrant), antiandrogens (for example bicalutamide,
flutamide, nilutamide and cyproterone acetate), LHRH antagonists or
LHRH agonists (for example goserelin, leuprorelin and buserelin),
progestogens (for example megestrol acetate), aromatase inhibitors
(for example as anastrozole, letrozole, vorazole and exemestane)
and inhibitors of 5.alpha.-reductase such as finasteride; (iii)
agents which inhibit cancer cell invasion (for example
metalloproteinase inhibitors like marimastat and inhibitors of
urokinase plasminogen activator receptor function); (iv) inhibitors
of growth factor function, for example such inhibitors include
growth factor antibodies, growth factor receptor antibodies (for
example the anti-erbb2 antibody trastuzumab [Herceptin] and the
anti-erbb1 antibody cetuximab [C225]), farnesyl transferase
inhibitors, tyrosine kinase inhibitors and serine/threonine kinase
inhibitors, for example inhibitors of the epidermal growth factor
family (for example EGFR family tyrosine kinase inhibitors such
asN-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-
-4-amine (gefitinib, AZD1839),
N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine
(erlotinib, OSI-774) and
6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)quinazoli-
n-4-amine (CI-1033)), for example inhibitors of the
platelet-derived growth factor family and for example inhibitors of
the hepatocyte growth factor family, for example inhibitors or
phosphotidylinositol 3-kinase (PI3K) and for example inhibitors of
mitogen activated protein kinase kinase (MEK1/2) and for example
inhibitors of protein kinase B (PKB/Akt), for example inhibitors of
Src tyrosine kinase family and/or Abelson (Abl) tyrosine kinase
family such as AZD0530 and dasatinib (BMS-354825) and imatinib
mesylate (Gleevec); and any agents that modify STAT signalling; (v)
antiangiogenic agents such as those which inhibit the effects of
vascular endothelial growth factor, (for example the anti-vascular
endothelial cell growth factor antibody bevacizumab [Avastin],
compounds such as those disclosed in International Patent
Applications WO 97/22596, WO 97/30035, WO 97/32856 and WO 98/13354)
and compounds that work by other mechanisms (for example linomide,
inhibitors of integrin .alpha.v.beta.3 function and angiostatin);
(vi) vascular damaging agents such as Combretastatin A4 and
compounds disclosed in International Patent Applications WO
99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 and WO
02/08213; (vii) antisense therapies, for example those which are
directed to the targets listed above, such as ISIS 2503, an
anti-ras antisense; (viii) gene therapy approaches, including for
example approaches to replace aberrant genes such as aberrant p53
or aberrant BRCA1 or BRCA2, GDEPT (gene-directed enzyme pro-drug
therapy) approaches such as those using cytosine deaminase,
thymidine kinase or a bacterial nitroreductase enzyme and
approaches to increase patient tolerance to chemotherapy or
radiotherapy such as multi-drug resistance gene therapy; (ix)
immunotherapy approaches, including for example ex-vivo and in-vivo
approaches to increase the immunogenicity of patient tumour cells,
such as transfection with cytokines such as interleukin 2,
interleukin 4 or granulocyte-macrophage colony stimulating factor,
approaches to decrease T-cell anergy, approaches using transfected
immune cells such as cytokine-transfected dendritic cells,
approaches using cytokine-transfected tumour cell lines and
approaches using anti-idiotypic antibodies and approaches using the
immunomodulatory drugs thalidomide and lenalidomide [Revlimid]; and
(x) other treatment regimes including: dexamethasone, proteasome
inhibitors (including bortezomib), isotretinoin (13-cis retinoic
acid), thalidomide, revemid, Rituxamab, ALIMTA, Cephalon's kinase
inhibitors CEP-701 and CEP-2563, anti-Trk or anti-NGF monoclonal
antibodies, targeted radiation therapy with
131I-metaiodobenzylguanidine (131I-MIBG), anti-G(D2) monoclonal
antibody therapy with or without granulocyte-macrophage
colony-stimulating factor (GM-CSF) following chemotherapy.
[0264] Such conjoint treatment may be achieved by way of the
simultaneous, sequential or separate dosing of the individual
components of the treatment. Such combination products employ the
compounds of this invention, or pharmaceutically acceptable salts
thereof, within the dosage range described hereinbefore and the
other pharmaceutically-active agent within its approved dosage
range.
Synthesis
[0265] The compounds, or pharmaceutically acceptable salts thereof,
of the present invention can be prepared in a number of ways well
known to one skilled in the art of organic synthesis. The
compounds, or pharmaceutically acceptable salts thereof, of the
present invention can be synthesized using the methods described
below, together with synthetic methods known in the art of
synthetic organic chemistry, or variations thereon as appreciated
by those skilled in the art. Such methods include, but are not
limited to, those described below. All references cited herein are
hereby incorporated in their entirety by reference.
[0266] The novel compounds, or pharmaceutically acceptable salts
thereof, of this invention may be prepared using the reactions and
techniques described herein. The reactions are performed in
solvents appropriate to the reagents and materials employed and are
suitable for the transformations being effected. Also, in the
description of the synthetic methods described below, it is to be
understood that all proposed reaction conditions, including choice
of solvent, reaction atmosphere, reaction temperature, duration of
the experiment and workup procedures, are chosen to be the
conditions standard for that reaction, which should be readily
recognized by one skilled in the art. It is understood by one
skilled in the art of organic synthesis that the functionality
present on various portions of the molecule must be compatible with
the reagents and reactions proposed. Such restrictions to the
substituents, which are compatible with the reaction conditions,
will be readily apparent to one skilled in the art and alternate
methods must then be used.
EXAMPLES
[0267] The invention will now be further described with reference
to the following illustrative examples in which, unless stated
otherwise: [0268] (i) temperatures are given in degrees Celsius
(.degree. C.); operations are carried out at room temperature or
ambient temperature, that is, in a range of 18-25.degree. C.;
[0269] (ii) organic solutions were dried over anhydrous magnesium
sulfate; evaporation of organic solvent was carried out using a
rotary evaporator under reduced pressure (4.5-30 mmHg) with a bath
temperature of up to 60.degree. C.; [0270] (iii) chromatography
means flash chromatography on silica gel; thin layer chromatography
(TLC) was carried out on silica gel plates; [0271] (iv) in general,
the course of reactions was followed by TLC or liquid
chromatography/mass spectroscopy (LC/MS) and reaction times are
given for illustration only; [0272] (v) final products have
satisfactory proton nuclear magnetic resonance (NMR) spectra and/or
mass spectra data; [0273] (vi) yields are given for illustration
only and are not necessarily those which can be obtained by
diligent process development; preparations were repeated if more
material was required; [0274] (vii) when given, NMR data is in the
form of delta values for major diagnostic protons, given in part
per million (ppm) relative to tetramethylsilane (TMS) as an
internal standard, determined at 300 MHz in DMSO-d.sub.6 unless
otherwise stated; [0275] (viii) chemical symbols have their usual
meanings; [0276] (ix) solvent ratio was given in volume:volume
(v/v) terms. [0277] (x) the following abbreviations have been used:
[0278] DMF N,N-dimethylformamide; [0279] THF tetrahydrofuran;
[0280] DCM dichloromethane; [0281] DMAP 4-dimethylaminopyridine;
[0282] DMSO dimethylsulphoxide; [0283] DIPEA
N,N-diisopropylethylamine; and [0284] EtOAc ethyl acetate; [0285]
(xi) an ISCO Combiflash refers to flash chromatography on silica
gel using Isco Combiflash.RTM. separation system: RediSep normal
phase flash column, flow rate, 30-40 ml/min.
Example 1
5-Chloro-N.sup.4-(5-isopropoxy-1H-pyrazol-3-yl)-N.sup.2-[1-(5-fluoropyrimi-
din-2-yl)ethyl]pyrimidine-2,4-diamine
[0286] A microwave reaction vessel was charged with
1-(5-fluoropyrimidin-2-yl)ethanamine (Method 1, 0.25 g, 1.77 mmol),
2,5-dichloro-N-(5-isopropoxy-1H-pyrazol-3-yl)pyrimidin-4-amine
(Method 2, 0.50 g, 1.77 mmol), and DIPEA (0.30 g, 2.34 mmol).
Anhydrous n-BuOH (2 ml) was added, and the tube was sealed and
heated in a microwave reactor at 160.degree. C. for 10 hours. The
reaction mixture was purified by silica gel chromatography twice
(by ISCO Combiflash with gradient EtOAc and DCM) to afford the
title compound as a white solid (0.19 g, 27%). LC-MS, 393 (M+1).
.sup.1H NMR (CDCl.sub.3) .delta. 8.50 (s, 2H), 7.75 (s, 1H), 5.50
(s, 1H), 5.20 (m, 1H), 4.68 (m, 1H), 1.55 (d, 3H), 1.20 (d,
6H).
Example 2
5-Chloro-N.sup.2-[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]-N.sup.4-(5-isoprop-
oxy-1H-pyrazol-3-yl)pyrimidine-2,4-diamine
Example 3
5-Chloro-N.sup.2-[(1R)-1-(5-fluoropyrimidin-2-yl)ethyl]-N.sup.4-(5-isoprop-
oxy-1H-pyrazol-3-yl)pyrimidine-2,4-diamine
[0287] The title compounds were separated from Example 1 using the
chiral HPLC system. Column and solvent conditions:
Column: Chiralpak AD, 250.times.20 mm, 10 g;
[0288] Conditions: 80% hexane, 20% isopropanol, 0.1% diethylamine;
Flow rate: 20 ml/min.
[0289] Post purification purity check. The sample purity was
checked using the following conditions:
Chiral HPLC using Diode Array
Column: Chiralpak AD, 250.times.20 mm, 10 g;
[0290] Conditions: 80% hexane, 20% isopropanol, 0.1% diethylamine;
Flow rate: 1 ml/min. The first peak (retention time: 9.21 min, with
(-) optical rotation reading) is the S-isomer The second peak
(retention time: 13.54 min, with (+) optical rotation reading) is
the R-isomer
[0291] Enantiomeric excess for each individual enantiomer (e.e.):
>99% calculated using area percent at 254 nm.
Example 2
[0292] LC-MS, 393 (M+1). .sup.1H NMR (CDCl.sub.3) .delta. 8.50 (s,
2H), 7.75 (s, 1H), 5.50 (s, 1H), 5.20 (m, 1H), 4.68 (m, 1H), 1.55
(d, 3H), 1.20 (d, 6H).
Example 3
[0293] LC-MS, 393 (M+1). .sup.1H NMR (CDCl.sub.3) .delta. 8.50 (s,
2H), 7.75 (s, 1H), 5.50 (s, 1H), 5.20 (m, 1H), 4.68 (m, 1H), 1.55
(d, 3H), 1.20 (d, 6H).
Example 4
5-Fluoro-N.sup.2-[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]-N.sup.4-(5-methyl--
1H-pyrazol-3-yl)pyrimidine-2,4-diamine
[0294] A mixture of (S)-1-(5-fluoropyrimidin-2-yl)ethanamine
hydrochloride (Method 7, 95 mg),
2-chloro-5-fluoro-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine
(Method 8, 114 mg) and DIPEA (0.13 ml) in n-BuOH (2.5 ml) was
charged into a microwave reaction vessel. The vessel was sealed and
heated in microwave reactor at 180.degree. C. for 6 hours. The
solvent was removed under reduced pressure and the residue was
purified by Gilson (10-50% MeCN/H.sub.2O, 15 min) to give the
titled compound as solid (40.7 mg). NMR 11.26 (s, 1H), 8.67-9.18
(m, 3H), 8.22 (s, 1H), 6.04 (s, 1H), 4.86-5.40 (m, 1H), 2.25 (s,
3H), 1.57 (d, 3H); m/z 333.
Example 5
5-Chloro-N.sup.2-[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]-N.sup.4-(5-methyl--
1H-pyrazol-3-yl)pyrimidine-2,4-diamine
[0295] A mixture of (S)-1-(5-fluoropyrimidin-2-yl)ethanamine
hydrochloride (Method 7, 80 mg),
2,5-dichloro-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (Method
9, 122 mg) and DIPEA (0.134 ml) in n-BuOH (2.5 ml) was charged into
a microwave reaction vessel. The vessel was sealed and heated in
microwave reactor at 180.degree. C. for 6 hours. The solvent was
removed under reduced pressure and the residue was purified by
Gilson (10-50% MeCN/H.sub.2O, 15 min) to give the titled compound
as solid (90 mg). NMR 10.34 (s, 1H), 8.91 (s, 3H), 8.30 (s, 1H),
5.94 (s, 1H), 4.96-5.34 (m, 1H), 2.25 (s, 3H), 1.56 (d, 3H); m/z
350.
Example 6
5-Bromo-N.sup.2-[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]-N.sup.4-(5-isopropo-
xy-1H-pyrazol-3-yl)pyrimidine-2,4-diamine
[0296] A mixture of
5-bromo-2-chloro-N-(5-isopropoxy-1H-pyrazol-3-yl)pyrimidin-4-amine
(Method 13, 150 mg, 0.45 mmol),
(S)-1-(5-fluoropyrimidin-2-yl)ethanamine hydrochloride (Method 7,
88 mg, 0.5 mmol) and DIPEA (0.12 ml) in n-BuOH (2 ml) was charged
into a microwave reaction vessel. The vessel was sealed and heated
in microwave reactor at 165.degree. C. for 4 hours. The solvent was
removed under reduced pressure and the residue was purified by
flash chromatography on silica gel (20-60% EtOAc in hexanes) to
give the titled compound as solid (118 mg, 60%). NMR: 11.98 (s,
1H), 9.36 (s, 1H), 8.82 (s, 2H), 8.10 (s, 1H), 7.96 (s, 1H), 5.56
(s, 1H), 5.13 (s, 1H), 4.66 (m, 1H), 1.48 (m, 3H), 1.26 (m, 6H);
m/z 437.
Example 7
5-Chloro-N.sup.2-[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]-N.sup.4-(5-methoxy-
-1H-pyrazol-3-yl)pyrimidine-2,4-diamine
[0297] 2,5-Dichloro-N-(5-methoxy-1H-pyrazol-3-yl)pyrimidin-4-amine
(Method 14, 0.25 mmol, 64 mg) and
(S)-1-(5-fluoropyrimidin-2-yl)ethanamine hydrochloride (Method 7,
0.25 mmol, 44.4 mg) were dissolved in n-BuOH (0.8 ml) and DIPEA
(0.13 mL) was added. The reaction was then stirred at 110.degree.
C. overnight. The solvent was evaporated and the remaining material
was separated between EtOAc and water, the combined organic extract
washed with brine, and dried. Evaporation of the solvent gave a
brown oil (59 mg). Purification by Gilson (10-50% MeCN/H.sub.2O, 15
minutes) afforded the title compound as a white solid (14.3 mg).
NMR: 9.64 (s, 1H), 8.78 (d, 2H), 8.18 (s, 1H), 7.86 (s, 1H), 5.52
(s, 1H), 4.99-5.15 (m, 1H), 3.65 (s, 3H), 1.43 (d, 3H); m/z
366.
Example 8
5-Chloro-N.sup.4-(5-cyclopropyl-1H-pyrazol-3-yl)-N.sup.2-[(1S)-1-(5-fluoro-
pyrimidin-2-yl)ethyl]pyrimidine-2,4-diamine
[0298] A mixture of (S)-1-(5-fluoropyrimidin-2-yl)ethanamine
hydrochloride (Method 7, 93 mg),
2,5-dichloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine
(Method 15, 135 mg) and DIPEA (0.26 ml) in n-BuOH (2.5 ml) was
charged into a microwave reaction vessel. The vessel was sealed and
heated in microwave reactor at 180.degree. C. for 6 hours. The
solvent was removed under reduced pressure and the residue was
purified by Gilson (10-50% MeCN/H.sub.2O, 15 minutes) to give the
titled compound as solid (435 mg). NMR: 10.64 (s, 1H), 8.91 (s,
3H), 8.30 (s, 1H), 5.97 (s, 1H), 5.17 (s, 1H), 1.83-1.97 (m, 1H),
1.56 (d, 3H), 0.93-1.09 (m, 2H), 0.63-0.77 (m, 2H). m/z 413.
Example 9
N.sup.4-(5-Cyclopropyl-1H-pyrazol-3-yl)-5-fluoro-N.sup.2-[(1S)-1-(5-fluoro-
pyrimidin-2-yl)ethyl]pyrimidine-2,4-diamine
[0299] A mixture of (S)-1-(5-fluoropyrimidin-2-yl)ethanamine
hydrochloride (Method 7, 93 mg),
2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)-5-fluoropyrimidin-4-amine
(Method 16, 127 mg) and DIPEA (0.22 ml) in n-BuOH (2.5 ml) was
charged into a microwave reaction vessel. The vessel was sealed and
heated in microwave reactor at 180.degree. C. for 6 hours. The
solvent was removed under reduced pressure and the residue was
purified by Gilson (10-50% MeCN/H.sub.2O, 15 minutes) to give the
titled compound as solid (435 mg). NMR 11.28 (s, 1H), 8.92 (s, 3H),
8.24 (s, 1H), 6.04 (s, 1H), 4.92-5.54 (m, 1H), 1.82-1.98 (m, 1H),
1.56 (d, 3H), 0.94-1.06 (m, 2H), 0.64-0.80 (m, 2H). m/z 395.
Example 10
N-[5-Chloro-2-[(1S)-1-(5-fluoro-pyrimidin-2-yl)-ethylamino]-6-(5-isopropox-
y-1H-pyrazol-3-ylamino)-pyrimidin-4-yl]-1-N-methyl-methanesulfonamide
[0300] To a solution of
N-[2,5-dichloro-6-(5-isopropoxy-1H-pyrazol-3-ylamino)-pyrimidin-4-yl]-N-m-
ethyl-methanesulfonamide (Method 18, 191 mg, 0.5 mmol) in n-BuOH (2
ml) was added S-1-(5-fluoro-pyrimidin-2-yl)-ethylamine
hydrochloride (Method 7, 172 mg, 1.2 mmol) and
ethyl-diisopropyl-amine (157 mg). The mixture was heated at
180.degree. C. in microwave for 2 hours. LC/MS showed the
completion of the reaction. The solvent was evaporated and the
residue was dissolved in DCM, which was then washed by aqueous
NaHCO.sub.3, dried and concentrated. Flash chromatography was
performed with EtOAc/Hex (75%) as eluent. A colourless solid (134
mg) was obtained, yield 56%. NMR (CDCl.sub.3) 8.64 (s, 2H), 7.61
(s, 1H), 5.74 (s, 0.6H), 5.42 (s, 0.9H), 5.25 (s, 1H), 4.83 (s,
1H), 3.20 (s, 3H), 3.18 (s, 3H), 1.63 (d, J=6.2 Hz, 3H), 1.40 (m,
6H). MS (ES.sup.-) m/z 498.19, 500.14 [M.sup.-].
Example 11
N-[5-Fluoro-2-[(1S)-1-(5-fluoro-pyrimidin-2-yl)-ethylamino]-6-(5-isopropox-
y-1H-pyrazol-3-ylamino)-pyrimidin-4-yl]-N-methyl-methanesulfonamide
[0301] To a solution of
N-[2-chloro-5-fluoro-6-(5-isopropoxy-1H-pyrazol-3-ylamino)-pyrimidin-4-yl-
]-N-methyl-methanesulfonamide (Method 20, 210 mg, 0.5 mmol) in
n-BuOH (2 ml) was added S-1-(5-fluoro-pyrimidin-2-yl)-ethylamine
hydrochloride (Method 7, 197 mg, 1.1 mmol) and
ethyl-diisopropyl-amine (142 mg). The mixture was heated at
180.degree. C. in microwave for 2 hours. LC/MS showed the
completion of the reaction. The solvent was evaporated and the
residue was dissolved in DCM, which was then washed by aqueous
NaHCO.sub.3, dried and concentrated. Flash chromatography was
performed with EtOAc/Hex (75%) as eluent. A colourless solid (147
mg) was obtained, yield 55%. NMR (CDCl.sub.3) 8.62 (m, 2H), 7.57
(s, 0.8H), 5.38 (s, 0.8H), 5.18 (m, 1H), 4.81 (s, 0.9H), 3.23 (s,
3H), 3.20 (s, 3H), 1.61 (d, J=6.8 Hz, 3H), 1.39 (m, 6H). MS (ES+)
m/z 484.32 [MH+]. MS (ES.sup.-) m/z 482.18 [M.sup.-].
Example 12
6-Chloro-N.sup.2-[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]-N.sup.4-(5-methyl--
1H-pyrazol-3-yl)pyrimidine-2,4-diamine
[0302] Following a similar procedure to that of Example 9, the
title compound was synthesized from
2,6-dichloro-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (Method
17) and (S)-1-(5-fluoropyrimidin-2-yl)ethanamine hydrochloride
(Method 7). m/z 348.
Example 13
N.sup.2-[(1S)-1-(5-Fluoropyrimidin-2-yl)ethyl]-N.sup.4-(5-methyl-1H-pyrazo-
l-3-yl)-6-morpholin-4-ylpyrimidine-2,4-diamine
[0303] A mixture of
6-chloro-N.sup.2-[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]-N.sup.4-(5-methyl-
-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (Example 12, 175 mg),
morpholine (0.09 ml) and DIPEA (0.13 ml) in n-BuOH (2.5 ml) was
heated to 110.degree. C. for 48 hours. The solvent was removed
under reduced pressure and the residue was purified by Gilson
(5-35% MeCN/H.sub.2O, 15 minutes) to give the titled compound as
solid (99 mg) .sup.1H NMR: 11.19 (s, 1H) 9.28 (s, 1H) 8.74-9.03 (m,
3H) 5.81-5.83 (m, 1H) 5.73 (s, 1H) 4.98-5.24 (m, 2H) 3.58-4.12 (m,
6H) 2.39 (s, 3H) 1.54 (d, 3H); m/z 436.
Example 14
N.sup.2-[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]-5-methyl-N.sup.4-(5-methyl--
1H-pyrazol-3-yl)pyrimidine-2,4-diamine
[0304] A microwave reaction vessel was charged with
(S)-1-(5-fluoropyrimidin-2-yl)ethanamine (Method 7, 111 mg, 0.63
mmol),
2-chloro-5-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine
(Method 22, 0.50 g, 1.77 mmol), and DIPEA (0.225 mL, 1.26 mmol).
Anhydrous n-BuOH (2.1 ml) was added, and the tube was sealed and
heated in a microwave reactor at 180.degree. C. for 4 hours. The
solvent was removed under reduced pressure and the residue was
purified by Gilson (5-95% MeCN/H.sub.2O, 15 minutes) to give the
titled compound as solid (75 mg) .sup.1H NMR (300 MHz, DMSO-d6)
.delta. 10.08 (s, 1H) 8.93 (s, 2H) 8.70 (s, 1H) 7.74 (s, 1H) 5.98
(s, 1H) 4.79-5.44 (m, 1H) 2.23 (s, 3H) 2.10 (s, 3H) 1.57 (d, 3H);
m/z 330.
Example 15
N.sup.2-[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]-N.sup.4-(5-methyl-1H-pyrazo-
l-3-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine
[0305] A microwave reaction vessel was charged with
(S)-1-(5-fluoropyrimidin-2-yl)ethanamine (Method 7, 111 mg, 0.63
mmol),
2-chloro-N-(5-methyl-1H-pyrazol-3-yl)-5-(trifluoromethyl)pyrimidin-4-amin-
e (Method 23, 0.50 g, 1.77 mmol), and DIPEA (0.225 mL, 1.26 mmol).
Anhydrous n-BuOH (2.1 ml) was added, and the tube was sealed and
heated in a microwave reactor at 180.degree. C. for 4 hours.) The
solvent was removed under reduced pressure and the residue was
purified by Gilson (5-95% MeCN/H.sub.2O, 15 minutes) to give the
titled compound as solid (50 mg) .sup.1H NMR (300 MHz, DMSO-d6)
.delta. 8.79 (s, 2H) 8.16 (s, 1H) 8.08 (s, 1H) 5.77 (s, 1H) 5.13
(m, 1H) 2.12 (s, 3H) 1.43 (d, 3H); m/z 383.
Example 16
5-chloro-N.sup.2-[(1R)-1-(5-fluoropyrimidin-2-yl)ethyl]-N.sup.4-(5-methyl--
1H-pyrazol-3-yl)pyrimidine-2,4-diamine
[0306] A mixture of rac-1-(5-fluoropyrimidin-2-yl)ethanamine
hydrochloride (Method 1, 100 mg),
2,5-dichloro-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (Method
9, 200 mg) and DIPEA (0.150 ml) in n-BuOH (2.5 ml) was charged into
a microwave reaction vessel. The vessel was sealed and heated in
microwave reactor at 180.degree. C. for 6 hours. The solvent was
removed under reduced pressure and the residue was purified by
Gilson (10-50% MeCN/H.sub.2O, 15 min) to give
5-chloro-N.sup.2-[1-(5-fluoropyrimidin-2-yl)ethyl]-N.sup.4-(5-methyl-1H-p-
yrazol-3-yl)pyrimidine-2,4-diamine as solid (55 mg). The tile
compound was obtained after chiral purification using SFC
conditions (Chiralpak AD-H, 20% i-PrOH/80% CO.sub.2/0.1%
Dimethylethylamine). .sup.1H NMR (300 MHz, DMSO-d6) .delta. 12.03
(s, 1H) 8.83 (s, 2H) 7.88 (s, 1H) 7.44 (s, 1H) 5.93 (s, 1H)
4.92-5.29 (m, 1H) 2.20 (s, 3H) 1.49 (d, 3H); m/z 350.
Example 17
N-{5-chloro-2-{[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]amino}-6-[(5-methyl-1-
H-pyrazol-3-yl)amino]pyrimidin-4-yl}-N,N',N'-trimethylsulfamide
[0307] A microwave reaction vessel was charged with
N-{2,5-dichloro-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-4-yl}-N,N',N-
'-trimethylsulfamide (Method 24, 83.9 mg, 0.221 mmol),
(S)-1-(5-fluoropyrimidin-2-yl)ethanamine hydrochloride (Method 7,
78.4 mg, 0.443 mmol), and DIPEA (0.120 ml, 0.682 mmol). Anhydrous
n-BuOH (1 ml) was added, and the tube was sealed and heated in a
microwave reactor at 160.degree. C. for 2 hours. The reaction
mixture was purified by silica gel chromatography (by ISCO
Combiflash with gradient EtOAc and hexane) to afford the title
compound as a white solid (95.8 mg, 89.6%). LC-MS, 485 (M+1).
.sup.1H NMR (DMSO-d6, 400 MHz, 80.degree. C.) .delta. 11.48-12.40
(br, 1H), 8.77 (s, 1H), 7.85-8.66 (br, 1H), 6.98-7.61 (br, 1H),
6.23 (s, 1H), 5.14-5.11 (m, 1H), 2.93 (s, 3H), 2.83 (s, 6H), 2.21
(s, 3H), 1.53 (d, 3H).
Example 18
N-{5-chloro-2-{[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]amino}-6-[(5-methoxy--
1H-pyrazol-3-yl)amino]pyrimidin-4-yl}-N,N',N'-trimethylsulfamide
[0308] A microwave reaction vessel was charged with
N-{2,5-dichloro-6-[(5-methoxy-1H-pyrazol-3-yl)amino]pyrimidin-4-yl}-N,N',-
N'-trimethylsulfamide
(Method 29, 44.1 mg, 0.112 mmol),
(S)-1-(5-fluoropyrimidin-2-yl)ethanamine hydrochloride (Method 7,
39.5 mg, 0.223 mmol), and DIPEA (0.062 ml, 0.352 mmol). Anhydrous
n-BuOH (1 ml) was added, and the tube was sealed and heated in a
microwave reactor at 160.degree. C. for 2 hours. The reaction
mixture was purified by silica gel chromatography (by ISCO
Combiflash with gradient EtOAc and hexane) to afford the title
compound as a white solid (48.6 mg, 87%). LC-MS, 501 (M+1). .sup.1H
NMR (DMSO-d6, 400 MHz) .delta. 12.01 (s, 1H), 9.76 (s, 1H), 8.83
(s, 2H), 8.21 (s, 1H), 5.60 (s, 1H), 5.04-5.06 (m, 1H), 3.76 (s,
3H), 2.80 (s, 3H), 2.70 (s, 6H), 1.59 (d, 3H).
Example 19
N-{5-chloro-2-{[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]amino}-6-[(5-methoxy--
1H-pyrazol-3-yl)amino]pyrimidin-4-yl}-N-methylmethanesulfonamide
[0309] A microwave reaction vessel was charged with
N-{2,5-dichloro-6-[(5-methoxy-1H-pyrazol-3-yl)amino]pyrimidin-4-yl}-N-met-
hylmethanesulfonamide (Method 25, 63.8 mg, 0.174 mmol),
(S)-1-(5-fluoropyrimidin-2-yl)ethanamine hydrochloride (Method 7,
61.7 mg, 0.348 mmol), and DIPEA (0.122 ml, 0.693 mmol) Anhydrous
n-BuOH (1 ml) was added, and the tube was sealed and heated in a
microwave reactor at 160.degree. C. for 2 hours. The reaction
mixture was purified by silica gel chromatography (by ISCO
Combiflash with gradient EtOAc and hexane) to afford the title
compound as a white solid (63.1 mg, 77%). LC-MS: 472 (M+1). .sup.1H
NMR (DMSO-d6 , 400 MHz) .delta. 11.71 (s, 1H), 9.40 (s, 1H), 8.77
(s, 2H), 7.91 (s, 1H), 5.65 (s, 1H), 5.07-5.10 (m, 1H), 3.79 (s,
3H), 3.01 (s, 6H), 1.54 (d, 3H).
Example 20
N-{2-{[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]amino}-6-[(5-methyl-1H-pyrazol-
-3-yl)amino]pyrimidin-4-yl}-N,N',N'-trimethylsulfamide
[0310] A microwave reaction vessel was charged with
N-{2-chloro-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-4-yl}-N,N',N'-tr-
imethylsulfamide (Method 30, 51.9 mg, 0.150 mmol),
(S)-1-(5-fluoropyrimidin-2-yl)ethanamine hydrochloride (Method 7,
53.3 mg, 0.301 mmol), and DIPEA (0.079 ml, 0.449 mmol). Anhydrous
n-BuOH (1 ml) was added, and the tube was sealed and heated in a
microwave reactor at 180.degree. C. for 4 hours. The reaction
mixture was purified by silica gel chromatography (by ISCO
Combiflash with gradient EtOAc and hexanes) to afford the title
compound as a white solid (47.4 mg, 70%). LC-MS, 451 (M+1). .sup.1H
NMR (DMSO-d6 , 400 MHz, 80.degree. C.) .delta. 11.61 (s, 1H), 8.95
(s, 1H), 8.77 (s, 2H), 5.84-6.89 (m, 3H), 5.17-5.23 (m, 1H), 3.17
(s, 3H), 2.74 (s, 6H), 2.18 (s, 3H), 1.54 (d, 3H).
Example 21
N-{5-fluoro-2-{[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]amino}-6-[(5-methyl-1-
H-pyrazol-3-yl)amino]pyrimidin-4-yl}-N-methylmethanesulfonamide
[0311] A microwave reaction vessel was charged with
N-{2-chloro-5-fluoro-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-4-yl}-N-
-methylmethanesulfonamide (Method 32, 111 mg, 0.332 mmol),
(S)-1-(5-fluoropyrimidin-2-yl)ethanamine hydrochloride (Method 7,
143 mg, 0.668 mmol), and DIEA (0.250 ml, 1.44 mmol). Anhydrous
n-BuOH (1 ml) was added, and the tube was sealed and heated in a
microwave reactor at 160.degree. C. for 2 hours. The reaction
mixture was purified by silica gel chromatography (by ISCO
Combiflash with gradient of 0-5% MeOH in DCM with 1% NH.sub.4OH) to
afford the title compound as a white solid (90 mg, 62%). .sup.1H
NMR (DMSO, 400 MHz, 80.degree. C.) .delta. 11.51 (br, 1H), 10.00
(br, 1H), 8.79 (s, 2H), 6.25 (s, 1H), 5.11 (m, 1H), 3.14 (s, 3H),
3.08 (s, 3H), 2.21 (s, 3H), 1.53 (d, 3H); m/z 441.
Example 22
N.sup.4-[5-(dimethylamino)-1H-pyrazol-3-yl]-5-fluoro-N.sup.2-[(15)-1-(5-fl-
uoropyrimidin-2-yl)ethyl]pyrimidine-2,4-diamine
[0312] A microwave reaction vessel was charged with
N.sup.3-(2-chloro-5-fluoropyrimidin-4-yl)-N.sup.5,N.sup.5-dimethyl-1H-pyr-
azole-3,5-diamine (Method 35, 50 mg, 0.2 mmol),
(S)-1-(5-fluoropyrimidin-2-yl)ethanamine hydrochloride (Method 7,
50 mg, 0.23 mmol), and DIPEA (0.15 ml, 0.86 mmol) in n-BuOH (1 ml)
was heated in a microwave reactor at 160.degree. C. for 2 hours.
Solvent was removed. The residue was purified by silica gel
chromatography (by ISCO Combiflash with gradient 0-5% Methanol in
methylene chloride with 1% NH4OH) to afford the title compound as a
white solid (49 mg, 67%). .sup.1H NMR (CD.sub.3OD, 400 MHz) .delta.
8.77 (s, 2H), 8.23 (s, 1H), 5.32 (br, 1H), 3.92 (q, 1H), 3.13 (s,
6H), 1.71 (d, 3H); m/z 362
Example 23
5-chloro-N.sup.4-[5-(dimethylamino)-1H-pyrazol-3-yl]-N.sup.2-[(1S)-1-(5-fl-
uoropyrimidin-2-yl)ethyl]pyrimidine-2,4-diamine
[0313] A microwave reaction vessel was charged with
N.sup.3-(2,5-dichloropyrimidin-4-yl)-N.sup.5,N.sup.5-dimethyl-1H-pyrazole-
-3,5-diamine (Method 36, 50 mg, 0.2 mmol),
(S)-1-(5-fluoropyrimidin-2-yl)ethanamine hydrochloride (Method 7,
50 mg, 0.23 mmol), and DIPEA (0.15 ml, 0.86 mmol) in n-BuOH (1 ml)
was heated in a microwave reactor at 160.degree. C. for 2 hours.
Solvent was removed. The residue was purified by silica gel
chromatography (by ISCO Combiflash with gradient 0-5% methanol in
DCM with 1% NH.sub.4OH) to afford the title compound as a white
solid. .sup.1H NMR (CD.sub.3OD, 400 MHz) .delta. 8.77 (s, 2H), 8.26
(br, 1H), 5.35 (br, 1H), 3.49 (q, 1H), 3.11 (s, 6H), 1.72 (d, 3H);
m/z 378.
Example 24
5-Nitro-N.sup.4-(5-cyclopropyl-1H-pyrazol-3-yl)-N.sup.2-[(1S)-1-(5-fluorop-
yrimidin-2-yl)ethyl]pyrimidine-2,4-diamine
[0314] A 20 mL round bottom flask was charged with
(S)-1-(5-Fluoropyrimidin-2-yl)ethanamine hydrochloride (Method 7,
0.25 g, 1.77 mmol),
2-Chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)-5-nitropyrimidin-4-amine
(Method 37, 0.3 g, 1.0 mmol), and DIEA (0.30 g, 2.34 mmol).
Anhydrous n-BuOH (5 mL) was added, and the flask was heated at
60.degree. C. for 4 hours. The reaction mixture was washed with
brine (5 mL.times.3), and the organic layer was dried and
concentrated. The resulting residue was separated by silica gel
column to afford desired product (0.3 g, 75%). LC-MS, 386 (M+1).
.sup.1H NMR (DMSO-d6) .delta. 12.3 (s, 1H), 10.5 (s, 1H), 9.1 (s,
1H), 9.0 (s, 1H), 8.80 (s, 2H), 6.1 (s, 1H), 5.2 (dd, 1H), 2.0 (m,
1H), 1.7 (d, 3H), 1.0 (m, 2H), 0.8 (m, 2H).
Example 25
5-bromo-N.sup.2-[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]-N.sup.4-(5-methyl-1-
H-pyrazol-3-yl)pyrimidine-2,4-diamine
[0315] To a microwave vial was added
(S)-1-(5-fluoropyrimidin-2-yl)ethanamine hydrochloride (Method 7,
369 mg, 2.08 mmol),
5-bromo-2-chloro-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine
(Method 38, 500 mg, 1.73 mmol), and DIEA (468 mg, 3.8 mmol).
Anhydrous n-BuOH (5 mL) was added, and the vial was heated in
microwave oven at 165.degree. C. for 5 hours. The reaction mixture
was concentrated. The resulting residue was separated by silica gel
column to afford desired product (320 mg, 47%). LC-MS, 393 (M+1).
.sup.1H NMR .delta. 12.02 (s, 1H), 8.82 (s, 2H), 7.94 (s, 1H), 7.48
(s, 0.55H), 5.90 (s, 0.41H), 5.09 (s, 1H), 2.19 (m, 3H), 1.49 (m,
3H).
Example 26
5-bromo-N.sup.2-[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]-N.sup.4-(5-methoxy--
1H-pyrazol-3-yl)pyrimidine-2,4-diamine
[0316] To a microwave vial was added
(S)-1-(5-fluoropyrimidin-2-yl)ethanamine hydrochloride (Method 7,
155 mg, 0.77 mmol),
5-bromo-2-chloro-N-(5-methoxy-1H-pyrazol-3-yl)pyrimidin-4-amine
(Method 39, 180 mg, 0.59 mmol), and DIEA (181 mg, 1.48 mmol).
Anhydrous n-BuOH (2.5 mL) was added, and the vial was heated in
microwave oven at 165.degree. C. for 5 hours. The reaction mixture
was concentrated. The resulting residue was separated by silica gel
column to afford desired product (80 mg, 33%). LC-MS, 409 (M+1).
.sup.1H NMR .delta. 12.03 (s, 1H), 9.38 (s, 1H), 8.82 (s, 2H),
7.97-8.12 (m, 2H), 5.60 (s, 1H), 5.13 (s, 1H), 3.75 (m, 3H), 1.49
(m, 3H).
Example 27
5-chloro-N.sup.2-[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]-N.sup.4-[5-(2,2,2--
trifluoroethoxy)-1H-pyrazol-3-yl]pyrimidine-2,4-diamine
[0317] To a microwave vial was added
(S)-1-(5-fluoropyrimidin-2-yl)ethanamine hydrochloride (Method 7,
81 mg, 0.46 mmol),
2,5-dichloro-N-[5-(2,2,2-trifluoroethoxy)-1H-pyrazol-3-yl]pyrimidin-4-ami-
ne (Method 40, 100 mg, 0.31 mmol), and DIEA (110 mg, 0.9 mmol).
Anhydrous n-BuOH (2.5 mL) was added, and the vial was heated in
microwave oven at 165.degree. C. for 5 hours. The reaction mixture
was concentrated. The resulting residue was separated by silica gel
column to afford desired product (80 mg, 62%). LC-MS, 433 (M+1).
.sup.1H NMR .delta. 12.19 (s, 1H), 9.76 (s, 1H), 8.83 (s, 2H),
7.92-8.10 (m, 2H), 5.67 (s, 1H), 5.13 (s, 1H), 4.75 (m, 2H), 1.49
(m, 3H).
Example 28
6-chloro-N.sup.2-[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]-N.sup.4-(5-methoxy-
-1H-pyrazol-3-yl)pyrimidine-2,4-diamine
[0318] A mixture of (S)-1-(5-fluoropyrimidin-2-yl)ethanamine
hydrochloride (Method 7, 512 mg),
2,6-dichloro-N-(5-methoxyl-1H-pyrazol-3-yl)pyrimidin-4-amine
(Method 42, 682 mg) and DIPEA (1.16 ml) in n-BuOH (13 ml) was
heated at 105.degree. C. over night. The solvent was removed under
reduced pressure and the residue was purified by Gilson (10-50%
MeCN/H.sub.2O, 15 minutes) to give the titled compound as solid
(500 mg). .sup.1H NMR .delta. 8.92 (s, 2H) 5.95 (s, 1 H) 5.18 (s,
1H) 3.77 (s, 3H) 1.49 (d, 3H); m/z 366.
Example 29
N.sup.2-[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]-N.sup.4-(5-methoxy-1H-pyraz-
ol-3-yl)-6-morpholin-4-ylpyrimidine-2,4-diamine
[0319] A mixture of
6-chloro-N.sup.2-[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]-N.sup.4-(5-methox-
y-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (Example 28, 300 mg),
morpholine (0.086 mL) and DIPEA (0.218 ml) in n-BuOH (4 ml) was
heated at 120.degree. C. over night in microwave tube. The solvent
was removed under reduced pressure and the residue was purified by
Gilson (10-50% MeCN/H.sub.2O, 15 minutes) to give the titled
compound as solid (174 mg). .sup.1H NMR .delta. 11.97 (s, 1H) 9.49
(s, 1H) 8.80 (s, 2H) 7.58 (s, 1H) 4.98-5.20 (m, 3H) 3.72 (s, 3H)
3.53 (bs, 4H) 3.18 (bs, 4H) 1.49 (d, 3H); m/z 416.
Example 30
5,6-dichloro-N.sup.2-[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]-N.sup.4-(5-met-
hoxy-1H-pyrazol-3-yl)pyrimidine-2,4-diamine
[0320] A mixture of (S)-1-(5-fluoropyrimidin-2-yl)ethanamine
hydrochloride (Method 7, 500 mg),
2,5,6-trichloro-N-(5-methoxy-1H-pyrazol-3-yl)pyrimidin-4-amine
(Method 43, 756 mg) and DIPEA (1.14 ml) in n-BuOH (13 ml) was
heated at 105.degree. C. for 6 hours. The solvent was removed under
reduced pressure and the residue was purified by Gilson (10-50%
MeCN/H.sub.2O, 35 minutes) to give the titled compound as solid
(210 mg). .sup.1H NMR .delta. 9.87 (s, 1H) 8.88 (s, 2 H) 8.78 (s,
1H) 8.38 (d, 1H) 5.62 (s, 1H) 5.06-5.17 (m, 1H) 3.77 (s, 3H) 1.49
(d, 3H); m/z 399.
Example 31
5-chloro-N.sup.2-[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]-N.sup.4-(5-methoxy-
-1H-pyrazol-3-yl)-6-morpholin-4-ylpyrimidine-2,4-diamine
[0321] A mixture of
5,6-dichloro-N.sup.2-[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]-N.sup.4-(5-me-
thoxy-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (Example 30, 100 mg),
morpholine (0.026 mL) and DIPEA (0.066 ml) in n-BuOH (2.0 ml) was
charged into a microwave reaction vessel. The vessel was sealed and
heated at 150.degree. C. for 24 hours. The solvent was removed
under reduced pressure and the residue was purified by Gilson
2%-40% MeCN/H.sub.2O, 15 minutes) to give the titled compound as
solid (21.8 mg). .sup.1H NMR .delta. 11.99 (s, 1H) 9.30 (s, 1H)
8.82 (s, 2H) 7.89 (d, 1H) 5.49 (s, 1H) 4.93-5.14 (m, 1H) 3.75 (s,
3H) 3.44-3.62 (m, 4H) 3.09-3.27 (m, 4 H) 1.47 (d, 3H) m/z 450.
Example 32
5-fluoro-N.sup.2-[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]-N.sup.4-(5-methyl--
1H-pyrazol-3-yl)-6-morpholin-4-ylpyrimidine-2,4-diamine
[0322] A mixture of (S)-1-(5-fluoropyrimidin-2-yl)ethanamine
hydrochloride (Method 7, 141 mg),
2-chloro-5-fluoro-N-(5-methyl-1H-pyrazol-3-yl)-6-morpholin-4-ylpyrimidin--
4-amine (Method 44, 313 mg) and DIPEA (0.266 ml) in n-BuOH (5.0 ml)
was charged into a microwave reaction vessel. The vessel was sealed
and heated in microwave reactor at 180.degree. C. for 9 hours. The
solvent was removed under reduced pressure and the residue was
purified by Gilson (2-40% MeCN/H.sub.2O, 15 minutes) to give the
titled compound as solid (38.4 mg). .sup.1H NMR .delta. 8.84 (s,
2H) 4.90-5.02 (m, 1H) 3.38-3.72 (m, 8H) 2.16 (s, 3H) 1.44 (d, 3H);
m/z 418.
Example 33
5-chloro-2-{[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]amino}-6-[(5-methoxy-1H--
pyrazol-3-yl)amino]pyrimidine-4-carbonitrile
[0323] A mixture of
5,6-dichloro-N.sup.2-[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]-N.sup.4-(5-me-
thoxy-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (Example 30, 100 mg),
zinc (17 mg), zinc cyanide (31 mg), DPPF (7 mg) and
Pd.sub.2(dba).sub.3 (12 mg) in DMA (2.0 ml) was degassed and heated
at 100.degree. C. for 2 hours. The solution was separated between
ethyl acetate and water. Organic solvent was removed under reduced
pressure and the residue was purified by Gilson (10-50%
MeCN/H.sub.2O, 15 minutes) to give the titled compound as solid
(42.5 mg). .sup.1H NMR .delta. 10.20 (s, 1H) 8.89 (s, 2H) 8.56 (bs,
1H) 5.63 (s, 1H) 5.03-5.29 (m, 1H) 3.75 (s, 3H) 1.47 (d, 3H); m/z
390.
Example 34
N.sup.2-[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]-N.sup.4-(5-methoxy-1H-pyraz-
ol-3-yl)-6-(trifluoromethyl)pyrimidine-2,4-diamine
[0324] A mixture of (S)-1-(5-fluoropyrimidin-2-yl)ethanamine
hydrochloride (Method 7, 139 mg),
N-(5-methoxy-1H-pyrazol-3-yl)-2-(methylsulfonyl)-6-(trifluoromethyl)pyrim-
idin-4-amine (Method 45, 265 mg) and DIPEA (0.35 ml) in n-BuOH (5.0
ml) was heated at 90.degree. C. for 6 hours. The solvent was
removed under reduced pressure and the residue was purified by
Gilson (10-50% MeCN/H.sub.2O, 15 minutes) to give the titled
compound as solid (16.3 mg). .sup.1H NMR .delta. 12.11 (s, 1H)
10.47 (s, 1H) 8.86 (s, 2H) 8.29 (s, 1H) 6.27 (s, 1H) 5.30 (s, 1H)
5.13-5.25 (m, 1H) 3.77 (s, 3H) 1.51 (d, 3H); m/z 399.
Example 35
5-fluoro-N.sup.2-[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]-N.sup.4-(5-methoxy-
-1H-pyrazol-3-yl)-6-morpholin-4-ylpyrimidine-2,4-diamine
[0325] A mixture of (S)-1-(5-fluoropyrimidin-2-yl)ethanamine
hydrochloride (Method 7, 232 mg),
2-chloro-5-fluoro-N-(5-methoxy-1H-pyrazol-3-yl)-6-morpholin-4-ylpyrimidin-
-4-amine (Method 46, 361 mg) and DIPEA (0.46 ml) in n-BuOH (2.5 ml)
was charged into a microwave reaction vessel. The vessel was sealed
and heated at 170.degree. C. for 24 hours. The solvent was removed
under reduced pressure and the residue was purified by Gilson
(2-40% MeCN/H.sub.2O, 15 minutes) to give the titled compound as
solid (74.2 mg). .sup.1H NMR .delta. 10.07 (s, 1H) 8.86 (s, 2H)
5.48 (s, 1H) 5.00 (m, 1H) 3.86 (s, 3H) 3.38-3.62 (m, 8H) 1.48 (d,
3H); m/z 434.
Example 36
N-{5-chloro-2-{[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]amino}-6-[(5-methyl-1-
H-pyrazol-3-yl)amino]pyrimidin-4-yl}-N-methylmethanesulfonamide
[0326] Following a similar procedure to that of Example 21, the
title compound was made from
N-{2,5-dichloro-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-4-yl}-N-meth-
ylmethanesulfonamide (Method 47) and
(S)-1-(5-fluoropyrimidin-2-yl)ethanamine hydrochloride (Method 7).
.sup.1H NMR (DMSO-d6 , 400 MHz, 80.degree. C.) .delta. 10.38 (br,
1H), 9.48 (br, 1H), 8.82 (s, 2H), 6.43 (s, 1H), 4.98 (m, 1H), 3.08
(s, 3H), 2.94 (s, 3H), 2.35 (s, 3H), 1.53 (d, 3H).
Example 37
N-{5-chloro-2-{[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]amino}-6-[(5-isopropo-
xy-1H-pyrazol-3-yl)amino]pyrimidin-4-yl}-N,N',N'-trimethylsulfamide
[0327] Following a similar procedure to that of Example 18, the
title compound was made from
N-{2,5-dichloro-6-[(5-isopropoxy-1H-pyrazol-3-yl)amino]pyrimidin-4-yl}-N,-
N',N'-trimethylsulfamide (Method 49) and
(S)-1-(5-fluoropyrimidin-2-yl)ethanamine hydrochloride (Method 7).
LC-MS, 529 (M+1). .sup.1H NMR (CD.sub.2Cl.sub.2, 400 MHz) .delta.
11.47 (br, 1H), 8.61 (s, 2H), 7.80 (s, 1H), 6.0-6.40 (br, 1H), 5.44
(s, 1H), 5.23 (m, 1H), 4.75 (s, 1H), 2.02 (s, 3H), 2.92 (s, 6H),
1.62 (s, 3H), 1.35 (s, 6H).
Preparation of Starting Materials
Method 1
1-(5-Fluoropyrimidin-2-yl)ethanamine
[0328] A round-bottom flask containing
2-(1-azidoethyl)-5-fluoropyrimidine (Method 3, 0.60 g, 3.59 mmol)
was charged with 10% Pd/C (0.191 g) and was evacuated and
backfilled with H.sub.2 via a filled balloon. MeOH (10 ml) was
added, and the mixture was allowed to stir at room temperature for
3 hours. The mixture was filtered through a plug of diatomaceous
earth, which was subsequently washed well with MeOH. The filtrates
were concentrated to give the title compound as a pale yellow oil
(0.50 g, 99%). .sup.1H NMR (CDCl.sub.3) .delta. 8.60 (s, 2H), 4.65
(br s 2H), 4.10 (m, 1H), 1.20 (d, 3H).
Method 2
2,5-Dichloro-N-(5-isopropoxy-1H-pyrazol-3-yl)pyrimidin-4-amine
[0329] A solution of 2,4,5-trichloropyrimidine (533 mg, 2.93 mmol),
5-isopropoxy-1H-pyrazol-3-amine (413 mg, 2.93 mmol) and
triethylamine (0.49 ml) in THF (5 ml) was stirred at room
temperature for 10 hours. Solvent was removed and EtOAc was added.
The solution was washed with water and dried over anhydrous sodium
sulfate and was concentrated to give title compound as a white
solid (582 mg, 69%). LC-MS, 246 (M-42); .sup.1H NMR (CDCl.sub.3)
.delta. 8.19 (s, 1H), 7.80 (s, 1H), 5.79 (s, 1H), 4.65 (m, 1H),
1.30 (d, 6H).
Method 3
2-(1-Azidoethyl)-5-fluoropyrimidine
[0330] A round-bottom flask containing
1-(5-fluoropyrimidin-2-yl)ethanol (Method 4, 0.79 g, 5.55 mmol) was
charged with triethylamine (0.67 g, 6.66 mmol) and anhydrous DCM
(10 ml). The solution was cooled to 0.degree. C., and
methanesulfonyl chloride (0.70 g, 4.1 mmol) was added dropwise. The
resulting mixture was allowed to stir at room temperature for 2
hours, at which point the volatile components were removed using a
rotary evaporator. The residue was dissolved in DMF (15 ml) and
treated with sodium azide (0.72 g, 11.1 mmol). The resulting
mixture was stirred at room temperature for 60 hours. It was then
partitioned between EtOAc and brine. The organic layer was
obtained, dried (Na.sub.2SO.sub.4), and evaporated to dryness. The
crude material was purified by silica gel chromatography (by ISCO
Combiflash with gradient EtOAc and hexanes) to afford the title
compound as a colourless oil (0.60 g, 65% yield over two steps).
GC-MS, 167 (M), 138 (M-N.sub.2), 125 (M-N.sub.3); .sup.1H NMR
(CDCl.sub.3) .delta. 8.60 (s, 2H), 4.60 (m, 1H), 1.65 (d, 3H).
Method 4
1-(5-Fluoropyrimidin-2-yl)ethanol
[0331] 1-(5-Fluoropyrimidin-2-yl)ethanone (Method 5, 0.77 g) was
dissolved in MeOH (15 ml), and the solution was cooled to 0.degree.
C. NaBH.sub.4 (0.210 g, 5.55 mmol) was added. The mixture was
stirred at room temperature for 1 hour and then partitioned between
EtOAc and H.sub.2O. The organic extract was washed with brine,
dried (Na.sub.2SO.sub.4), filtered, and concentrated to give the
title compound as a yellowish oil (0.79 g, 99%). .sup.1H NMR
(CDCl.sub.3) .delta. 8.65 (s, 2H), 5.20 (m, 1H), 4.00 (br s, 1H),
1.80 (d, 3H).
Method 5
1-(5-Fluoropyrimidin-2-yl)ethanone
[0332] A round-bottom-flask containing
5-fluoropyrimidine-2-carbonitrile (Method 6, 1.50 g, 12.19 mmol)
was charged with anhydrous THF (30 ml) under N.sub.2. The solution
was cooled to 0.degree. C., and a solution of MeMgBr (4.90 ml of a
3.0 M solution in ether, 14.62 mmol) was added dropwise. After 2
hours at 0.degree. C., the reaction mixture was quenched with ice
water and extracted with EtOAc. The organic extract was washed with
brine, dried over Na.sub.2SO.sub.4, and evaporated to dryness to
give the title compound as an oil (0.778 g, yield 46%). GC-MS, 140
(M); .sup.1H NMR (CDCl.sub.3) .delta. 8.65 (s, 2H), 2.65 (s,
2H).
Method 6
5-Fluoropyrimidine-2-carbonitrile
[0333] A 10 ml microwave vial was charged with
2-chloro-5-fluoropyrimidine (2.0 g, 15.09 mmol),
Pd.sub.2(dba).sub.3 (0.549 g, 0.6 mmol), DPPF (0.67 g, 1.21 mmol),
zinc cyanide (1.15 g, 9.81 mmol), and zinc dust (0.237 mg, 3.62
mmol). The flask was evacuated and backfilled with N.sub.2, and
anhydrous dimethylacetamide. The vial was mounted onto a Personal
Chemistry microwave reactor and heated at 100.degree. C. for 10
hours. The reaction mixture was diluted with EtOAc and then washed
with brine three times. The organic layer was obtained and
evaporated to dryness. The dried residue was purified by silica gel
chromatography (By ISCO Combiflash with gradient EtOAc and hexanes)
to afford the title compound as a creamy solid (1.50 g, 80%).
GC-MS: 123 (M); .sup.1H NMR (CDCl.sub.3) .delta. 8.80 (s, 2H).
Method 7
(S)-1-(5-Fluoropyrimidin-2-yl)ethanamine hydrochloride
[0334] To a solution of
(S)-tert-butyl-1-(5-fluoropyrimidin-2-yl)ethylcarbamate (Method 10,
0.21 g, 0.87 mmol) in DCM (5 ml) was added HCl (1.3 ml, 5.2 mmol)
in dioxane. The reaction was stirred at room temperature for 3
hours. The solvent was removed give the title compound as white
solid (quantitative). MS: Calcd.: 141. Found: [M+H].sup.+ 142.
[0335] An alternative process for synthesizing
(S)-1-(5-Fluoropyrimidin-2-yl)ethanamine hydrochloride is presented
in Methods 50 to 53.
Method 8
2-Chloro-5-fluoro-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine
[0336] To a solution of 5-methyl-1H-pyrazol-3-amine (612 mg, 6.0
mmol) in absolute EtOH (10 ml) was added triethylamine (1.1 ml) and
2,4-dichloro-5-fluoropyrimidine (1.0 g, 6.0 mmol) and the resulting
solution was aged at room temperature for 12 hours. The mixture was
partitioned between EtOAc and water. The organic layer was washed
with brine and dried. The solvents were removed under reduced
pressure to give the title compound as a solid (679 mg). m/z:
228.
Method 9
2,5-Dichloro-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine
[0337] To a solution of 5-methyl-1H-pyrazol-3-amine (2.78 g, 27.3
mmol) in absolute EtOH (30 ml) was added triethylamine (5 ml) and
2,4,5-trichloropyrimidine (5.0 g, 27.3 mmol) and the resulting
solution was aged at room temperature for 12 hours. The mixture was
partitioned between EtOAc and H.sub.2O, the organic layer was
washed with brine and dried. The solvents were removed under
reduced pressure to give the title compound (4.1 g). m/z: 245.
Method 10
(S)-tert-butyl-1-(5-Fluoropyrimidin-2-yl)ethylcarbamate
[0338] (S)--N-(1-(5-Fluoropyrimidin-2-yl)ethyl)acetamide (Method
11, 0.20 g, 1.09 mmol), DMAP (0.027 g, 0.22 mmol) and
di-tert-butyl-dicarbonate (0.60 g, 2.73 mmol) in THF (10 ml) was
stirred at 50.degree. C. for 40 hours. After cooling to room
temperature, lithium hydroxide monohydrate (0.094 g, 2.24 mmol) and
water (10 ml) was added. The reaction was stirred at room
temperature for 9 hours. Ether (30 ml) was added, organic layer was
separated, washed with brine (20 ml) and dried over sodium sulfate.
After removal of solvent, the resulted residue was purified by
column chromatography (Hex-EtOAc=5:1) to give the title compound as
a pale yellow oil (0.21 g, 80%). NMR (400 MHz) 8.84 (s, 2H), 7.24
(d, J=7.6 Hz, 1H), 4.74 (m, 1H), 1.35 (s, 12H). MS: Calcd.: 241.
Found: [M+H].sup.+ 242.
Method 11
(S)--N-(1-(5-Fluoropyrimidin-2-yl)ethyl)acetamide
[0339] N-(1-(5-Fluoropyrimidin-2-yl)vinyl)acetamide (Method 12,
0.10 g, 0.55 mmol) in MeOH (5 ml) under N.sub.2 was added
(+)-1,2-bis((2S,5S)-2,5-diethylphospholano)benzene
(cyclooctadiene)rhodium(I)trifluoromethanesulfonate (0.04 g, 0.0055
mmol). The solution was transferred to a high pressure bomb and
charged 150 psi H.sub.2. The reaction was stirred at room
temperature for 4 hours. The solvent was removed and the resulted
residue was purified by column chromatography (EtOAc) to give the
title compound as a white solid (0.096 g, 95%). .sup.1H NMR (400
MHz) 8.84 (d, J=0.8 Hz, 2H), 8.34 (d, J=7.6 Hz, 1H), 5.00 (m, 1H),
1.84 (s, 3H), 1.37 (d, J=6.8 Hz, 3H). MS: Calcd.: 183. Found:
[M+H].sup.+ 184. Enantiomeric excess determined by HPLC (Chiralpak
IA; 95:5 CO.sub.2/MeOH), >99% ee.
Method 12
N-(1-(5-Fluoropyrimidin-2-yl)vinyl)acetamide
[0340] 5-Fluoropyrimidine-2-carbonitrile (Method 6, 1.0 g, 8.1
mmol) in THF (10 ml) was added a solution of MeMgBr (3.3 ml, 9.75
mmol) in ether drop wise at 0.degree. C. After addition, the
reaction was warmed to room temperature, stirred at room
temperature for 1 hour and then diluted with DCM (10 ml). Acetic
anhydride (1.23 ml, 13.0 mmol) was added in one portion. The
reaction was stirred at room temperature for 1 hour and 40.degree.
C. for 1 hour. Saturated sodium bicarbonate solution (10 ml) was
added and extracted with EtOAc (2.times.20 ml). The combined
organic was dried over sodium sulfate. After removal of solvent,
the resulted residue was purified by column chromatography
(hexane-EtOAc=2.5:1) to give the title compound as a white solid
(0.38 g, 26%). .sup.1H NMR (400 MHz) 9.34 (s, 1H), 8.95 (s, 2H),
6.25 (s, 1H), 6.03 (s, 1H), 2.11 (s, 3H). MS: Calcd.: 181. Found:
[M+H].sup.+ 182.
Method 13
5-Bromo-2-chloro-N-(5-isopropoxy-1H-pyrazol-3-yl)pyrimidin-4-amine
[0341] To a solution of 5-isopropoxy-1H-pyrazol-3-amine (11.6 g,
82.1 mmol) in THF (85 ml) was added DIPEA (16 ml) and
2,4-dichloro-5-bromopyrimidine (17 g, 74.6 mmol) and the resulting
solution was aged at 40.degree. C. for 16 hours. The mixture was
partitioned between EtOAc and H.sub.2O, the organic layer was
washed with brine and dried. The solvents were removed under
reduced pressure and column chromatography gave the title compound
as a solid. m/z: 332.
Method 14
2,5-Dichloro-N-(5-methoxy-1H-pyrazol-3-yl)pyrimidin-4-amine
[0342] To a solution of 5-methoxy-1H-pyrazol-3-amine (890 mg, 7.8
mmol) in absolute EtOH (20 ml) was added triethylamine (3.3 ml,
23.6 mmol) and 2,4,5-trichloropyrimidine (1.4 g, 7.8 mmol) and the
resulting solution was aged at room temperature for 12 hours. The
mixture was partitioned between EtOAc and H.sub.2O, the organic
layer was washed with brine and dried. The solvents were removed
under reduced pressure to give the title compound as an oil which
crystallized upon standing (1.8 g). m/z: 261.
Method 15-17
[0343] The following compounds were prepared by the procedure of
Method 14, using the appropriate starting material.
TABLE-US-00001 Meth Compound m/z SM 15
2,5-Dichloro-N-(5-cyclopropyl- 271 5-cyclopropyl-1H-
1H-pyrazol-3-yl)pyrimidin- pyrazol-3-amine and 4-amine
2,4,5-trichloropyrimidine 16 2-Chloro-N-(5-cyclopropyl- 254
5-cyclopropyl-1H- 1H-pyrazol-3-yl)-5- pyrazol-3-amine and
fluoropyrimidin-4-amine 2,4-dichloro-5- fluoropyrimidine 17
2,6-Dichloro-N-(5-methyl- 245 5-methyl-1H-pyrazol-
1H-pyrazol-3-yl)pyrimidin- 3-amine and 2,4,6- 4-amine
trichloropyrimidine
Method 18
N-[2,5-Dichloro-6-(5-isopropoxy-1H-pyrazol-3-ylamino)-pyrimidin-4-yl]-N-me-
thyl-methanesulfonamide
[0344] To a solution of
N-methyl-N-(2,5,6-trichloro-pyrimidin-4-yl)-methanesulfonamide
(Method 19, 1.236 g, 4.3 mmol) in n-BuOH (8 ml) was added
5-isopropoxy-1H-pyrazol-3-ylamine (601 mg, 4.3 mmol) and
ethyl-diisopropyl-amine (556 mg). The mixture was heated at
70.degree. C. overnight. LC/MS showed the completion of the
reaction. The solvent was evaporated and the residue was dissolved
in DCM, which was then washed by aqueous NaHCO.sub.3, dried and
concentrated. Flash chromatography was performed with EtOAc/Hex
(50%) as eluent. A colourless solid (669 mg) was obtained, yield
39%. NMR (CDCl.sub.3) 8.06 (s, 1H), 5.78 (s, 1H), 4.61 (m, 1H),
3.21 (s, 3H), 3.16 (s, 3H), 1.32 (d, J=6.0 Hz, 6H). MS (ES+) m/z
395.2, 397.1 [MH+]. MS (ES.sup.-) m/z 393.1, 395.0 [M.sup.-].
Method 19
N-Methyl-N-(2,5,6-trichloro-pyrimidin-4-yl)-methanesulfonamide
[0345] To N-Methyl methanesulfonate (954 mg, 8.7 mmol) in THF (20
ml) was added NaH (367 mg, 9.2 mmol, 60% in mineral oil). This was
stirred for 10 min at room temperature and then added to the
solution of 2,4,5,6-tetrachloro-pyrimidine (1.904 g, 8.7 mol) in
THF (10 ml) at 0.degree. C. The reaction mixture was stirred at
0.degree. C. for 3 hours. LC/MS showed the completion of the
reaction. The solvent was evaporated and the residue was dissolved
in DCM, which was then washed by aqueous NaHCO.sub.3, dried and
concentrated. Flash chromatography was performed with EtOAc/Hex
(25%) as eluent. A colourless solid (1.236 g) was obtained, yield
49%. NMR (400 MHz, CDCl.sub.3) 3.30 (s, 3H), 3.32 (s, 3H).
.sup.13C-NMR (400 MHz, CDCl.sub.3) 162.2, 161.2, 156.0, 124.7,
39.5, 37.1. MS (ES+) m/z 289.83, 291.82 [MH+].
Method 20
N-[2-Chloro-5-fluoro-6-(5-isopropoxy-1H-pyrazol-3-ylamino)-pyrimidin-4-yl]-
-N-methyl-methanesulfonamide
[0346] To a solution of
N-(2,6-dichloro-5-fluoro-pyrimidin-4-yl)-N-methyl-methanesulfonamide
(Method 21, 440 mg, 1.6 mmol) in n-BuOH (3 ml) was added
5-isopropoxy-1H-pyrazol-3-ylamine (227 mg, 1.6 mmol) and DIPEA (207
mg). The mixture was heated at 70.degree. C. overnight. LC/MS
showed the completion of the reaction. The solvent was evaporated
and the residue was dissolved in DCM, which was then washed by
aqueous NaHCO.sub.3, dried and concentrated. Flash chromatography
was performed with EtOAc/Hex (50%) as eluent. A colourless solid
(280 mg) was obtained, yield 46%. .sup.1H-NMR (300 MHz, CD.sub.3OD)
5.84 (s, 0.8H), 4.61 (m, 1H), 3.32 (s, 3H), 3.27 (s, 3H), 1.36 (d,
J=6.0; 6H). MS (ES+) m/z 378.86, 380.86 [MH+]. MS (ES.sup.-) m/z
376.88, 378.87 [M.sup.-].
Method 21
N-(2,6-Dichloro-5-fluoro-pyrimidin-4-yl)-N-methyl-methanesulfonamide
[0347] To N-methyl methanesulfonate (546 mg, 5 mmol) in THF (20 ml)
was added NaH (220 mg, 5.5 mmol, 60% in mineral oil). This was
stirred for 10 minutes at room temperature and then added to the
solution of 2,4,6-trichloro-5-fluoro-pyrimidine (1.007 g, 5 mol) in
THF (5 ml) at 0.degree. C. The reaction mixture was stirred at
0.degree. C. for 3 hours. LC/MS showed the completion of the
reaction. The solvent was evaporated and the residue was dissolved
in DCM, which was then washed by aqueous NaHCO.sub.3, dried and
concentrated. Flash chromatography was performed with EtOAc/Hex
(25%) as eluent. A colourless solid (986 mg) was obtained, yield
72%. NMR (CDCl.sub.3) 3.45 (d, J=1.9 Hz, 3H), 3.37 (s, 3H). MS
(ES.sup.-) m/z 274.0, 276.0 [M].sup.-.
Method 22
2-Chloro-5-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine
[0348] To a solution of 2,4-dichloro-5-methylpyrimidine (1.25 g,
7.8 mmol) in EtOH (30 ml) was added 5-methyl-1H-pyrazol-3-ylamine
(756 mg, 7.8 mmol) and DIPEA (2.8 mL). The mixture was heated at
70.degree. C. overnight. LC/MS showed the completion of the
reaction. The title compound was obtained by filtration under
vacuum as a white solid (700 mg). m/z 224.
Method 23
2-Chloro-N-(5-methyl-1H-pyrazol-3-yl)-5-(trifluoromethyl)pyrimidin-4-amine
[0349] To a solution of 2,4-dichloro-5-trifluoromethylpyrimidine
(1.27 g, 5.8 mmol) in MeCN (20 ml) was added
5-methyl-1H-pyrazol-3-ylamine (568 mg, 5.8 mmol) and Et.sub.3N (1.6
mL). The mixture was stirred at ambient temperature overnight.
LC/MS showed the completion of the reaction. Evaporation of the
solvent afforded yellow oil that was purified by Gilson (5-95%
MeCN/H.sub.2O, 15 minutes) to give the titled compound as solid
(300 mg). m/z 278.
Method 24
N-{2,5-Dichloro-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-4-yl}-N,N',N'-
-trimethylsulfamide
[0350] To a solution of
N,N,N'-trimethyl-N'-(2,5,6-trichloropyrimidin-4-yl)sulfamide
(Method 26, 0.505 g, 1.59 mmol) in n-BuOH (3 ml) was added
5-methyl-1H-pyrazol-3-amine (159 mg, 1.59 mmol, 97% purity) and
DIPEA (0.419 mL, 2.38 mmol). The mixture was heated at 50.degree.
C. overnight. LC/MS showed the completion of the reaction. The
solvent was evaporated and the residue was partitioned between DCM
and H.sub.2O. Then the organic layer was dried over
Na.sub.2SO.sub.4, filtered to remove solid, then concentrated in
vacuo. The residue was purified by silica gel chromatography (by
ISCO Combiflash with gradient EtOAc and hexane) to afford the title
compound as a light yellow solid (453 mg, 75%). LC-MS, 380 (M+1).
NMR (DMSO, 400 MHz) .delta. 12.33 (s, 1H), 9.82 (s, 1H), 6.24 (s,
1H), 3.08 (s, 3H), 2.91 (s, 6H), 2.25 (s, 3H).
Method 25
[0351] The following compound was prepared by the procedure of
Method 24, using the appropriate starting material.
TABLE-US-00002 Meth Compound m/z SM NMR 25 N-{2,5-dichloro-6- 367
5-methoxy-1H- .sup.1H (DMSO-d6, [(5-methoxy-1H- pyrazol-3-amine 400
MHz) 11.26 pyrazol-3-yl)amino] and N-methyl-N- (s, 1H), 9.91 (s,
pyrimidin-4-yl}-N- (2,5,6-trichloro- 1H), 5.81 (s, 1H),
methylmethane- pyrimidin-4- 3.81 (s, 3H), 3.28 sulfonamide
yl)methanesulfon- (s, 3H), 3.19 (s, amide 3H).
Method 26
N,N',N'-Trimethyl-N'-(2,5,6-trichloropyrimidin-4-yl)sulfamide
[0352] To a solution of NaH (343 mg, 8.58 mmol, 0% in mineral oil)
in anhydrous DMF (2 mL), N,N',N'-trimethylsulfamide (Method 28, 492
mg, 3.56 mmol) in DMF (2 ml) was added. This reaction mixture was
stirred for 30 min at room temperature and then added to the
solution of 2,4,5,6-tetrachloro-pyrimidine (726 mg, 3.26 mmol) in
THF (30 ml) at 0.degree. C. The reaction mixture was stirred from
0.degree. C. to room temperature overnight. The solvent was
evaporated and the residue was dissolved in DCM, which was then
washed by aqueous NH.sub.4Cl, dried and concentrated. Flash
chromatography was performed with EtOAc/Hex (10%) as eluent. A
white solid (553 mg) was obtained, yield 53%. NMR (400 MHz, DMSO)
.delta. 3.18 (s, 3H), 2.93 (s, 6H).
Method 27
[0353] The following compound was prepared by the procedure of
Method 26, using the appropriate starting material.
TABLE-US-00003 Meth Compound m/z SM NMR 27 N-(2,6-dichloro- 367
N,N,N'- .sup.1H (400 MHz, pyrimidin-4-yl)- trimethyl- DMSO) 3.43
(s, N,N',N'-trimethyl- sulfamide and 3H), 2.90 (s, 6H). sulfamide
2,4,6-trichloro- pyrimidine
Method 28
N,N',N'-Trimethylsulfamide
[0354] To a solution of dimethylsulfamoyl chloride (1.49 mL, 13.8
mmol) in DCM (2.0 mL) and K.sub.2CO.sub.3(1.24 g, 8.9 mmol),
Methylamine (16 mL, 32 mmol, 2M in THF) was added at 0.degree. C.
slowly. The reaction mixture was stirred at 0.degree. C. for 1 hr,
then warm up to room temperature for another 1 hr. The solvent was
removed in vacuo, then anhydrous DCM (30 mL) was added, filtered to
remove solid, and then yellow liquid product (1.84 g, 97% yield)
was obtained by removing the solvent. NMR (400 MHz, CDCl.sub.3)
.delta. 4.40 (s, 1H), 2.74 (s, 6H), 1.70 (s, 3H).
Method 29
N-{2,5-Dichloro-6-[(5-methoxy-1H-pyrazol-3-yl)amino]pyrimidin-4-yl}-N,N',N-
'-trimethylsulfamide
[0355] To a solution of
N,N',N'-trimethyl-N-(2,5,6-trichloropyrimidin-4-yl)sulfamide
(Method 26, 318 mg, 1.0 mmol) in n-BuOH (1 ml) was added
5-methoxy-1H-pyrazol-3-amine (102 mg) and DIPEA (0.240 mL, 1.36
mmol). The mixture was heated at 50.degree. C. overnight. The
solvent was evaporated and the residue was partitioned between DCM
and H.sub.2O. Then the organic layer was dried over
Na.sub.2SO.sub.4, filtered to remove solid, then concentrated in
vacuo. The residue was purified by silica gel chromatography (by
ISCO Combiflash with gradient EtOAc and hexane) to afford the title
compound as a dry film (123 mg, 34%). LC-MS, 396 (M+1). NMR (DMSO,
400 MHz) .delta. 9.74 (s, 1H), 5.81 (s, 1H), 3.81 (s, 3H), 3.12 (s,
3H), 2.93 (s, 6H).
Method 30
N-{2-Chloro-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-4-yl}-N',N',N'-tr-
imethylsulfamide
[0356] To a solution of
N-(2,6-dichloropyrimidin-4-yl)-N,N',N'-trimethylsulfamide (Method
27, 1.72 g, 6.05 mmol) in n-BuOH (6 ml) was added
5-methyl-1H-pyrazol-3-amine (0.605 g, 6.05 mmol) and DIPEA (1.6 mL,
9.09 mmol). The mixture was heated at 70.degree. C. overnight. The
reaction mixture was filtered; the solid was washed by MeOH three
times to give pure white solid. (0.205 g, 9.7% yield). LC-MS, 346
(M+1). NMR (DMSO-d6 , 400 MHz, 80.degree. C.) .delta. 11.89 (s,
1H), 9.82 (s, 1H), 7.22 (s, 1H), 5.97 (s, 1H), 3.32 (s, 3H), 2.87
(s, 6H), 2.21 (s, 3H).
Method 31
N-(2,6-Dichloro-5-fluoropyrimidin-4-yl)-N-methylmethanesulfonamide
[0357] To a solution of NaH (60% in mineral oil, 176 mg, 8.58 mmol)
in anhydrous DMF (2 mL), N-methylmethanesulfonamide (436 mg, 4.0
mmol) in DMF (2 ml) was added. This reaction mixture was stirred
for 30 min at room temperature and then added dropwise to the
solution of 2,4,6-trichloro-5-fluoropyrimidine (804 mg, 4.0 mmol)
in THF (30 ml) at 0.degree. C. The reaction mixture was stirred
from 0.degree. C. to room temperature overnight. The solvent was
evaporated and the residue was purified by silica gel
chromatography (by ISCO Combiflash with gradient 0-30% ethyl
acetate in Hexane with 1% TEA. A white solid (700 mg) was obtained,
yield 64%. NMR (400 MHz, DMSO) 63.38 (s, 3H), 3.31 (s, 3H).
Method 32
N-{2-Chloro-5-fluoro-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-4-yl}-N--
methylmethanesulfonamide
[0358] To a solution of
N-(2,6-dichloro-5-fluoropyrimidin-4-yl)-N-methylmethanesulfonamide
(Method 31, 914 mg, 3.35 mmol) in n-BuOH (3 ml) was added
5-methyl-1H-pyrazol-3-amine (351 mg, 3.62 mmol, 97% purity) and
DIPEA (1.2 ml, 6.9 mmol). The mixture was heated at 50.degree. C.
overnight. LC/MS showed the completion of the reaction. The solvent
was evaporated and the residue was purified by silica gel
chromatography (by ISCO Combiflash with gradient 0-5% methanol in
DCM with 1% NH.sub.4OH) to afford the title compound as a light
yellow solid (1.06 g, 95%). LC-MS, 335 (M+1). NMR (DMSO-d6 , 400
MHz) .delta.12.27 (s, 1H), 10.53 (s, 1H), 6.32 (s, 1H), 3.27 (s,
3H), 3.20 (s, 3H), 2.25 (s, 3H).
Method 33
(2E or Z)-3-(Dimethylamino)-3-(methylthio)acrylonitrile
[0359] Actetonitrile (12 ml, 228 mmol) in THF (100 ml) was cooled
at -78.degree. C., Butyllithium (2.5M in Hexane, 92 ml, 230 mmol)
was added dropwise trough an addition funnel. The reaction was
stirred for additional 30 minutes. Methyl dimethyldithiocarbamate
(Method 41, 14.09 g, 104 mmol) was added in one portion as solid
under nitrogen flow. It was stirred at -78.degree. C. for 30
minutes and room temperature 6 hours. The reaction was then cooled
into an ice-bath. Methyl iodide (10 ml, 125 mmol) was added to the
reaction through a syringe. The reaction was allowed to warm to
room temperature and was stirred at room temperature overnight.
Ethyl acetate (200 ml) was added to the reaction, and the reaction
was washed with water (2.times.100 ml). The organic phase was
combined and concentrated down, The residue was purified by silica
gel chromatography (by ISCO Combiflash with gradient 0-20% ethyl
acetate in hexane) to afford the title compound as a white solid
(10.5 g, 71%) as a mixture of EZ isomers in the form of brownish
liquid. NMR (major isomer) (CDCl.sub.3, 400 MHz) 64.08 (s, 1H),
3.00 (s, 6H), 2.39 (s, 3H).
Method 34
N.sup.5,N.sup.5-Dimethyl-1H-pyrazole-3,5-diamine
[0360] A mixture of (2E or
Z)-3-(dimethylamino)-3-(methylthio)acrylonitrile (Method 33, 9.525
g, 67 mmol) and hydrazine hydrate (10.06 g, 201 mmol) in ethanol
(70 ml) was heated at 85.degree. C. overnight. Solvent was removed.
The residue was purified by silica gel column chromatography (by
ISCO Combiflash with a gradient of 0-10% methanol in
methylenechloride with 1% NH4OH). 5.8 g (69%) product as obtained
brownish thick oil. LC-MS, 127 (M+1). NMR (DMSO, 400 MHz)
.delta.9.51 (br, 1H), 4.67 (s, 1H), 2.62 (s, 6H).
Method 35
N.sup.3-(2-Chloro-5-fluoropyrimidin-4-yl)-N.sup.5,N.sup.5-dimethyl-1H-pyra-
zole-3,5-diamine
[0361] 2,4-dichloro-5-fluoropyrimidine (166 mg, 1 mmol),
N.sup.5,N.sup.5-dimethyl-1H-pyrazole-3,5-diamine (Method 34, 150
mg, 1.2 mmol), and DIEA (0.35 ml, 2 mmol) in ethanol (3 ml) was
heated at 55.degree. C. overnight. Solvent was removed, and the
residue was purified by silica gel chromatography (by ISCO
Combiflash with a gradient of 0-5% methaol in methylene chloride
with 1% NH4OH). 100 mg product was obtained as a white solid (40%).
MS: 257 (M+1); NMR (DMSO-d6 , 400 MHz, 80.degree. C.) .delta.11.60
(br, 1H), 10.26 (br, 1H), 8.23 (s, 1H), 5.73 (s, 1H), 2.76 (s,
6H).
Method 36
[0362] The following compound was prepared by the procedure of
Method 26, using the appropriate starting material.
TABLE-US-00004 Meth Compound m/z SM NMR 36 N.sup.3-(2,5-dichloro-
273 N.sup.5,N.sup.5-dimethyl- .sup.1H (DMSO,
pyrimidin-4-yl)-N.sup.5,N.sup.5- 1H-pyrazole- 400 MHz,
dimethyl-1H-pyrazole- 3,5-diamine and 80.degree. C.) .delta.11.67
3,5-diamine 2,4,5-trichloro- (br, 1H), 9.51 pyrimidine (br, 1H),
8.34 (s, 1H), 5.68 (s, 1H), 2.76 (s, 6H).
Method 37
2-Chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)-5-nitropyrimidin-4-amine
[0363] To a solution of 2,4-dichloro-5-nitropyrimidine (3.0 g, 15
mmol) and DIEA (2.4 g, 18.5 mmol) in n-BuOH (30 ml) was slowly
added 5-cyclopropyl-1H-pyrazol-3-amine (2.0 g, 16.2 mmol) at
25.degree. C. The resulting solution was stirred at 25.degree. C.
for 5 minutes and concentrated to dryness to give the title
compound (3.1 g). NMR (CDCl.sub.3) 0.80 (m, 2H), 1.05 (m, 2H), 6.60
(s, 1H), 9.20 (s, 1H), 9.70 (br s, 1H), 10.40 (br s, 1H).
Method 38
5-Bromo-2-chloro-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine
[0364] To a solution of 5-bromo-2,4-dichloropyrimidine (1.29 g,
5.66 mmol) in EtOH (15 ml) at room temperature was added a solution
of 5-methyl-1H-pyrazol-3-amine (549 mg, 5.66 mmol) in EtOH (3 ml)
and triethylamine (628 mg, 6.22 mmol) and the reaction mixture was
stirred at room temperature overnight. The suspension was filtered
and washed with water and dried to give the desired product as a
white solid (1.27 g, 78%). NMR (CDCl.sub.3) 2.24 (s, 3 H), 6.24 (s,
1H), 8.41 (s, 1H), 9.29 (s, 1H), 12.32 (s, 1H).
Method 39
5-Bromo-2-chloro-N-(5-methoxy-1H-pyrazol-3-yl)pyrimidin-4-amine
[0365] To a solution of 5-bromo-2,4-dichloropyrimidine (1.20 g,
5.26 mmol) in THF (10 ml) at room temperature was added
5-methoxy-1H-pyrazol-3-amine (594 mg, 5.26 mmol) and triethylamine
(685 mg, 6.3 mmol) and the reaction mixture was stirred at
40.degree. C. overnight. The suspension was filtered and washed
with water and dried to give the desired product as a white solid.
MS: 305 (M+1).
Method 40
2,5-Dichloro-N-[5-(2,2,2-trifluoroethoxy)-1H-pyrazol-3-yl]pyrimidin-4-amin-
e
[0366] To a solution of 2,4,5-trichloropyrimidine (1.00 g, 5.45
mmol) in THF (10 ml) at room temperature was added
5-(2,2,2-trifluoroethoxy)-1H-pyrazol-3-amine (986 mg, 5.45 mmol)
and triethylamine (606 mg, 6.0 mmol) and the reaction mixture was
stirred at 40.degree. C. overnight. The suspension was filtered and
washed with water and dried to give the desired product as a white
solid. MS: 328 (M+1).
Method 41
Methyl dimethyldithiocarbamate
[0367] Dimethylamine (2M in THF, 60 ml, 120 mmol) was cooled into
an ice-bath. Carbon dioxide (6 ml, 100 mmol) was added portionwise,
followed by the addition of NaOH (4.8 g)/H.sub.2O (40 mL). The
reaction was stirred at ice-bath for 30 minutes and room
temperature for 2 hours. The reaction was then cooled to ice-bath,
and methyl iodide (7.5 ml, 120 mmol) was added slowly through a
syringe. The reaction was stirred at ice-bath for 1 h, and room
temperature overnight. Ethyl ether (100 ml) was added to extract
product. Organic phase was combined and dried over MgSO.sub.4.
14.32 g product as white solid (100% yield) was obtained by
removing the solvent. NMR (400 MHz, CDCl.sub.3) .delta.3.52 (s,
3H), 3.35 (s, 3H), 2.61 (s, 3H).
Method 42
2,6-Dichloro-N-(5-methoxy-1H-pyrazol-3-yl)pyrimidin-4-amine
[0368] To a solution of 2,4,6-trichloro-pyrimidine (1.7 g) in
absolute ethanol (100 mL) was added DIEPA (4.1 mL) and
5-methoxy-1H-pyrazol-3-amine hydrogen chloride salt (1.46 g). The
resulting solution was stirred at room temperature for over night.
The solvent was evaporated under reduced pressure. The crude
compound was purified by Gilson (10-60% MeCN/H.sub.2O, 15 minutes)
to give the titled compound as solid (1.23 g). .sup.1H NMR .delta.
12.19 (s, 1 H) 10.68 (s, 1H) 6.76 (s, 1H) 5.40 (s, 1H) 3.82 (s,
3H); m/z 260.
Method 43
2,5,6-Trichloro-N-(5-methoxy-1H-pyrazol-3-yl)pyrimidin-4-amine
[0369] To a solution of 2,4,5,6-tetrachloro-pyrimidine (2.18 g) in
absolute ethanol (100 mL) was added DIEPA (4.4 mL) and
5-methoxy-1H-pyrazol-3-amine hydrogen chloride salt (1.50 g). The
resulting solution was stirred at room temperature for over night.
The solvent was evaporated under reduced pressure. The crude
compound was purified by Gilson (10-60% MeCN/H.sub.2O, 15 minutes)
to give the titled compound as solid (0.76 g). m/z 294.
Method 44
2-Chloro-5-fluoro-N-(5-methyl-1H-pyrazol-3-yl)-6-morpholin-4-ylpyrimidin-4-
-amine
[0370] To a solution of 2,4,6-trichloro-5-fluoropyrimidine (4.03 g)
in absolute ethanol (100 mL) was added DIEPA (5.3 mL) and
5-methyl-1H-pyrazol-3-amine (2.03 g). The resulting solution was
stirred at room temperature for 6 hours. The precipitation was
filtered and washed with cold ethanol. The compound was dried by
vacuum oven give
2,6-dichloro-5-fluoro-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine
as solid (3.7 g). m/z 262. A mixture of morpholine (0.181 mL),
2,6-dichloro-5-fluoro-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine
(500 mg) and DIPEA (0.505 ml) in absolute ethanol (10.0 ml) was
heated at 80.degree. C. for 5 hours. The solvent was removed under
reduced pressure and the residue was purified by Gilson (10-50%
MeCN/H.sub.2O, 15 minutes) to give the titled compound as solid
(236 mg). .sup.1H NMR .delta. 12.05 (bs, 1H) 9.57 (s, 1H) 6.21 (s,
1H) 3.67 (t, 4H) 3.57 (t, 4H) 2.22 (s, 3H); m/z 313.
Method 45
N-(5-Methoxy-1H-pyrazol-3-yl)-2-(methylsulfonyl)-6-(trifluoromethyl)pyrimi-
din-4-amine
[0371] To a solution of
4-chloro-2-(methylthio)-6-(trifluoromethyl)pyrimidine (2.29 g) in
absolute ethanol (50 mL) was added DIEPA (4.4 mL) and
5-methoxy-1H-pyrazol-3-amine hydrogen chloride salt (1.46 g). The
resulting solution was heated at 90.degree. C. for over night. The
solvent was evaporated under reduced pressure. The crude compound
was purified by Gilson (10-60% MeCN/H.sub.2O, 15 minutes) to give
N-(3-methoxy-1H-pyrazol-5-yl)-2-(methylthio)-6-(trifluoromethyl)pyrimidin-
-4-amine as solid (0.64 g). m/z 306.
N-(3-methoxy-1H-pyrazol-5-yl)-2-(methylthio)-6-(trifluoromethyl)pyrimidin-
-4-amine (240 mg) was dissolved in methylene chloride (5 mL), MCPBA
(529 mg) was added. The resulting solution was stirred at room
temperature for 0.5 hours and separate between methylene chloride
and saturated sodium carbonate water solution. The organic layer
was dried and solvent was removed under reduced pressure and low
temperature. The crude product (270 mg) was carried on to do next
step without further purification. m/z 338.
Method 46
2-Chloro-5-fluoro-N-(5-methoxy-1H-pyrazol-3-yl)-6-morpholin-4-ylpyrimidin--
4-amine
[0372] To a solution of 2,4,6-trichloro-5-fluoropyrimidine (2.01 g)
in absolute ethanol (50 mL) was added DIEPA (4.4 mL) and
5-methoxy-1H-pyrazol-3-amine (2.24 g). The resulting solution was
stirred at room temperature for over night. The solvent was removed
by reduced pressure and the residue was purified by Gilson (10-50%
MeCN/H.sub.2O, 15 minutes) to give the titled compound
2,6-dichloro-5-fluoro-N-(5-methoxy-1H-pyrazol-3-yl)pyrimidin-4-amine
as solid (0.776 g). m/z 278. A mixture of morpholine (0.256 mL),
2,6-dichloro-5-fluoro-N-(5-methoxy-1H-pyrazol-3-yl)pyrimidin-4-amine
(776 mg) and DIPEA (0.742 ml) in n-butanol (14.0 ml) was heated at
90.degree. C. for 5 hours. The solvent was removed under reduced
pressure and the residue was purified by Gilson (10-50%
MeCN/H.sub.2O, 15 minutes) to give the titled compound as solid
(310 mg). .sup.1H NMR 9.80 (s, 1H) 5.66 (s, 1H) 3.77 (s, 3H)
3.64-3.71 (m, 4H) 3.53-3.64 (m, 4H); m/z 329.
Method 47
N-{2,5-Dichloro-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-4-yl}-N-methy-
lmethanesulfonamide
[0373] Following a procedure similar to that of Method 32, the
title compound was prepared from
N-(2,5,6-trichloro-pyrimidin-4-yl)-N-methylmethanesulfonamide
(Method 48). MS: 351 (M+1).
Method 48
N-(2,5,6-Trichloro-pyrimidin-4-yl)-N-methylmethanesulfonamide
[0374] Following a procedure similar to that of Method 32, the
title compound was prepared from N-methylmethanesulfonamide and
2,4,5,6-tetrachloropyrimidine. MS: 290 (M+1).
Method 49
N-{2,5-Dichloro-6-[(5-isopropoxy-1H-pyrazol-3-yl)amino]pyrimidin-4-yl}-N,N-
',N'-trimethylsulfamide
[0375] Following a procedure similar to that of Method 29, the
title compound was prepared from
N,N',N'-trimethyl-N'-(2,5,6-trichloropyrimidin-4-yl)sulfamide
(Method 26). MS: 424 (M+1).
Method 50
5-Fluoropyrimidine-2-carbaldehyde
[0376] To a solution of 5-fluoropyrimidine-2-carbonitrile (Method
6, 1.0 g, 8.1 mmol) in anhydrous THF at -78.degree. C. was added a
solution of DIBAL-H (8.1 mL) over a period of 20 minutes. The
resulting mixture was stirred at this temperature for 2 hours
whereupon MeOH was added. The solution was allowed to warm to room
temperature whereupon a solution of conc. HCl was added. The
resulting mixture was stirred for 2 hours at ambient temperature
and the aqueous layer was washed with EtOAc (3.times.). The
combined organic extracts were washed with brine and dried
(MgSO.sub.4). Evaporation of the solvent afforded the titled
compound (780 mg, 76%). MS: [M+H].sup.+ 127.
Method 51
N-[(5-Fluoropyrimidin-2-yl)methylene]-2-(R)-methylpropane-2-sulfinamide
[0377] To a solution of 5-fluoropyrimidine-2-carbaldehyde (Method
50, 1.55 g, 12.3 mmol) in anhydrous DCM at room temperature were
added 2-(R)-methylpropane-2-sulfinamide (1.79 g, 14.7 mmol) and
anhydrous copper(II) sulphate (1.96 g, 12.28 mmol). The resulting
mixture was stirred at this temperature for 24 hours, the solid was
filtered under vacuum, washed with DCM (3.times.) and evaporation
of the solvents afforded a yellow oil. The resulted residue was
purified by column chromatography (Hex-EtOAc=3:1) to give the title
compound (1.94 g, 69%). .sup.1H NMR (300 MHz, DMSO-D6) ppm 9.13 (s,
2H) 8.47 (s, 1H) 0.99 (s, 9H). MS:[M+H].sup.+ 232.
The procedure described in Method 51 may be used to obtain
N-[(5-fluoropyrimidin-2-yl)methylene]-2-(S)-methylpropane-2-sulfinamide
by replacing 2-(R)-methylpropane-2-sulfinamide with
2-(S)-methylpropane-2-sulfinamide as a starting material.
Method 52
N-[(1S)-1-(5-Fluoropyrimidin-2-yl)ethyl]-(2R)-methylpropane-2-sulfinamide
[0378] To a solution of
N-[(5-fluoropyrimidin-2-yl)methylene]-2-(R)-methylpropane-2-sulfinamide
(Method 51, 1.94 g, 8.5 mmol) in anhydrous THF at -20.degree. C.
was added slowly a solution of MeMgBr (9.3 mL g, 9.3 mmol). The
resulting mixture was stirred at this temperature for 3 hours
whereupon it partitioned between H.sub.2O and EtOAc. The aqueous
layer was extracted with EtOAc (3.times.) washed with brine, dried
(MgSO.sub.4). Evaporation of the solvents under reduced pressure
under vacuum afforded yellow oil. The resulted residue was purified
by column chromatography (100% EtOAc) to give the title compound
(660 mg, 50%). .sup.1H NMR (300 MHz, DMSO-D6) ppm 8.89 (s, 2H) 5.53
(d, 1H) 4.43-4.65 (m, 1H) 1.46 (d, 3H) 1.11 (s, 9H). MS:[M+H].sup.+
246
[0379] The procedure described in Method 52 may be used to obtain
N-[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]-(2S)-methylpropane-2-sulfinamide
by replacing
N-[(5-fluoropyrimidin-2-yl)methylene]-2-(R)-methylpropane-2-sulfinamide
with
N-[(5-fluoropyrimidin-2-yl)methylene]-2-(S)-methylpropane-2-sulfinam-
ide as a starting material.
Method 53
(S)-1-(5-Fluoropyrimidin-2-yl)ethanamine hydrochloride
[0380] To a solution of
N-[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]-(2R)-methylpropane-2-sulfinamide
(Method 52, 655 mg, 2.67 mmol) in dry dioxane (20 ml) was added HCl
(3.4 ml, 13.3 mmol) in dioxane. The reaction was stirred at room
temperature for 3 hours. The solvent was removed to give the title
compound as white solid (quantitative). MS: Calcd.: 141. Found:
[M+H].sup.+ 142.
[0381] (S)-1-(5-Fluoropyrimidin-2-yl)ethanamine hydrochloride may
also obtained using the process described in Method 53 by replacing
N-[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]-(2R-methylpropane-2-sulfinamide
with
N-[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]-(25)-methylpropane-2-sulfin-
amide as a starting material.
UTILITY
[0382] The compounds of the present invention have utility for the
treatment of cancer by inhibiting the tyrosine kinases,
particularly the Trks and more particularly Trk A and B. Methods of
treatment target tyrosine kinase activity, particularly the Trk
activity and more particularly Trk A and B activity, which is
involved in a variety of cancer related processes. Thus, inhibitors
of tyrosine kinase, particularly the Trks and more particularly Trk
A and B, are expected to be active against neoplastic disease such
as carcinoma of the breast, ovary, lung, colon, prostate or other
tissues, as well as leukemias and lymphomas, tumours of the central
and peripheral nervous system, and other tumour types such as
melanoma, fibrosarcoma and osteosarcoma. Tyrosine kinase
inhibitors, particularly the Trk inhibitors and more particularly
Trk A and B inhibitors are also expected to be useful for the
treatment other proliferative diseases including but not limited to
autoimmune, inflammatory, neurological, and cardiovascular
diseases.
[0383] In addition, the compounds of the invention are expected to
be of value in the treatment or prophylaxis of cancers selected
with up regulated of constitutively activated Trk kinases,
including but not limited to, oncogenic rearrangements leading to
ETV6-TrkC fusions, TRP-TrkA fusions proteins, AML-ETO (t8; 21),
autocrine or paracrine signalling leading to elevated serum levels
of NGF, BDNF, neurotropins or tumours with constitutively active
Trk associated with disease aggressiveness, tumour growth and
proliferation or survival signalling.
[0384] Compounds of the present invention have been shown to
inhibit tyrosine kinases, particularly the Trks and more
particularly Trk A and B, as determined by the Trk A Assay
described herein.
[0385] Compounds provided by this invention should also be useful
as standards and reagents in determining the ability of a potential
pharmaceutical to inhibit tyrosine kinases, particularly the Trks
and more particularly Trk A and B. These would be provided in
commercial kits comprising a compound of this invention.
Trk A Assay Format
[0386] Trk A kinase activity was measured for its ability to
phosphorylate synthetic tyrosine residues within a generic
polypeptide substrate using an Amplified Luminescent Proximity
Assay (Alphascreen) technology (PerkinElmer, 549 Albany Street,
Boston, Mass.).
[0387] To measure Trk A kinase activity, the intracellular domain
of a HIS-tagged human Trk A kinase (amino acids 442-796 of Trk A,
Swiss-Prot Primary Accession Number P04629) was expressed in SF9
cells and purified using standard nickel column chromatography.
After incubation of the kinase with a biotinylated substrate and
adenosine triphosphate (ATP) for 20 minutes at room temperature,
the kinase reaction was stopped by the addition of 30 mM
ethylenediaminetetraacetic acid (EDTA). The reaction was performed
in 384 well microtitre plates and the reaction products were
detected with the addition of strepavidin coated Donor Beads and
phosphotyrosine-specific antibodies coated Acceptor Beads using the
EnVision Multilabel Plate Reader after an overnight incubation at
room temperature.
TABLE-US-00005 Peptide substrate PolyEY-biotin (PGT-bio.) ATP Km 70
.mu.M Assay conditions 0.838 ng/ml Trk A, 9 mM HEPES, 45 .mu.g/ml
BSA, 10 mM MnCl.sub.2, 5 nM PGT-bio, 0.01% Triton .RTM. X-100, 70
.mu.M ATP Incubation 20 minutes, room temperature
Termination/Detection 6.3 mM HEPES, 30 mM EDTA, conditions 525
.mu.g/ml BSA, 40 mM NaCl, 0.007% Triton .RTM. X-100, 12 ng/ml of
Donor Beads, 12 ng/ml of Acceptor Beads Detection incubation
overnight, room temperature Fluometer settings Excitation = 680 nM
Emission = 570 nM Excitation Time = 180 ms Total Measurement Time =
550 ms
[0388] Although the pharmacological properties of the compounds of
the formula (I) vary with structural change, in general activity
possessed by compounds of the formula (I) may be demonstrated at
IC.sub.50 concentrations (concentrations to achieve 50% inhibition)
or doses in the range of (0.01 .mu.M to 10 .mu.M).
[0389] When tested in the above in-vitro assay the Trk inhibitory
activity of the following example was measured at the following
IC.sub.50s.
TABLE-US-00006 Ex IC.sub.50 (.mu.M) 1 0.033
[0390] The compounds of the present invention have utility for the
treatment of myeloproliferative disorders, myelodysplastic syndrome
and cancer by inhibiting the tyrosine kinases, particularly the JAK
family and more particularly JAK2. Methods of treatment target
tyrosine kinase activity, particularly the JAK family activity and
more particularly JAK2 activity, which is involved in a variety of
myeloproliferative disorders, myelodysplastic syndrome and cancer
related processes. Thus, inhibitors of tyrosine kinase,
particularly the JAK family and more particularly JAK2, are
expected to be active against myeloproliferative disorders such as
chronic myeloid leukemia, polycythemia vera, essential
thrombocythemia, myeloid metaplasia with myelofibrosis, idiopathic
myelofibrosis, chronic myelomonocytic leukemia and
hypereosinophilic syndrome, myelodysplastic syndromes and
neoplastic disease such as carcinoma of the breast, ovary, lung,
colon, prostate or other tissues, as well as leukemias, myelomas
and lymphomas, tumours of the central and peripheral nervous
system, and other tumour types such as melanoma, fibrosarcoma and
osteosarcoma. Tyrosine kinase inhibitors, particularly the JAK
family inhibitors and more particularly JAK2 inhibitors are also
expected to be useful for the treatment other proliferative
diseases including but not limited to autoimmune, inflammatory,
neurological, and cardiovascular diseases.
[0391] The compounds of the present invention have been shown to
inhibit tyrosine kinases, particularly the JAK family and more
particularly JAK2, as determined by the JAK2 Assay described
herein.
[0392] The compounds provided by this invention should also be
useful as standards and reagents in determining the ability of a
potential pharmaceutical to inhibit tyrosine kinases, particularly
the JAK family and more particularly JAK2. These would be provided
in commercial kits comprising a compound of this invention.
JAK2 Assay
[0393] JAK2 kinase activity was measured for its ability to
phosphorylate synthetic tyrosine residues within a generic
polypeptide substrate using an Amplified Luminescent Proximity
Assay (Alphascreen) technology (PerkinElmer, 549 Albany Street,
Boston, Mass.).
[0394] To measure JAK2 kinase activity, commercially available
purifed enzyme, C-terminal His6-tagged, recombinant, human JAK2,
amino acids 808-end, (Genbank Accession number NM 004972) expressed
by baculovirus in Sf21 cells from Upstate Biotechnology #14-640 was
used. After incubation of the kinase with a biotinylated substrate
and adenosine triphosphate (ATP) for 60 minutes at room
temperature, the kinase reaction was stopped by the addition of 30
mM ethylenediaminetetraacetic acid (EDTA). The reaction was
performed in 384 well microtitre plates and the reaction products
were detected with the addition of streptavidin coated Donor Beads
and phosphotyrosine-specific antibodies coated Acceptor Beads using
the EnVision Multilabel Plate Reader after an overnight incubation
at room temperature.
TABLE-US-00007 Peptide substrate TYK2 (Tyr 1054/1055 biotinylated
peptide) Cell Signalling Technology #2200B. 402 uM stock. ATP Km 30
.mu.M Assay conditions 150 pM JAK2 enzyme, 30 uM ATP, 80 nM Tyk2,
10 mM MgCl.sub.2, 50 mM Hepes buffer pH 7.5, 1 mM DTT, 0.025% DTT.
Incubation 60 minutes, room temperature Termination/Detection 6.3
mM HEPES, 30 mM EDTA, conditions 525 .mu.g/ml BSA, 40 mM NaCl,
0.007% Triton .RTM. X-100, 12 ng/ml of Donor Beads, 12 ng/ml of
Acceptor Beads Detection incubation overnight, room temperature
Fluometer settings Excitation = 680 nM Emission = 570 nM Excitation
Time = 180 ms Total Measurement Time = 550 ms
[0395] When tested in the above in-vitro assay the JAK inhibitory
activity of the following example was measured at the following
IC.sub.50.
TABLE-US-00008 Ex IC.sub.50 (nM) 7 3.9
* * * * *