U.S. patent application number 13/617881 was filed with the patent office on 2013-01-10 for compounds and compositions as protein kinase inhibitors.
Invention is credited to Guido BOLD, Werner BREITENSTEIN, Giorgio CARAVATTI, Qiang DING, Pascal FURET, Nathanael Schiander GRAY, Vito GUAGNANO, Marc LANG, Bing LI, Yi LIU, Paul W. MANLEY, Carole Pissot Soldermann, Joseph SCHOEPFER, Taebo SIM, Carsten SPANKA, Tetsuo UNO, Guobao ZHANG.
Application Number | 20130012704 13/617881 |
Document ID | / |
Family ID | 34855683 |
Filed Date | 2013-01-10 |
United States Patent
Application |
20130012704 |
Kind Code |
A1 |
DING; Qiang ; et
al. |
January 10, 2013 |
COMPOUNDS AND COMPOSITIONS AS PROTEIN KINASE INHIBITORS
Abstract
The invention relates to compounds of formula (I) ##STR00001##
wherein the substituents X.sup.1, R.sup.1, R.sup.2, R.sup.3 and
R.sup.4 have the meaning as set forth and explained in the
description of the invention, to processes for the preparation of
these compounds, pharmaceutical compositions containing same, the
use thereof optionally in combination with one or more other
pharmaceutically active compounds for the therapy of a disease
which responds to an inhibition of protein kinase activity, and a
method for the treatment of such a disease.
Inventors: |
DING; Qiang; (Beijing,
CN) ; GRAY; Nathanael Schiander; (Boston, MA)
; LI; Bing; (Westborough, MA) ; LIU; Yi;
(San Diego, CA) ; SIM; Taebo; (Seoul, KR) ;
UNO; Tetsuo; (San Diego, CA) ; ZHANG; Guobao;
(San Diego, CA) ; Pissot Soldermann; Carole;
(Village Neuf, FR) ; BREITENSTEIN; Werner; (Basel,
CH) ; BOLD; Guido; (Gipf-Oberfrick, CH) ;
CARAVATTI; Giorgio; (Bottmingen, CH) ; FURET;
Pascal; (Thann, FR) ; GUAGNANO; Vito; (Basel,
CH) ; LANG; Marc; (Mulhouse, FR) ; MANLEY;
Paul W.; (Arlesheim, CH) ; SCHOEPFER; Joseph;
(Riehen, CH) ; SPANKA; Carsten; (Lorrach,
DE) |
Family ID: |
34855683 |
Appl. No.: |
13/617881 |
Filed: |
September 14, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11570983 |
Oct 15, 2008 |
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PCT/EP2005/006815 |
Jun 23, 2005 |
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13617881 |
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60582425 |
Jun 24, 2004 |
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Current U.S.
Class: |
544/122 ;
544/295; 544/322; 560/358; 564/442 |
Current CPC
Class: |
A61P 9/10 20180101; A61P
19/00 20180101; A61P 35/00 20180101; A61P 7/02 20180101; A61P 17/06
20180101; A61P 11/06 20180101; A61P 37/02 20180101; C07D 401/12
20130101; A61P 3/10 20180101; A61P 43/00 20180101; A61P 29/00
20180101; A61P 15/00 20180101; C07D 239/48 20130101; C07D 409/12
20130101; A61P 19/08 20180101; C07D 403/12 20130101; A61P 35/02
20180101; A61P 37/06 20180101; A61P 13/12 20180101; A61P 37/00
20180101; A61P 35/04 20180101; C07D 405/12 20130101; C07D 251/48
20130101; A61P 27/02 20180101 |
Class at
Publication: |
544/122 ;
544/295; 564/442; 560/358; 544/322 |
International
Class: |
C07D 403/12 20060101
C07D403/12; C07C 265/12 20060101 C07C265/12; C07D 413/12 20060101
C07D413/12; C07D 405/12 20060101 C07D405/12; C07D 409/14 20060101
C07D409/14; C07D 401/12 20060101 C07D401/12; C07D 401/14 20060101
C07D401/14; C07C 217/84 20060101 C07C217/84; C07D 239/48 20060101
C07D239/48 |
Foreign Application Data
Date |
Code |
Application Number |
Jun 16, 2005 |
GB |
0512324.5 |
Claims
1. A process for the preparation of a compound of formula (I):
##STR00346## wherein the following fragment is referred to as the
"left hand ring" ##STR00347## the left hand ring wherein X.sup.1 is
oxygen, X is C--R.sup.5, R.sup.5 is H, R.sup.2 is H, and Y and Z
are both N, whereby the left hand ring has the structure of
Fragment (B): ##STR00348## wherein R.sup.1 is of the formula
R.sup.z--NR.sup.a-- wherein R.sup.a is hydrogen; and R.sup.z is
##STR00349## a group of the formula where: ring A represents a
6-membered carbocyclic or heterocyclic ring; m is 0, 1 or 2; the or
each R.sup.b is independently selected from
-L.sup.2-NR.sup.cR.sup.d; -L.sup.2-RING where RING is a mono- or
bi-cyclic ring optionally substituted as defined below; halogen;
hydroxy; protected hydroxyl; amino; amidino; guanidino;
hydroxyguanidino; formamidino; isothioureido; ureido; mercapto;
acyl having 4 in-chain atoms; acyloxy having 4 in-chain atoms;
carboxy; sulfo; sulfamoyl; carbamoyl; cyano; azo; or nitro; and
linear or branched alkyl having 1, 2, 3 or 4 carbon atoms
optionally substituted by one or more halogens and/or one or two
functional groups selected from hydroxy, protected hydroxy, amino,
amidino, guanidino, hydroxyguanidino, formamidino, isothioureido,
ureido, mercapto, acyl having 4 in-chain atoms, acyloxy having 4
in-chain atoms, carboxy, sulfo, sulfamoyl, carbamoyl, cyano, azo,
or nitro; all of which hydroxy, amino, amidino, guanidino,
hydroxyguanidino, formamidino, isothioureido, ureido, mercapto,
carboxy, sulfo, sulfamoyl, carbamoyl and cyano groups are in turn
optionally substituted on at least one heteroatom by one or, where
possible, more C.sub.1-C.sub.7 aliphatic groups, wherein L.sup.2 is
a direct bond; a linkage selected from --O--; --S--; --C(O)--;
--OC(O)--; --NR.sup.aC(O)--; --C(O)--NR.sup.a--;
--OC(O)--NR.sup.a--; cyclopropyl and --NR.sup.a--; or is a linear
or branched alkyl group having 1, 2, 3 or 4 carbon atoms optionally
interrupted and/or terminated at a single end or at both ends by a
said linkage; and wherein R.sup.c and R.sup.d are each
independently selected from hydrogen, and linear or branched alkyl
having 1, 2, 3 or 4 carbon atoms optionally substituted by one or
more halogens, by an optionally substituted 5- or 6-membered
heterocyclic or carbocyclic ring, and/or one or two functional
groups selected from hydroxy, protected hydroxy, amino, amidino,
guanidino, hydroxyguanidino, formamidino, isothioureido, ureido,
mercapto, acyl having 4 in-chain atoms, acyloxy having 4 in-chain
atoms, carboxy, sulfo, sulfamoyl, carbamoyl, cyano, azo, or nitro,
which hydroxy, amino, amidino, guanidino, hydroxyguanidino,
formamidino, isothioureido, ureido, mercapto, carboxy, sulfo,
sulfamoyl, carbamoyl and cyano groups are in turn optionally
substituted on at least one heteroatom by one or more
C.sub.1-C.sub.7 aliphatic groups, or R.sup.c and R.sup.d together
with their adjoining nitrogen form a 5- or 6-membered ring
optionally substituted as described below, said optionally
substituted rings independently of each other being substituted by
0, 1, 2, 3, 4 or 5 substituents selected from halogen; hydroxy;
protected hydroxy; amino; amidino; guanidino; hydroxyguanidino;
formamidino; isothioureido; ureido; mercapto; acyl having 4
in-chain atoms; acyloxy having 4 in-chain atoms; carboxy; sulfo;
sulfamoyl; carbamoyl; cyano; azo; nitro; C.sub.1-C.sub.7 aliphatic
optionally substituted by one or more halogens and/or one or two
functional groups selected from hydroxy, protected hydroxy, amino,
amidino, guanidino, hydroxyguanidino, formamidino, isothioureido,
ureido, mercapto, acyl having 4 in-chain atoms, acyloxy having 4
in-chain atoms, carboxy, sulfo, sulfamoyl, carbamoyl, cyano, azo,
or nitro; all of the aforesaid hydroxy, amino, amidino, guanidino,
hydroxyguanidino, formamidino, isothioureido, ureido, mercapto,
carboxy, sulfo, sulfamoyl and carbamoyl groups in turn optionally
being substituted on at least one heteroatom by one or, where
possible, more C.sub.1-C.sub.7 aliphatic groups; R.sup.3 is H, a
straight chain or branched C.sub.1-C.sub.4 alkyl or a straight
chain or branched C.sub.1-C.sub.4 alkyl substituted by a 5- or
6-membered saturated or unsaturated carbocyclic or heterocyclic
ring; or pharmaceutically acceptable salts, hydrates, solvates,
esters, N-oxides, protected derivatives, individual stereoisomers
and mixture of stereoisomers thereof; said process comprising, a)
reacting 4,6-Dichloropyrimidine, ##STR00350## with a compound of
formula R.sup.3NH.sub.2 to provide a compound of formula:
##STR00351## b) reacting said compound of formula: ##STR00352##
with a compound of formula R.sup.zNH.sub.2 to provide a compound of
formula: ##STR00353## and then, b) reacting said compound of
formula: ##STR00354## with
2,6-dichloro-3,5-dimethoxyphenylisocyanate.
2. The process according to claim 1, wherein said
2,6-dichloro-3,5-dimethoxyphenylisocyanate is obtained by reacting
2,6-dichloro-3,5-dimethoxyaniline with phosgene (COCl.sub.2).
3. The process according to claim 1, wherein the left hand ring has
a structure corresponding to Fragment (D1), (D2), (E1) or (E2):
##STR00355##
4. The process according to claim 3, wherein the phenyl ring of
said Fragments has 1, 2, 3 or 4 further substituents, selected from
halogen, methyl, methoxy and trifluoromethyl.
5. The process according to claim 1 wherein RING is a saturated
heterocycle which contains an in-ring nitrogen.
6. The process according to claim 1 in which the compound of
formula (I) contains a moiety NR.sup.cR.sup.d and wherein R.sup.c
and R.sup.d are the same or different and selected from straight
chain or branched alkyl having 1, 2, 3 or 4 carbon atoms.
7. The process according to claim 1 in which the compound of
formula (I) contains a moiety NR.sup.cR.sup.d and wherein R.sup.c
and R.sup.d together with the adjoining nitrogen form a 5- or
6-membered heterocyclic ring, optionally substituted as by 0, 1, 2,
3, 4 or 5 substituents selected from straight chain or branched
C.sub.1, C.sub.2, C.sub.3 or C.sub.4 alkyl, halogen and C.sub.1,
C.sub.2, C.sub.3 or C.sub.4 alkoxy, wherein alkyl and the alkyl
part of alkoxy are unsubstituted or substituted by halogen.
8. The process according to claim 7 wherein L.sup.2NR.sup.cR.sup.d
is selected from -Pip, -Morph, --OCH.sub.2Pip, --OCH.sub.2-Morph,
--OCH.sub.2CH.sub.2Pip, --OCH.sub.2CH.sub.2-Morph,
--OCH.sub.2CH.sub.2CH.sub.2Pip, --OCH.sub.2CH.sub.2CH.sub.2-Morph,
--CH.sub.2Pip, --CH.sub.2-Morph, --CH.sub.2CH.sub.2Pip,
--CH.sub.2CH.sub.2-Morph, --CH.sub.2CH.sub.2CH.sub.2Pip,
--CH.sub.2CH.sub.2CH.sub.2-Morph, --C(O)Pip and --C(O)Morph, where
"Pip" stands for piperazine and "Morph" for morpholine, piperazine
optionally being N-substituted by straight chain or branched
C.sub.1, C.sub.2, C.sub.3 or C.sub.4 alkyl.
9. The process according to claim 3 wherein the left hand ring has
the structure of the following Fragment (F): ##STR00356##
10. The process according to claim 1, wherein the compound
according to formula (I) is selected from:
3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-methyl-1-{6-[4-(4-methyl-piperazi-
n-1-yl)-phenylamino]-pyrimidin-4-yl}-urea;
3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-methyl-1-{6-[3-(4-methyl-piperazi-
n-1-yl)-phenylamino]-pyrimidin-4-yl}-urea;
3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-ethyl-1-{6-[4-(4-methyl-piperazin-
e-1-carbonyl)-phenylamino]-pyrimidin-4-yl}-urea;
3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-ethyl-1-{6-[4-(4-methyl-piperazin-
-1-yl)-phenylamino]-pyrimidin-4-yl}-urea;
3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-[6-(3-dimethylaminomethyl-phenyla-
mino)-pyrimidin-4-yl]-1-methyl-urea;
3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-ethyl-piperazin-1-yl)-ph-
enylamino]-pyrimidin-4-yl}-1-methyl-urea;
3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-methyl-1-(6-{4-[3-(4-methyl-piper-
azin-1-yl)-propoxy]-phenylamino}-pyrimidin-4-yl)-urea;
3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(3-dimethylamino-propyl)-ph-
enylamino]-pyrimidin-4-yl}-1-methyl-urea;
3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-methyl-1-{6-[4-(2-pyrrolidin-1-yl-
-ethoxy)-phenylamino]-pyrimidin-4-yl}-urea;
3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-ethyl-piperazin-1-ylmeth-
yl)-phenylamino]-pyrimidin-4-yl}-1-methyl-urea;
3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-{6-[3-(4-ethyl-piperazin-1-ylmeth-
yl)-phenylamino]-pyrimidin-4-yl}-1-methyl-urea;
3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-[6-(3-dimethylaminomethyl-phenyla-
mino)-pyrimidin-4-yl]-1-ethyl-urea;
3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(2-diethylamino-ethoxy)-phe-
nylamino]-pyrimidin-4-yl}-1-methyl-urea;
3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-[6-(2,6-dimethyl-pyridin-3-ylamin-
o)-pyrimidin-4-yl]-1-methyl-urea;
3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-methyl-1-[6-(6-trifluoromethyl-py-
ridin-3-ylamino)-pyrimidin-4-yl]-urea;
1-(2,6-Dichloro-3,5-dimethoxy-phenyl)-3-{6-[4-(2-pyrrolidin-1-yl-ethoxy)--
phenylamino]-pyrimidin-4-yl}-urea;
3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-ethyl-1-{6-[4-(2-pyrrolidin-1-yl--
ethoxy)-phenylamino]-pyrimidin-4-yl}-urea;
1-(2,6-Dichloro-3,5-dimethoxy-phenyl)-3-[6-(3-dimethylaminomethyl-phenyla-
mino)-pyrimidin-4-yl]-urea;
1-(2,6-Dichloro-3,5-dimethoxy-phenyl)-3-(6-{4-[2-(4-methyl-piperazin-1-yl-
)-ethoxy]-phenylamino}-pyrimidin-4-yl)-urea;
1-(2,6-Dichloro-3,5-dimethoxy-phenyl)-3-[6-(4-dimethylaminomethyl-3-trifl-
uoromethyl-phenylamino)-pyrimidin-4-yl]-urea;
1-(2,6-Dichloro-3,5-dimethoxy-phenyl)-3-{6-[4-(4-ethyl-piperazin-1-yl)-ph-
enylamino]-pyrimidin-4-yl}-urea;
3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-{6-[3-(4-isopropyl-piperazin-1-yl-
methyl)-phenylamino]-pyrimidin-4-yl}-1-methyl-urea;
3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-[6-(3-{[(2-dimethylamino-ethyl)-m-
ethyl-amino]-methyl}-phenylamino)-pyrimidin-4-yl]-1-methyl-urea;
3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-isopropyl-piperazin-1-yl-
)-phenylamino]-pyrimidin-4-yl}-1-methyl-urea;
1-(2,6-Dichloro-3,5-dimethoxy-phenyl)-3-{6-[4-(1-methyl-piperidin-4-yloxy-
)-phenylamino]-pyrimidin-4-yl}-urea;
3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-methyl-{6-[4-(1-methyl-piperidin--
4-yloxy)-phenylamino]-pyrimidin-4-yl}-urea;
3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-ethyl-{6-[4-(1-methyl-piperidin-4-
-yloxy)-phenylamino]-pyrimidin-4-yl}-urea;
3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-[6-(4-dimethylaminomethyl-3-trifl-
uoromethyl-phenylamino)-pyrimidin-4-yl]-1-methyl-urea;
1-(2,6-Dichloro-3,5-dimethoxy-phenyl)-3-{6-[4-(4-ethyl-piperazin-1-ylmeth-
yl)-3-trifluoromethyl-phenylamino]-pyrimidin-4-yl}-urea;
3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-ethyl-piperazin-1-ylmeth-
yl)-3-trifluoromethyl-phenylamino]-pyrimidin-4-yl}-methyl-urea;
1-(2,6-Dichloro-3,5-dimethoxy-phenyl)-3-{6-[4-(4-isopropyl-piperazin-1-yl-
)-phenylamino]-pyrimidin-4-yl}-urea;
3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-methyl-1-(6-{4-[2-(4-methyl-piper-
azin-1-yl)-ethoxy]-phenylamino}-pyrimidin-4-yl)-urea;
3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-isopropyl-piperazin-1-yl-
)-phenylamino]-pyrimidin-4-yl}-1-methyl-urea;
1-(2,6-Dichloro-3,5-dimethoxy-phenyl)-3-[6-(4-dimethylaminomethyl-3-trifl-
uoromethyl-phenylamino)-pyrimidin-4-yl]-urea;
3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-[6-(4-dimethylaminomethyl-3-trifl-
uoromethyl-phenylamino)-pyrimidin-4-yl]-1-methyl-urea;
3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-[6-(3-{[(2-dimethylamino-ethyl)-m-
ethyl-amino]-methyl}-phenylamino)-pyrimidin-4-yl]-1-methyl-urea;
3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-{6-[3-(4-isopropyl-piperazin-1-yl-
methyl)-phenylamino]-pyrimidin-4-yl}-1-methyl-urea;
1-(2,6-Dichloro-3,5-dimethoxy-phenyl)-3-{6-[3-(1-methyl-piperidin-4-yloxy-
)-phenylamino]-pyrimidin-4-yl}-urea;
3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-methyl-{6-[3-(1-methyl-piperidin--
4-yloxy)-phenylamino]-pyrimidin-4-yl}-urea; and
3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-[6-(3-diethylaminomethyl-phenylam-
ino)-pyrimidin-4-yl]-1-methyl-urea.
11. The process according to claim 10, wherein the compound
according to formula (I) is
3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-ethyl-piperazin-1-yl)-ph-
enylamino]-pyrimidin-4-yl}-1-methyl-urea.
12. The process according to claim 10, wherein the compound
according to formula (I) is
1-(2,6-Dichloro-3,5-dimethoxy-phenyl)-3-{6-[4-(4-ethyl-piperazin-1-yl)-ph-
enylamino]-pyrimidin-4-yl}-urea.
13. The process according to claim 1, wherein the compound
according to formula: ##STR00357## is
N-[4-(4-ethyl-piperazin-1-yl)-phenyl]-N'-methyl-pyrimidine-4,6-diamine.
14. The compound 2,6-dichloro-3,5-dimethoxyaniline.
15. The compound 2,6-dichloro-3,5-dimethoxyphenylisocyanate.
16. The compound
N-[4-(4-ethyl-piperazin-1-yl)-phenyl]-N'-methyl-pyrimidine-4,6-diamine.
Description
[0001] The invention relates to novel compounds, formulations,
methods and uses. More particularly it relates to compounds, which
may be described as heteroaryl aryl ureas, useful for the treatment
of protein kinase dependent diseases, or for the manufacture of
pharmaceutical compositions for use in the treatment of said
diseases. The invention further relates to methods of use of such
compounds in the treatment of said diseases, pharmaceutical
preparations comprising heteroaryl aryl ureas, and processes for
the manufacture of heteroaryl aryl ureas. The invention relates to
other subject matter as disclosed below.
BACKGROUND
[0002] Protein kinases (PKs) are enzymes which catalyze the
phosphorylation of specific serine, threonine or tyrosine residues
in cellular proteins. These post-translational modifications of
substrate proteins act as molecular switch regulating cell
proliferation, activation and/or differentiation. Aberrant or
excessive PK activity has been observed in many disease states
including benign and malignant proliferative disorders. In many
cases, it has been possible to treat diseases in vitro and in many
cases in vivo, such as proliferative disorders, by making use of PK
inhibitors.
[0003] The kinases fall largely into two groups, those specific for
phosphorylating serine and threonine, and those specific for
phosphorylating tyrosine. Some kinases, referred to as "dual
specificity" kinases, are able to phosphorylate tyrosine as well as
serine/threonine residues.
[0004] Protein kinases can also be characterized by their location
within the cell. Some kinases are transmembrane receptor proteins
capable of binding ligands external to the cell membrane. Binding
the ligands alters the receptor protein kinase's catalytic
activity. Others are non-receptor proteins lacking a transmembrane
domain and yet others are ecto-kinases that have a catalytic domain
on the extracellular (ecto) portion of a transmembrane protein or
which are secreted as soluble extracellular proteins.
[0005] Many kinases are involved in regulatory cascades where their
substrates may include other kinases whose activities are regulated
by their phosphorylation state. Thus, activity of a downstream
effector is modulated by phosphorylation resulting from activation
of the pathway.
[0006] Receptor protein tyrosine kinases (RPTKs) are a sub-class of
transmembrane-spanning receptors endowed with intrinsic,
ligand-stimulatable tyrosine kinase activity. RPTK activity is
tightly controlled. When mutated or altered structurally, RPTKs can
become potent oncoproteins, causing cellular transformation. In
principle, for all RPTKs involved in cancer, oncogenic deregulation
results from relief or perturbation of one or several of the
autocontrol mechanisms that ensure the normal repression of
catalytic domains. More than half of the known RPTKs have been
repeatedly found in either mutated or overexpressed forms
associated with human malignancies (including sporadic cases;
Blume-Jensen et al., Nature 411: 355-365 (2001)).
[0007] RPTK over expression leads to constitutive kinase activation
by increasing the concentration of dimers. Examples are Neu/ErbB2
and epidermal growth factor receptor (EGFR), which are often
amplified in breast and lung carcinomas and the fibroblast growth
factors (FGFR) associated with skeletal and proliferative disorders
(Blume-Jensen et al., 2001).
[0008] Angiogenesis is the mechanism by which new capillaries are
formed from existing vessels. When required, the vascular system
has the potential to generate new capillary networks in order to
maintain the proper functioning of tissues and organs. In the
adult, however, angiogenesis is fairly limited, occurring only in
the process of wound healing and neovascularization of the
endometrium during menstruation. See Merenmies et al., Cell Growth
& Differentiation, 8, 3-10 (1997). On the other hand, unwanted
angiogenesis is a hallmark of several diseases, such as
retinopathies, psoriasis, rheumatoid arthritis, age-related macular
degeneration (AMD), and cancer (solid tumors). Folkman, Nature
Med., 1, 27-31 (1995). Protein kinases which have been shown to be
involved in the angiogenic process include three members of the
growth factor receptor tyrosine kinase family: VEGF-R2 (vascular
endothelial growth factor receptor 2, also known as KDR (kinase
insert domain receptor) and as FLK-1); FGF-R (fibroblast growth
factor receptor); and TEK (also known as Tie-2).
[0009] TEK (also known as Tie-2) is a receptor tyrosine kinase
expressed only on endothelial cells which has been shown to play a
role in angiogenesis. The binding of the factor angiopoietin-1
results in autophosphorylation of the kinase domain of TEK and
results in a signal transduction process which appears to mediate
the interaction of endothelial cells with peri-endothelial support
cells, thereby facilitating the maturation of newly formed blood
vessels. The factor angiopoietin-2, on the other hand, appears to
antagonize the action of angiopoietin-1 on TEK and disrupts
angiogenesis. Maisonpierre et al., Science, 277, 55-60 (1997).
[0010] Administration of Ad-ExTek, a soluble adenoviral expressed
extracellular domain of Tie-2, inhibited tumour metastasis when
delivered at the time of surgical excision of primary tumours in a
clinically relevant mouse model of tumor metastasis (Lin et al.,
Proc Natl Acad Sci USA 95, 8829-8834 (1998)). The inhibition of
Tie-2 function by ExTek may be a consequence of sequestration of
the angiopoietin ligand and/or heterodimerisation with the native
Tie-2 receptor. This study demonstrates that disruption of Tie-2
signalling pathways, first, may be well tolerated in healthy
organisms and, second, may provide therapeutic benefit.
[0011] The Philadelphia Chromosome is a hallmark for chronic
myelogenous leukaemia (CML) and carries a hybrid gene that contains
N-terminal exons of the bcr gene and the major C-terminal part
(exons 2-11) of the c-abl gene. The gene product is a 210 kD
protein (p210 Bcr-Abl). The Abl-part of the Bcr-Abl protein
contains the abl-tyrosine kinase which is tightly regulated in the
wild type c-abl, but constitutively activated in the Bcr-Abl fusion
protein. This deregulated tyrosine kinase interacts with multiple
cellular signalling pathways leading to transformation and
deregulated proliferation of the cells (Lugo et al., Science 247,
1079 [1990]).
[0012] Mutant forms of the Bcr-Abl protein have also been
identified. A detailed review of Bcr-Abl mutant forms has been
published (Cowan-Jones et al, Mini Reviews in Medicinal Chemistry,
2004, 4 285-299).
[0013] EphB4 (also named HTK) and its ligand, ephrinB2 (HTKL) have
critical roles in establishing and determining vascular networks.
On the venous epithelium, EphB4 is expressed specifically, while,
during early stages of vascular development, ephrinB2 is
specifically and reciprocally expressed on arterial endothelial
cells. Dysfunctional genes lead to embryonic lethality in mice, and
the embryos show identical defects in forming capillary connections
in case of either defect ephrinB2 and EphB4. Both are expressed at
the first site of hematopoiesis and vascular development during
embryogenesis. An essential role for proper hematopoietic,
endothelial, hemangioblast and primitive mesoderm development was
established. EphB4 deficiency results in an alteration in the
mesodermal differentiation outcome of embryonic stem cells. Ectopic
expression of EphB4 in mammary tissue results in disordered
architecture, abnormal tissue function and a predisposition to
malignancy (see e.g. N. Munarini et al., J. Cell. Sci. 115, 25-37
(2002)). From these and other data, it has been concluded that
inadequate EphB4 expression may be involved in the formation of
malignancies and thus that inhibition of EphB4 can be expected to
be a tool to combat malignancies, e.g. cancer and the like.
[0014] c-Src (also known as p60 c-Src) is cytosolic, non-receptor
tyrosine kinase. c-Src is involved in the transduction of mitogenic
signals from a number of polypeptide growth factors such as
epidermal growth factor (EGF) and platelet-derived growth factor
(PDGF). c-Src is over expressed in mammary cancers, pancreatic
cancers, neuroblastomas, and others. Mutant c-Src has been
identified in human colon cancer. c-Src phosphorylates a number of
proteins that are involved in regulating cross-talk between the
extracellular matrix and the cytoplasmic actin cytoskeleton.
Modulation cSrc activity could have implications in diseases
relating to cell proliferation, differentiation and death. See
Bjorge, J. D., et. al. (2000) Oncogene 19(49):5620-5635; Halpern,
M. S., et. al. (1996) Proc. Natl. Acad. Sci. U.S.A. 93(2), 824-7;
Belsches, A. P., et. al. (1997) Frontiers in Bioscience [Electronic
Publication] 2:D501-D518; Zhan, X., et. al (2001) Chemical Reviews
101: 2477-2496; Haskell, M. D., et. al. (2001) Chemical Reviews
101: 2425-2440.
[0015] The fms-like tyrosine kinase 3 (FLT3) receptor tyrosine
kinase is now recognized to be a critical mediator in the
pathogenesis of myeloid and some lymphoid leukemias. Activation of
FLT3 on leukemic cells by FLT3 ligand leads to receptor
dimerization and signal transduction in pathways that promote cell
growth and inhibit apoptosis (Blood, Vol. 98, No. 3, pp. 885-887
(2001)).
[0016] Use of tyrosine kinase inhibitors for AML therapy is
hindered by the acquisition of mutations in the kinase catalytic
domain, and in the case of BCR-ABL, these mutations confer
resistance to imatinib.
[0017] FLT3 is widely expressed in AML and some cases of acute
lymphocytic leukemia. Activating mutations in FLT3 confer a poor
risk in patients with AML. Thus, FLT3 is a promising target for
therapeutic intervention.
[0018] Platelet-derived growth factor receptor (PDGFR) tyrosine
kinase is expressed in a numberof tumours such as small-cell lung
cancer, prostate cancer, and glioblastoma as well as in the stromal
and vascular compartments of many tumors. Expression of both PDGF
and PDGF receptors (PDGFRs) has been observed in pancreatic cancer
(Ebert M et al., Int J Cancer, 62: 529-535 (1995).
Fibroblast Growth Factors
[0019] Normal growth, as well as tissue repair and remodeling,
require specific and delicate control of activating growth factors
and their receptors. Fibroblast Growth Factors (FGFs) constitute a
family of over twenty structurally related polypeptides that are
developmentally regulated and expressed in a wide variety of
tissues. FGFs stimulate proliferation, cell migration and
differentiation and play a major role in skeletal and limb
development, wound healing, tissue repair, hematopoiesis,
angiogenesis, and tumorigenesis (reviewed in Omitz, Novartis Found
Symp 232: 63-76; discussion 76-80, 272-82 (2001)).
[0020] The biological action of FGFs is mediated by specific cell
surface receptors belonging to the RPTK family of protein kinases.
These proteins consist of an extracellular ligand binding domain, a
single transmembrane domain and an intracellular tyrosine kinase
domain which undergoes phosphorylation upon binding of FGF. Four
FGFRs have been identified to date: FGFR1 (also called Flg,
fms-like gene, flt-2, bFGFR, N-bFGFR or Cek1), FGFR2 (also called
Bek-Bacterial Expressed Kinase-, KGFR, Ksam, Ksaml and Cek3), FGFR3
(also called Cek2) and FGFR4. All mature FGFRs share a common
structure consisting of an amino terminal signal peptide, three
extracellular immunoglobulin-like domains (Ig domain I, Ig domain
II, Ig domain III), with an acidic region between Ig domains
(the"acidic box" domain), a transmembrane domain, and intracellular
kinase domains (Ullrich and Schlessinger, Cell 61: 203, 1990;
Johnson and Williams (1992) Adv. Cancer Res. 60: 1-41). The
distinct FGFR isoforms have different binding affinities for the
different FGF ligands, thus FGF8 (androgen-induced growth factor)
and FGF9 (glial activating factor) appear to have increased
selectivity for FGFR3 (Chellaiah et al. J. Biol. Chem. 1994; 269:
11620).
[0021] Another major class of cell surface binding sites includes
binding sites for heparan sulfateproteoglycans (HSPG) that are
required for high affinity interaction and activation of all
members of the FGF family. Tissue-specific expression of heparan
sulfate structural variants confer ligand-receptor specificity and
activityof FGFs
FGFR-Related Diseases
[0022] Recent discoveries show that a growing number of skeletal
abnormalities, including achondroplasia, the most common form of
human dwarfism, result from mutations in FGFRs.
[0023] Specific point mutations in different domains of FGFR3 are
associated with autosomal dominant human skeletal disorders
including hypochondroplasia, severe achondroplasia with
developmental delay and acanthosis nigricans (SADDAN) and
thanatophoric dysplasia (TD) (Cappellen et al., Nature Genetics,
23: 18-20 (1999); Webster et al., Trends Genetics 13 (5): 178-182
(1997); Tavormina et al., Am. J. Hum. Genet., 64: 722-731 (1999)).
FGFR3 mutations have also been described in two craniosynostosis
phenotypes: Muenke coronal craniosynostosis (Bellus et al., Nature
Genetics, 14: 174-176 (1996); Muenke et al., Am. J. Hum. Genet.,
60: 555-564 (1997)) and Crouzon syndrome with acanthosis nigricans
(Meyers et al., Nature Genetics, 11: 462-464 (1995)). Crouzon
syndrome is associated with specific point mutations in FGFR2 and
both familial and sporadic forms of Pfeiffer syndrome are
associated with mutations in FGFR1 and FGFR2 (Galvin et al., PNAS
USA, 93: 7894-7899 (1996); Schell et al., Hum Mol Gen, 4: 323-328
(1995)). Mutations in FGFRs result in constitutive activation of
the mutated receptors and increased receptor protein tyrosine
kinase activity, rendering cells and tissue unable to
differentiate.
[0024] Specifically, the achondroplasia mutation results in
enhanced stability of the mutated receptor, dissociating receptor
activation from down-regulation, leading to restrained chondrocyte
maturation and bone growth inhibition (reviewed in Vajo et al.,
Endocrine Reviews, 21(1): 23-39 (2000)).
[0025] There is accumulating evidence for mutations activating
FGFR3 in various types of cancer.
[0026] Constitutively activated FGFR3 in two common epithelial
cancers, bladder and cervix, as well as in multiple myeloma, is the
first evidence of an oncogenic role for FGFR3 in carcinomas. In
addition, a very recent study reports the presence of FGFR3
activating mutations in a large proportion of benign skin tumors
(Logie et al., Hum Mol Genet. 2005). FGFR3 currently appears to be
the most frequently mutated oncogene in bladder cancer where it is
mutated in almost 50% of the total bladder cancer cases and in
about 70% of cases having superficial bladder tumors (Cappellen, et
al., Nature Genetics 1999, 23; 19-20; van Rhijn, et al., Cancer
Research 2001, 61: 1265-1268; Billerey, et al, Am. J. Pathol. 2001,
158:1955-1959, WO 2004/085676). FGFR3 aberrant overexpression as a
consequence of the chromosomal translocation t(4,14) is reported in
10-25% of multiple myeloma cases (Chesi et al., Nature Genetics
1997, 16: 260-264; Richelda et al., Blood 1997, 90: 4061-4070;
Sibley et al., BJH 2002, 118: 514-520; Santra et al., Blood 2003,
101: 2374-2476). FGFR3 activating mutations are seen in 5-10% of
multiple myelomas with t(4,14) and are associated with tumor
progression (Chesi et al., Nature Genetics 1997, 16: 260-264; Chesi
et al., Blood, 97 (3): 729-736 (2001); Intini, et al, BJH 2001,
114: 362-364).
[0027] In this context, the consequences of FGFR3 signaling appear
to be cell type-specific. In chondrocytes, FGFR3 hyperactivation
results in growth inhibition (reviewed in Omitz, 2001), whereas in
the myeloma cell it contributes to tumor progression (Chesi et al.,
2001).
[0028] The inhibition of FGFR3 activity has been found to represent
a means for treating T cell mediated inflammatory or autoimmune
diseases, as for example in treatment of T-cell mediated
inflammatory or autoimmune diseases including but not limited to
rheumatoid arthritis (RA), collagen II arthritis, multiple
sclerosis (MS), systemic lupus erythematosus (SLE), psoriasis,
juvenile onset diabetes, Sjogren's disease, thyroid disease,
sarcoidosis, autoimmune uveitis, inflammatory bowel disease
(Crohn's and ulcerative colitis), celiac disease and myasthenia
gravis. See WO 2004/110487.
[0029] Disorders resulting from FGFR3 mutations are described also
in WO 03/023004 and WO 02/102972.
[0030] Gene amplification and/or overexpression of FGFR1, FGFR2 and
FGFR4 has been implicated in breast cancer (Penault-Llorca et al.,
Int J Cancer 1995; Theillet et al., Genes Chrom. Cancer 1993;
Adnane et al., Oncogene 1991; Jaakola et al., Int J Cancer 1993;
Yamada et al., Neuro Res 2002). Overexpression of FGFR1 and FGFR4
is also associated with pancreatic adenocarcinomas and astrocytomas
(Kobrin et al., Cancer Research 1993; Yamanaka et al., Cancer
Research 1993; Shah et al., Oncogene 2002; Yamaguchi et al., PNAS
1994; Yamada et al., Neuro Res 2002). Prostate cancer has also been
related to FGFR1 overexpression (Girl et al., Clin Cancer Res
1999).
[0031] There is an unmet need for highly selective molecules
capable of blocking aberrant constitutive receptor protein tyrosine
kinase activity, in particular FGFR activity, thereby addressing
the clinical manifestations associated with the above-mentioned
mutations, and modulating various biological functions.
[0032] In view of the large number of protein kinase inhibitors and
the multitude of proliferative and other PK-related diseases, there
is an ever-existing need to provide novel classes of compounds that
are useful as PK inhibitors and thus in the treatment of these
Protein Tyrosine Kinase (PTK) related diseases. What is required
are new classes of pharmaceutically advantageous PK inhibiting
compounds.
Epidermal Growth Factor Family and Related Diseases
[0033] The epidermal growth factor receptor (EGF-R) and ErbB-2
kinase are protein tyrosine kinase receptors which, together with
their family members ErbB-3 and ErbB-4, play a key role in signal
transmission in a large number of mammalian cells, including human
cells, especially epithelial cells, cells of the immune system and
cells of the central and peripheral nervous system. For example, in
various cell types, EGF-induced activation of receptor-associated
protein tyrosine kinase is a prerequisite for cell division and
hence for the proliferation of the cell population. Most
importantly, overexpression of the EGF-R (HER-1) and/or ErbB-2
(HER-2) has been observed in substantial fractions of many human
tumours. EGF-R, e.g., was found to be overexpressed in non
small-cell lung cancers, squameous carcinoma (head and neck),
breast, gastric, ovarian, colon and prostate cancers as well as in
gliomas. ErbB-2 was found to be overexpressed in squameous
carcinoma (head and neck), breast, gastric, and ovarian cancers as
well as in gliomas.
[0034] Citation of any document herein is not intended as an
admission that such document is pertinent prior art, or considered
material to the patentability of any claim of the present
application. Any statement as to content or a date of any document
is based on the information available to applicant at the time of
filing and does not constitute an admission as to the correctness
of such a statement.
SUMMARY OF THE INVENTION
[0035] The present invention relates to compounds of Formula (I)
and salts, esters, N-oxides or prodrugs thereof:
##STR00002##
where n is 0, 1, 2, 3, 4 or 5; X, Y and Z are each independently
selected from N or C--R.sup.5, wherein at least two of X, Y and Z
are N; and X.sup.1 is oxygen, R.sup.1, R.sup.2, R.sup.3 and R.sup.4
if present, are each independently selected from an organic or
inorganic moiety,
[0036] where the inorganic moiety is especially selected from halo,
especially chloro, hydroxyl, cyano, azo (N.dbd.N=N), nitro; and
[0037] where the organic moiety is substituted or unsubstituted and
may be attached via a linker, -L.sup.1-, the organic moiety being
especially selected from hydrogen; lower aliphatic (especially
C.sub.1, C.sub.2, C.sub.3 or C.sub.4 aliphatic) e.g. lower alkyl,
lower alkenyl, lower alkynyl; amino; guanidino; hydroxyguanidino;
formamidino; isothioureido; ureido; mercapto; C(O)H or other acyl;
acyloxy; substituted hydroxy; carboxy; sulfo; sulfamoyl; carbamoyl;
a substituted or unsubstituted cyclic group, for example the cyclic
group (whether substituted or unsubstituted) may be cycloalkyl,
e.g. cyclohexyl, phenyl, pyrrole, imidazole, pyrazole, isoxazole,
oxazole, thiazole, pyridazine, pyrimidine, pyrazine, pyridyl,
indole, isoindole, indazole, purine, indolizidine, quinoline,
isoquinoline, quinazoline, pteridine, quinolizidine, piperidyl,
piperazinyl, pyrollidine, morpholinyl or thiomorpholinyl and, for
example, substituted lower aliphatic or substituted hydroxy may be
substituted by such substituted or unsubstituted cyclic groups.
[0038] and -L.sup.1- having 1, 2, 3, 4 or 5 in-chain atoms (e.g.
selected from C, N, O and S) and optionally being selected from (i)
C.sub.1, C.sub.2, C.sub.3 or C.sub.4 alkyl, such an alkyl group
optionally being interrupted and/or terminated by [0039] an --O--,
--C(O)-- or --NR.sup.a-- linkage; --O--; --S--; --C(O)--;
cyclopropyl (regarded as having two in-chain atoms) and chemically
appropriate combinations thereof; and --NR.sup.a--, wherein R.sup.a
is hydrogen, hydroxy, hydrocarbyloxy or hydrocarbyl, wherein
hydrocarbyl is optionally interrupted by an --O-- or --NH-- linkage
and may be, for example, selected from an aliphatic group (e.g.
having 1 to 7 carbon atoms, for example 1, 2, 3, or 4), cycloalkyl,
especially cyclohexyl, cycloalkenyl, especially cyclohexenyl, or
another carbocyclic group, for example phenyl; where the
hydrocarbyl moiety is substituted or unsubstituted; each R.sup.4 is
the same or different and selected from an organic or inorganic
moiety, for example, each R.sup.4 is the same or different and
selected from halogen; hydroxy; protected hydroxy for example
trialkylsilylhydroxy; amino; amidino; guanidino; hydroxyguanidino;
formamidino; isothioureido; ureido; mercapto; C(O)H or other acyl;
acyloxy; carboxy; sulfo; sulfamoyl; carbamoyl; cyano; azo; nitro;
C.sub.1-C.sub.7 aliphatic optionally substituted by one or more
halogens and/or one or two functional groups selected from hydroxy,
protected hydroxy for example trialkylsilylhydroxy, amino, amidino,
guanidino, hydroxyguanidino, formamidino, isothioureido, ureido,
mercapto, C(O)H or other acyl, acyloxy, carboxy, sulfo, sulfamoyl,
carbamoyl, cyano, azo, or nitro; all of the aforesaid hydroxy,
amino, amidino, guanidino, hydroxyguanidino, formamidino,
isothioureido, ureido, mercapto, carboxy, sulfo, sulfamoyl and
carbamoyl groups in turn optionally being substituted on at least
one heteroatom by one or more C.sub.1-C.sub.7 aliphatic groups.
[0040] In a particular embodiment, there is provided a compound of
Formula (I), wherein:
n is 0, 1, 2, 3, 4 or 5; X, Y and Z are each independently selected
from N or C--R.sup.5, wherein at least two of X, Y and Z are N; and
R.sup.1, R.sup.2 and R.sup.5 are each independently selected from
H, R.sup.z-L.sup.1-; halogen; hydroxy; protected hydroxy for
example trialkylsilylhydroxy; amino; amidino; guanidino;
hydroxyguanidino; formamidino; isothioureido; ureido; mercapto;
C(O)H or other acyl; acyloxy; carboxy; sulfo; sulfamoyl; carbamoyl;
cyano; azo; nitro; C.sub.1-C.sub.7 aliphatic optionally substituted
by one or more halogens and/or one or two functional groups
selected from hydroxy, protected hydroxy for example
trialkylsilylhydroxy, amino, amidino, guanidino, hydroxyguanidino,
formamidino, isothioureido, ureido, mercapto, C(O)H or other acyl,
acyloxy, carboxy, sulfo, sulfamoyl, carbamoyl, cyano, azo, or
nitro; all of the aforesaid hydroxy, amino, amidino, guanidino,
hydroxyguanidino, formamidino, isothioureido, ureido, mercapto,
carboxy, sulfo, sulfamoyl and carbamoyl groups in turn optionally
being substituted on at least one heteroatom by one or, where
possible, more C.sub.1-C.sub.7 aliphatic groups, [0041] wherein
-L.sup.1- has 1, 2, 3, 4 or 5 in-chain atoms and is selected from
[0042] C.sub.1, C.sub.2, C.sub.3 or C.sub.4 aliphatic optionally
interrupted and/or terminated by a linkage selected from the group
consisting of --NR.sup.a--; --O--; --S--; --C(O)--; cyclopropyl
(regarded as having two in-chain atoms) and chemically appropriate
combinations thereof; [0043] --NR.sup.a--; --O--; --S--; --C(O)--;
cyclopropyl (regarded as having two in-chain atoms) and chemically
appropriate combinations thereof; and [0044] wherein R.sup.a is
hydrogen, hydroxy, hydrocarbyloxy or hydrocarbyl, wherein
hydrocarbyl has from 1 to 15 carbon atoms, is optionally
interrupted by an --O-- or --NH-- linkage and is unsubstituted or
is substituted by hydroxy, halo, amino or mono- or
di-(C.sub.1-C.sub.4)alkylamino, lower alkanoyl, trifluoromethyl,
cyano, azo or nitro; [0045] and R.sup.z is a moiety containing from
1 to 30 plural valent atoms selected from C, N, O, S and Si as well
as monovalent atoms selected from H and halo; R.sup.3 is H or a
moiety containing from 1 to 30 plural valent atoms selected from C,
N, O, S and Si as well as monovalent atoms selected from H and
halo; each R.sup.4 is the same or different and selected from
halogen; hydroxy; protected hydroxy for example
trialkylsilylhydroxy; amino; amidino; guanidino; hydroxyguanidino;
formamidino; isothioureido; ureido; mercapto; C(O)H or other acyl;
acyloxy; carboxy; sulfo; sulfamoyl; carbamoyl; cyano; azo; nitro;
C.sub.1-C.sub.7 aliphatic optionally substituted by one or more
halogens and/or one or two functional groups selected from hydroxy,
protected hydroxy for example trialkylsilylhydroxy, amino, amidino,
guanidino, hydroxyguanidino, formamidino, isothioureido, ureido,
mercapto, C(O)H or other acyl, acyloxy, carboxy, sulfo, sulfamoyl,
carbamoyl, cyano, azo, or nitro; all of the aforesaid hydroxy,
amino, amidino, guanidino, hydroxyguanidino, formamidino,
isothioureido, ureido, mercapto, carboxy, sulfo, sulfamoyl and
carbamoyl groups in turn optionally being substituted on at least
one heteroatom by one or, where possible, more C.sub.1-C.sub.7
aliphatic groups, or pharmaceutically acceptable salts, esters,
N-oxides or prodrugs thereof.
[0046] Often, at least one of R.sup.1, R.sup.2 and R.sup.5 is not
H; in exemplary compounds a single one of R.sup.1, R.sup.2 and
R.sup.5 is not H. Normally R.sup.1 is not H. The invention includes
amongst others compounds in which at least one of R.sup.1, R.sup.2
and R.sup.5 is R.sup.z-L.sup.1-. It includes a class of compounds
in which a single one of R.sup.1, R.sup.2 and R.sup.5 is
R.sup.z-L.sup.1-, particularly R.sup.1. The invention includes a
class of compounds in which R.sup.2 and R.sup.5 are H and R.sup.1
is not H, e.g. is R.sup.z-L.sup.1-.
[0047] Chemically appropriate combinations of --NIR.sup.a--; --O--;
--S--; --C(O)--; cyclopropyl are combinations which form a
chemically stable moiety, such as --NR.sup.aC(O)--;
--C(O)NR.sup.a--; --C(O)O-- and --OC(O)--, for example. In many
classes of compounds, L.sup.1 does not comprise cyclopropyl.
[0048] It has now been found that the above compounds, which may be
described as belonging to the heteroaryl aryl urea class, show
inhibition of a number of protein tyrosine kinases.
[0049] It is believed that certain compound of formula (I) lack
novelty per se. In one embodiment, therefore, the invention
provides compounds of formula (I) and salts, esters, N-oxides or
prodrugs thereof excluding compounds of formula (I) in which:
(A) n is 0; R.sup.3 is H; Y and Z are N; X is N, C--SO.sub.2(NH) or
C--NO.sub.2 (or in a wider exclusionary embodiment any C--R.sup.5
group); R.sup.2 is H, SCH.sub.2CH.dbd.CH.sub.2 or SMe; and R.sup.1
is of the formula NR'R'' where R' and R'' together with their
adjoining nitrogen form morpholino or one of R' and R'' is H and
the other is phenyl, phenyl substituted by a single substituent
selected from Me and Cl, or is --C(O)NHPh; (B) n is 1; R.sup.4 is
methoxy; R.sup.3 is H; X is CH; Y and Z are N; R.sup.1 is NH.sub.2;
and R.sup.2 is H or SMe; (C) n is 1; R.sup.4 is Cl; R.sup.3 is
ethyl; X, Y and Z are N; and one of R.sup.1 and R.sup.2 is H whilst
the other is NEt.sub.2; or (D) n is 2; one R.sup.4 is meta-Cl and
the other is para-methyl, R.sup.3 is H; X, Y and Z are N; and one
of R.sup.1 and R.sup.2 is H whilst the other is PhNH--,
m-chloroPhNH--, p-chloroPhNH--, m-methylPhNH-- or
p-methylPhNH--.
[0050] In embodiments, there are additionally excluded (a) salts of
the excluded compounds, (b) esters of excluded compounds, (c)
N-oxides of excluded compounds, (d) prodrugs of excluded compounds,
or (e) 1, 2, 3 or 4 of (a), (b), (c) and (d), e.g. all thereof.
[0051] Included in the invention is a method of treating a protein
kinase-dependent disease in a warm-blooded animal, for example a
human, comprising administering to the animal a therapeutically
effective amount of a compound of Formula I or a salt, ester,
N-oxide or prodrug thereof.
[0052] Also included is the use of a compound of Formula I or a
salt, ester, N-oxide or prodrug thereof for the manufacture of a
medicament for use in the treatment of a protein kinase-dependent
disease.
[0053] As another aspect of the invention may be mentioned oral
pharmaceutical formulations comprising compounds of Formula I or
salts, esters, N-oxides or prodrugs thereof. Also to be mentioned
as a further aspect are intravenous pharmaceutical formulations
comprising compounds of Formula I or salts, esters, N-oxides or
prodrugs thereof.
[0054] In embodiments of the aforesaid method, use and
formulations, the compound is in the form of the compound of
Formula (I) as such. In other embodiments, the compound is in the
form of a salt, ester, N-oxide or prodrug thereof. Thus, in certain
embodiments the compound is in the form of a salt whilst in others
it is not.
[0055] The compounds of Formula (I) (or exemplary formula thereof),
described below in more detail, especially show inhibition of
protein kinases e.g. protein tyrosine kinases. As examples of
kinases inhibited by the compounds of the disclosure may be
mentioned FGFR1, FGFR2, FGFR3 and FGFR4. Another inhibited kinase
is the receptor tyrosine kinase VEGF-R, in particular the VEGF
receptor KDR (VEGF-R2). The disclosed compounds are appropriate for
the inhibition of one or more of these and/or other protein
tyrosine kinases and/or for the inhibition of mutants of these
enzymes. In view of these activities, the compounds can be used for
the treatment of diseases related to, especially, aberrant or
excessive activity of such types of kinases, especially those
mentioned.
[0056] The compounds of the disclosure can exist in different
forms, such as free acids, free bases, esters and other prodrugs,
salts and tautomers, for example, and the disclosure includes all
variant forms of the compounds.
[0057] The extent of protection includes counterfeit or fraudulent
products which contain or purport to contain a compound of the
invention irrespective of whether they do in fact contain such a
compound and irrespective of whether any such compound is contained
in a therapeutically effective amount. Included in the scope of
protection therefore are packages which include a description or
instructions which indicate that the package contains a species or
pharmaceutical formulation or composition of the invention and a
product which is or comprises, or purports to be or comprise, such
a formulation, composition or species.
[0058] Throughout the description and claims of this specification,
the singular encompasses the plural unless the context otherwise
requires. In particular, where the indefinite article is used, the
specification is to be understood as contemplating plurality as
well as singularity, unless the context requires otherwise.
[0059] Features, integers, characteristics, compounds, chemical
moieties or groups described in conjunction with a particular
aspect, embodiment or example of the invention are to be understood
to be applicable to any other aspect, embodiment or example
described herein unless incompatible therewith.
[0060] Throughout the description and claims of this specification,
the words "comprise" and "contain" and variations of the words, for
example "comprising" and "comprises", mean "including but not
limited to", and are not intended to (and do not) exclude other
moieties, additives, components, integers or steps.
[0061] Further aspects and embodiments of the disclosure are set
forth in the following description and claims.
DETAILED DESCRIPTION
[0062] The present invention relates to compounds of Formula I as
described above and salts, esters, N-oxides or prodrugs thereof. In
an aspect, therefore, the invention provides products which are
compounds of Formula I and salts, esters, N-oxides or prodrugs
thereof.
[0063] In embodiments, the products do not include compounds which
are believed to be included in the prior art and in which:
(A) n is 0; R.sup.3 is H; Y and Z are N; X is N, C--SO.sub.2(NH) or
C--NO.sub.2 (or in a wider exclusionary embodiment any C--R.sup.5
group); R.sup.2 is H, SCH.sub.2CH.dbd.CH.sub.2 or SMe; and R.sup.1
is of the formula NR'R'' where R' and R'' together with their
adjoining nitrogen form morpholino or one of R' and R'' is H and
the other is phenyl, phenyl substituted by a single substituent
selected from Me and Cl, or is --C(O)NHPh; (B) n is 1; R.sup.4 is
methoxy; R.sup.3 is H; X is CH; Y and Z are N; R.sup.1 is NH.sub.2;
and R.sup.2 is H or SMe; (C) n is 1; R.sup.4 is Cl; R.sup.3 is
ethyl; X, Y and Z are N; and one of R.sup.1 and R.sup.2 is H whilst
the other is NEt.sub.2; or (D) n is 2; one R.sup.4 is meta-Cl and
the other is para-methyl, R.sup.3 is H; X, Y and Z are N; and one
of R.sup.1 and R.sup.2 is H whilst the other is PhNH--,
m-chloroPhNH--, p-chloroPhNH--, m-methylPhNH-- or
p-methylPhNH--.
[0064] In another embodiment, 1, 2, 3 or 4 of excluded categories
(A), (B), (C) and (D) is expanded to read as follows:
(A) n is 0; R.sup.3 is H; Y and Z are N; X is N or C--R.sup.5;
R.sup.2 is H or a substituent; and R.sup.1 is of the formula NR'R''
where R' and R'' together with the nitrogen form a substituted or
unsubstituted ring or R' and R'' are each independently H or a
substituent; (B) n is 1; R.sup.4 is a substituent; R.sup.3 is H; Y
and Z are N; X is CH (or in other embodiments is C--R.sup.5);
R.sup.2 is H OR SMe (or in some excluded compounds S substituted by
any substituent); and R.sup.1 is NH.sub.2 (or in a class of
excluded compounds is substituted amino or--in some instances--any
substituent) (C) n is 1; R.sup.4 is halo or alkyl (or in a class of
embodiments is any substituent); R.sup.3 is alkyl; X, Y and Z are
N; and one of R.sup.1 and R.sup.2 is H whilst the other is a
substituent; or (D) n is 2; each R.sup.4 is independently selected
from halo and alkyl (or in a class of embodiments is any
substituent); R.sup.3 is H; X, Y and Z are N; and one of R.sup.1
and R.sup.2 is H whilst the other is amino or substituted amino (or
in an embodiment is any substituent).
[0065] In embodiments, there are additionally excluded (a) salts of
the excluded compounds, (b) esters of excluded compounds, (c)
N-oxides of excluded compounds, (d) prodrugs of excluded compounds,
or (e) 1, 2, 3 or 4 of (a), (b), (c) and (d), e.g. all thereof.
[0066] Structural fragments and substituents of the compounds of
Formula (I) will now be considered in turn:
The Left Hand Ring
[0067] By the "left hand ring" is meant the fragment:
##STR00003##
[0068] In a class of compounds, two of X, Y and Z are N, and in one
sub-class X and Y are N while in another or X and Z are N; in an
alternative class all of X, Y and Z are N. A particular class
consists of compounds in which Y and Z are N, thus forming by way
of example Fragment (A):
##STR00004##
Substituent R.sup.5
[0069] Considering now the left hand ring without restriction, i.e.
without limitation to Fragment (A), the or each R.sup.5 may
independently be an R.sup.1 group, for example as more particularly
defined below, independently of the identity of R.sup.1.
[0070] In some compounds the or each R.sup.5 is independently H;
hydroxy; halo; amino or mono- or di-alkylamino; cyano; azo or
nitro; an aliphatic group having 1 to 7 carbon atoms and optionally
interrupted by an --O-- or --NH-- linkage and/or linked to the left
hand ring by a said linkage and/or substituted by hydroxy, halo,
amino or mono- or di-alkylamino, cyano, azo or nitro; or acyl
wherein the carbonyl moiety is substituted by a said aliphatic
group; hydroxy, amino, mono- or dialkylamino, cyano, azo or nitro.
Alkyl groups may have for example 1 to 7, e.g. 1, 2, 3 or 4 carbon
atoms.
[0071] Often, R.sup.5 is H, halo, hydroxy, amino, mono- or
dialkylamino, alkyl (e.g. methyl), alkyl interrupted by an --O-- or
--NH-- linkage and/or linked to the left hand ring by a said
linkage (e.g. to form alkoxy, for example methoxy),
trifluoromethyl, hydroxy, amino, mono- or dialkylamino; any alkyl
moiety (interrupted or not) typically has 1, 2, 3 or 4 carbon
atoms.
[0072] In a class of compounds, R.sup.5 is H or halo, particularly
H, F or Cl, for example is H or F. In a particular class of
compounds, the or each R.sup.5 is H.
[0073] The above description of R.sup.5 applies of course to
Fragment (A) as much as to other left hand ring structures.
Substituent R.sup.2
[0074] Again considering the left hand ring without restriction,
R.sup.2 may be any moiety described above in relation to R.sup.5
(e.g. may be any R.sup.1 group as described more particularly
below) and of course R.sup.2 and R.sup.5 may be the same or
different.
[0075] In some compounds, R.sup.2 and the or each R.sup.5 are
independently H; halo; an aliphatic group (e.g. having 1 to 7
carbon atoms, for example 1, 2, 3, or 4), the aliphatic group
optionally being interrupted by an --O-- or --NH-- linkage and/or
linked to the left hand ring by a said linkage and/or substituted
by hydroxy, halo, amino or mono- or di-alkylamino, acyl wherein the
carbonyl moiety is substituted by a said aliphatic group,
trifluoromethyl, hydroxy, amino, mono- or di-alkylamino, cyano, azo
or nitro.
[0076] Often, both R.sup.2 and the or each R.sup.5 are
independently H, halo, alkyl, alkyl interrupted by an --O-- or
--NH-- linkage and/or linked to the left hand ring by a said
linkage, trifluoromethyl, hydroxy, amino, mono- or dialkylamino;
any alkyl moiety (interrupted or not) typically has 1, 2, 3 or 4
carbon atoms.
[0077] In a class of compounds, both R.sup.2 and the or each
R.sup.5 are independently H or halo, particularly H, F or Cl, for
example are H or F. In a particular class of compounds, R.sup.2 and
the or each R.sup.5 are H.
[0078] The above descriptions of R.sup.2 and of R.sup.2 and R.sup.5
apply of course to Fragment (A) as much as to other left hand ring
structures.
[0079] It will be understood from the aforegoing description that a
particular left hand ring structure is Fragment (B):
##STR00005##
Substituent R.sup.1
[0080] As previously described, R.sup.1 is an organic or inorganic
moiety.
[0081] As inorganic moieties may be mentioned halo, hydroxyl,
amino, cyano, azo (N.dbd.N.dbd.N) and nitro. F and Clare exemplary
halogens.
[0082] The organic moiety, designated R.sup.z, is substituted or
unsubstituted and may be attached via a linker, -L.sup.1-, the
organic moiety being especially selected from hydrogen; lower
aliphatic (especially C.sub.1, C.sub.2, C.sub.3 or C.sub.4
aliphatic) e.g. lower alkyl, lower alkenyl, lower alkynyl; amino;
guanidino; hydroxyguanidino; formamidino; isothioureido; ureido;
mercapto; carboxy; sulfo; sulfamoyl; carbamoyl; C(O)H or other
acyl; acyloxy; substituted hydroxy; a substituted or unsubstituted
cyclic group, for example the cyclic group (whether substituted or
unsubstituted) may be cycloalkyl, e.g. cyclohexyl, phenyl, pyrrole,
imidazole, pyrazole, isoxazole, oxazole, thiazole, pyridazine,
pyrimidine, pyrazine, pyridyl, indole, isoindole, indazole, purine,
indolizidine, quinoline, isoquinoline, quinazoline, pteridine,
quinolizidine, piperidyl, piperazinyl, pyrollidine, morpholinyl or
thiomorpholinyl and, for example, substituted lower aliphatic or
substituted hydroxy may be substituted by such substituted or
unsubstituted cyclic groups. See below for a description of
particular classes of R.sup.z moiety.
[0083] Linker -L.sup.1- has 1, 2, 3, 4 or 5 in-chain atoms and is
selected from C.sub.1, C.sub.2, C.sub.3 or C.sub.4 aliphatic
(notably linear aliphatic, and aliphatic particularly being alkyl)
optionally interrupted and/or terminated by a linkage selected from
the group consisting of --NR.sup.a--; --O--; --S--; --C(O)--;
cyclopropyl (regarded as having two in-chain atoms) and chemically
appropriate combinations thereof; --NR.sup.a--; --O--; --S--;
--C(O)--; cyclopropyl (regarded as having two in-chain atoms) and
chemically appropriate combinations thereof; and --NR.sup.a--,
wherein R.sup.a is hydrogen, hydroxy, hydrocarbyloxy or
hydrocarbyl, wherein hydrocarbyl has from 1 to 15 carbon atoms
(e.g. 1 to 7), is optionally interrupted by an --O-- or --NH--
linkage and may be, for example, selected from an aliphatic group
(e.g. having 1 to 7 carbon atoms, for example 1, 2, 3, or 4,
aliphatic particularly being alkyl), cycloalkyl, especially
cyclohexyl, cycloalkenyl, especially cyclohexenyl, or another
carbocyclic group, for example phenyl; where the hydrocarbyl moiety
is substituted or unsubstituted. Exemplary substituents are
hydroxy, halo, amino or mono- or di-(C.sub.1-C.sub.4)alkylamino,
lower alkanoyl, trifluoromethyl, cyano, azo or nitro. W is
particularly H.
[0084] In a class of compounds, R.sup.1 includes a linker L.sup.1;
in a sub-class, the linker is --NR.sup.a--, alkyl terminated at the
left hand ring by (i.e joined to the left hand ring by)
--NR.sup.a--, alkyl terminated at its end remote from the left hand
ring by --NR.sup.a--, or alkyl interrupted by --NR.sup.a-- wherein
alkyl has 1, 2, 3 or 4 carbon atoms. In this class of compounds, W
is particularly H. A preferred linker is --NH--.
[0085] In other words, a common left hand ring structure is
represented by Fragment (C):
##STR00006##
where R.sup.a is as described above and preferably H, and R.sup.z
is a substituted or unsubstituted organic moiety as mentioned above
and as further described below. Also to be mentioned are compounds
in which R.sup.z is H, i.e. in which R.sup.1 is amino when R.sup.a
is also H, as well as variants in which R.sup.1 is another
substituted or unsubstituted basic group, for example amidino,
guanidino; hydroxyguanidino; formamidino; isothioureido or
ureido.
[0086] As previously described, therefore, R.sup.1 may in certain
compounds comprise a substituted or unsubstituted organic moiety,
optionally joined to the left hand ring through a linker L.sup.1.
Thus, R.sup.1 in such compounds may be represented as
R.sup.z-L.sup.1-, where R.sup.z is a substituted or an
unsubstituted organic moiety. This applies equally to left hand
ring structures which do not correspond to fragment (C) as to those
which do.
[0087] R.sup.z is commonly a moiety containing from 1 to 30
in-chain and/or in-ring atoms selected from C, N, O, S and Si and
in which one or more hydrogens are optionally replaced by halogen.
Alternatively stated, such R.sup.z groups have from 1 to 30 plural
valent atoms selected from C, N, O, S and Si as well as monovalent
atoms selected from H and halo, e.g. selected from H, F, Cl and Br,
for example H, F and Cl. In some R.sup.z moieties there are from 1
to 25 plural valent atoms, e.g. 1 to 20, such as 1 to 16, for
example.
[0088] Included are compounds in which R.sup.z contains one or a
combination of moieties selected from categories 1), 2) and 3)
below and optionally one or more moieties selected from category 4)
below: [0089] 1) aliphatic moieties, in particular having from 1 to
7 carbon atoms, e.g. 1, 2, 3 or 4, particularly alkyl or alkenyl
moieties, e.g. alkyl; [0090] 2) carbocyclic rings, which may be
saturated or unsaturated (e.g. aromatic), particularly to be
mentioned are bicyclic and monocyclic rings and especially
monocyclic rings having 5 or 6 ring members; [0091] 3) heterocyclic
rings, which may be saturated or unsaturated (e.g. aromatic),
particularly to be mentioned are bicyclic and monocyclic rings and
especially monocyclic rings having 5 or 6 ring members; [0092] 4)
linking moieties selected from O, N, Si and C(O), wherein two or
more linking moieties may be combined to form a larger linking
group for example C(O)O, C(O)NH or OC(O)NH.
[0093] In these compounds, a plurality of moieties selected from
1), 2) and 3) may be linked together either directly or through a
linking moiety 4). Of course, one compound may contain one or more
linking moieties. Tri- or more valent linking moieties such as N
and Si may serve to link together just two moieties selected from
1), 2) and 3), in which case the remaining valencies are suitably
occupied by hydrogen; alternatively N or Si may link together three
said moieties, or Si may link together four said moieties. Where
R.sup.z contains a plurality of moieties selected from 1), 2) and
3), the moieties may be the same of different and may independently
be selected from categories 1), 2) and 3).
[0094] Moieties 1), 2) and 3) may be substituted by one or more
substituents selected from, in particular, hydroxy, amino, amidino,
guanidino, hydroxyguanidino, formamidino, isothioureido, ureido,
mercapto, C(O)H or other lower acyl, lower acyloxy, carboxy, sulfo,
sulfamoyl, carbamoyl, cyano, azo, or nitro, which hydroxy, amino,
amidino, guanidino, hydroxyguanidino, formamidino, isothioureido,
ureido, mercapto, carboxy, sulfo, sulfamoyl, carbamoyl and cyano
groups are in turn optionally substituted on at least one
heteroatom by one or, where possible, more C.sub.1-C.sub.7
aliphatic groups. Often, but not always, R.sup.z has 0, 1, 2, 3, or
4 such substituents; sometimes there are a larger number of
substituents as can happen, for example, when Fe contains one or
more perfluorinated alkyl or cyclic groups, e.g. CF.sub.3, as well
as other optional substituents.
[0095] Particular moieties 1), 2) and 3) to mention are straight
chain and branched alkyl, 5- and 6-membered carbocyclic rings
(notably phenyl and cyclohexyl), and 5- and 6-membered heterocyclic
rings (notably 5-membered rings containing a single heteroatom,
e.g. furan, thiophene, pyrrole; and 6-membered rings containing one
or two heteroatoms, e.g. piperidine, piperazine, morpholine,
pyridine, pyrimidine and pyrazine).
[0096] The invention includes compounds of Formula (I) wherein
R.sup.1 is of the formula R.sup.z--NR.sup.a--, as described above,
and R.sup.z is selected from
(i) C.sub.1-C.sub.7 aliphatic moities, (ii) C.sub.1-C.sub.7
aliphatic substituted by one or more halogens and/or one or two
functional groups selected from hydroxy, amino, amidino, guanidino,
hydroxyguanidino, formamidino, isothioureido, ureido, mercapto,
C(O)H or other lower acyl, lower acyloxy, carboxy, sulfo,
sulfamoyl, carbamoyl, cyano, azo, or nitro, which hydroxy, amino,
amidino, guanidino, hydroxyguanidino, formamidino, isothioureido,
ureido, mercapto, carboxy, sulfo, sulfamoyl, carbamoyl and cyano
groups are in turn optionally substituted on at least one
heteroatom by one or, where possible, more C.sub.1-C.sub.7
aliphatic groups, (iii) a group of the formula
##STR00007## [0097] where: [0098] ring A represents a mono- or
bi-cyclic ring, particularly a 5- or 6-membered carbocyclic or
heterocyclic ring; [0099] m is 0, 1, 2; 3, 4 or 5, e.g. 0, 1 or 2;
[0100] the or each R.sup.b is independently selected from
-L.sup.2-NR.sup.cR.sup.d; -L.sup.2-RING where RING is a mono- or
bi-cyclic ring, particularly a 5- or 6-membered carbocyclic or
heterocyclic ring, optionally substituted as defined below;
halogen; hydroxy; protected hydroxy for example
trialkylsilylhydroxy; amino; amidino; guanidino; hydroxyguanidino;
formamidino; isothioureido; ureido; mercapto; C(O)H or other lower
acyl; lower acyloxy; carboxy; sulfo; sulfamoyl; carbamoyl; cyano;
azo; or nitro; and C.sub.1-C.sub.7 aliphatic optionally substituted
by one or more halogens and/or one or two functional groups
selected from hydroxy, protected hydroxy for example
trialkylsilylhydroxy, amino, amidino, guanidino, hydroxyguanidino,
formamidino, isothioureido, ureido, mercapto, C(O)H or other lower
acyl, lower acyloxy, carboxy, sulfo, sulfamoyl, carbamoyl, cyano,
azo, or nitro; all of which hydroxy, amino, amidino, guanidino,
hydroxyguanidino, formamidino, isothioureido, ureido, mercapto,
carboxy, sulfo, sulfamoyl, carbamoyl and cyano groups are in turn
optionally substituted on at least one heteroatom by one or, where
possible, more C.sub.1-C.sub.7 aliphatic groups, [0101] wherein
L.sup.2 is a direct bond; a linkage selected [0102] from --O--;
--S--; --C(O)--; --OC(O)--; --NR.sup.aC(O)--; --C(O)--NR.sup.a--;
--OC(O)--NR.sup.a--; cyclopropyl and --NR.sup.a--; or is a
C.sub.1-C.sub.7 aliphatic group optionally interrupted and/or
terminated at a single end or at both ends by a said linkage
(R.sup.a being as previously defined and typically H); [0103] and
wherein R.sup.c and R.sup.d are each independently selected from
hydrogen, and C.sub.1-C.sub.7 aliphatic optionally substituted by
one or more halogens, by an optionally substituted 5- or 6-membered
heterocyclic or carbocyclic ring, and/or one or two functional
groups selected from hydroxy, protected hydroxy for example
trialkylsilylhydroxy, amino, amidino, guanidino, hydroxyguanidino,
formamidino, isothioureido, ureido, mercapto, C(O)H or other lower
acyl, lower acyloxy, carboxy, sulfo, sulfamoyl, carbamoyl, cyano,
azo, or nitro, which hydroxy, amino, amidino, guanidino,
hydroxyguanidino, formamidino, isothioureido, ureido, mercapto,
carboxy, sulfo, sulfamoyl, carbamoyl and cyano groups are in turn
optionally substituted on at least one heteroatom by one or more
C.sub.1-C.sub.7 aliphatic groups, [0104] or R.sup.c and R.sup.d
together with their adjoining nitrogen form a 5- or 6-membered ring
optionally substituted as described below, said optionally
substituted rings independently of each other being substituted by
0, 1, 2, 3, 4 or 5 substituents selected from halogen; hydroxy;
protected hydroxy for example trialkylsilylhydroxy; amino; amidino;
guanidino; hydroxyguanidino; formamidino; isothioureido; ureido;
mercapto; C(O)H or other lower acyl; lower acyloxy; carboxy; sulfo;
sulfamoyl; carbamoyl; cyano; azo; nitro; C.sub.1-C.sub.7 aliphatic
optionally substituted by one or more halogens and/or one or two
functional groups selected from hydroxy, protected hydroxy for
example trialkylsilylhydroxy, amino, amidino, guanidino,
hydroxyguanidino, formamidino, isothioureido, ureido, mercapto,
C(O)H or other lower acyl; lower acyloxy carboxy, sulfo, sulfamoyl,
carbamoyl, cyano, azo, or nitro; all of the aforesaid hydroxy,
amino, amidino, guanidino, hydroxyguanidino, formamidino,
isothioureido, ureido, mercapto, carboxy, sulfo, sulfamoyl and
carbamoyl groups in turn optionally being substituted on at least
one heteroatom by one or, where possible, more C.sub.1-C.sub.7
aliphatic groups (for example, therefore, a ring may be substituted
by an alkoxy group, e.g. methoxy or ethoxy).
[0105] Still considering compounds wherein R.sup.1 is of the
formula R.sup.z--NR.sup.a-- and R.sup.z is selected from categories
(i), (ii) and (iii) above, aliphatic often has 1, 2, 3 or 4 carbon
atoms and is often linear, but sometimes branched. In a class of
compounds, aliphatic is alkyl, e.g. linear or branched alkyl having
1, 2, 3 or 4 carbon atoms; linear alkyl is more common,
irrespective of the number of carbon atoms.
[0106] In a sub-class of those compounds wherein R.sup.1 is of the
formula R.sup.z--NR.sup.a--, R.sup.z is alkyl, e.g. linear or
branched alkyl having 1, 2, 3 or 4 carbon atoms; linear alkyl being
more common, irrespective of the number of carbon atoms. As already
described, there also included compounds in which R.sup.z is H.
This sub-class therefore comprises compounds in which R.sup.1 is
amino or mono- or di-alkylamino.
[0107] Turning now to those compounds in which R.sup.z is a
category (iii) group, i.e. is of the formula
##STR00008##
ring A is typically a 6-membered carbocyclic or heterocyclic ring,
particularly phenyl, cyclohexyl or cyclohexenyl. Of these, phenyl
is preferred. In other instances, ring A is a 5-membered
carbocyclic or heterocyclic ring. Other exemplary residues forming
ring A are pyridyl and pyrimidyl.
[0108] Integer m may be 0.
[0109] Integer m is often 1. Where m is greater than one, all the
R.sup.b groups or all the R.sup.b groups except one are often
halogen (notably F or Cl), methyl or trifluoromethyl. Also to be
mentioned in this regard are hydroxy and amino. Often, a single
R.sup.b group is selected from -L.sup.2-NR.sup.cR.sup.d and
-L.sup.2-RING and there are 0, 1 or 2 additional substituents which
are not -L.sup.2-NR.sup.cR.sup.d or -L.sup.2-RING but are, for
example, halogen (notably F or Cl), lower alkyl (e.g. methyl),
lower alkoxy (e.g. methoxy), hydroxy, amino or trifluoromethyl.
[0110] Accordingly, the invention includes compounds in which
R.sup.z is, e.g. a 6-membered carbocyclic ring (notably phenyl)
substituted by 1, 2, 3, 4 or 5 halogens, e.g. selected from F, Cl
and Br; typically, such phenyl rings are mono- or di-substituted,
e.g. are 2- and/or 4-substituted by F or 3-substituted by Cl. In
some cases of plural substitution by halogen, all the halogens are
the same. Thus, in a class of compounds R.sup.z is a monocyclic
ring, particularly a 6-membered carbocyclic ring (notably phenyl),
substituted solely by one or more halogens, particularly selected
from F and Cl; sometimes the or each halogen is F but in some other
cases the or each halogen is Cl.
[0111] In another class of compounds, R.sup.z is a monocyclic ring,
particularly a 6-membered carbocyclic ring (notably phenyl),
substituted by 1, 2, 3, 4 or 5 substituents, e.g. 1 or 2
substituents, selected from alkyl, alkoxy, alkanoyl, alkanoyloxy,
haloalkyl, amino, mono- or di-alkylamino, cyano, halogen, hydroxy
or protected hydroxy, wherein alkyl or the alkyl part of alkoxy and
alkanoyl(oxy) has 1, 2, 3 or 4 carbon atoms; exemplary substituents
in this case are methyl, ethyl, methoxy, ethoxy, acetyl,
trifluoromethyl, cyano, F, Cl and OH. Certain such rings have 0, 1
or 2 substituents, e.g. 0 or 1.
[0112] In one class of compounds, L.sup.2 is a direct bond, linear
alkyl, linear alkyl terminated adjacent ring A by a said linkage,
or is a said linkage. In a sub-class, any said linkage is --O-- or
--C(O)--, of which --O-- may be particularly mentioned.
[0113] The invention includes a class of compounds in which ring A
is a 6-membered ring, particularly phenyl, cyclohexyl or
cyclohexenyl and has one or two substituents R.sup.b independently
selected from -L.sup.2-NR.sup.cR.sup.d and -L.sup.2-RING, as
defined previously. In a sub-class, there is a single substituent
at, in particular, the 3-position or 4-position selected from
-L.sup.2-NR.sup.cR.sup.d and -L.sup.2-RING such that the left hand
ring has a structure corresponding to Fragments (D1), (D2), (E1) or
(E2):
##STR00009##
[0114] As previously described, R.sup.a is commonly H. Also as
previously described, the phenyl ring may be replaced by cyclohexyl
or cyclohexenyl, particularly cyclohexyl. It may alternatively be
replaced by a 5- or 6-membered heterocycle, particularly
pyridine.
[0115] In some embodiments, the phenyl ring of the above fragments
(or other ring replacing phenyl) has 1, 2, 3 or 4 further
substituents, for example selected from halogen (notably F or Cl),
methyl, methoxy or trifluoromethyl, e.g. 1 or 2 such substituents.
Also to be mentioned in this regard are hydroxy and amino.
[0116] L.sup.2 is as previously described, that is a direct bond; a
linkage selected from --O--; --S--; --C(O)--; --OC(O)--;
--NR.sup.aC(O)--; --C(O)--NR.sup.a--; --OC(O)--NR.sup.a--;
cyclopropyl and --NR.sup.a--; or C.sub.1-C.sub.7 aliphatic
optionally interrupted and/or terminated at a single end or at both
ends by a said linkage (R.sup.2 being as previously defined and
typically H). Any aliphatic moiety is often alkyl, e.g. alkyl or
other aliphatic having 1, 2, 3 or 4 carbon atoms, as in the case of
a sub-class of linkers L.sup.2 in which aliphatic moieties are
methyl, ethyl or n-propyl.
[0117] In particular fragments (D) and (E), L.sup.2 is a direct
bond, linear alkyl, linear alkyl terminated adjacent the phenyl
ring in the above representations of the fragments by a said
linkage, or is a said linkage; suitably but not necessarily any
said linkage is --O-- or --C(O)--, of which --O-- may be
particularly mentioned. Thus, the above fragments (D) and (E) may
comprise sub-fragments -Ph-NR.sup.cR.sup.d, -Ph-RING,
-Ph-O-alkyl-NR.sup.cR.sup.d, -Ph-alkyl-NR.sup.cR.sup.d,
-Ph-alkyl-RIN G, and also to be mentioned are sub-fragments
-Ph-O--NR.sup.cR.sup.d, -Ph-O-RING, -Ph-C(O)--NR.sup.1R.sup.d and
-Ph-C(O)--RING, where, in all these sub-fragments which contain
alkyl, alkyl may be e.g. methyl, ethyl or n-propyl, or n-butyl.
[0118] Considering now in more detail fragments (D1) and (D2),
these contain a moiety RING which is a cyclic moiety and in many
cases a 5- or 6-membered carbocyclic or heterocyclic ring
optionally substituted as defined previously. Exemplary rings are
saturated, e.g. cyclopentane or cyclohexane. In particular
compounds, RING is a 5- or 6-membered heterocycle, often containing
one or two heteroatoms, typically selected from O and N; in a
sub-class, the heterocycles contain one or two nitrogens and, where
there is a single nitrogen, optionally an oxygen. Particular
heterocycles include a nitrogen which is not a member of a double
bond and these are more particularly saturated heterocycles. As
heterocycles may be mentioned pyrrolidine, piperidine, piperazine
and morpholine; in some compounds, RING is piperidine having its
nitrogen at the 4-position relative to L.sup.2. As already
described, RING may be substituted and, in one class of compounds,
is substituted by 0, 1, 2, 3, 4 or 5 substituents, e.g. selected
from C.sub.1-C.sub.7 aliphatic groups, optionally substituted as
described above, and less frequently C.sub.1-C.sub.7 aliphatic-oxy
of which the aliphatic group is optionally substituted as described
above. Any aliphatic group is often alkyl (straight chain or
branched), e.g. alkyl or other aliphatic having 1, 2, 3 or 4 carbon
atoms, as in the case of a sub-class of fragments (D1) and (D2)
having substituents which are methyl, ethyl or n-propyl. Exemplary
substituents on RING include straight chain or branched C.sub.1,
C.sub.2, C.sub.3 or O.sub.4 alkyl such as, e.g., methyl, ethyl
n-propyl, isopropyl or t-butyl, of which methyl may be particularly
mentioned, halogen (notably F or Cl) and C.sub.1, C.sub.2, C.sub.3
or C.sub.4 alkoxy; also to be mentioned are hydroxy and amino.
Alkyl moieties may be unsubstituted or substituted, e.g. by halogen
(notably F or Cl) or in some cases by hydroxy or amino.
[0119] In some classes of RING moieties, there are 0, 1, 2, 3, 4 or
5 such substituents selected from alkyl, alkoxy, alkanoyl,
alkanoyloxy, haloalkyl, amino, mono- or di-alkylamino, cyano,
halogen, hydroxy or protected hydroxy, wherein alkyl or the alkyl
part of alkoxy and alkanoyl(oxy) has 1, 2, 3 or 4 carbon atoms;
exemplary substituents in this case are methyl, ethyl, methoxy,
ethoxy, acetyl, trifluoromethyl, cyano, F, Cl and OH. Certain RING
moieties have 0, 1 or 2 substituents, e.g. 0 or 1.
[0120] Considering now in more detail fragments (E1) and (E2),
these contain a moiety NR.sup.cR.sup.d. R.sup.c and R.sup.d are as
previously described. In one class of these fragments, R.sup.c and
R.sup.d are the same or different (but more usually the same) and
selected from C.sub.1-C.sub.7, e.g. C.sub.1-C.sub.4 aliphatic
groups, optionally substituted as described above. As aliphatic
R.sup.c and R.sup.d moieties may be mentioned alkyl, e.g having 1,
2, 3 or 4 carbon atoms, as in the case of a sub-class of fragments
(E1) and (E2) having substituents which are methyl, ethyl or
n-propyl. Alkyl or other aliphatic moieties may be substituted e.g.
by amino or mono- or di (C.sub.1-C.sub.4) alkylamino, or e.g. by a
5- or 6-membered heterocyclic or carbocyclic ring optionally
substituted as previously described, or be unsubstituted. Thus,
particular L.sup.2NR.sup.cR.sup.d moieties are
--OCH.sub.2NMe.sub.2, --OCH.sub.2NEt.sub.2,
--OCH.sub.2CH.sub.2NMe.sub.2, --OCH.sub.2CH.sub.2NEt.sub.2,
--OCH.sub.2CH.sub.2CH.sub.2NMe.sub.2, --OCH.sub.2CH.sub.2C
H.sub.2NEt.sub.2, --CH.sub.2NMe.sub.2, --CH.sub.2NEt.sub.2,
--CH.sub.2CH.sub.2NMe.sub.2, --CH.sub.2CH.sub.2NEt.sub.2,
--CH.sub.2CH.sub.2CH.sub.2NMe.sub.2, and
--CH.sub.2CH.sub.2CH.sub.2NEt.sub.2.
[0121] In another class of fragments (E1) and (E2), R.sup.c and
R.sup.d together with the adjoining nitrogen form a heterocyclic
moiety (normally a 5- or 6-membered heterocyclic ring), optionally
substituted as previously described. In addition to the nitrogen of
moiety NR.sup.cR.sup.d, the heterocyclic ring may contain at least
one further heteroatom, and often exactly one further heteroatom,
in either case typically selected from O and N; in a sub-class, the
heterocycles contain altogether one or two nitrogens and, where
there is a single nitrogen, optionally an oxygen. Particular
heterocycles include a nitrogen which is not a member of a double
bond and these are more particularly saturated heterocycles. As
heterocycles may be mentioned pyrrolidine, piperidine, piperazine
and morpholine; of these particular heterocycles are piperazine and
morpholine. As already described, the heterocycle may be
substituted and, in one class of compounds, is substituted by 0, 1,
2, 3, 4 or 5 substituents, e.g. selected from C.sub.1-C.sub.7
aliphatic groups, optionally substituted as described above, and
less frequently C.sub.1-C.sub.7 aliphatic-oxy of which the
aliphatic group is optionally substituted as described above. Any
aliphatic group is often alkyl (straight chain or branched), e.g.
alkyl or other aliphatic having 1, 2, 3 or 4 carbon atoms, as in
the case of a sub-class of cyclic (E1) and (E2) fragments having
substituents which are methyl, ethyl or n-propyl. Exemplary
substituents on cyclic (E1) and (E2) fragments include straight
chain or branched C.sub.1, C.sub.2, C.sub.3 or C.sub.4 alkyl such
as, e.g., methyl, ethyl n-propyl, isopropyl or t-butyl, of which
methyl may be particularly mentioned, halogen (notably F or Cl) and
C.sub.1, C.sub.2, C.sub.3 or C.sub.4 alkoxy; also to be mentioned
are hydroxy and amino. Alkyl moieties may be unsubstituted or
substituted, e.g. by halogen (notably F or Cl) or in some cases by
hydroxy or amino.
[0122] In some classes of cyclic (E1) and (E2) fragments (that is
to say fragments in which R.sup.c and R.sup.d together with the
adjoining nitrogen form a ring), there are 0, 1, 2, 3, 4 or 5 such
substituents selected from alkyl, alkoxy, alkanoyl, alkanoyloxy,
haloalkyl, amino, mono- or di-alkylamino, cyano, halogen, hydroxy
or protected hydroxy, wherein alkyl or the alkyl part of alkoxy and
alkanoyl(oxy) has 1, 2, 3 or 4 carbon atoms; exemplary substituents
in this case are methyl, ethyl, methoxy, ethoxy, acetyl,
trifluoromethyl, cyano, F, Cl and OH. Certain cyclic fragments have
0, 1 or 2 substituents, e.g. 0 or 1.
[0123] Particular L.sup.2NR.sup.cR.sup.d moieties are -Pip, -Morph,
--OCH.sub.2Pip, --OCH.sub.2-Morph, --OCH.sub.2CH.sub.2Pip,
--OCH.sub.2CH.sub.2-Morph, --OCH.sub.2CH.sub.2CH.sub.2Pip,
--OCH.sub.2CH.sub.2CH.sub.2-Morph, --CH.sub.2Pip, --CH.sub.2-Morph,
--CH.sub.2CH.sub.2Pip, --CH.sub.2CH.sub.2-Morph,
--CH.sub.2CH.sub.2CH.sub.2Pip, and
--CH.sub.2CH.sub.2CH.sub.2-Morph. Also to be mentioned are
--C(O)Pip and --C(O)Morph. The abbreviation "Pip" stands for
piperazine and "Morph" for morpholine, and these rings may be
substituted as previously described. In particular piperazine is
optionally N-substituted. piperazine and morpholine may be
substituted by a C.sub.1-C.sub.7 aliphatic group as mentioned in
the previous paragraph, for example a straight chain or branched
C.sub.1, C.sub.2, C.sub.3 or C.sub.4 moiety selected from alkyl and
haloalkyl such as, e.g., methyl, trifluoromethyl, ethyl n-propyl,
isopropyl or t-butyl, of which methyl and trifluoromethyl are
exemplary. As described before, R.sup.a is in particular
hydrogen.
[0124] Amongst the classes of compounds which are particularly to
be mentioned are those in which the left hand ring has a structure
corresponding to Fragment (D1) or (E1). Particularly exemplary are
such compounds having a fragment (E1) in which R.sup.c and R.sup.d
together with the adjoining nitrogen form a 5- or 6-membered
heterocyclic ring as described above. These rings may be
substituted as previously described. In particular they are
optionally N-substituted by a C.sub.1-C.sub.7 aliphatic group as
mentioned earlier, for example a straight chain or branched
C.sub.1, C.sub.2, C.sub.3 or C.sub.4 moiety selected from alkyl and
haloalkyl such as, e.g., methyl, trifluoromethyl, ethyl n-propyl,
isopropyl or t-butyl, of which methyl and trifluoromethyl are
exemplary. As described before, R.sup.a is in particular
hydrogen.
[0125] It will be appreciated from the aforegoing that the
invention includes compounds having a left hand ring having the
structure of the following Fragment (F):
##STR00010##
where L.sup.2NR.sup.cR.sup.d is in particular -Pip, -Morph,
--OCH.sub.2Pip, --OCH.sub.2-Morph, --OCH.sub.2CH.sub.2Pip,
--OCH.sub.2CH.sub.2-Morph, --OCH.sub.2CH.sub.2CH.sub.2Pip,
--OCH.sub.2CH.sub.2CH.sub.2-Morph, --CH.sub.2Pip, --CH.sub.2-Morph,
--CH.sub.2CH.sub.2Pip, --CH.sub.2CH.sub.2-Morph,
--CH.sub.2CH.sub.2CH.sub.2Pip, and
--CH.sub.2CH.sub.2CH.sub.2-Morph, or is --C(O)Pip or --C(O)Morph.
"Pip" and "Morph" are as described in the last but one
paragraph.
Substituent R.sup.3
[0126] Substituent R.sup.3 is as previously described in relation
to Formula (I).
[0127] In embodiments, R.sup.3 is selected from H, R.sup.b groups,
and categories (i), (ii) and (iii) described above in relation to
R.sup.z, independently of the identity of R.sup.z. In one class of
embodiments, R.sup.3 is H or a C.sub.1-C.sub.7 aliphatic group, for
example straight chain or branched C.sub.1-C.sub.4 alkyl such as,
e.g., methyl, ethyl or n-propyl, of which methyl is exemplary. In
other compounds, R.sup.3 is a C.sub.1-C.sub.7 aliphatic group (for
example straight chain or branched C.sub.1-C.sub.4 alkyl such as,
e.g., methyl, ethyl or n-propyl) substituted by a mono- or
bi-cyclic ring, particularly a 5- or 6-membered saturated or
unsaturated carbocyclic or heterocyclic ring, for example by
phenyl, pyrrolidine, piperidine, piperazine, morpholine, thiophene,
furan, pyrrole, pyridine, pyrazine or pyran. R.sup.3 may therefore
be straight chain alkyl (or other straight chain aliphatic group,
for example in either case having up to 4 carbon atoms) substituted
at its free end by such a mono- or bi-cyclic ring.
[0128] In one class of compounds R.sup.3 is a category (iii)
moiety, that is, a moiety having the structure:
##STR00011##
as previously described. The identity of R.sup.3 is independent of
that of R.sup.z, as already stated.
[0129] However, as particular compounds, may be mentioned those in
which just one of R.sup.z and R.sup.3 is a category (iii) moiety.
In a subclass, one of R.sup.z and R.sup.3 is a category (iii)
moiety and the other is H; to be mentioned in this regard are
compounds in which R.sup.3 is a category (iii) moiety and R.sup.1
is NH.sub.2, or alternatively mono- or di-alkyl amino.
[0130] Where R.sup.3 is a category (iii) moiety, it may have a
structure corresponding to the category (iii) structures found in
Fragments (D1), (D2), (E1), (E2) or (F), as previously
described.
The Right Hand Ring
[0131] By the "right hand ring" is meant the fragment:
##STR00012##
[0132] It has previously been mentioned that n is 0, 1, 2, 3, 4 or
5 and that each R.sup.4 is the same or different and selected from
an organic or inorganic moiety, for example, each R.sup.4 is the
same or different and selected from halogen; hydroxy; protected
hydroxy for example trialkylsilylhydroxy; amino; amidino;
guanidino; hydroxyguanidino; formamidino; isothioureido; ureido;
mercapto; C(O)H or other acyl; acyloxy; carboxy; sulfo; sulfamoyl;
carbamoyl; cyano; azo; nitro; C.sub.1-C.sub.7 aliphatic optionally
substituted by one or more halogens and/or one or two functional
groups selected from hydroxy, protected hydroxy for example
trialkylsilylhydroxy, amino, amidino, guanidino, hydroxyguanidino,
formamidino, isothioureido, ureido, mercapto, C(O)H or other acyl,
acyloxy, carboxy, sulfo, sulfamoyl, carbamoyl, cyano, azo, or
nitro; all of the aforesaid hydroxy, amino, amidino, guanidino,
hydroxyguanidino, formamidino, isothioureido, ureido, mercapto,
carboxy, sulfo, sulfamoyl and carbamoyl groups in turn optionally
being substituted on at least one heteroatom by one or, where
possible, more C.sub.1-C.sub.7 aliphatic groups (for example,
therefore, R.sup.4 ring may be an alkoxy group, e.g. methoxy or
ethoxy).
[0133] Integer n is more usually 1, 2, 3 or 4, e.g. 2, 3 or 4. In
particular, there are often R.sup.4 groups substituted at both
ortho-positions and optionally at least one or two other positions,
e.g. there may be a single further meta or para substituent.
[0134] R.sup.4 is particularly selected from hydroxy, protected
hydroxy, lower alkoxy, lower alkyl, trifluoromethyl and halo,
notably F or Cl. R.sup.4 may also be Br. Alkyl and the alkyl part
of alkoxy may be branched or, more usually, straight chain, and
often have 1, 2, 3, or 4 carbon atoms, as for example in the case
of methyl, ethyl, methoxy and ethoxy. R.sup.4 is especially
selected from Cl, F, hydroxy, methyl, methoxy and trifluoromethyl,
e.g. is selected from Cl, F, methyl, methoxy and trifluoromethyl,
as in those compounds where R.sup.4 is Cl, F, methyl or methoxy. In
some of the compounds mentioned in this paragraph, chlorine is the
sole halogen, in some others fluorine is the sole halogen. The
reader is reminded that, where there are plural R.sup.4 groups,
they may be the same or different.
[0135] Included are compounds in which there is halogen selected
from F and Cl at one or both ortho positions.
[0136] To be mentioned are right hand rings corresponding to
Fragment (G):
##STR00013##
[0137] where: [0138] Q is selected from F and Cl; [0139] U is
selected from H, F, Cl, methyl, trifluoromethyl and methoxy, and
particularly Q and U are the same or different and both selected
from F and Cl; [0140] T and V are the same or different and
selected from H, methyl, trifluoromethyl and methoxy, e.g. from H,
methyl and methoxy.
[0141] In some Fragments (G), all of U, T and V are H. In other
Fragments (G), Q and U are the same and selected from F and Cl.
[0142] A particular right hand ring is Fragment (H):
##STR00014##
[0143] To be mentioned are right hand rings corresponding to
Fragment (I):
##STR00015## [0144] where: [0145] Q is selected from F and Cl;
[0146] U.sup.a and U.sup.b are each independently selected from H,
F, Cl, methyl, trifluoromethyl and methoxy; in some compounds
U.sup.a and U.sup.b are the same.
[0147] In exemplary Fragment (I) structures, all of Q, U.sup.a and
U.sup.b are the same and are fluorine or more particularly
chlorine. In other exemplary structures, Q is F or, particularly,
Cl whilst U.sup.a and U.sup.b are the same or different and
selected from methyl, trifluoromethyl and methoxy; both U.sup.a and
U.sup.b may be the same, e.g both may be methoxy.
The Compounds of Formula (I)
[0148] It has been described above how the compounds of formula (I)
have the following variable domains: [0149] left hand ring [0150]
R.sup.3 [0151] right hand ring.
[0152] Various particular moieties have been described for each of
these variable domains and it will be appreciated that any
combination of such moieties is permissible.
[0153] To be mentioned are compounds having the following
combinations, amongst many others:
TABLE-US-00001 Left hand ring R.sup.3 Right hand ring Fragment (A)
H, C.sub.1-C.sub.4 alkyl or C.sub.1-C.sub.4 alkyl n = 1, 2, 3, or
4. substituted by an optionally R.sup.4 = selected from Cl, F,
substituted 5- or 6- hydroxy, methyl, methoxy membered ring and
trifluoromethyl. Fragment (B) H, C.sub.1-C.sub.4 alkyl or
C.sub.1-C.sub.4 alkyl n = 1, 2, 3, or 4. substituted by an
optionally R.sup.4 = selected from Cl, F, substituted 5- or 6-
hydroxy, methyl, methoxy membered ring and trifluoromethyl.
Fragment (C) H, C.sub.1-C.sub.4 alkyl or C.sub.1-C.sub.4 alkyl n =
1, 2, 3, or 4. substituted by an optionally R.sup.4 = selected from
Cl, F, substituted 5- or 6- hydroxy, methyl, methoxy membered ring
and trifluoromethyl. Fragment (C), R.sup.a = H, H, C.sub.1-C.sub.4
alkyl or C.sub.1-C.sub.4 alkyl n = 1, 2, 3, or 4. Rz = category (i)
or (ii) substituted by an optionally R.sup.4 = selected from Cl, F,
substituted 5- or 6- hydroxy, methyl, methoxy membered ring and
trifluoromethyl. Fragment (C), R.sup.a = H, Category (iii) moiety,
e.g. n = 1, 2, 3, or 4. Rz = category (i) or (ii) having a
structure R.sup.4 = selected from Cl, F, corresponding to the
hydroxy, methyl, methoxy category (iii) structure of and
trifluoromethyl. Fragment (D1) Fragment (C), R.sup.a = H, Category
(iii) moiety, e.g. n = 1, 2, 3, or 4. Rz = category (i) or (ii)
having a structure R.sup.4 = selected from Cl, F, corresponding to
the hydroxy, methyl, methoxy category (iii) structure of and
trifluoromethyl. Fragment (D2) Fragment (C), R.sup.a = H, Category
(iii) moiety, e.g. n = 1, 2, 3, or 4. Rz = category (i) or (ii)
having a structure R.sup.4 = selected from Cl, F, corresponding to
the hydroxy, methyl, methoxy category (iii) structure of and
trifluoromethyl. Fragment (E1). Fragment (C), R.sup.a = H, Category
(iii) moiety, e.g. n = 1, 2, 3, or 4. Rz = category (i) or (ii)
having a structure R.sup.4 = selected from Cl, F, corresponding to
the hydroxy, methyl, methoxy category (iii) structure of and
trifluoromethyl. Fragment (E2). Fragment (C), R.sup.a = H, Category
(iii) moiety, e.g. n = 1, 2, 3, or 4. Rz = category (i) or (ii)
having a structure R.sup.4 = selected from Cl, F, corresponding to
the hydroxy, methyl, methoxy category (iii) structure of and
trifluoromethyl. Fragment (F). Fragment (C), R.sup.a = H,
C.sub.1-C.sub.4 alkyl or C.sub.1-C.sub.4 alkyl n = 1, 2, 3, or 4.
R.sup.z = category (iii) substituted by an optionally R.sup.4 =
selected from Cl, F, substituted 5- or 6- hydroxy, methyl, methoxy
membered ring and trifluoromethyl. Fragment (D1) C.sub.1-C.sub.4
alkyl or C.sub.1-C.sub.4 alkyl n = 1, 2, 3, or 4. substituted by an
optionally R.sup.4 = selected from Cl, F, substituted 5- or 6-
hydroxy, methyl, methoxy membered ring and trifluoromethyl.
Fragment (D2) C.sub.1-C.sub.4 alkyl or C.sub.1-C.sub.4 alkyl n = 1,
2, 3, or 4. substituted by an optionally R.sup.4 = selected from
Cl, F, substituted 5- or 6- hydroxy, methyl, methoxy membered ring
and trifluoromethyl. Fragment (E1) C.sub.1-C.sub.4 alkyl or
C.sub.1-C.sub.4 alkyl n = 1, 2, 3, or 4. substituted by an
optionally R.sup.4 = selected from Cl, F, substituted 5- or 6-
hydroxy, methyl, methoxy membered ring and trifluoromethyl.
Fragment (E2) C.sub.1-C.sub.4 alkyl or C.sub.1-C.sub.4 alkyl n = 1,
2, 3, or 4. substituted by an optionally R.sup.4 = selected from
Cl, F, substituted 5- or 6- hydroxy, methyl, methoxy membered ring
and trifluoromethyl. Fragment (F) C.sub.1-C.sub.4 alkyl or
C.sub.1-C.sub.4 alkyl n = 1, 2, 3, or 4. substituted by an
optionally R.sup.4 = selected from Cl, F, substituted 5- or 6-
hydroxy, methyl, methoxy membered ring and trifluoromethyl.
Fragment (C), R.sup.a H n = 1, 2, 3, or 4. typically = H, R.sup.z =
category (iii) R.sup.4 = selected from Cl, F, hydroxy, methyl,
methoxy and trifluoromethyl. Fragment (D1); R.sup.a H n = 1, 2, 3,
or 4. typically = H, R.sup.4 = selected from Cl, F, hydroxy,
methyl, methoxy and trifluoromethyl. Fragment (D2); R.sup.a H n =
1, 2, 3, or 4. typically = H, R.sup.4 = selected from Cl, F,
hydroxy, methyl, methoxy and trifluoromethyl. Fragment (E1);
R.sup.a H n = 1, 2, 3, or 4. typically = H, R.sup.4 = selected from
Cl, F, hydroxy, methyl, methoxy and trifluoromethyl. Fragment (E2);
R.sup.a H n = 1, 2, 3, or 4. typically = H, R.sup.4 = selected from
Cl, F, hydroxy, methyl, methoxy and trifluoromethyl. Fragment (F) H
n = 1, 2, 3, or 4. R.sup.4 = selected from Cl, F, hydroxy, methyl,
methoxy and trifluoromethyl. Fragment (A) H, C.sub.1-C.sub.4 alkyl
or C.sub.1-C.sub.4 alkyl R.sup.4 is Fragment substituted by an
optionally (G), (H) or (I). substituted 5- or 6- membered ring
Fragment (B) H, C.sub.1-C.sub.4 alkyl or C.sub.1-C.sub.4 alkyl
R.sup.4 is Fragment substituted by an optionally (G), (H) or (I).
substituted 5- or 6- membered ring Fragment (C) H, C.sub.1-C.sub.4
alkyl or C.sub.1-C.sub.4 alkyl R.sup.4 is Fragment substituted by
an optionally (G), (H) or (I). substituted 5- or 6- membered ring
Fragment (C), R.sup.a = H, H, C.sub.1-C.sub.4 alkyl or
C.sub.1-C.sub.4 alkyl R.sup.4 is Fragment Rz = category (i) or (ii)
substituted by an optionally (G), (H) or (I). substituted 5- or 6-
membered ring Fragment (C), R.sup.a = H, Category (iii) moiety,
e.g. R.sup.4 is Fragment Rz = category (i) or (ii) having a
structure (G), (H) or (I). corresponding to the category (iii)
structure of Fragment (D1) Fragment (C), R.sup.a = H, Category
(iii) moiety, e.g. R.sup.4 is Fragment Rz = category (i) or (ii)
having a structure (G), (H) or (I). corresponding to the category
(iii) structure of Fragment (D2) Fragment (C), R.sup.a = H,
Category (iii) moiety, e.g. R.sup.4 is Fragment Rz = category (i)
or (ii) having a structure (G), (H) or (I). corresponding to the
category (iii) structure of Fragment (E1). Fragment (C), R.sup.a =
H, Category (iii) moiety, e.g. R.sup.4 is Fragment Rz = category
(i) or (ii) having a structure (G), (H) or (I). corresponding to
the category (iii) structure of Fragment (E2). Fragment (C),
R.sup.a = H, Category (iii) moiety, e.g. R.sup.4 is Fragment Rz =
category (i) or (ii) having a structure (G), (H) or (I).
corresponding to the category (iii) structure of Fragment (F).
Fragment (C), R.sup.a = H, C.sub.1-C.sub.4 alkyl or C.sub.1-C.sub.4
alkyl R.sup.4 is Fragment R.sup.z = category (iii) substituted by
an optionally (G), (H) or (I). substituted 5- or 6- membered ring
Fragment (D1) C.sub.1-C.sub.4 alkyl or C.sub.1-C.sub.4 alkyl
R.sup.4 is Fragment substituted by an optionally (G), (H) or (I).
substituted 5- or 6- membered ring Fragment (D2) C.sub.1-C.sub.4
alkyl or C.sub.1-C.sub.4 alkyl R.sup.4 is Fragment substituted by
an optionally (G), (H) or (I). substituted 5- or 6- membered ring
Fragment (E1) C.sub.1-C.sub.4 alkyl or C.sub.1-C.sub.4 alkyl
R.sup.4 is Fragment substituted by an optionally (G), (H) or (I).
substituted 5- or 6- membered ring Fragment (E2) C.sub.1-C.sub.4
alkyl or C.sub.1-C.sub.4 alkyl R.sup.4 is Fragment substituted by
an optionally (G), (H) or (I). substituted 5- or 6- membered ring
Fragment (F) C.sub.1-C.sub.4 alkyl or C.sub.1-C.sub.4 alkyl R.sup.4
is Fragment substituted by an optionally (G), (H) or (I).
substituted 5- or 6- membered ring Fragment (C), R.sup.a H R.sup.4
is Fragment typically = H, R.sup.z = category (iii) (G), (H) or
(I). Fragment (D1); R.sup.a H R.sup.4 is Fragment typically = H,
(G), (H) or (I). Fragment (D2); R.sup.a H R.sup.4 is Fragment
typically = H, (G), (H) or (I). Fragment (E1); R.sup.a H R.sup.4 is
Fragment typically = H, (G), (H) or (I). Fragment (E2); R.sup.a H
R.sup.4 is Fragment typically = H, (G), (H) or (I). Fragment (F) H
R.sup.4 is Fragment (G), (H) or (I).
[0154] When R.sup.3 is an optionally substituted ring, substituents
are as described previously, e.g. methyl, ethyl, methoxy,
trifluoromethyl, amino or hydroxy.
[0155] Each row of the above table provides support for an
individual patent claim, presented by itself or with one or more
other claims, each corresponding to a respective row of the table.
The previous text provides support for claims dependent on such
claims in describing sub-classes of the respective features or
feature combinations of each row. For each row in the Table, a
patent claim or claims may be written to protect individually a
sub-class or sub-classes of the subject matter represented by the
row.
[0156] It will be understood from the aforegoing that a sub-set of
the Compounds of Formula (I) are of the following Formulae (II) and
(III):
##STR00016##
[0157] In Formulae (II) and (III), it is often the case that two of
X, Y and Z are N and that R.sup.5 and R.sup.2 are H, e.g. in many
compounds X is CH, Y and Z are N and R.sup.2 is H. Alternatively,
all of X, Y and Z are N and R.sup.2 is H. Ring A is typically
phenyl or a wholly or partially hydrogenated analogue thereof.
Alternatively it may be a heterocycle, typically of six members,
e.g. pyridine or pyrimidine. Integer m may be 0, 1 or 2, e.g. 1. In
some cases there are one or more R.sup.b moieties which are F or
Cl, as previously described, e.g. the only R.sup.b moieties may be
one or two moieties selected from F and Cl.
[0158] Accordingly, Formulae (II) and (III) encompass the following
sub-classes, amongst others: [0159] 1) Two of X, Y and Z are N,
R.sup.5 and R.sup.2 are H, ring A is phenyl or a wholly or
partially hydrogenated analogue thereof, m is 0, 1 or 2, e.g. 1;
[0160] 2) Two of X, Y and Z are N, R.sup.5 and R.sup.2 are H, ring
A is a heterocycle, typically of six members, e.g. pyridine or
pyrimidine, m is 0, 1 or 2, e.g. 1; [0161] 3) All of X, Y and Z are
N, R.sup.2 is H, ring A is phenyl or a wholly or partially
hydrogenated analogue thereof, m is 0, 1 or 2, e.g. 1; [0162] 4)
All of X, Y and Z are N, R.sup.2 is H, ring A is a heterocycle,
typically of six members, e.g. pyridine or pyrimidine, m is 0, 1 or
2, e.g. 1; [0163] 5) X is CH, Y and Z are N, R.sup.2 is H, ring A
is phenyl or a wholly or partially hydrogenated analogue thereof, m
is 0, 1 or 2, e.g. 1; [0164] 6) X is CH, Y and Z are N, R.sup.2 is
H, ring A is a heterocycle, typically of six members, e.g. pyridine
or pyrimidine, m is 0, 1 or 2, e.g. 1.
[0165] In some instances of sub-classes 1), 2), 3) 4), 5) and 6)
there are one or more R.sup.b moieties which are F or Cl, as
previously described, e.g. the only R.sup.b moieties may be one or
two moieties selected from F and Cl.
[0166] More commonly, ring A is substituted by one or two R.sup.b
moieties (and normally a single R.sup.b moiety) comprising
-L.sup.2-RING or -L.sup.2-NR.sup.cR.sup.d, and optionally other
substituents (e.g. numbering 1, 2 or 3) selected from e.g. halogen;
hydroxy; protected hydroxy for example trialkylsilylhydroxy; amino;
amidino; guanidino; hydroxyguanidino; formamidino; isothioureido;
ureido; mercapto; C(O)H or other lower acyl; lower acyloxy;
carboxy; sulfo; sulfamoyl; carbamoyl; cyano; azo; nitro; which
substituents are in turn optionally substituted on at least one
heteroatom by one or, where possible, more C.sub.1, C.sub.2,
C.sub.3 or C.sub.4 alkyl groups. Particular additional substituents
on ring A are halogen, lower alkyl (e.g. methyl), lower alkoxy
(e.g. methoxy), hydroxy, amino or trifluoromethyl.
[0167] Also to be mentioned therefore are compounds of the
following formulae (IV), (V), (VI) and (VII):
##STR00017##
where [0168] L.sup.2NR.sup.cR.sup.d is in particular -Pip, -Morph,
--OCH.sub.2Pip, --OCH.sub.2-Morph, --OCH.sub.2CH.sub.2Pip,
--OCH.sub.2CH.sub.2-Morph, --OCH.sub.2CH.sub.2CH.sub.2Pip,
--OCH.sub.2CH.sub.2CH.sub.2-Morph, --CH.sub.2Pip, --CH.sub.2-Morph,
--CH.sub.2CH.sub.2Pip, --CH.sub.2CH.sub.2-Morph,
--CH.sub.2CH.sub.2CH.sub.2Pip, and
--CH.sub.2CH.sub.2CH.sub.2-Morph, or is --C(O)Pip or --C(O)Morph
(or of course these heterocycles are replaced by another described
herein, or in other embodiments R.sup.c and R.sup.d form a
non-cyclic structure as previously described); [0169] L.sup.2RING
is in particular -RING, --OCH.sub.2RING, --OCH.sub.2CH.sub.2RING,
--OCH.sub.2CH.sub.2CH.sub.2RING, --CH.sub.2RING,
--CH.sub.2CH.sub.2RING, --CH.sub.2CH.sub.2CH.sub.2RING, or is
--C(O)RING, where RING is in particular pyrrolidine, piperidine,
piperazine or morpholine, or it may be another RING moiety
disclosed herein; [0170] R.sup.3 is as previously described and is
particularly but not necessarily H; [0171] R.sup.4 is as previously
described and is particularly but not necessarily selected from Cl,
F, hydroxy, methyl, methoxy and trifluoromethyl; [0172] n is 0, 1,
2, 3, 4 or 5, e.g. is 1, 2, 3, or 4.
[0173] In embodiments, RING or a heterocycle formed by
L.sup.2NR.sup.cR.sup.d is substituted by 1, 2, 3, 4 or 5
substituents, e.g. 1 or 2 substituents, selected from alkyl,
alkoxy, alkanoyl, alkanoyloxy, haloalkyl, amino, mono- or
di-alkylamino, cyano, halogen, hydroxy or protected hydroxy,
wherein alkyl or the alkyl part of alkoxy and alkanoyl(oxy) has 1,
2, 3 or 4 carbon atoms; exemplary substituents in this case are
methyl, ethyl, methoxy, ethoxy, acetyl, trifluoromethyl, cyano, F,
Cl and OH. N-alkyl substituted piperazine or piperadine are
exemplary, as are RING moieties as a class substituted by one or
two substituents or more, selected from alkyl and haloalkyl (e.g.
trifluoromethyl). As an alternative to substitution, there may be
no substitution.
[0174] Another embodiment comprises compounds of formula (XX):
##STR00018##
where R.sup.zl and R.sup.z2 are selected from hydrogen and straight
chain or branched alkyl having 1, 2, 3 or 4 carbon atoms, e.g.
methyl or ethyl. In embodiments, one of R.sup.z1 and R.sup.z2 is
hydrogen and more particularly both are hydrogen. It is often the
case that X is CH, Y and Z are N and R.sup.2 is H. Particular
classes of compounds are of formulae (XXI), (XXII), (XXIII) and
(XXIV):
##STR00019##
where R.sup.z1 and R.sup.z2 are selected from hydrogen and straight
chain or branched alkyl having 1, 2, 3 or 4 carbon atoms, e.g.
methyl or ethyl, and L.sup.2NR.sup.cR.sup.d, L.sup.2RING, R.sup.3
and R.sup.4 are as described in relation to formulae
(IV)-(VII).
[0175] The invention includes classes of compounds which correspond
to Formulae (IV), (V), (VI), (VII), (XXI), (XXII), (XXIII) and
(XXIV) in which the pyrimidine ring is replaced by a triazine
ring
[0176] One embodiment of the present invention relates to compounds
to Formula (I*), which represent a subgroup of the compounds of
Formula I, and salts, esters, N-oxides or prodrugs thereof:
##STR00020##
in which compounds of Formula (I*) the radicals and symbols have
the following meaning: g is 0, 1, 2, 3, 4 or 5; n is 0, 1, 2, 3 or
4; X, Y and Z are each independently selected from N or
C--R.sup.15, wherein at least one of X, Y and Z is N; X.sup.1 is
oxygen, L.sup.1 is a linker; RING* A is a mono- or bicyclic ring;
and R.sup.1, R.sup.2, R.sup.3, R.sup.15 and R.sup.16, if present,
are each independently selected from an organic or inorganic
moiety, [0177] where the inorganic moiety is especially selected
from halo, especially chloro, hydroxyl, cyano, azo (N.dbd.N.dbd.N),
nitro; and [0178] where the organic moiety is substituted or
unsubstituted and may be attached via a linker, -L.sup.2-, the
organic moiety being especially selected from hydrogen; lower
aliphatic (especially C.sub.1, C.sub.2, C.sub.3 or C.sub.4
aliphatic) e.g. lower alkyl, lower alkenyl, lower alkynyl; amino;
guanidino; hydroxyguanidino; formamidino; isothioureido; ureido;
mercapto; C(O)H or other acyl; acyloxy; substituted hydroxy;
carboxy; sulfo; sulfamoyl; carbamoyl; a substituted or
unsubstituted cyclic group, for example the cyclic group (whether
substituted or unsubstituted) may be cycloalkyl, e.g. cyclohexyl,
phenyl, pyrrole, imidazole, pyrazole, isoxazole, oxazole, thiazole,
pyridazine, pyrimidine, pyrazine, pyridyl, indole, isoindole,
indazole, purine, indolizidine, quinoline, isoquinoline,
quinazoline, pteridine, quinolizidine, piperidyl, piperazinyl,
pyrollidine, morpholinyl or thiomorpholinyl and, for example,
substituted lower aliphatic or substituted hydroxy may be
substituted by such substituted or unsubstituted cyclic groups,
L.sup.1 and L.sup.2 each independently being selected from moieties
having 1, 2, 3, 4 or 5 in-chain atoms (e.g. selected from C, N, O
and S) and optionally being selected from (i) C.sub.1, C.sub.2,
C.sub.3 or C.sub.4 alkyl, such an alkyl group optionally being
interrupted and/or terminated by an --O--, --C(O)-- or --NR.sup.a--
linkage; --O--; --S--; --C(O)--; cyclopropyl (regarded as having
two in-chain atoms) and chemically appropriate combinations
thereof; and --NR.sup.a--, wherein R.sup.a is hydrogen, hydroxy,
hydrocarbyloxy or hydrocarbyl, wherein hydrocarbyl is optionally
interrupted by an --O-- or --NH-- linkage and may be, for example,
selected from an aliphatic group (e.g. having 1 to 7 carbon atoms,
for example 1, 2, 3, or 4), cycloalkyl, especially cyclohexyl,
cycloalkenyl, especially cyclohexenyl, or another carbocyclic
group, for example phenyl; where the hydrocarbyl moiety is
substituted or unsubstituted; each R.sup.4 is the same or different
and selected from an organic or inorganic moiety, for example, each
R.sup.4 is the same or different and selected from halogen;
hydroxy; protected hydroxy for example trialkylsilylhydroxy; amino;
amidino; guanidino; hydroxyguanidino; formamidino; isothioureido;
ureido; mercapto; C(O)H or other acyl; acyloxy; carboxy; sulfo;
sulfamoyl; carbamoyl; cyano; azo; nitro; C.sub.1-C.sub.7 aliphatic
optionally substituted by one or more halogens and/or one or two
functional groups selected from hydroxy, protected hydroxy for
example trialkylsilylhydroxy, amino, amidino, guanidino,
hydroxyguanidino, formamidino, isothioureido, ureido, mercapto,
C(O)H or other acyl, acyloxy, carboxy, sulfo, sulfamoyl, carbamoyl,
cyano, azo, or nitro; all of the aforesaid hydroxy, amino, amidino,
guanidino, hydroxyguanidino, formamidino, isothioureido, ureido,
mercapto, carboxy, sulfo, sulfamoyl and carbamoyl groups in turn
optionally being substituted on at least one heteroatom by one or
more C.sub.1-C.sub.7 aliphatic groups.
[0179] The disclosure concerning pharmaceutical compositions,
dosages, combinations, pharmacological assays etc provided for the
compounds of Formula I apply to the compounds of Formula I*
accordingly.
[0180] Chemically appropriate combinations of --NR.sup.a--; --O--;
--S--; --C(O)--; cyclopropyl are combinations which form a
chemically stable moiety, such as --NR.sup.aC(O)--;
--C(O)NR.sup.a--; --C(O)O-- and --OC(O)--, for example. In many
classes of compounds, L.sup.1 does not comprise cyclopropyl.
[0181] L.sup.1 is in particular selected from --NR.sup.aCO-- and
--CONR.sup.a--.
[0182] In another particular embodiment, there is provided a
compound of Formula (II*):
##STR00021##
wherein L.sup.11 is selected from --NR.sup.aCO-- and --CONR.sup.a--
and the other symbols are as defined in relation to Formula
(I*).
[0183] Often, at least one of R.sup.1, R.sup.2 and R.sup.16 is not
H; in exemplary compounds a single one of R.sup.1, R.sup.2 and
R.sup.16 is not H. Normally R.sup.1 is not H. The invention
includes amongst others compounds in which at least one of R.sup.1,
R.sup.2 and R.sup.16 is Rz*-L.sup.3-. It includes a class of
compounds in which a single one of R.sup.1, R.sup.2 and R.sup.16 is
Rz*-L.sup.3-, particularly R.sup.1. The invention includes a class
of compounds in which R.sup.2 and R.sup.16 are H and R.sup.1 is not
H, e.g. is Rz*-L.sup.3- where L.sup.3 may be as hereinbefore
defined for L.sup.1.
[0184] In particular, the present invention pertains to compounsd
of formula I* wherein
(a) all of X, Y and Z are N,
(b) one of X, Y and Z is N,
[0185] (c) two or three of X and Y are N, or (d) both of X and Z
are N.
[0186] The compounds of Formula I* and II* are in particular useful
to treat AML via inhibition of the tyrosine kinase domain of Flt-3.
A further embodiment of the present invention is a method of
treating acute myeloid leukemia (AML) which comprises administering
a therapeutically effective amount of a claimed compound.
[0187] The Raf serine/threonine kinases are essential components of
the Ras/Mitogen-Activated Protein Kinase (MAPK) signaling module
that controls a complex transcriptional program in response to
external cellular stimuli. Raf genes code for highly conserved
serine-threonine-specific protein kinases which are known to bind
to the ras oncogene. They are part of a signal transduction pathway
believed to consist of receptor tyrosine kinases, p21 ras, Raf
protein kinases, Mek1 (ERK activator or MAPKK) kinases and ERK
(MAPK) kinases, which ultimately phosphorylate transcription
factors. In this pathway Raf kinases are activated by Ras and
phosphorylate and activate two isoforms of Mitogen-Activated
Protein Kinase Kinase (called Mek1 and Mek2), that are dual
specificity threonine/tyrosine kinases. Both Mek isoforms activate
Mitogen Activated Kinases 1 and 2 (MAPK, also called Extracellular
Ligand Regulated Kinase 1 and 2 or Erk1 and Erk2). The MAPKs
phosphorylate many substrates including transcription factors and
in so doing set up their transcriptional program. Raf kinase
participation in the Ras/MAPK pathway influences and regulates many
cellular functions such as proliferation, differentiation,
survival, oncogenic transformation and apoptosis.
[0188] Both the essential role and the position of Raf in many
signaling pathways have been demonstrated from studies using
deregulated and dominant inhibitory Raf mutants in mammalian cells
as well as from studies employing biochemical and genetic
techniques model organisms. In many cases, the activation of Raf by
receptors that stimulate cellular tyrosine phosphorylation is
dependent on the activity of Ras, indicating that Ras functions
upstream of Raf. Upon activation, Raf-1 then phosphorylates and
activates Mek1, resulting in the propagation of the signal to
downstream effectors, such as MAPK (mitogen-activated protein
kinase) (Crews et al. (1993) Cell 74:215). The Raf serine/threonine
kinases are considered to be the primary Ras effectors involved in
the proliferation of animal cells (Avruch et al. (1994) Trends
Biochem. Sci. 19:279).
[0189] Raf kinase has three distinct isoforms, Raf-1 (c-Raf),
A-Raf, and B-Raf, distinguished by their ability to interact with
Ras, to activate MAPK kinase pathway, tissue distribution and
sub-cellular localization (Manias et al., Biochem. J. 351: 289-305,
2000; Weber et. al., Oncogene 19:169-176, 2000; Pritchard et al.,
Mol. Cell. Biol. 15:6430-6442, 1995).
[0190] Recent studies have shown that B-Raf mutation in the skin
nevi is a critical step in the initiation of melanocytic neoplasia
(Pollock et. al., Nature Genetics 25: 1-2, 2002). Furthermore, most
recent studies have emerged that activating mutation in the kinase
domain of B-Raf occurs in .about.66% of melanomas, 12% of colon
carcinoma and 14% of liver cancer (Davies et. al., Nature
417:949-954, 2002) (Yuen et. al., Cancer Research 62:6451-6455,
2002) (Brose et. al., Cancer Research 62:6997-7000, 2002).
[0191] Inhibitors of Raf/MEK/ERK pathway at the level of Raf
kinases can potentially be effective as therapeutic agents against
tumors with over-expressed or mutated receptor tyrosine kinases,
activated intracellular tyrosine kinases, tumors with aberrantly
expressed Grb2 (an adapter protein that allows stimulation of Ras
by the Sos exchange factor) as well as tumors harboring activating
mutations of Raf itself. In early clinical trails an inhibitor of
Raf-1 kinase, that also inhibits B-Raf, has shown promise as a
therapeutic agent in cancer therapy (Crump, Current Pharmaceutical
Design 8: 2243-2248, 2002; Sebastien et. al., Current
Pharmaceutical Design 8: 2249-2253, 2002).
[0192] Disruption of Raf expression in cell lines through the
application of RNA antisense technology has been shown to suppress
both Ras and Raf-mediated tumorigenicity (Kolch et al., Nature
349:416-428, 1991; Monia et al., Nature Medicine 2(6):668-675,
1996).
[0193] As examples of kinases inhibited by the compounds of the
disclosure may be mentioned c-Abl and Bcr-Abl, in particular,
inhibition of Bcr-Abl may be mentioned. Another inhibited kinase is
the receptor tyrosine kinase VEGF-R, in particular the VEGF
receptor KDR (VEGF-R2). The compounds of the present invention also
inhibit mutant forms of the Bcr-Abl kinases. The disclosed
compounds are appropriate for the inhibition of one or more of
these and/or other protein tyrosine kinases and/or the non-receptor
tyrosine kinase Raf, and/or for the inhibition of mutants of these
enzymes. In view of these activities, the compounds can be used for
the treatment of diseases related to, especially, aberrant or
excessive activity of such types of kinases, especially those
mentioned.
[0194] For example, as inhibitors of VEGF-receptor tyrosine kinase
activity, the compounds of the invention may primarily inhibit the
growth of blood vessels and are thus, for example, effective
against a number of diseases associated with deregulated
angiogenesis, especially diseases caused by ocular
neovascularisation, especially retinopathies, such as diabetic
retinopathy or age-related macula degeneration, psoriasis,
haemangioblastoma, such as haemangioma, mesangial cell
proliferative disorders, such as chronic or acute renal diseases,
e.g. diabetic nephropathy, malignant nephrosclerosis, thrombotic
microangiopathy syndromes or transplant rejection, or especially
inflammatory renal disease, such as glomerulonephritis, especially
mesangioproliferative glomerulonephritis, haemolytic-uraemic
syndrome, diabetic nephropathy, hypertensive nephrosclerosis,
atheroma, arterial restenosis, autoimmune diseases, diabetes,
endometriosis, chronic asthma, and especially neoplastic diseases
(solid tumors, but also leukemias and other "liquid tumors",
especially those expressing c-kit, KDR, Flt-1 or Flt-3), such as
especially breast cancer, cancer of the colon, lung cancer
(especially small-cell lung cancer), cancer of the prostate or
Kaposi's sarcoma. A compound of Formula I*, II*, III*, IV*, V*,
VI*, VII*, VIII* or IX* (or exemplary formula thereof) (or an
N-oxide thereof) inhibits the growth of tumours and is especially
suited to preventing the metastatic spread of tumors and the growth
of micrometastases.
[0195] One class of target kinases of the compounds of the present
invention are Bcr-Abl mutants. The mutants Glu255.fwdarw.Lysine,
Glu255.fwdarw.Valine or the Thr315.fwdarw.Isoleucine may be
especially mentioned, most especially the Thr315.fwdarw.Isoleucine
mutant.
[0196] Other Bcr-Abl mutants include Met244.fwdarw.NaI,
Phe317.fwdarw.Leu, Leu248.fwdarw.Val, Met343.fwdarw.Thr,
Gly250.fwdarw.Ala, Met351.fwdarw.Thr, Phe358.fwdarw.Ala,
Gln252.fwdarw.Arg, Phe359.fwdarw.NaI, Tyr253.fwdarw.His,
Val379.fwdarw.Ile, Tyr253.fwdarw.Phe, Phe382.fwdarw.Leu,
Glu255.fwdarw.Lys, Leu387.fwdarw.Met, Glu255.fwdarw.NaI,
His396.fwdarw.Pro, Phe311.fwdarw.Ile, His396.fwdarw.Arg,
Phe311.fwdarw.Leu, Ser417.fwdarw.Tyr, Thr315.fwdarw.Ile,
Glu459.fwdarw.Lys and Phe486.fwdarw.Ser.
[0197] Structural fragments and substituents of the compounds of
Formula (I*) will now be considered in turn:
The Left Hand Ring
[0198] By the "left hand ring" is meant the fragment:
##STR00022##
[0199] In a class of compounds, two of X, Y and Z are N, and in one
sub-class X and Y are N while in another or X and Z are N; in an
alternative class at of X, Y and Z are N. A particular class
consists of compounds in which Y and Z are N, thus forming by way
of example Fragment (A*):
##STR00023##
Substituent R.sup.15
[0200] Considering now the left hand ring without restriction, i.e.
without limitation to Fragment (A*), the or each R.sup.15 may
independently be an R.sup.1 group, for example as more particularly
defined below, independently of the identity of R.sup.1.
[0201] In some compounds the or each R.sup.15 is independently H;
hydroxy; halo; amino or mono- or di-alkylamino; cyano; azo or
nitro; an aliphatic group having 1 to 7 carbon atoms and optionally
interrupted by an --O-- or --NH-- linkage and/or linked to the left
hand ring by a said linkage and/or substituted by hydroxy, halo,
amino or mono- or di-alkylamino, cyano, azo or nitro; or acyl
wherein the carbonyl moiety is substituted by a said aliphatic
group; hydroxy, amino, mono- or dialkylamino, cyano, azo or nitro.
Alkyl groups may have for example 1 to 7, e.g. 1, 2, 3 or 4 carbon
atoms.
[0202] Often, R.sup.15 is H, halo, hydroxy, amino, mono- or
dialkylamino, alkyl (e.g. methyl), alkyl interrupted by an --O-- or
--NH-- linkage and/or linked to the left hand ring by a said
linkage (e.g. to form alkoxy, for example methoxy),
trifluoromethyl, hydroxy, amino, mono- or dialkylamino; any alkyl
moiety (interrupted or not) typically has 1, 2, 3 or 4 carbon
atoms.
[0203] In a class of compounds, R.sup.15 is H or halo, particularly
H, F or Cl, for example is H or F. In a particular class of
compounds, the or each R.sup.15 is H.
[0204] The above description of R.sup.15 applies of course to
Fragment (A*) as much as to other left hand ring structures.
Substituent R.sup.2
[0205] Again considering the left hand ring without restriction,
R.sup.2 may be any moiety described above in relation to R.sup.15
(e.g. may be any R.sup.1 group as described more particularly
below) and of course R.sup.2 and R.sup.15 may be the same or
different.
[0206] In some compounds, R.sup.2 and the or each R.sup.15 are
independently H; halo; an aliphatic group (e.g. having 1 to 7
carbon atoms, for example 1, 2, 3, or 4), the aliphatic group
optionally being interrupted by an --O-- or --NH-- linkage and/or
linked to the left hand ring by a said linkage and/or substituted
by hydroxy, halo, amino or mono- or di-alkylamino, acyl wherein the
carbonyl moiety is substituted by a said aliphatic group,
trifluoromethyl, hydroxy, amino, mono- or di-alkylamino, cyano, azo
or nitro.
[0207] Often, both R.sup.2 and the or each R.sup.15 are
independently H, halo, alkyl, alkyl interrupted by an --O-- or
--NH-- linkage and/or linked to the left hand ring by a said
linkage, trifluoromethyl, hydroxy, amino, mono- or dialkylamino;
any alkyl moiety (interrupted or not) typically has 1, 2, 3 or 4
carbon atoms.
[0208] In a class of compounds, both R.sup.2 and the or each
R.sup.15 are independently H or halo, particularly H, F or Cl, for
example are H or F. In a particular class of compounds, R.sup.2 and
the or each R.sup.15 are H.
[0209] The above descriptions of R.sup.2 and of R.sup.2 and
R.sup.15 apply of course to Fragment (A*) as much as to other left
hand ring structures.
[0210] It will be understood from the aforegoing description that a
particular left hand ring structure is Fragment (B*):
##STR00024##
Substituent R.sup.1
[0211] As previously described, R.sup.1 is an organic or inorganic
moiety.
[0212] As inorganic moieties may be mentioned halo, hydroxyl,
amino, cyano, azo (N.dbd.N.dbd.N) and nitro. F and Clare exemplary
halogens. [0213] The organic moiety, designated Rz*, is substituted
or unsubstituted and may be attached via a linker, -L.sup.3-, the
organic moiety being especially selected from hydrogen; [0214]
lower aliphatic (especially C.sub.1, C.sub.2, C.sub.3 or C.sub.4
aliphatic) e.g. lower alkyl, lower alkenyl, lower alkynyl,
particularly lower and especially C.sub.1, C.sub.2, C.sub.3 or
C.sub.4 alkyl; [0215] substituted or unsubstituted functional
groups selected from amino; guanidino; hydroxyguanidino;
formamidino; isothioureido; ureido; mercapto; carboxy; sulfo; and
hydroxy, exemplary substituents being a protecting group, a said
lower aliphatic group, acyl particularly lower alkanoyl e.g. of
which the alkyl part has 1, 2, 3 or 4 carbon atoms, carboxy,
esterified carboxy (e.g. esterified by a said lower aliphatic
group); [0216] sulfamoyl; carbamoyl; C(O)H or other acyl; acyloxy;
where acyl is particularly lower alkanoyl e.g. of which the alkyl
part has 1, 2, 3 or 4 carbon atoms; [0217] substituted or
unsubstituted cyclic groups, for example the cyclic group (whether
substituted or unsubstituted) may be cycloalkyl, e.g. cyclohexyl,
phenyl, pyrrole, imidazole, pyrazole, isoxazole, oxazole, thiazole,
pyridazine, pyrimidine, pyrazine, pyridyl, indole, isoindole,
indazole, purine, indolizidine, quinoline, isoquinoline,
quinazoline, pteridine, quinolizidine, piperidyl, piperazinyl,
pyrollidine, morpholinyl or thiomorpholinyl and, for example,
substituted lower aliphatic or substituted hydroxy may be
substituted by such substituted or unsubstituted cyclic groups. See
below for a description of particular classes of Rz* moiety.
[0218] Linker -L.sup.3- has 1, 2, 3, 4 or 5 in-chain atoms and is
selected from C1, C2, C3 or C4 aliphatic (notably linear aliphatic,
and aliphatic particularly being alkyl) optionally interrupted
and/or terminated by a linkage selected from the group consisting
of --NR.sup.a--; --O--; --S--; --C(O)--; cyclopropyl (regarded as
having two in-chain atoms) and chemically appropriate combinations
thereof; --NR.sup.a--; --O--; --S--; --C(O)--; cyclopropyl
(regarded as having two in-chain atoms) and chemically appropriate
combinations thereof; and --NR.sup.a--, wherein R.sup.a is
hydrogen, hydroxy, hydrocarbyloxy or hydrocarbyl, wherein
hydrocarbyl has from 1 to 15 carbon atoms (e.g. 1 to 7), is
optionally interrupted by an --O-- or --NH-- linkage and may be,
for example, selected from an aliphatic group (e.g. having 1 to 7
carbon atoms, for example 1, 2, 3, or 4, aliphatic particularly
being alkyl), cycloalkyl, especially cyclohexyl, cycloalkenyl,
especially cyclohexenyl, or another carbocyclic group, for example
phenyl; where the hydrocarbyl moiety is substituted or
unsubstituted. Exemplary substituents are hydroxy, halo, amino or
mono- or di-(C.sub.1-C.sub.4)alkylamino, lower alkanoyl,
trifluoromethyl, cyano, azo or nitro. R.sup.a is particularly
H.
[0219] In a class of compounds, R.sup.1 includes a linker L.sup.3;
in a sub-class, the linker is --NR.sup.a--, alkyl terminated at the
left hand ring by (i.e joined to the left hand ring by)
--NR.sup.a--, alkyl terminated at its end remote from the left hand
ring by --NR.sup.a--, or alkyl interrupted by --NR.sup.a-- wherein
alkyl has 1, 2, 3 or 4 carbon atoms. In this class of compounds,
R.sup.a is particularly H. A preferred linker is --NH--.
[0220] In other words, a common left hand ring structure is
represented by Fragment (C*):
##STR00025##
where R.sup.a is as described above and preferably H, and Rz* is a
substituted or unsubstituted organic moiety as mentioned above and
as further described below. Also to be mentioned are compounds in
which Rz* is H, i.e. in which R.sup.1 is amino when R.sup.a is also
H, as well as variants in which R.sup.1 is another substituted or
unsubstituted basic group, for example amidino, guanidino;
hydroxyguanidino; formamidino; isothioureido or ureido.
[0221] As previously described, therefore, R.sup.1 may in certain
compounds comprise a substituted or unsubstituted organic moiety,
optionally joined to the left hand ring through a linker L.sup.3.
Thus, R.sup.1 in such compounds may be represented as Rz*-L.sup.3-,
where Rz* is a substituted or an unsubstituted organic moiety. This
applies equally to left hand ring structures which do not
correspond to Fragment (C*) as to those which do.
[0222] Rz* is commonly a moiety containing from 1 to 30 in-chain
and/or in-ring atoms selected from C, N, O, S and Si and in which
one or more hydrogens are optionally replaced by halogen.
Alternatively stated, such Rz* groups have from 1 to 30 plural
valent atoms selected from C, N, O, S and Si as well as monovalent
atoms selected from H and halo, e.g. selected from H, F, Cl and Br,
for example H, F and Cl. In some Rz* moieties there are from 1 to
25 plural valent atoms, e.g. 1 to 20, such as 1 to 16, for
example.
[0223] Included are compounds in which Rz* contains one or a
combination of moieties selected from categories 1), 2) and 3)
below and optionally one or more moieties selected from category 4)
below: [0224] 5) aliphatic moieties, in particular having from 1 to
7 carbon atoms, e.g. 1, 2, 3 or 4, particularly alkyl or alkenyl
moieties, e.g. alkyl; [0225] 6) carbocyclic rings, which may be
saturated or unsaturated (e.g. aromatic), particularly to be
mentioned are bicyclic and monocyclic rings and especially
monocyclic rings having 5 or 6 ring members; [0226] 7) heterocyclic
rings, which may be saturated or unsaturated (e.g. aromatic),
particularly to be mentioned are bicyclic and monocyclic rings and
especially monocyclic rings having 5 or 6 ring members; [0227] 8)
linking moieties selected from O, N, Si and C(O), wherein two or
more linking moieties may be combined to form a larger linking
group for example C(O)O, C(O)NH or OC(O)NH.
[0228] In these compounds, a plurality of moieties selected from
1), 2) and 3) may be linked together either directly or through a
linking moiety 4). Of course, one compound may contain one or more
linking moieties. Tri- or more valent linking moieties such as N
and Si may serve to link together just two moieties selected from
1), 2) and 3), in which case the remaining valencies are suitably
occupied by hydrogen; alternatively N or Si may link together three
said moieties, or Si may link together four said moieties. Where
Rz* contains a plurality of moieties selected from 1), 2) and 3),
the moieties may be the same of different and may independently be
selected from categories 1), 2) and 3).
[0229] Moieties 1), 2) and 3) may be substituted by one or more
substituents selected from, in particular, hydroxy, amino, amidino,
guanidino, hydroxyguanidino, formamidino, isothioureido, ureido,
mercapto, C(O)H or other lower acyl, lower acyloxy, carboxy, sulfo,
sulfamoyl, carbamoyl, cyano, azo, or nitro, which hydroxy, amino,
amidino, guanidino, hydroxyguanidino, formamidino, isothioureido,
ureido, mercapto, carboxy, sulfo, sulfamoyl, carbamoyl and cyano
groups are in turn optionally substituted on at least one
heteroatom by one or, where possible, more C.sub.1-C.sub.7
aliphatic groups. Often, but not always, Rz* has 0, 1, 2, 3, or 4
such substituents; sometimes there are a larger number of
substituents as can happen, for example, when Rz* contains one or
more perfluorinated alkyl or cyclic groups, e.g. CF.sub.3, as well
as other optional substituents.
[0230] Particular moieties 1), 2) and 3) to mention are straight
chain and branched alkyl, 5- and 6-membered carbocyclic rings
(notably phenyl and cyclohexyl), and 5- and 6-membered heterocyclic
rings (notably 5-membered rings containing a single heteroatom,
e.g. furan, thiophene, pyrrole; and 6-membered rings containing one
or two heteroatoms, e.g. piperidine, piperazine, morpholine,
pyridine, pyrimidine and pyrazine).
[0231] The invention includes compounds of Formula (I*) or (II*)
wherein R.sup.1 is of the formula Rz*-NR.sup.a--, as described
above, and Rz* is selected from
(i) -G-R.sup.x where G is a direct bond, C(.dbd.O) or C(.dbd.O)O
and R.sup.x is selected from H and C.sub.1-C.sub.7 aliphatic
moieties, (II*) -G-R.sup.y where G is a direct bond, C(.dbd.O) or
C(.dbd.O)O and R.sup.y is selected from C.sub.1-C.sub.7 aliphatic
substituted by one or more halogens and/or one or two functional
groups selected from hydroxy, amino, amidino, guanidino,
hydroxyguanidino, formamidino, isothioureido, ureido, mercapto,
C(O)H or other lower acyl, lower acyloxy, carboxy, sulfo,
sulfamoyl, carbamoyl, cyano, azo, or nitro, which hydroxy, amino,
amidino, guanidino, hydroxyguanidino, formamidino, isothioureido,
ureido, mercapto, carboxy, sulfo, sulfamoyl, carbamoyl and cyano
groups are in turn optionally substituted on at least one
heteroatom by one or, where possible, more C.sub.1-C.sub.7
aliphatic groups, (iii) a group of the formula
##STR00026## [0232] where: [0233] J represents a direct bond, alkyl
or alkyl terminated or interrupted by C(.dbd.O) or C(.dbd.O)O,
where J has 1, 2, 3, 4 or 5 in-chain atoms; [0234] ring B
represents a mono- or bi-cyclic ring, particularly a 5- or
6-membered carbocyclic or heterocyclic ring; [0235] p is 0, 1, 2;
3, 4 or 5, e.g. 0, 1 or 2; [0236] the or each R.sup.b is
independently selected from -L.sup.4-NR.sup.cR.sup.d;
-L.sup.4-RING* where RING* is a mono- or bi-cyclic ring,
particularly a 5- or 6-membered carbocyclic or heterocyclic ring,
optionally substituted as defined below; halogen; hydroxy;
protected hydroxy for example trialkylsilylhydroxy; amino; amidino;
guanidino; hydroxyguanidino; formamidino; isothioureido; ureido;
mercapto; C(O)H or other lower acyl; lower acyloxy; carboxy; sulfo;
sulfamoyl; carbamoyl; cyano; azo; or nitro; and C.sub.1-C.sub.7
aliphatic optionally substituted by one or more halogens and/or one
or two functional groups selected from hydroxy, protected hydroxy
for example trialkylsilylhydroxy, amino, amidino, guanidino,
hydroxyguanidino, formamidino, isothioureido, ureido, mercapto,
C(O)H or other lower acyl, lower acyloxy, carboxy, sulfo,
sulfamoyl, carbamoyl, cyano, azo, or nitro; all of which hydroxy,
amino, amidino, guanidino, hydroxyguanidino, formamidino,
isothioureido, ureido, mercapto, carboxy, sulfo, sulfamoyl,
carbamoyl and cyano groups are in turn optionally substituted on at
least one heteroatom by one or, where possible, more
C.sub.1-C.sub.7 aliphatic groups, [0237] wherein L.sup.4 is a
direct bond; a linkage selected from --O--; --S--; --C(O)--;
--OC(O)--; --NR.sup.aC(O)--; --C(O)--NR.sup.a--;
--OC(O)--NR.sup.a--; cyclopropyl and --NR.sup.a--; or is a
C.sub.1-C.sub.7 aliphatic group optionally interrupted and/or
terminated at a single end or at both ends by a said linkage
(R.sup.a being as previously defined and typically H); and wherein
R.sup.c and R.sup.d are each independently selected from hydrogen,
and C.sub.1-C.sub.7 aliphatic optionally substituted by one or more
halogens, by an optionally substituted 5- or 6-membered
heterocyclic or carbocyclic ring, and/or one or two functional
groups selected from hydroxy, protected hydroxy for example
trialkylsilylhydroxy, amino, amidino, guanidino, hydroxyguanidino,
formamidino, isothioureido, ureido, mercapto, C(O)H or other lower
acyl, lower acyloxy, carboxy, sulfo, sulfamoyl, carbamoyl, cyano,
azo, or nitro, which hydroxy, amino, amidino, guanidino,
hydroxyguanidino, formamidino, isothioureido, ureido, mercapto,
carboxy, sulfo, sulfamoyl, carbamoyl and cyano groups are in turn
optionally substituted on at least one heteroatom by one or more
C.sub.1-C.sub.7 aliphatic groups, or R.sup.c and R.sup.d together
with their adjoining nitrogen form a 5- or 6-membered ring
optionally substituted as described below, said optionally
substituted rings independently of each other being substituted by
0, 1, 2, 3, 4 or 5 substituents selected from halogen; hydroxy;
protected hydroxy for example trialkylsilylhydroxy; amino; amidino;
guanidino; hydroxyguanidino; formamidino; isothioureido; ureido;
mercapto; C(O)H or other lower acyl; lower acyloxy; carboxy; sulfo;
sulfamoyl; carbamoyl; cyano; azo; nitro; C.sub.1-C.sub.7 aliphatic
optionally substituted by one or more halogens and/or one or two
functional groups selected from hydroxy, protected hydroxy for
example trialkylsilylhydroxy, amino, amidino, guanidino,
hydroxyguanidino, formamidino, isothioureido, ureido, mercapto,
C(O)H or other lower acyl; lower acyloxy carboxy, sulfo, sulfamoyl,
carbamoyl, cyano, azo, or nitro; all of the aforesaid hydroxy,
amino, amidino, guanidino, hydroxyguanidino, formamidino,
isothioureido, ureido, mercapto, carboxy, sulfo, sulfamoyl and
carbamoyl groups in turn optionally being substituted on at least
one heteroatom by one or, where possible, more C.sub.1-C.sub.7
aliphatic groups (for example, therefore, a ring may be substituted
by an alkoxy group, e.g. methoxy or ethoxy).
[0238] Still considering compounds wherein R.sup.1 is of the
formula Rz*-NR.sup.a and Rz* is selected from categories (i), (ii)
and (iii) above, aliphatic often has 1, 2, 3 or 4 carbon atoms and
is often linear, but sometimes branched. In a class of compounds,
aliphatic is alkyl, e.g. linear or branched alkyl having 1, 2, 3 or
4 carbon atoms; linear alkyl is more common, irrespective of the
number of carbon atoms.
[0239] In a sub-class of the above category (i) compounds, -G- is a
direct bond and R.sup.x is H or a said aliphatic group and more
particularly R.sup.x is H or alkyl, e.g. linear or branched alkyl
having 1, 2, 3 or 4 carbon atoms; linear alkyl being more common,
irrespective of the number of carbon atoms. This sub-class
therefore comprises compounds in which R.sup.1 is amino or mono- or
di-alkylamino. Included are members of this sub-class in which
R.sup.x is not H but a said aliphatic group.
[0240] In another sub-class of category (i) compounds, -G- is
C(.dbd.O) or C(.dbd.O)O and R.sup.x is H or a said aliphatic group
and more particularly R.sup.x is H or alkyl, e.g. linear or
branched alkyl having 1, 2, 3 or 4 carbon atoms, linear alkyl being
more common, irrespective of the number of carbon atoms. Included
are members of this sub-class in which R.sup.x is not H but a said
aliphatic group. Methyl may be mentioned as an exemplary R.sup.x
group. It will be understood that in some compounds of this
sub-class -G- is C(.dbd.O) whereas in other compounds G is
C(.dbd.O)O. As R.sup.1 groups formed by this sub-class may be
mentioned alkanoylamino, particularly acetylamino (--NHC(O)Me), and
alkoxycarbonylamino, particularly methoxycarbonylamino
(--NHC(O)OMe).
[0241] It will be appreciated from the preceding two paragraphs
that the invention includes category (i) compounds in which R.sup.x
is not H but a said aliphatic group as in the case of alkyl, e.g.
linear or branched alkyl having 1, 2, 3 or 4 carbon atoms.
[0242] A particular genus of compounds are those in which R.sup.a
is as previously defined, e.g. is selected from hydrogen and
aliphatic groups, particularly alkyl groups (e.g. in either case
having 1 to 7 carbon atoms, for example 1, 2, 3, or 4, and R.sup.1
is selected from the group consisting of: [0243] 1) moieties
falling within category (i) above, wherein -G- is a direct bond and
R.sup.x is H or a said aliphatic group, and aliphatic often has 1,
2, 3 or 4 carbon atoms and is typically linear, but sometimes
branched. In a sub-genus of these compounds, aliphatic is alkyl,
e.g. linear or branched alkyl having 1, 2, 3 or 4 carbon atoms;
linear alkyl is more common, irrespective of the number of carbon
atoms; [0244] 2) moieties of the formula Rz*-NR.sup.a--, where Rz*
is acyl; acyloxy; where acyl is particularly lower alkanoyl e.g. of
which the alkyl part has 1, 2, 3 or 4 carbon atoms; [0245] 3)
moieties falling within category (i) above, wherein -G- is
C(.dbd.O) or C(.dbd.O)O and R.sup.x is H or a said aliphatic group
and more particularly R.sup.x is H or alkyl, e.g. linear or
branched alkyl having 1, 2, 3 or 4 carbon atoms, linear alkyl being
more common, irrespective of the number of carbon atoms. Included
are members of this sub-class in which R.sup.x is not H but a said
aliphatic group; methyl may be mentioned as an exemplary R.sup.x
group; [0246] 4) C.sub.1, C.sub.2, C.sub.3 or C.sub.4 alkyl,
C.sub.1, C.sub.2, C.sub.3 or C.sub.4 haloalkyl (e.g.
trifluoromethyl), halo (e.g. F or Cl), hydroxy, alkoxy (e.g.
methoxy), cyano, azo (N.dbd.N.dbd.N) or nitro.
[0247] In many compounds of this genus, R.sup.a is H. Commonly, Rz*
is as defined in sub-clause 1) or 3) of the preceding paragraph,
e.g. is H; C.sub.1, C.sub.2, C.sub.3 or C.sub.4 alkyl; C.sub.1,
C.sub.2, C.sub.3 or C.sub.4 alkanoyl; or alkoxycarbonyl of which
the alkoxy part has 1, 2, 3 or 4 carbon atoms.
[0248] Particular compounds falling in category (ii) are those in
which -G- is a direct bond. Also to be mentioned are category (ii)
compounds in which -G- is C(.dbd.O) or C(.dbd.O)O.
[0249] Turning now to those compounds in which Rz* is a category
(iii) group, i.e. is of the formula
##STR00027##
ring B is typically a 6-membered carbocyclic or heterocyclic ring,
particularly phenyl, cyclohexyl or cyclohexenyl. Of these, phenyl
is preferred. In other instances, ring B is a 5-membered
carbocyclic or heterocyclic ring. Other exemplary residues forming
ring B are pyridyl and pyrimidyl.
[0250] J is often a direct bond, thus forming Fragment H of the
formula:
##STR00028##
[0251] Integer p may be 0.
[0252] Integer p is often 1. Where p is greater than one, all the
R.sup.b groups or all the R.sup.b groups except one are often
halogen (notably F or Cl), methyl or trifluoromethyl. Also to be
mentioned in this regard are hydroxy and amino. Often, a single
R.sup.b group is selected from -L.sup.4-NR.sup.cR.sup.d and
-L.sup.4-RING* and there are 0, 1 or 2 additional substituents
which are not -L.sup.4-NR.sup.cR.sup.d or -L.sup.4-RING* but are,
for example, halogen (notably F or Cl), lower alkyl (e.g. methyl),
lower alkoxy (e.g. methoxy), hydroxy, amino or trifluoromethyl.
[0253] Accordingly, the invention includes compounds in which Rz*
is, e.g. a 6-membered carbocyclic ring (notably phenyl) substituted
by 1, 2, 3, 4 or 5 halogens, e.g. selected from F, Cl and Br;
typically, such phenyl rings are mono- or di-substituted, e.g. are
2- and/or 4-substituted by F or 3-substituted by Cl. In some cases
of plural substitution by halogen, all the halogens are the same.
Thus, in a class of compounds Rz* is a monocyclic ring,
particularly a 6-membered carbocyclic ring (notably phenyl),
substituted solely by one or more halogens, particularly selected
from F and Cl; sometimes the or each halogen is F but in some other
cases the or each halogen is Cl.
[0254] In another class of compounds, Rz* is a monocyclic ring,
particularly a 6-membered carbocyclic ring (notably phenyl),
substituted by 1, 2, 3, 4 or 5 substituents, e.g. 1 or 2
substituents, selected from alkyl, alkoxy, alkanoyl, alkanoyloxy,
haloalkyl, amino, mono- or di- alkylamino, cyano, halogen, hydroxy
or protected hydroxy, wherein alkyl or the alkyl part of alkoxy and
alkanoyl(oxy) has 1, 2, 3 or 4 carbon atoms; exemplary substituents
in this case are methyl, ethyl, methoxy, ethoxy, acetyl,
trifluoromethyl, cyano, F, Cl and OH. Certain such rings have 0, 1
or 2 substituents, e.g. 0 or 1.
[0255] In one class of compounds, L.sup.4 is a direct bond, linear
alkyl, linear alkyl terminated adjacent ring A by a said linkage,
or is a said linkage. In a sub-class, any said linkage is --O--,
--C(O)-- or a direct bond, of which --O-- and a direct bond may be
particularly mentioned, for example --O--
[0256] The invention includes a class of compounds in which ring A
is a 6-membered ring, particularly phenyl, cyclohexyl or
cyclohexenyl and has one or two substituents R.sup.b independently
selected from -L.sup.4-NR.sup.cR.sup.d and -L.sup.4-RING*, as
defined previously. In a sub-class, there is a single substituent
at, in particular, the 3-position or 4-position selected from
-L.sup.4-NR.sup.cR.sup.d and -L.sup.4-RING* such that the left hand
ring has a structure corresponding to Fragments (D1), (D2), (E1) or
(E2):
##STR00029##
[0257] As previously described, R.sup.a is commonly H. Also as
previously described, the phenyl ring may be replaced by cyclohexyl
or cyclohexenyl, particularly cyclohexyl. It may alternatively be
replaced by a 5- or 6-membered heterocycle, particularly
pyridine.
[0258] In some embodiments, the phenyl ring of the above fragments
(or other ring replacing phenyl) has 1, 2, 3 or 4 further
substituents, for example selected from halogen (notably F or Cl),
methyl, methoxy or trifluoromethyl, e.g. 1 or 2 such substituents.
Also to be mentioned in this regard are hydroxy and amino.
[0259] L.sup.4 is as previously described, that is a direct bond; a
linkage selected from --O--; --S--; --C(O)--; --OC(O)--;
--NR.sup.aC(O)--; --C(O)--NR.sup.a--; --OC(O)--NR.sup.a;
cyclopropyl and --NR.sup.a--; or C.sub.1-C.sub.7 aliphatic
optionally interrupted and/or terminated at a single end or at both
ends by a said linkage (R.sup.a being as previously defined and
typically H). Any aliphatic moiety is often alkyl, e.g. alkyl or
other aliphatic having 1, 2, 3 or 4 carbon atoms, as in the case of
a sub-class of linkers L.sup.2 in which aliphatic moieties are
methyl, ethyl or n-propyl.
[0260] In particular fragments (D) and (E), L.sup.4 is a direct
bond, linear alkyl, linear alkyl terminated adjacent the phenyl
ring in the above representations of the fragments by a said
linkage, or is a said linkage; suitably but not necessarily any
said linkage is --O-- or --C(O)--, of which --O-- may be
particularly mentioned. Thus, the above fragments (D) and (E) may
comprise sub-fragments -Ph-NR.sup.cR.sup.d, -Ph-RING*,
-Ph-O-alkyl-NR.sup.cR.sup.d, -Ph-O-alkyl-RING*,
-Ph-alkyl-NR.sup.cR.sup.d, -Ph-alkyl-RING*, and also to be
mentioned are sub-fragments -Ph-O--NR.sup.cR.sup.d, -Ph-O-RING*,
-Ph-C(O)--NR.sup.cR.sup.d and -Ph-C(O)--RING*, where, in all these
sub-fragments which contain alkyl, alkyl may be e.g. methyl, ethyl
or n-propyl, or n-butyl.
[0261] In some embodiments L.sup.4 is H, thus providing fragment
(E3) and (E4):
##STR00030##
[0262] Considering now in more detail fragments (D1) and (D2),
these contain a moiety RING* which is a cyclic moiety and in many
cases a 5- or 6-membered carbocyclic or heterocyclic ring
optionally substituted as defined previously. Exemplary rings are
saturated, e.g. cyclopentane or cyclohexane. In particular
compounds, RING* is a 5- or 6-membered heterocycle, often
containing one or two heteroatoms, typically selected from O and N;
in a sub-class, the heterocycles contain one or two nitrogens and,
where there is a single nitrogen, optionally an oxygen. Particular
heterocycles include a nitrogen which is not a member of a double
bond and these are more particularly saturated heterocycles. As
heterocycles may be mentioned pyrrolidine, piperidine, piperazine
and morpholine; in some compounds, RING* is piperidine having its
nitrogen at the 4-position relative to L.sup.2. As already
described, RING* may be substituted and, in one class of compounds,
is substituted by 0, 1, 2, 3, 4 or 5 substituents, e.g. selected
from C.sub.1-C.sub.7 aliphatic groups, optionally substituted as
described above, and less frequently C.sub.1-C.sub.7 aliphatic-oxy.
Any aliphatic group is often alkyl (straight chain or branched),
e.g. alkyl or other aliphatic having 1, 2, 3 or 4 carbon atoms, as
in the case of a sub-class of fragments (D1) and (D2) having
substituents which are methyl, ethyl or n-propyl. Exemplary
substituents on RING* include straight chain or branched C.sub.1,
C.sub.2, C.sub.3 or C.sub.4 alkyl such as, e.g., methyl, ethyl
n-propyl, isopropyl or t-butyl, of which methyl may be particularly
mentioned, halogen (notably F or Cl) and C.sub.1, C.sub.2, C.sub.3
or C.sub.4 alkoxy; also to be mentioned are hydroxy and amino.
Alkyl moieties may be unsubstituted or substituted, e.g. by halogen
(notably F or Cl) or in some cases by hydroxy or amino.
[0263] In some classes of RING* moieties, there are 0, 1, 2, 3, 4
or 5 such substituents selected from alkyl, alkoxy, alkanoyl,
alkanoyloxy, haloalkyl, amino, mono- or di-alkylamino, cyano,
halogen, hydroxy or protected hydroxy, wherein alkyl or the alkyl
part of alkoxy and alkanoyl(oxy) has 1, 2, 3 or 4 carbon atoms;
exemplary substituents in this case are methyl, ethyl, methoxy,
ethoxy, acetyl, trifluoromethyl, cyano, F, Cl and OH. Certain RING*
moieties have 0, 1 or 2 substituents, e.g. 0 or 1.
[0264] Considering now in more detail fragments (E1) and (E2),
these contain a moiety NR.sup.cR.sup.d. R.sup.c and R.sup.d are as
previously described. In one class of these fragments, R.sup.c and
R.sup.d are the same or different (but more usually the same) and
selected from C.sub.1-C.sub.7, e.g. C.sub.1-C.sub.4 aliphatic
groups, optionally substituted as described above. As aliphatic
R.sup.c and R.sup.d moieties may be mentioned alkyl, e.g having 1,
2, 3 or 4 carbon atoms, as in the case of a sub-class of fragments
(E1) and (E2) having substituents which are methyl, ethyl or
n-propyl. Alkyl or other aliphatic moieties may be substituted e.g.
by amino or mono- or di (C.sub.1-C.sub.4) alkylamino, or e.g. by a
5- or 6-membered heterocyclic or carbocyclic ring optionally
substituted as previously described, or be unsubstituted. Thus,
particular L.sup.4NR.sup.cR.sup.d moieties are
--OCH.sub.2NMe.sub.2, --OCH.sub.2NEt.sub.2,
--OCH.sub.2CH.sub.2NMe.sub.2, --OCH.sub.2CH.sub.2NEt.sub.2,
--OCH.sub.2CH.sub.2CH.sub.2NMe.sub.2, --OCH.sub.2CH.sub.2C
H.sub.2NEt.sub.2, --CH.sub.2NMe.sub.2, --CH.sub.2NEt.sub.2,
--CH.sub.2CH.sub.2NMe.sub.2, --CH.sub.2CH.sub.2NEt.sub.2,
--CH.sub.2CH.sub.2CH.sub.2NMe.sub.2, and
--CH.sub.2CH.sub.2CH.sub.2NEt.sub.2.
[0265] In some compounds, R.sup.c and R.sup.d may each
independently contain a carbonyl moiety. Where one of R.sup.c or
R.sup.d contain a carbonyl moiety, the carbonyl moiety may form,
for example, an amide bond with the nitrogen. Derivatives including
an amide bond include moieties terminating in a carbocyclic acid
residue or an ester, for example an alkyl ester, for example a
methyl or ethyl ester. Typically compounds containing a carbonyl
moiety are of the form of an ester.
[0266] Typically, when one of R.sup.c or R.sup.d contain a carbonyl
moiety, the other of R.sup.c or R.sup.d is hydrogen.
[0267] In one class of fragments, L.sup.4 is a direct bond and
R.sup.c and R.sup.d are each independently selected from hydrogen,
--C(O)-alkyl, --C(O)-alkyl where alkyl may be substituted or
unsubstituted. Typically, alkyl is C.sub.1, C.sub.2, C.sub.3 or
C.sub.4 alkyl such as, for example, methyl, ethyl, n-propyl,
isopropyl or t-butyl, of which methyl may be particularly
mentioned.
[0268] In another class of fragments (E1) and (E2), R.sup.c and
R.sup.d together with the adjoining nitrogen form a heterocyclic
moiety (normally a 5- or 6-membered heterocyclic ring), optionally
substituted as previously described. In addition to the nitrogen of
moiety NR.sup.cR.sup.d, the heterocyclic ring may contain at least
one further heteroatom, and often exactly one further heteroatom,
in either case typically selected from O and N; in a sub-class, the
heterocycles contain altogether one or two nitrogens and, where
there is a single nitrogen, optionally an oxygen. Particular
heterocycles include a nitrogen which is not a member of a double
bond and these are more particularly saturated heterocycles. As
heterocycles may be mentioned pyrrolidine, piperidine, piperazine
and morpholine; of these particular heterocycles are piperazine and
morpholine. As already described, the heterocycle may be
substituted and, in one class of compounds, is substituted by 0, 1,
2, 3, 4 or 5 substituents, e.g. selected from C.sub.1-C.sub.7
aliphatic groups, optionally substituted as described above, and
less frequently C.sub.1-C.sub.7 aliphatic-oxy. Any aliphatic group
is often alkyl (straight chain or branched), e.g. alkyl or other
aliphatic having 1, 2, 3 or 4 carbon atoms, as in the case of a
sub-class of cyclic (E1) and (E2) fragments having substituents
which are methyl, ethyl or n-propyl. Exemplary substituents on
cyclic (E1) and (E2) fragments include straight chain or branched
C.sub.1, C.sub.2, C.sub.3 or C.sub.4 alkyl such as, e.g., methyl,
ethyl n-propyl, isopropyl or t-butyl, of which methyl may be
particularly mentioned, halogen (notably F or Cl) and C.sub.1,
C.sub.2, C.sub.3 or C.sub.4 alkoxy; also to be mentioned are
hydroxy and amino. Alkyl moieties may be unsubstituted or
substituted, e.g. by halogen (notably F or Cl) or in some cases by
hydroxy or amino.
[0269] In some classes of cyclic (E1) and (E2) fragments (that is
to say fragments in which R.sup.c and R.sup.d together with the
adjoining nitrogen form a ring), there are 0, 1, 2, 3, 4 or 5 such
substituents selected from alkyl, alkoxy, alkanoyl, alkanoyloxy,
haloalkyl, amino, mono- or di-alkylamino, cyano, halogen, hydroxy
or protected hydroxy, wherein alkyl or the alkyl part of alkoxy and
alkanoyl(oxy) has 1, 2, 3 or 4 carbon atoms; exemplary substituents
in this case are methyl, ethyl, methoxy, ethoxy, acetyl,
trifluoromethyl, cyano, F, Cl and OH. Certain cyclic fragments have
0, 1 or 2 substituents, e.g. 0 or 1.
[0270] Particular L.sup.4NR.sup.cR.sup.d moieties are -Pip, -Morph,
--OCH.sub.2Pip, --OCH.sub.2-Morph, --OCH.sub.2CH.sub.2Pip,
--OCH.sub.2CH.sub.2-Morph, --OCH.sub.2CH.sub.2CH.sub.2Pip,
--OCH.sub.2CH.sub.2CH.sub.2-Morph, --CH.sub.2Pip, --CH.sub.2-Morph,
--CH.sub.2CH.sub.2Pip, --CH.sub.2CH.sub.2-Morph,
--CH.sub.2CH.sub.2CH.sub.2Pip, and
--CH.sub.2CH.sub.2CH.sub.2-Morph. Also to be mentioned are
--C(O)Pip and --C(O)Morph. The abbreviation "Pip" stands for
piperazine and "Morph" for morpholine, and these rings may be
substituted as previously described. In particular piperazine is
optionally N-substituted. Piperazine and morpholine may be
substituted by a C.sub.1-C.sub.7 aliphatic group as mentioned in
the previous paragraph, for example a straight chain or branched
C.sub.1, C.sub.2, C.sub.3 or C.sub.4 moiety selected from alkyl and
haloalkyl such as, e.g., methyl, trifluoromethyl, ethyl n-propyl,
isopropyl or t-butyl, of which methyl and trifluoromethyl are
exemplary. As described before, R.sup.a is in particular
hydrogen.
[0271] Amongst the classes of compounds which are particularly to
be mentioned are those in which the left hand ring has a structure
corresponding to Fragment (D1*) or (E1). Particularly exemplary are
such compounds having a Fragment (E1*) in which R.sup.c and R.sup.d
together with the adjoining nitrogen form a 5- or 6-membered
heterocyclic ring as described above. These rings may be
substituted as previously described. In particular they are
optionally N-substituted by a C.sub.1-C.sub.7 aliphatic group as
mentioned earlier, for example a straight chain or branched
C.sub.1, C.sub.2, C.sub.3 or C.sub.4 moiety selected from alkyl and
haloalkyl such as, e.g., methyl, trifluoromethyl, ethyl n-propyl,
isopropyl or t-butyl, of which methyl and trifluoromethyl are
exemplary. As described before, R.sup.a is in particular
hydrogen.
[0272] It will be appreciated from the aforegoing that the
invention includes compounds having a left hand ring having the
structure of the following Fragment (F*):
##STR00031##
where R.sup.w is selected from the group consisting of: (i) H;
C.sub.1, C.sub.2, C.sub.3 or C.sub.4 alkyl; C.sub.1, C.sub.2,
C.sub.3 or C.sub.4 alkanoyl; or alkoxycarbonyl of which the alkoxy
part has 1, 2, 3 or 4 carbon atoms, (ii) 4-phenyl or 4-phenyl
substituted by -L.sup.4NR.sup.cR.sup.d, where
-L.sup.4NR.sup.cR.sup.d is as defined previously and in particular
is: [0273] (a) -Pip, -Morph, --OCH.sub.2Pip, --OCH.sub.2-Morph,
--OCH.sub.2CH.sub.2Pip, --OCH.sub.2CH.sub.2-Morph,
--OCH.sub.2CH.sub.2CH.sub.2Pip, --OCH.sub.2CH.sub.2CH.sub.2-Morph,
--CH.sub.2Pip, --CH.sub.2-Morph, --CH.sub.2CH.sub.2Pip,
--CH.sub.2CH.sub.2-Morph, --CH.sub.2CH.sub.2CH.sub.2Pip, or
--CH.sub.2CH.sub.2CH.sub.2-Morph, or is --C(O)Pip or --C(O)Morph,
where "Pip" and "Morph" are as described in the last but one
paragraph; or [0274] (b) --OCH.sub.2NMe.sub.2,
--OCH.sub.2NEt.sub.2, --OCH.sub.2CH.sub.2NMe.sub.2,
--OCH.sub.2CH.sub.2NEt.sub.2, --OCH.sub.2CH.sub.2CH.sub.2NMe.sub.2,
--OCH.sub.2CH.sub.2CH.sub.2NEt.sub.2, --CH.sub.2NMe.sub.2,
--CH.sub.2NEt.sub.2, --CH.sub.2CH.sub.2NMe.sub.2,
--CH.sub.2CH.sub.2NEt.sub.2, --CH.sub.2CH.sub.2CH.sub.2NMe.sub.2,
or --CH.sub.2CH.sub.2CH.sub.2NEt.sub.2.
[0275] In certain compounds, R.sup.w is H, formyl, acetyl or
methoxycarbonyl.
[0276] In embodiments, the pyrimidine rings of Fragments (D1),
(D2), (E1), (E2) and (F) are replaced by a pyridine or triazine
ring.
Substituent R.sup.3
[0277] Substituent R.sup.3 is as previously described in relation
to Formula (I*) or (II*).
[0278] In embodiments, R.sup.3 is selected from H, R.sup.b groups,
and categories (i), (ii) and (iii) described above in relation to
Rz*, independently of the identity of Rz*. In one class of
embodiments, R.sup.3 is H or a C.sub.1-C.sub.7 aliphatic group, for
example straight chain or branched C.sub.1-C.sub.4 alkyl such as,
e.g., methyl, ethyl or n-propyl, of which methyl is exemplary. In
other compounds, R.sup.3 is a C.sub.1-C.sub.7 aliphatic group (for
example straight chain or branched C.sub.1-C.sub.4 alkyl such as,
e.g., methyl, ethyl or n-propyl) substituted by a mono- or
bi-cyclic ring, particularly a 5- or 6-membered saturated or
unsaturated carbocyclic or heterocyclic ring, for example by
phenyl, pyrrolidine, piperidine, piperazine, morpholine, thiophene,
furan, pyrrole, pyridine, pyrazine or pyran. R.sup.3 may therefore
be straight chain alkyl (or other straight chain aliphatic group,
for example in either case having up to 4 carbon atoms) substituted
at its free end by such a mono- or bi-cyclic ring.
[0279] In one class of compounds R.sup.3 is a category (iii)
moiety, that is, it is in particular a moiety having the structure
of Fragment H:
##STR00032##
as previously described. The identity of R.sup.3 is independent of
that of Rz*, as already stated.
[0280] However, as particular compounds, may be mentioned those in
which just one of Rz* and R.sup.3 is a category (iii) moiety. In a
subclass, one of Rz* and R.sup.3 is a category (iii) moiety and the
other is H; to be mentioned in this regard are compounds in which
R.sup.3 is a category (iii) moiety and R.sup.1 is NH.sub.2, or
alternatively mono- or di-alkyl amino.
[0281] Where R.sup.3 is a category (iii) moiety, it may have a
structure corresponding to the category (iii) structures found in
Fragments (D1), (D2), (E1), (E2) or (F), as previously
described.
[0282] In many compounds R.sup.3 is H; where it is not H it is
often C.sub.1, C.sub.2, C.sub.3 or C.sub.4 alkyl (e.g. ethyl or
methyl). It may also be, for example, such an alkyl group
substituted, e.g. at a free end thereof, by a 5- or 6-membered
heterocyclic ring; typically the ring is saturated, for example it
may be selected from piperidine, piperizine, thiazolidine,
morpholine and thiomorpholine
The Right Hand Ring
[0283] By the "right hand ring" is meant the Fragment (G*):
##STR00033##
[0284] It has previously been mentioned that: n is 0, 1, 2, 3 or 4;
m is m is 0, 1, 2, 3, 4 or 5; each R.sup.4 is the same or different
and selected from organic and inorganic moieties; L.sup.1 is a
linker; ring A is a mono- or bicyclic ring; and each R.sup.16 is
the same or different and selected from organic and inorganic
moieties.
[0285] Integer m is normally 1. Typically, there is an L.sup.1
group at the 3-position of the phenyl ring relative to L.sup.1.
Accordingly, preferred compounds are of Formula (III*):
##STR00034##
[0286] In Formulae (I*) and (II*), L.sup.1 is typically a linker
L.sup.11 selected from --NR.sup.aCO-- and --CONR.sup.a--, in which
R.sup.a is as previously defined and is typically H or lower (e.g.
1, 2, 3 or 4C) alkyl, particularly H. L.sup.1 is more especially
--NR.sup.aCO--, e.g. --NHCO--, to form compounds of Formula
(IV*):
##STR00035##
[0287] Integer n is often 0, 1, 2 or 3, e.g. 0, 1 or 2. In one
class of compounds, n is 0; in another, n is 1.
[0288] In embodiments, each R.sup.4 is the same or different and
selected from halogen; hydroxy; protected hydroxy for example
trialkylsilylhydroxy; amino; amidino; guanidino; hydroxyguanidino;
formamidino; isothioureido; ureido; mercapto; C(O)H or other acyl;
acyloxy; carboxy; sulfo; sulfamoyl; carbamoyl; cyano; azo; nitro;
C.sub.1-C.sub.7 aliphatic optionally substituted by one or more
halogens and/or one or two functional groups selected from hydroxy,
protected hydroxy for example trialkylsilylhydroxy, amino, amidino,
guanidino, hydroxyguanidino, formamidino, isothioureido, ureido,
mercapto, C(O)H or other acyl, acyloxy, carboxy, sulfo, sulfamoyl,
carbamoyl, cyano, azo, or nitro; all of the aforesaid hydroxy,
amino, amidino, guanidino, hydroxyguanidino, formamidino,
isothioureido, ureido, mercapto, carboxy, sulfo, sulfamoyl and
carbamoyl groups in turn optionally being substituted on at least
one heteroatom by one or, where possible, more C.sub.1-C.sub.7
aliphatic groups (for example, therefore, R.sup.4 may be an alkoxy
group, e.g. methoxy or ethoxy).
[0289] R.sup.4 is particularly selected from hydroxy, protected
hydroxy, lower alkoxy, lower alkyl, trifluoromethyl and halo,
notably F or Cl. R.sup.4 may also be Br. Alkyl and the alkyl part
of alkoxy may be branched or, more usually, straight chain, and
often have 1, 2, 3, or 4 carbon atoms, as for example in the case
of methyl, ethyl, methoxy and ethoxy. R.sup.4 is especially
selected from Cl, F, hydroxy, methyl, methoxy and trifluoromethyl,
e.g. is selected from Cl, F, methyl, methoxy and trifluoromethyl,
as in those compounds where R.sup.4 is Cl, F, methyl or methoxy. In
certain compounds. R.sup.4 is methyl or methoxy, of which methyl
may be mentioned in particular. In some of the compounds mentioned
in this paragraph, chlorine is the sole halogen, in some others
fluorine is the sole halogen. The reader is reminded that, where
there are plural R.sup.4 groups, they may be the same or
different.
[0290] In a particular class of compounds, n is 1, i.e. there is a
single R.sup.4 group, such as methyl, methoxy or trifluoromethyl,
for example.
[0291] Included are compounds in which there is an R.sup.4 group at
one or both ortho positions, relative to the urea moiety
(--NR.sup.3C(O)NH--). Also included in the invention are compounds
in which there is a single R.sup.4 group (e.g. methyl, methoxy or
trifluoromethyl), which is at the 6-position relative to the urea
moiety. Accordingly, there are included compounds of the formula
(V*):
##STR00036##
where R.sup.4a and R.sup.4b are each independently selected from H,
halo (especially F or Cl), alkyl, haloalkyl or alkoxy, wherein
alkyl and the alkyl part of alkoxy are branched or straight chain
and often have 1, 2, 3, or 4 carbon atoms; in embodiments, R.sup.4a
and R.sup.4b may additionally be selected from hydroxy and amino.
Typically R.sup.4a is H, alkyl, haloalkyl, or alkoxy, for example
H, lower alkyl, lower haloalkyl or lower alkoxy, such as H, methyl,
ethyl, trifluoromethyl, methoxy or ethoxy, for example. In a
particular class of compounds R.sup.4c is H, methyl or methoxy or,
in another class is trifluoromethyl. Typically, R.sup.4b is H or
alkoxy, such as methoxy or ethoxy, for example.
[0292] Included are embodiments in which at least one of R.sup.4a
or R.sup.4b is not H as well as embodiments in which both of
R.sup.4a or R.sup.4b are H. In one particular class of compounds,
one of R.sup.4a or R.sup.4b is H and the other is not H.
[0293] Frequently, there is no R.sup.4 group. For example, in
particular compounds there is no R.sup.4 group, and either (i)
R.sup.4a is methyl or methoxy or, in some case, trifluoromethyl and
R.sup.4b is H, or (ii) R.sup.4a is H and R.sup.4b is methoxy.
[0294] In embodiments, each R.sup.16 is the same or different and
selected from halogen; hydroxy; protected hydroxy for example
trialkylsilylhydroxy; amino; amidino; guanidino; hydroxyguanidino;
formamidino; isothioureido; ureido; mercapto; C(O)H or other acyl;
acyloxy; carboxy; sulfo; sulfamoyl; carbamoyl; cyano; azo; nitro;
C.sub.1-C.sub.7 aliphatic optionally substituted by one or more
halogens and/or one or two functional groups selected from hydroxy,
protected hydroxy for example trialkylsilylhydroxy, amino, amidino,
guanidino, hydroxyguanidino, formamidino, isothioureido, ureido,
mercapto, C(O)H or other acyl, acyloxy, carboxy, sulfo, sulfamoyl,
carbamoyl, cyano, azo, or nitro; all of the aforesaid hydroxy,
amino, amidino, guanidino, hydroxyguanidino, formamidino,
isothioureido, ureido, mercapto, carboxy, sulfo, sulfamoyl and
carbamoyl groups in turn optionally being substituted on at least
one heteroatom by one or, where possible, more C.sub.1-C.sub.7
aliphatic groups (for example, therefore, R16 may be an alkoxy
group, e.g. methoxy or ethoxy).
[0295] Ring A and any substituents R.sup.16 will for convenience be
referred to subsequently as Fragment I:
##STR00037##
[0296] Fragment I may have any structure described herein for
Fragment H, and may be the same as Fragment H, if present, or
different. Thus, Ring A may be a mono- or bi-cyclic ring,
particularly a 5- or 6-membered carbocyclic or heterocyclic ring,
for example phenyl, cyclohexyl or cyclohexenyl. Of these, phenyl is
preferred. In other instances, ring A is a 5-membered carbocyclic
or heterocyclic ring. Other exemplary residues forming ring A are
pyridyl and pyrimidyl.
[0297] Integer m is often 0, 1, 2 or 3, for example 0, 1 or 2, as
in the case of compounds where m is 0 or 1. For example, where ring
A is a 6-membered ring, there is often a substituent at the 3- or
4-position.
[0298] Interger m is often 1. Where m is greater than 1, all the
R.sup.16 groups except 1 are often halogen (notably F or Cl),
methyl or trifluoromethyl. Also to be mentioned in this regard are
hydroxyl and amino. Often a single R.sup.16 group is selected from
-L.sup.5-NR.sup.cR.sup.d and -L.sup.5-RING* and there are 0, 1 or 2
additional substituants which are not -L.sup.5-NR.sup.cR.sup.d or
-L.sup.5-RING* but are, for example, halogen (notably F or Cl),
lower alkyl (e.g. methyl), lower alkoxy (e.g. methoxy), hydroxyl,
amino or trifluoromethyl.
[0299] Accordingly, the invention includes compounds in which
R.sup.16 is, e.g. a 6-membered carbo cyclic ring (notably phenyl)
substituted by 1, 2, 3, 4 or 5 halogens, e.g. selected from F, Cl
and Br; typically, such phenyl rings are mono- or di-substituted,
e.g. R.sup.2 and/or 4-substituted by F or 3-substituted by Cl. In
some cases of plural substitution by halogen, all the halogens are
the same. Thus, in a class of compounds R.sup.16 is a monocyclic
ring, particularly a 6-membered carbocyclic ring (notably phenyl),
substituted solely by one or more halogens, particularly selected
from F and Cl; sometimes V or each halogen is F but in some other
cases V or each halogen is Cl.
[0300] In another class of compounds, R.sup.16 is a monocyclic
ring, particulary a 6-membered carbocyclic ring (notably phenyl),
substituted by 1, 2, 3, 4 or 5 substituents, e.g. 1 or 2
substituents, selected from alkyl alkoxy alkanoyl, alkanoyl oxy,
halo alkyl, amino, mono- or di-alkyl amino, cyano, halogen, hydroxy
or protected hyrdoxy, where alkyl or the alkyl part of alkoxy and
alkanoyl (oxy) has 1, 2, 3 or 4 carbon atoms; exemplary
substituents in this case are methyl, ethyl, methoxy, ethoxy,
acetyl, trifluoromethyl, cyano, F, Cl and OH. Certain such rings
have 0, 1 or 2 substituents, e.g. 0 or 1.
[0301] In one class of compounds, L.sup.5 is a direct bond, linear
alkyl, lineal alkyl terminated by a moiety RING*. In a sub-class,
L.sup.5 is --O or --C(O)-- or linear alkyl having 1, 2, 3, or 4, in
-chain carbon atoms, or which --CH.sub.2-- may be particularly
mentioned as may --C(O)--.
[0302] The invention includes a class of compounds in which ring A
is a six-membered ring, particularly phenyl, cyclohexyl or
cyclohexenyl and has 1 or 2 substituents R.sup.16 indepdendetly
selected from -L.sup.5-NR.sup.cR.sup.d and -L.sup.5-RING*, as
defined previously. In a sub-class, there is a single substituent
at, in particular, the 3-position or 4-position selected from
-L.sup.5-NR.sup.cR.sup.d and -L.sup.5-RING* such that the right
hand ring has a structure corresponding to fragments (J1), (J2),
K1), (K2) or (JK):
##STR00038##
[0303] In some embodiments, the phenyl ring of the above fragments
(J1), (J2), K1), (K2) or (JK) (or other ring replacing phenyl, such
as cyclohexyl, for example) has 1, 2, 3 or 4 further substituents,
for example selected from halogen (notably F or Cl), methyl,
methoxy or trifluoromethyl, e.g. 1 or 2 such substituents. Also to
be mentioned in this regard are hydroxy and amino.
[0304] L.sup.5 is as previously described, that is a direct bond; a
linkage selected from --O--; --S--; --C(O)--; --OC(O)--;
--NR.sup.aC(O)--; --C(O)--NR.sup.a; --OC(O)--NR.sup.a--;
cyclopropyl and --NR.sup.a--; or C.sub.1-C.sub.7 aliphatic
optionally interrupted and/or terminated at a single end or at both
ends by a said linkage (R.sup.a being as previously defined and
typically H). Any aliphatic moiety is often alkyl, e.g. alkyl or
other aliphatic having 1, 2, 3 or 4 carbon atoms, as in the case of
a sub-class of linkers L.sup.2 in which aliphatic moieties are
methyl, ethyl or n-propyl.
[0305] In particular fragments (J) and (K), L.sup.2 is a direct
bond, linear alkyl, linear alkyl terminated adjacent the phenyl
ring in the above representations of the fragments by a said
linkage, or is a said linkage; suitably but not necessarily any
said linkage is --O-- or --C(O)--, of which --O-- may be
particularly mentioned. Thus, the above fragments (J) and (K) may
comprise sub-fragments -Ph-NR.sup.cR.sup.d, -Ph-RING'',
-Ph-O-alkyl-NR.sup.cR.sup.d, -Ph-O-alkyl-RING*,
-Ph-alkyl-NR.sup.cR.sup.d, -Ph-alkyl-RING*, and also to be
mentioned are sub-fragments -Ph-O--NR.sup.cR.sup.d, -Ph-O-RING*,
-Ph-C(O)--NR.sup.cR.sup.d and -Ph-C(O)--RING*, where, in all these
sub-fragments which contain alkyl, alkyl may be e.g. methyl, ethyl
or n-propyl, or n-butyl.
[0306] In fragment (JK), the linker L.sup.5 may be the same or
different.
[0307] Considering now in more detail fragments (K1) and (K2),
these contain a moiety RING* which is a cyclic moiety and in many
cases a 5- or 6-membered carbocyclic or heterocyclic ring
optionally substituted as defined previously. Exemplary rings are
saturated, e.g. cyclopentane or cyclohexane. In particular
compounds, RING* is a 5- or 6-membered heterocycle, often
containing one or two heteroatoms, typically selected from O and N;
in a sub-class, the heterocycles contain one or two nitrogens and,
where there is a single nitrogen, optionally an oxygen. Particular
heterocycles include a nitrogen which is not a member of a double
bond and these are more particularly saturated heterocycles. As
heterocycles may be mentioned pyrrolidine, piperidine, piperazine
and morpholine; in some compounds, RING* is piperidine having its
nitrogen at the 4-position relative to L.sup.2. As already
described, RING* may be substituted and, in one class of compounds,
is substituted by 0, 1, 2, 3, 4 or 5 substituents, e.g. selected
from C.sub.1-C.sub.7 aliphatic groups, optionally substituted as
described above, and less frequently C.sub.1-C.sub.7 aliphatic-oxy.
Any aliphatic group is often alkyl (straight chain or branched),
e.g. alkyl or other aliphatic having 1, 2, 3 or 4 carbon atoms, as
in the case of a sub-class of fragments (H1) and (H2) having
substituents which are methyl, ethyl or n-propyl. Exemplary
substituents on RING* include straight chain or branched C1, C2, C3
or C4 alkyl such as, e.g., methyl, ethyl n-propyl, isopropyl or
t-butyl, of which methyl may be particularly mentioned, halogen
(notably F or Cl) and C.sub.1, C.sub.2, C.sub.3 or C.sub.4 alkoxy;
also to be mentioned are hydroxy and amino. Alkyl moieties may be
unsubstituted or substituted, e.g. by halogen (notably F or Cl) or
in some cases by hydroxy or amino.
[0308] In some classes of RING* moieties, there are 0, 1, 2, 3, 4
or 5 such substituents selected from alkyl, alkoxy, alkanoyl,
alkanoyloxy, haloalkyl, amino, mono- or di-alkylamino, cyano,
halogen, hydroxy or protected hydroxy, wherein alkyl or the alkyl
part of alkoxy and alkanoyl(oxy) has 1, 2, 3 or 4 carbon atoms;
exemplary substituents in this case are methyl, ethyl, methoxy,
ethoxy, acetyl, trifluoromethyl, cyano, F, Cl and OH. Certain RING*
moieties have 0, 1 or 2 substituents, e.g. 0 or 1.
[0309] Considering now in more detail fragments (J1) and (J2),
these contain a moiety NR.sup.cR.sup.d. R.sup.c and R.sup.d are as
previously described. In one class of these fragments, R.sup.c and
R.sup.d are the same or different (but more usually the same) and
selected from C.sub.1-C.sub.7, e.g. C.sub.1-C.sub.4 aliphatic
groups, optionally substituted as described above. As aliphatic
R.sup.c and R.sup.d moieties may be mentioned alkyl, e.g having 1,
2, 3 or 4 carbon atoms, as in the case of a sub-class of fragments
(J1) and (J2) having substituents which are methyl, ethyl or
n-propyl. Alkyl or other aliphatic moieties may be substituted e.g.
by amino or mono- or di (C.sub.1-C.sub.4) alkylamino, or e.g. by a
5- or 6-membered heterocyclic or carbocyclic ring optionally
substituted as previously described, or be unsubstituted. Thus,
particular L.sup.2NR.sup.cR.sup.d moieties are --
[0310] OCH.sub.2NMe.sub.2, --OCH.sub.2NEt.sub.2,
--OCH.sub.2CH.sub.2NMe.sub.2, --OCH.sub.2CH.sub.2NEt.sub.2,
--OCH.sub.2CH.sub.2CH.sub.2NMe.sub.2, --OCH.sub.2CH.sub.2C
H.sub.2NEt.sub.2, --CH.sub.2NMe.sub.2, --CH.sub.2NEt.sub.2,
--CH.sub.2CH.sub.2NMe.sub.2, --CH.sub.2CH.sub.2NEt.sub.2,
--CH.sub.2CH.sub.2CH.sub.2NMe.sub.2, and
--CH.sub.2CH.sub.2CH.sub.2NEt.sub.2.
[0311] In another class of fragments (J1) and (J2), R.sup.c and
R.sup.d together with the adjoining nitrogen form a heterocyclic
moiety (normally a 5- or 6-membered heterocyclic ring), optionally
substituted as previously described. In addition to the nitrogen of
moiety NR.sup.cR.sup.d, the heterocyclic ring may contain at least
one further heteroatom, and often exactly one further heteroatom,
in either case typically selected from O and N; in a sub-class, the
heterocycles contain altogether one or two nitrogens and, where
there is a single nitrogen, optionally an oxygen. Particular
heterocycles include a nitrogen which is not a member of a double
bond and these are more particularly saturated heterocycles. As
heterocycles may be mentioned pyrrolidine, piperidine, piperazine
and morpholine; of these particular heterocycles are piperazine and
morpholine. As already described, the heterocycle may be
substituted and, in one class of compounds, is substituted by 0, 1,
2, 3, 4 or 5 substituents, e.g. selected from C.sub.1-C.sub.7
aliphatic groups, optionally substituted as described above, and
less frequently C.sub.1-C.sub.7 aliphatic-oxy. Any aliphatic group
is often alkyl (straight chain or branched), e.g. alkyl or other
aliphatic having 1, 2, 3 or 4 carbon atoms, as in the case of a
sub-class of cyclic (K.sub.1) and (K.sub.2) fragments having
substituents which are methyl, ethyl or n-propyl. Exemplary
substituents on cyclic (K.sub.1) and (K.sub.2) fragments include
straight chain or branched C1, C2, C3 or C4 alkyl such as, e.g.,
methyl, ethyl n-propyl, isopropyl or t-butyl, of which methyl may
be particularly mentioned, halogen (notably F or Cl) and C.sub.1,
C.sub.2, C.sub.3 or C.sub.4 alkoxy; also to be mentioned are
hydroxy and amino. Alkyl moieties may be unsubstituted or
substituted, e.g. by halogen (notably F or Cl) or in some cases by
hydroxy or amino. In some classes of cyclic (J1) and (J2) fragments
(that is to say fragments in which R.sup.c and R.sup.d together
with the adjoining nitrogen form a ring), there are 0, 1, 2, 3, 4
or 5 such substituents selected from alkyl, alkoxy, alkanoyl,
alkanoyloxy, haloalkyl, amino, mono- or di-alkylamino, cyano,
halogen, hydroxy or protected hydroxy, wherein alkyl or the alkyl
part of alkoxy and alkanoyl(oxy) has 1, 2, 3 or 4 carbon atoms;
exemplary substituents in this case are methyl, ethyl, methoxy,
ethoxy, acetyl, trifluoromethyl, cyano, F, Cl and OH. Certain
cyclic fragments have 0, 1 or 2 substituents, e.g. 0 or 1.
[0312] Particular L.sup.2NR.sup.cR.sup.d moieties are -Pip, -Morph,
--OCH.sub.2Pip, --OCH.sub.2-Morph, --OCH.sub.2CH.sub.2Pip,
--OCH.sub.2CH.sub.2-Morph, --OCH.sub.2CH.sub.2CH.sub.2Pip,
--OCH.sub.2CH.sub.2CH.sub.2-Morph, --CH.sub.2Pip, --CH.sub.2-Morph,
--CH.sub.2CH.sub.2Pip, --CH.sub.2CH.sub.2-Morph,
--CH.sub.2CH.sub.2CH.sub.2Pip, and
--CH.sub.2CH.sub.2CH.sub.2-Morph. Also to be mentioned are
--C(O)Pip and --C(O)Morph. The abbreviation "Pip" stands for
piperazine and "Morph" for morpholine, and these rings may be
substituted as previously described. In particular piperazine is
optionally N-substituted. Piperazine and morpholine may be
substituted by a C.sub.1-C.sub.7 aliphatic group as mentioned in
the previous paragraph, for example a straight chain or branched
C.sub.1, C.sub.2, C.sub.3 or C.sub.4 moiety selected from alkyl and
haloalkyl such as, e.g., methyl, trifluoromethyl, ethyl n-propyl,
isopropyl or t-butyl, of which methyl and trifluoromethyl are
exemplary. As described before, R.sup.a is in particular
hydrogen.
[0313] Amongst the classes of compounds which are particularly to
be mentioned are those in which the left hand ring has a structure
corresponding to Fragment (J1) or (K1). Particularly exemplary are
such compounds having a fragment (K1) in which R.sup.c and R.sup.d
together with the adjoining nitrogen form a 5- or 6-membered
heterocyclic ring as described above. These rings may be
substituted as previously described. In particular they are
optionally N-substituted by a C.sub.1-C.sub.7 aliphatic group as
mentioned earlier, for example a straight chain or branched
C.sub.1, C.sub.2, C.sub.3 or C.sub.4 moiety selected from alkyl and
haloalkyl such as, e.g., methyl, trifluoromethyl, ethyl n-propyl,
isopropyl or t-butyl, of which methyl and trifluoromethyl are
exemplary. As described before, R.sup.a is in particular
hydrogen.
[0314] To be mentioned are right hand rings corresponding to
Fragment (L):
##STR00039## [0315] where: [0316] R.sup.4a and R.sup.4b are as
previously defined; [0317] Q and U are the same or different and
selected from H, F and Cl, e.g. are both H; [0318] T and V are the
same or different and selected from H, methyl, trifluoromethyl and
methoxy, e.g. from H and trifluoromethyl, as in the case where one
of T and V is H and the other is trifluoromethyl; [0319] Y.sup.2 is
selected from H, C.sub.1, C.sub.2, C.sub.3 or C.sub.4 alkyl (e.g.
methyl or ethyl), which may be unsubstituted or substituted, for
example at a free end thereof, by a 5 or 6 membered heterocyclic
ring optionally substituted by 1C, 2C, 3C or 4C alkyl; typically
the optionally substituted ring is saturated and may be selected
from, for example, piperidine, 4-(C.sub.1-C.sub.4)alkylpiperidine,
piperazine, 4-(C.sub.1-C.sub.4)alkylpiperazine, thiazolidine,
morpholine or thiomorpholine.
[0320] A particular right hand ring is Fragment (M):
##STR00040##
where R.sup.4a and R.sup.4b are as previously defined.
[0321] To be mentioned are right hand rings corresponding to
Fragment (N):
##STR00041## [0322] where: [0323] R.sup.4a and R.sup.4b are as
previously defined; [0324] K is selected from H, methyl,
trifluoromethyl and methoxy, and in particular is H or
trifluoromethyl; and [0325] D is selected from 1C, 2C, 3C and 4C
alkyl, and 1C, 2C, 3C or 4C alkyl substituted by piperidine,
4-(C.sub.1-C.sub.4)alkylpiperidine, piperazine,
4-(C.sub.1-C.sub.4)alkylpiperazine, thiazolidine, morpholine or
thiomorpholine. A particular D group is 4-methylpiperazine; for
example in many compounds D is 4-methylpiperazine and K is H or
trifluoromethyl.
[0326] In fragments L and N, alkyl is particularly linear alkyl and
in many cases is methyl.
[0327] Any formula disclosed herein may have its illustrated right
hand ring replaced by a right hand ring of formula L, M or N.
The Compounds of Formula (I*)
[0328] It has been described above how the compounds of formula
(I*) have the following variable domains: [0329] left hand ring
[0330] R.sup.3 [0331] right hand ring.
[0332] Various particular moieties have been described for each of
these variable domains and it will be appreciated that any
combination of such moieties is permissible.
[0333] To be mentioned are compounds having the following
combinations, amongst many others:
TABLE-US-00002 Left hand ring R.sup.3 Right hand ring Fragment (A*)
H, C.sub.1-C.sub.4 alkyl or C.sub.1-C.sub.4 alkyl n = 1, 2, 3, or
4. substituted by an optionally R.sup.4 = selected from Cl, F,
substituted 5- or 6- hydroxy, methyl, methoxy, membered ring
trifluoromethyl, and alkyl substituted by an optionally substituted
5- or 6- membered ring Fragment (B*) H, C.sub.1-C.sub.4 alkyl or
C.sub.1-C.sub.4 alkyl n = 1, 2, 3, or 4. substituted by an
optionally R.sup.4 = selected from Cl, F, substituted 5- or 6-
hydroxy, methyl, methoxy, membered ring trifluoromethyl, and alkyl
substituted by an optionally substituted 5- or 6- membered ring
Fragment (C*) H, C.sub.1-C.sub.4 alkyl or C.sub.1-C.sub.4 alkyl n =
1, 2, 3, or 4. substituted by an optionally R.sup.4 = selected from
Cl, F, substituted 5- or 6- hydroxy, methyl, methoxy, membered ring
trifluoromethyl, and alkyl substituted by an optionally substituted
5- or 6- membered ring Fragment (C*), R.sup.a = H, H,
C.sub.1-C.sub.4 alkyl or C.sub.1-C.sub.4 alkyl n = 1, 2, 3, or 4.
Rz* = category (i) or (ii) substituted by an optionally R.sup.4 =
selected from Cl, F, substituted 5- or 6- hydroxy, methyl, methoxy,
membered ring trifluoromethyl, and alkyl substituted by an
optionally substituted 5- or 6- membered ring Fragment (C*),
R.sup.a = H, Category (iii) moiety, e.g. n = 1, 2, 3, or 4. Rz* =
category (i) or (ii) having a structure R.sup.4 = selected from Cl,
F, corresponding to the hydroxy, methyl, methoxy, category (iii)
structure of trifluoromethyl, and alkyl Fragment (D1*) substituted
by an optionally substituted 5- or 6- membered ring Fragment (C*),
R.sup.a = H, Category (iii) moiety, e.g. n = 1, 2, 3, or 4. Rz* =
category (i) or (ii) having a structure R.sup.4 = selected from Cl,
F, corresponding to the hydroxy, methyl, methoxy, category (iii)
structure of trifluoromethyl, and alkyl Fragment (D2*) substituted
by an optionally substituted 5- or 6- membered ring Fragment (C*),
R.sup.a = H, Category (iii) moiety, e.g. n = 1, 2, 3, or 4. Rz* =
category (i) or (ii) having a structure R.sup.4 = selected from Cl,
F, corresponding to the hydroxy, methyl, methoxy, category (iii)
structure of trifluoromethyl, and alkyl Fragment (E1*). substituted
by an optionally substituted 5- or 6- membered ring Fragment (C*),
R.sup.a = H, Category (iii) moiety, e.g. n = 1, 2, 3, or 4. Rz* =
category (i) or (ii) having a structure R.sup.4 = selected from Cl,
F, corresponding to the hydroxy, methyl, methoxy, category (iii)
structure of trifluoromethyl, and alkyl Fragment (E2*). substituted
by an optionally substituted 5- or 6- membered ring Fragment (C*),
R.sup.a = H, Category (iii) moiety, e.g. n = 1, 2, 3, or 4. Rz* =
category (i) or (ii) having a structure R.sup.4 = selected from Cl,
F, corresponding to the hydroxy, methyl, methoxy, category (iii)
structure of trifluoromethyl, and alkyl Fragment (E3). substituted
by an optionally substituted 5- or 6- membered ring Fragment (C*),
R.sup.a = H, Category (iii) moiety, e.g. n = 1, 2, 3, or 4. Rz* =
category (i) or (ii) having a structure R.sup.4 = selected from Cl,
F, corresponding to the hydroxy, methyl, methoxy, category (iii)
structure of trifluoromethyl, and alkyl Fragment (E4). substituted
by an optionally substituted 5- or 6- membered ring Fragment (C*),
R.sup.a = H, Category (iii) moiety, e.g. n = 1, 2, 3, or 4. Rz* =
category (i) or (ii) having a structure R.sup.4 = selected from Cl,
F, corresponding to the hydroxy, methyl, methoxy, category (iii)
structure of trifluoromethyl, and alkyl Fragment (F*). substituted
by an optionally substituted 5- or 6- membered ring Fragment (C*),
R.sup.a = H, C.sub.1-C.sub.4 alkyl or C.sub.1-C.sub.4 alkyl n = 1,
2, 3, or 4. Rz* = category (iii) substituted by an optionally
R.sup.4 = selected from Cl, F, substituted 5- or 6- hydroxy,
methyl, methoxy, membered ring trifluoromethyl, and alkyl
substituted by an optionally substituted 5- or 6- membered ring
Fragment (D1*) C.sub.1-C.sub.4 alkyl or C.sub.1-C.sub.4 alkyl n =
1, 2, 3, or 4. substituted by an optionally R.sup.4 = selected from
Cl, F, substituted 5- or 6- hydroxy, methyl, methoxy, membered ring
trifluoromethyl, and alkyl substituted by an optionally substituted
5- or 6- membered ring Fragment (D2*) C.sub.1-C.sub.4 alkyl or
C.sub.1-C.sub.4 alkyl n = 1, 2, 3, or 4. substituted by an
optionally R.sup.4 = selected from Cl, F, substituted 5- or 6-
hydroxy, methyl, methoxy, membered ring trifluoromethyl, and alkyl
substituted by an optionally substituted 5- or 6- membered ring
Fragment (E1*) C.sub.1-C.sub.4 alkyl or C.sub.1-C.sub.4 alkyl n =
1, 2, 3, or 4. substituted by an optionally R.sup.4 = selected from
Cl, F, substituted 5- or 6- hydroxy, methyl, methoxy, membered ring
trifluoromethyl, and alkyl substituted by an optionally substituted
5- or 6- membered ring Fragment (E2*) C.sub.1-C.sub.4 alkyl or
C.sub.1-C.sub.4 alkyl n = 1, 2, 3, or 4. substituted by an
optionally R.sup.4 = selected from Cl, F, substituted 5- or 6-
hydroxy, methyl, methoxy, membered ring trifluoromethyl, and alkyl
substituted by an optionally substituted 5- or 6- membered ring
Fragment (E3) C.sub.1-C.sub.4 alkyl or C.sub.1-C.sub.4 alkyl n = 1,
2, 3, or 4. substituted by an optionally R.sup.4 = selected from
Cl, F, substituted 5- or 6- hydroxy, methyl, methoxy, membered ring
trifluoromethyl, and alkyl substituted by an optionally substituted
5- or 6- membered ring Fragment (E4) C.sub.1-C.sub.4 alkyl or
C.sub.1-C.sub.4 alkyl n = 1, 2, 3, or 4. substituted by an
optionally R.sup.4 = selected from Cl, F, substituted 5- or 6-
hydroxy, methyl, methoxy, membered ring trifluoromethyl, and alkyl
substituted by an optionally substituted 5- or 6- membered ring
Fragment (F*) C.sub.1-C.sub.4 alkyl or C.sub.1-C.sub.4 alkyl n = 1,
2, 3, or 4. substituted by an optionally R.sup.4 = selected from
Cl, F, substituted 5- or 6- hydroxy, methyl, methoxy, membered ring
trifluoromethyl, and alkyl substituted by an optionally substituted
5- or 6- membered ring Fragment (C*), R.sup.a H n = 1, 2, 3, or 4.
typically = H, R.sup.4 = selected from Cl, F, Rz* = category (iii)
hydroxy, methyl, methoxy, trifluoromethyl, and alkyl substituted by
an optionally substituted 5- or 6- membered ring Fragment (D1*);
R.sup.a H n = 1, 2, 3, or 4. typically = H, R.sup.4 = selected from
Cl, F, hydroxy, methyl, methoxy, trifluoromethyl, and alkyl
substituted by an optionally substituted 5- or 6- membered ring
Fragment (D2*); R.sup.a H n = 1, 2, 3, or 4. typically = H, R.sup.4
= selected from Cl, F, hydroxy, methyl, methoxy, trifluoromethyl,
and alkyl substituted by an optionally substituted 5- or 6-
membered ring Fragment (E1*); R.sup.a H n = 1, 2, 3, or 4.
typically = H, R.sup.4 = selected from Cl, F, hydroxy, methyl,
methoxy, trifluoromethyl, and alkyl substituted by an optionally
substituted 5- or 6- membered ring Fragment (E2*); R.sup.a H n = 1,
2, 3, or 4. typically = H, R.sup.4 = selected from Cl, F, hydroxy,
methyl, methoxy, trifluoromethyl, and alkyl substituted by an
optionally substituted 5- or 6- membered ring Fragment (F*) H n =
1, 2, 3, or 4. R.sup.4 = selected from Cl, F, hydroxy, methyl,
methoxy, trifluoromethyl, and alkyl substituted by an optionally
substituted 5- or 6- membered ring Fragment (A*) H, C.sub.1-C.sub.4
alkyl or C.sub.1-C.sub.4 alkyl R.sup.4 is Fragment substituted by
an optionally (L), (M) or (N). substituted 5- or 6- membered ring
Fragment (B*) H, C.sub.1-C.sub.4 alkyl or C.sub.1-C.sub.4 alkyl
R.sup.4 is Fragment substituted by an optionally (L), (M) or (N).
substituted 5- or 6- membered ring Fragment (C*) H, C.sub.1-C.sub.4
alkyl or C.sub.1-C.sub.4 alkyl R.sup.4 is Fragment substituted by
an optionally (L), (M) or (N). substituted 5- or 6- membered ring
Fragment (C*), R.sup.a = H, H, C.sub.1-C.sub.4 alkyl or
C.sub.1-C.sub.4 alkyl R.sup.4 is Fragment Rz* = category (i) or
(ii) substituted by an optionally (L), (M) or (N). substituted 5-
or 6- membered ring Fragment (C*), R.sup.a = H, Category (iii)
moiety, e.g. R.sup.4 is Fragment Rz* = category (i) or (ii) having
a structure (L), (M) or (N). corresponding to the category (iii)
structure of Fragment (D1*) Fragment (C*), R.sup.a = H, Category
(iii) moiety, e.g. R.sup.4 is Fragment Rz* = category (i) or (ii)
having a structure (L), (M) or (N). corresponding to the category
(iii) structure of Fragment (D2*) Fragment (C*), R.sup.a = H,
Category (iii) moiety, e.g. R.sup.4 is Fragment Rz* = category (i)
or (ii) having a structure (L), (M) or (N). corresponding to the
category (iii) structure of Fragment (E1*). Fragment (C*), R.sup.a
= H, Category (iii) moiety, e.g. R.sup.4 is Fragment Rz* = category
(i) or (ii) having a structure (L), (M) or (N). corresponding to
the category (iii) structure of Fragment (E2*).
Fragment (C*), R.sup.a = H, Category (iii) moiety, e.g. R.sup.4 is
Fragment Rz* = category (i) or (ii) having a structure (L), (M) or
(N). corresponding to the category (iii) structure of Fragment
(E3). Fragment (C*), R.sup.a = H, Category (iii) moiety, e.g.
R.sup.4 is Fragment Rz* = category (i) or (ii) having a structure
(L), (M) or (N). corresponding to the category (iii) structure of
Fragment (E4). Fragment (C*), R.sup.a = H, Category (iii) moiety,
e.g. R.sup.4 is Fragment Rz* = category (i) or (ii) having a
structure (L), (M) or (N). corresponding to the category (iii)
structure of Fragment (F*). Fragment (C*), R.sup.a = H,
C.sub.1-C.sub.4 alkyl or C.sub.1-C.sub.4 alkyl R.sup.4 is Fragment
Rz* = category (iii) substituted by an optionally (L), (M) or (N).
substituted 5- or 6- membered ring Fragment (D1*) C.sub.1-C.sub.4
alkyl or C.sub.1-C.sub.4 alkyl R.sup.4 is Fragment substituted by
an optionally (L), (M) or (N). substituted 5- or 6- membered ring
Fragment (D2*) C.sub.1-C.sub.4 alkyl or C.sub.1-C.sub.4 alkyl
R.sup.4 is Fragment substituted by an optionally (L), (M) or (N).
substituted 5- or 6- membered ring Fragment (E1*) C.sub.1-C.sub.4
alkyl or C.sub.1-C.sub.4 alkyl R.sup.4 is Fragment substituted by
an optionally (L), (M) or (N). substituted 5- or 6- membered ring
Fragment (E2*) C.sub.1-C.sub.4 alkyl or C.sub.1-C.sub.4 alkyl
R.sup.4 is Fragment substituted by an optionally (L), (M) or (N).
substituted 5- or 6- membered ring Fragment (E3) C.sub.1-C.sub.4
alkyl or C.sub.1-C.sub.4 alkyl R.sup.4 is Fragment substituted by
an optionally (L), (M) or (N). substituted 5- or 6- membered ring
Fragment (E4) C.sub.1-C.sub.4 alkyl or C.sub.1-C.sub.4 alkyl
R.sup.4 is Fragment substituted by an optionally (L), (M) or (N).
substituted 5- or 6- membered ring Fragment (F*) C.sub.1-C.sub.4
alkyl or C.sub.1-C.sub.4 alkyl R.sup.4 is Fragment substituted by
an optionally (L), (M) or (N). substituted 5- or 6- membered ring
Fragment (C*), R.sup.a H R.sup.4 is Fragment typically = H, (L),
(M) or (N). Rz* = category (iii) Fragment (D1*); R.sup.a H R.sup.4
is Fragment typically = H, (L), (M) or (N). Fragment (D2*); R.sup.a
H R.sup.4 is Fragment typically = H, (L), (M) or (N). Fragment
(E1*); R.sup.a H R.sup.4 is Fragment typically = H, (L), (M) or
(N). Fragment (E2*); R.sup.a H R.sup.4 is Fragment typically = H,
(L), (M) or (N). Fragment (E3); R.sup.a H R.sup.4 is Fragment
typically = H, (L), (M) or (N). Fragment (E4); R.sup.a H R.sup.4 is
Fragment typically = H, (L), (M) or (N). Fragment (F*) H R.sup.4 is
Fragment (L), (M) or (N).
[0334] When R.sup.3 is an optionally substituted ring, substituents
are as described previously, e.g. methyl, ethyl, methoxy,
trifluoromethyl, amino or hydroxy.
[0335] Each row of the above table provides support for an
individual patent claim, presented by itself or with one or more
other claims, each corresponding to a respective row of the table.
The previous text provides support for claims dependent on such
claims in describing sub-classes of the respective features or
feature combinations of each row. For each row in the Table, a
patent claim or claims may be written to protect individually a
sub-class or sub-classes of the subject matter represented by the
row.
[0336] It will be understood from the aforegoing that a sub-set of
the Compounds of Formula (I*) are of the following Formulae (VI*)
and (VII*):
##STR00042##
[0337] In Formulae (VI*) and (VII*), it is often the case that two
of X, Y and Z are N and that R.sup.3 and R.sup.2 are H, e.g. in
many compounds X is CH, Y and Z are N and R.sup.2 is H.
Alternatively, all of X, Y and Z are N and R.sup.2 is H. Ring A is
typically phenyl or a wholly or partially hydrogenated analogue
thereof. Alternatively it may be a heterocycle, typically of six
members, e.g. pyridine or pyrimidine. Integer m may be 0, 1 or 2,
e.g. 1. In some cases there are one or more R.sup.b moieties which
are F or Cl, as previously described, e.g. the only R.sup.b
moieties may be one or two moieties selected from F and Cl.
[0338] Accordingly, Formulae (VI*) and (VII*) encompass the
following sub-classes, amongst others: [0339] 1) One of X, Y and Z
are N, R.sup.15 and R.sup.2 are H, ring A is phenyl or a wholly or
partially hydrogenated analogue thereof, m is 0, 1 or 2, e.g. 1;
[0340] 2) One of X, Y and Z are N, R.sup.15 and R.sup.2 are H, ring
A is a heterocycle, typically of six members, e.g. pyridine or
pyrimidine, m is 0, 1 or 2, e.g. 1; [0341] 3) Two of X, Y and Z are
N, R.sup.15 and R.sup.2 are H, ring A is phenyl or a wholly or
partially hydrogenated analogue thereof, m is 0, 1 or 2, e.g. 1;
[0342] 4) Two of X, Y and Z are N, R.sup.15 and R.sup.2 are H, ring
A is a heterocycle, typically of six members, e.g. pyridine or
pyrimidine, m is 0, 1 or 2, e.g. 1; [0343] 5) All of X, Y and Z are
N, R.sup.2 is H, ring A is phenyl or a wholly or partially
hydrogenated analogue thereof, m is 0, 1 or 2, e.g. 1; [0344] 6)
All of X, Y and Z are N, R.sup.2 is H, ring A is a heterocycle,
typically of six members, e.g. pyridine or pyrimidine, m is 0, 1 or
2, e.g. 1; [0345] 7) X is CH, Y and Z are N, R.sup.2 is H, ring A
is phenyl or a wholly or partially hydrogenated analogue thereof, m
is 0, 1 or 2, e.g. 1; [0346] 8) X is CH, Y and Z are N, R.sup.2 is
H, ring A is a heterocycle, typically of six members, e.g. pyridine
or pyrimidine, m is 0, 1 or 2, e.g. 1.
[0347] In some instances of sub-classes 1), 2), 3) 4), 5) and 6)
there are one or more R.sup.b moieties which are F or Cl, as
previously described, e.g. the only R.sup.b moieties may be one or
two moieties selected from F and Cl.
[0348] More commonly, ring A is substituted by one or two R.sup.b
moieties (and normally a single R.sup.b moiety) comprising
-L.sup.2-RING* or -L.sup.2-NR.sup.bR.sup.d, and optionally other
substituents (e.g. numbering 1, 2 or 3) selected from e.g. halogen;
hydroxy; protected hydroxy for example trialkylsilylhydroxy; amino;
amidino; guanidino; hydroxyguanidino; formamidino; isothioureido;
ureido; mercapto; C(O)H or other lower acyl; lower acyloxy;
carboxy; sulfo; sulfamoyl; carbamoyl; cyano; azo; nitro; which
substituents are in turn optionally substituted on at least one
heteroatom by one or, where possible, more C.sub.1, C.sub.2,
C.sub.3 or C.sub.4 alkyl groups. Particular additional substituents
on ring A are halogen, lower alkyl (e.g. methyl), lower alkoxy
(e.g. methoxy), hydroxy, amino or trifluoromethyl.
[0349] Also to be mentioned therefore are compounds of the
following formulae (VIII*), (IX*), (X*) and (XI*):
##STR00043##
where [0350] L.sup.2NR.sup.cR.sup.d is in particular -Pip, -Morph,
--OCH.sub.2Pip, --OCH.sub.2-Morph, --OCH.sub.2CH.sub.2Pip,
--OCH.sub.2CH.sub.2-Morph, --OCH.sub.2CH.sub.2CH.sub.2Pip,
--OCH.sub.2CH.sub.2CH.sub.2-Morph, --CH.sub.2Pip, --CH.sub.2-Morph,
--CH.sub.2CH.sub.2Pip, --CH.sub.2CH.sub.2-Morph,
--CH.sub.2CH.sub.2CH.sub.2Pip, and
--CH.sub.2CH.sub.2CH.sub.2-Morph, or is --C(O)Pip or --C(O)Morph
(or of course these heterocycles are replaced by another described
herein, or in other embodiments R.sup.c and R.sup.d form a
non-cyclic structure as previously described); [0351] L.sup.2RING*
is in particular -RING*, --OCH.sub.2RING*,
--OCH.sub.2CH.sub.2RING*, --OCH.sub.2CH.sub.2CH.sub.2RING*,
--CH.sub.2RING*, --CH.sub.2CH.sub.2RING*,
--CH.sub.2CH.sub.2CH.sub.2RING*, or is --C(O)RING*, where RING* is
in particular pyrrolidine, piperidine, piperazine or morpholine, or
it may be another RING* moiety disclosed herein; [0352] R.sup.3 is
as previously described and is particularly but not necessarily H;
[0353] R.sup.4 is as previously described and is particularly but
not necessarily selected from Cl, F, hydroxy, methyl, methoxy and
trifluoromethyl; [0354] L.sup.1 is in particular --NR.sup.aCO-- and
--CONR.sup.a--; [0355] R.sup.16 is as previously described but is
in particular substituted alkyl, where the substitutents are in
particular fluorine and piperizine, [0356] m is 0, 1, 2, 3, 4 or 5,
e.g. is 1 or 2; [0357] n is 0, 1, 2, 3, 4 or 5, e.g. is 1, 2, 3, or
4.
[0358] In embodiments, RING* or a heterocycle formed by
L.sup.2NR.sup.cR.sup.d is substituted by 1, 2, 3, 4 or 5
substituents, e.g. 1 or 2 substituents, selected from alkyl,
alkoxy, alkanoyl, alkanoyloxy, haloalkyl, amino, mono- or
di-alkylamino, cyano, halogen, hydroxy or protected hydroxy,
wherein alkyl or the alkyl part of alkoxy and alkanoyl(oxy) has 1,
2, 3 or 4 carbon atoms; exemplary substituents in this case are
methyl, ethyl, methoxy, ethoxy, acetyl, trifluoromethyl, cyano, F,
Cl and OH. N-alkyl substituted piperazine or piperadine are
exemplary, as are RING* moieties as a class substituted by one or
two substituents or more, selected from alkyl and haloalkyl (e.g.
trifluoromethyl). As an alternative to substitution, there may be
no substitution.
[0359] Another embodiment comprises compounds of formula
(XXI*):
##STR00044##
where Rz*.sup.1 and Rz*.sup.2 are selected from hydrogen and
straight chain or branched alkyl having 1, 2, 3 or 4 carbon atoms,
e.g. methyl or ethyl. In embodiments, one of Rz*.sup.1 and
Rz*.sup.2 is hydrogen and more particularly both are hydrogen. It
is often the case that X is CH, Y and Z are N and R.sup.2 is H.
Particular classes of compounds are of formulae (XXI*), (XXII*),
(XXIII*) and (XXIV*):
##STR00045##
where Rz*.sup.1 and Rz*.sup.2 are selected from hydrogen and
straight chain or branched alkyl having 1, 2, 3 or 4 carbon atoms,
e.g. methyl or ethyl, and L.sup.2NR.sup.cR.sup.d, L.sup.2RING*,
R.sup.3 and R.sup.4 are as described in relation to formulae
(IV*)-(VII*).
[0360] The invention includes classes of compounds which correspond
to Formulae (IV*), (V*), (VI*), (VII*), (XXI*), (XXII*), (XXIII*)
and (XXIV*) in which the pyrimidine ring is replaced by a triazine
ring
Substituents
[0361] The following definitions apply to the compounds of the
invention as appropriate and expedient and if not mentioned
otherwise.
[0362] "Substituted", wherever used for a moiety, means that one or
more hydrogen atoms in the respective moiety, especially up to 5,
more especially 1, 2 or 3 of the hydrogen atoms are replaced
independently of each other by the corresponding number of
substituents which preferably are independently selected from the
group consisting of lower alkyl, for example methyl, ethyl or
propyl, halo-lower alkyl, for example trifluoromethyl,
C.sub.6-C.sub.16-aryl, especially phenyl pyridine. [0363]
C.sub.6-C.sub.16-aryl is unsubstituted or substituted by one or
more, especially 1, 2 or 3 moieties selected from, for example,
lower alkyl, halogen, carboxy, lower alkoxycarbonyl, hydroxy,
etherified or esterified hydroxy, lower alkoxy, phenyl-lower
alkoxy, lower alkanoyloxy, lower alkanoyl, amino, mono- or
di-substituted amino, halo, halo-lower alkyl, e.g. trifluoromethyl,
sulfo, sulfamoyl, carbamoyl, N-mono substituted or
N,N-disubstituted carbamoyl, N-lower alkyl-carbamoyl,
N-(hydroxy-lower alkyl)-carbamoyl, such as
N-(2-hydroxyethyl)-carbamoyl, cyano, cyano-lower alkyl and nitro;
[0364] Substituents also include hydroxy,
C.sub.3-C.sub.10-cycloalkyl, especially cyclopropyl or cyclohexyl,
hydroxy-C.sub.3-C.sub.8-cycloalkyl, such as hydroxy-cyclohexyl,
heterocyclyl with 5 or 6 ring atoms and 1 to 3 ring heteroatoms
selected from O, N and S, especially piperidinyl, especially
piperidin-1-yl, piperazinyl, especially piperazin-1-yl,
morpholinyl, especially morpholin-1-yl, hydroxy, lower alkoxy, for
example methoxy, halo-lower alkoxy, especially
2,2,2-trifluoroethoxy, phenyl-lower alkoxy, amino-lower alkoxy,
such as 2-eminoethoxy; lower alkanoyloxy, hydroxy-lower alkyl, such
as hydroxymethyl or 2-hydroxyethyl, amino, mono- or di-substituted
amino, carbamoyl-lower alkoxy, N-lower alkylcarbamoyl-lower alkoxy
or N,N-di-lower alkylcarbamoyl-lower alkoxy, amidino, ureido,
mercapto, N-hydroxy-amidino, guanidino, amidino-lower alkyl, such
as 2-amidinoethyl, N-hydroxyamidino-lower alkyl, such as
N-hydroxy-amidino-methyl or -2-ethyl, halogen, for example fluoro,
chloro, bromo or iodo, carboxy, esterified carboxy, lower
alkoxycarbonyl, phenyl-, naphthyl- or fluorenyl-lower
alkoxycarbonyl, such as benzyloxycarbonyl, benzoyl, lower alkanoyl,
sulfo, lower alkanesul-fonyl, for example methanesulfonyl
(CH.sub.3--S(O).sub.2--), lower alkylthio, phenylthio, phenyl-lower
alkylthio, lower alkylphenylthio, lower alkylsulfinyl,
phenylsulfinyl, phenyl-lower alkylsulfinyl, lower
alkylphenylsulfinyl, halogen-lower alkylmercapto, halogen-lower
alkylsulfonyl, such as especially trifluoromethanesulfonyl,
dihydroxybora (--B(OH).sub.2), phosphono (--P(.dbd.O)(OH).sub.2),
hydroxy-lower alkoxy phosphoryl or di-lower alkoxyphosphoryl,
carbamoyl, mono- or di-lower alkylcarbamoyl, mono- or
di-(hydroxy-lower alkyl)-carbamoyl, sulfamoyl, mono- or di-lower
alkylaminosulfonyl, nitro, cyano-lower alkyl, such as cyanomethyl,
and cyano, lower alkenyl, lower alkynyl.
[0365] It goes without saying that substituents are only at
positions where they are chemically pos-sible, the person skilled
in the art being able to decide (either experimentally or
theoretically) without inappropriate effort which substitutions are
possible and which are not. For example, amino or hydroxy groups
with free hydrogen may be unstable if bound to carbon atoms with
unsaturated (e.g. olefinic) bonds. Additionally, it will of course
be understood that the substituents as listed above may themselves
be substituted by any substituent, subject to the aforementioned
restriction to appropriate substitutions as recognised by the
skilled man.
Other Definitions
[0366] The general terms used hereinbefore and hereinafter
preferably have within the context of this disclosure the following
meanings, unless otherwise indicated:
[0367] The prefix "lower" denotes a radical having up to and
including a maximum of 7 in-chain atoms, especially up to and
including a maximum of 4 in-chain atoms. Particular classes of
alkyl and aliphatic comprise 1, 2, 3 or 4 carbon atoms. The
radicals in question being either linear or branched with single or
multiple branching.
[0368] Lower alkyl is preferably alkyl with from and including 1 up
to and including 7 carbon atoms, preferably 1, 2, 3 or 4 carbon
atoms, and is linear or branched; for example, lower alkyl is
butyl, such as n-butyl, sec-butyl, isobutyl, tert-butyl, propyl,
such as n-propyl or isopropyl, ethyl or methyl. Exemplary lower
alkyl is methyl, propyl or tert-butyl.
[0369] Where the plural form is used for compounds, salts, and the
like, this is taken to mean also a single compound, salt, or the
like.
[0370] Any asymmetric carbon atoms may be present in the (R)-, (S)-
or (R,S)-configuration, preferably in the (R)- or
(S)-configuration. Radicals having any unsaturation are present in
cis-, trans- or (cis, trans) form. The compounds may thus be
present as mixtures of isomers or as pure isomers, preferably as
enantiomer-pure diastereomers.
[0371] The invention relates also to possible tautomers of the
disclosed compounds.
[0372] In view of the close relationship between the heteroaryl
aryl ureas in free form and in the form of their salts, including
those salts that can be used as intermediates, for example in the
purification or identification of the novel compounds, tautomers or
tautomeric mixtures and their salts, any reference hereinbefore and
hereinafter to these compounds, is to be understood as referring
also to the corresponding tautomers of these compounds, or salts of
any of these, as appropriate and expedient and if not mentioned
otherwise.
[0373] Tautomers can, e.g., be present in cases where amino or
hydroxy, each with a least one bound hydrogen, are bound to carbon
atoms that are bound to adjacent atoms by double bonds (e.g.
keto-enol or imine-enamine tautomerism).
[0374] Where "a compound . . . , a tautomer thereof; or a salt
thereof" or the like is mentioned, this means "a compound . . . , a
tautomer thereof, or a salt of the compound or the tautomer".
[0375] By acyl is meant an organic radical corresponding to the
residue of, for example, an organic acid from which the hydroxyl
group has been removed, i.e., a radical having the formula
R--C(O)--, where R may in particular be aliphatic or substituted
aliphatic, or it may for example be a substituted or unsubstituted
mono- or bi-cyclic ring. Thus, R may be selected from lower
C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.7 cycloalkyl, phenyl, benzyl
or phenethyl group. Amongst others. Exemplary acyl is
alkyl-carbonyl. Examples of acyl groups, include, but are not
limited to, formyl, acetyl, propionyl and butyryl. Lower acyl is
for example formyl or lower alkylcarbonyl, in particular
acetyl.
[0376] Aliphatic may have up to 20, e.g up to 12, carbon atoms and
is linear or branched one or more times; preferred is lower
aliphatic, especially C.sub.1-C.sub.4-aliphatic. Aliphatic moieties
may be alkyl, alkenyl or alkynyl; alkenyl and alkynyl may contain
one or more, e.g. one or two, unsaturated carbon-carbon bonds.
[0377] Alkyl may have up to 20, e.g up to 12, carbon atoms and is
linear or branched one or more times; preferred is lower alkyl,
especially C.sub.1-C.sub.4-alkyl, in particular methyl, ethyl or
i-propyl or t-butyl. Where alkyl may be substituted by one or more
substituents independently selected from those mentioned above
under the title "Substituents". Unsubstituted alkyl, preferably
lower alkyl, is especially preferred. The term alkyl also
encompasses cycloalkyl as defined further below:
[0378] Alkyl may be optionally interrupted by one or more in-chain
heteroatoms, for example --O--, thus forming, for example, an ether
linkage.
[0379] Cycloalkyl is preferably C.sub.3-C.sub.10-cycloalkyl,
especially cyclopropyl, dimethylcyclopropyl, cyclo-butyl,
cyclopentyl, cyclohexyl or cycloheptyl, cycloalkyl being
unsubstituted or substituted by one or more, especially 1, 2 or 3,
substituents independently selected from the group consisting of
the substituents defined above under the title "Substituents".
[0380] Alkenyl may have one or more double bonds and preferably has
2 to 20, more preferably up to 12, carbon atoms; it is linear or
branched one or more times (as far as possible in view of the
number of carbon atoms). Preferred is C.sub.2-C.sub.7-alkenyl,
especially C.sub.3 or C.sub.4-alkenyl, such as allyl or crotyl.
Alkenyl can be unsubstituted or substituted, especially by one or
more, more especially up to three, of the substituents mentioned
above under "the title "Substituents". Substituents such as amino
or hydroxy (with free dissociable hydrogen) preferably are not
bound to carbon atoms that participate at a double bond, and also
other substituents that are not sufficiently stable are preferably
excluded. Unsubstituted alkenyl, in particular
C.sub.2-C.sub.7-alkenyl, is preferred.
[0381] Alkynyl is preferably a moiety with one or more triple bonds
and preferably has 2 to 20, more preferably up to 12, carbon atoms;
it is linear of branched one or more times (as far as pos-sible in
view of the number of carbon atoms). Preferred is
C.sub.2-C.sub.7-alkynyl, especially C.sub.3 or C.sub.4-alkynyl,
such as ethinyl or propin-2-yl. Alkynyl can be unsubstituted or
substituted, especially by one or more, more especially up to
three, of the substituents mentioned above under the title
"Substituents". Substituents such as amino or hydroxy (with free
dissociable hydrogen) preferably are not bound to carbon atoms that
participate at a triple bond, and also other substituents that are
not sufficiently stable are preferably excluded. Unsubstituted
alkynyl, in particular C.sub.2-C.sub.7-alkynyl, is preferred.
[0382] An aryl group is an aromatic radical and may be heterocyclic
or carbocyclic. Preferably, aryl is carbocyclic and is bound to the
molecule via a bond located at an aromatic ring carbon atom of the
radical (or optionally bound via a linking group, such as --O-- or
--CH.sub.2--). Preferably aryl has a ring system of not more than
16 carbon atoms and is preferably mono- bi- or tri-cyclic and may
be fully or partially substituted, for example substituted by at
least two substituents. Preferably, aryl is selected from phenyl,
naphthyl, indenyl, azulenyl and anthryl, and is preferably in each
case unsubstituted or lower alkyl, especially methyl, ethyl or
n-propyl, halo (especially fluoro, chloro, bromo or iodo),
halo-lower alkyl (especially trifluoromethyl), hydroxy, lower
alkoxy (especially methoxy), halo-lower alkoxy (especially
2,2,2-trifluoroethoxy), amino-lower alkoxy (especially
2-amino-ethoxy), lower alkyl (especially methyl or ethyl)
carbamoyl, N-(hydroxy-lower alkyl)-carbamoyl (especially
N-(2-hydroxyethyl)-carbamoyl) and/or sulfamoyl-substituted aryl,
especially a corresponding substituted or unsubstituted phenyl.
Also, heterocyclic groups can be mentioned here, as defined
below.
[0383] Any carbocyclic group especially comprises 3, 4, 5, 6 or 7
in ring carbon atoms and may be aromatic (aryl) or non aromatic.
Where the carbocycle is non-aromatic, it may be saturated or
unsaturated. Especially preferred carbocycles are phenyl,
cyclohexyl and cyclopentyl.
[0384] Heterocyclyl (or heterocyclic group) is preferably a
heterocyclic radical that is unsaturated, saturated or partially
saturated and is preferably a monocyclic or in a broader aspect of
the invention bicyclic or tricyclic ring; has 3 to 24, more
preferably 4 to 16 ring atoms. Heterocycles may contain one or
more, preferably one to four, especially one or two ring-forming
heteroatoms selected from the group consisting of nitrogen, oxygen
and sulfur, the ring preferably having 4 to 12, especially 5 to 7
ring atoms. Heterocycles may be unsubstituted or substituted by one
or more, especially 1 to 3, substituents independently selected
from the group consisting of the substituents defined above under
the tile "Substituents". Heterocycle especially is a radical
selected from the group consisting of oxiranyl, azirinyl,
1,2-oxathiolanyl, imidazolyl, thienyl, furyl, tetrahydrofuryl,
pyranyl, thiopyranyl, thianthrenyl, isobenzofuranyl, benzofuranyl,
chromenyl, 2H-pyrrolyl, pyrrolyl, pyrrolinyl, pyrrolidinyl,
imidazolyl, imidazolidinyl, benzimidazolyl, pyrazolyl, pyrazinyl,
pyrazolidinyl, pyranyol, thiazolyl, isothiazolyl, dithiazolyl,
oxazolyl, isoxazolyl, pyridyl, pyr-azinyl, pyrimidinyl, piperidyl,
especially piperidin-1-yl, piperazinyl, especially piperazin-1-yl,
pyridazinyl, morpholinyl, especially morpholino, thiomorpholinyl,
especially thiomorpholino, indolizinyl, isoindolyl, 3H-indolyl,
indolyl, benzimidazolyl, cumaryl, indazolyl, triazolyl, tetrazolyl,
purinyl, 4H-quinolizinyl, isoquinolyl, quinolyl,
tetrahydroquinolyl, tetrahydroiso-quinolyl, decahydroquinolyl,
octahydroisoquinolyl, benzofuranyl, dibenzofuranyl,
benzothiophenyl, dibenzothiophenyl, phthalazinyl, naphthyridinyl,
quinoxalyl, quinazolinyl, quinazolinyl, cinnolinyl, pteridinyl,
carbazolyl, .beta.-carbolinyl, phenanthridinyl, acridinyl,
perimidinyl, phen-anthrolinyl, furazanyl, phenazinyl,
phenothiazinyl, phenoxazinyl, chromenyl, isochromanyl and
chromanyl, each of these radicals being unsubstituted or
substituted by one to two radicals selected from the group
consisting of lower alkyl, especially methyl or tert-butyl, lower
alkoxy, especially methoxy, and halo, especially bromo or chloro.
Unsubstituted heterocyclyl, especially piperidyl, piperazinyl,
thiomorpholino or morpholino, is preferred.
[0385] Any heterocyclic group especially comprises five or six
in-chain atoms of which at least one is a heteroatom selected from
N, O or S. Especially preferred heterocycles are pyridine,
pyrrolidine, piperidine and morpholine.
[0386] Mono- or disubstituted amino may be an amino group
substituted by one or more of the substituents as listed under the
heading "Substituents" and may form a secondary or tertiary amine
group and/or is especially an amino and having the formula
NR.sup.k.sub.2, NR.sup.kOH, NR.sup.kCOR.sup.k (e.g. NHCO-alkyl),
NR.sup.kCOOR.sup.k (e.g NR.sup.kCOO-alkyl), NR.sup.kC(NR.sup.k)H
(e.g. NHC(NH)H), NR.sup.kC(NR.sup.k)NR.sup.kOH (e.g. NHC(NH)NHOH),
NR.sup.kC(NR.sup.k)NR.sup.kCN, (e.g. NHC(NH)NHCN),
NR.sup.kC(NR.sup.k)NR.sup.kCOR.sup.k, (e.g. NHC(NH)NHCOR.sup.k),
NR.sup.kC(NR.sup.k)NR.sup.kR.sup.2, (e.g. NHC(NH)NHR.sup.k),
N(COOR.sup.k)C(NH.sub.2).dbd.NCOOR.sup.k, (e.g.
N(COOR.sup.k)C(NH.sub.2).dbd.NCOOR.sup.k), where
each R.sup.k is independently selected from the substituents as
listed under the heading "Substituents" and may especially be
selected from hydrogen, hydroxy, alkyl, substituted alkyl, lower
alkyl, such as methyl; hydroxy-lower alkyl, such as 2-hydroxyethyl;
halo-lower alkyl, lower alkoxy lower alkyl, such as methoxy ethyl;
alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl,
cycloalkyl, substituted cycloalkyl, heteroaryl, heterocyclyl, lower
alkanoyl, such as acetyl; benzoyl; substituted benzoyl, phenyl,
phenyl-lower alkyl, such as benzyl or 2-phenylethyl.
[0387] Any R.sup.k group may be substituted by the substituents as
defined under the heading "Substituents" and the substituents may
be selected from, preferably one or two of, nitro, amino, halogen,
hydroxy, cyano, carboxy, lower alkoxycarbonyl, lower alkanoyl, and
carbamoyl; and phenyl-lower alkoxycarbonyl.
[0388] As such, exemplary substituted amino groups are N-lower
alkylamino, such as N-methylamino, N,N-di-lower alkylamino, N-lower
alkylaminoamino-lower alkyl, such as aminomethyl or 2-aminoethyl,
hydroxy-lower alkylamino, such as 2-hydroxyethylamino or
2-hydroxypropyl, lower alkoxy lower alkyl, such as methoxy ethyl,
phenyl-lower alkylamino, such as benzylamino, N,N-di-lower
alkylamino, N-phenyl-lower alkyl-N-lower alkylamino, N,N-di-lower
alkylphenylamino, lower alkanoylamino, such as acetylamino,
benzoylamino, phenyl-lower alkoxycarbonylamino, carbamoyl or
aminocarbonylamino, amino-lower alkyl-oxyphenyl-amino,
sulfamoylphenylamino, [N-(hydroxy-lower
alkyl)-carbamoyl]-phenylamino. An example of a substituted amino is
an amino substituted by a 4-substituted cyclohexyl, for example
cyclohexan-4-ol.
[0389] Disubstituted amino may also be lower alkylene-amino, e.g.
pyrrolidino, 2-oxopyrrolidino or piperidino; lower
oxaalkylene-amino, e.g. morpholino, or lower azaalkylene-amino,
e.g. piperazino or N-substituted piperazino, such as
N-methylpiperazine, N-methoxycarbonylpiperazino, N-mono substituted
or N,N-disubstituted carbamoyl, N-lower alkyl-carbamoyl or
N-(hydroxy-lower alkyl)-carbamoyl, such as
N-(2-hydroxyethyl)-carbamoyl. It is also contemplated that an
alkanoylamino extends to a carbamate, such as carbamic acid methyl
ester.
[0390] Halogen (halo) is especially fluorine, chlorine, bromine, or
iodine, especially fluorine, chlorine, or bromine most especially
chlorine or fluorine.
[0391] Etherified hydroxy is especially C.sub.8-C.sub.20alkyloxy,
such as n-decyloxy, lower alkoxy (preferred), such as methoxy,
ethoxy, isopropyloxy, or tert-butyloxy, phenyl-lower alkoxy, such
as benzyloxy, phenyloxy, halogen-lower alkoxy, such as
trifluoromethoxy, 2,2,2-trifluoroethoxy or
1,1,2,2-tetrafluoroethoxy, or lower alkoxy which is substituted by
mono- or bicyclic hetero-aryl comprising one or two nitrogen atoms,
preferably lower alkoxy which is substituted by imidazolyl, such as
1H-imidazol-1-yl, pyrrolyl, benzimidazolyl, such as
1-benzimidazolyl, pyridyl, especially 2-, 3- or 4-pyridyl,
pyrimidinyl, especially 2-pyrimidinyl, pyrazinyl, isoquinolinyl,
especially 3-isoquinolinyl, quinolinyl, indolyl or thiazolyl.
[0392] Esterified hydroxy is especially lower alkanoyloxy,
benzoyloxy, lower alkoxycarbonyloxy, such as
tert-butoxycarbonyloxy, or phenyl-lower alkoxycarbonyloxy, such as
benzyloxycarbonyloxy.
[0393] Esterified carboxy is especially lower alkoxycarbonyl, such
as tert-butoxycarbonyl, iso-propoxycarbonyl, methoxycarbonyl or
ethoxycarbonyl, phenyl-lower alkoxycarbonyl, or
phenyloxycarbonyl.
[0394] Alkanoyl is alkylcarbonyl, especially lower alkanoyl, e.g.
acetyl. The alkyl part of the alkanoyl group may be substituted to
form a moiety R.sup.10.
[0395] N-Mono- or N,N-disubstituted carbamoyl is especially
substituted by one or two substituents independently selected from
lower alkyl, phenyl-lower alkyl and hydroxy-lower alkyl, or lower
alkylene, oxa-lower alkylene or aza-lower alkylene optionally
substituted at the terminal nitrogen atom.
[0396] Salts are especially the pharmaceutically acceptable salts
of compounds of Formula (I) (or exemplary formula thereof),
especially if they are forming salt-forming groups.
[0397] Salt-forming groups are groups or radicals having basic or
acidic properties. Compounds ha-ving at least one basic group or at
least one basic radical, for example amino, a secondary amino group
not forming a peptide bond or a pyridyl radical, may form acid
addition salts, for example with inorganic acids, such as
hydrochloric acid, sulfuric acid or a phosphoric acid, or with
suitable organic carboxylic or sulfonic acids, for example
aliphatic mono- or di-carboxylic acids, such as trifluoroacetic
acid, acetic acid, propionic acid, glycolic acid, succinic acid,
maleic acid, fumaric acid, hydroxymaleic acid, malic acid, tartaric
acid, citric acid or oxalic acid, or amino acids such as arginine
or lysine, aromatic carboxylic acids, such as benzoic acid,
2-phenoxy-benzoic acid, 2-acetoxy-benzoic acid, salicylic acid,
4-aminosalicylic acid, aromatic-aliphatic carboxylic acids, such as
mandelic acid or cinnamic acid, heteroaromatic carboxylic acids,
such as nicotinic acid or isonicotinic acid, aliphatic sulfonic
acids, such as methane-, ethane- or 2-hydroxyethanesulfonic acid,
or aromatic sulfonic acids, for example benzene-, p-toluene- or
naphthalene-2-sulfonic acid. When several basic groups are present
mono- or poly-acid addition salts may be formed.
[0398] Compounds having acidic groups, a carboxy group or a
phenolic hydroxy group, may form metal or ammonium salts, such as
alkali metal or alkaline earth metal salts, for example so-dium,
potassium, magnesium or calcium salts, or ammonium salts with
ammonia or suitable organic amines, such as tertiary monoamines,
for example triethylamine or tri-(2-hydroxy-ethyl)-amine, or
heterocyclic bases, for example N-ethyl-piperidine or
N,N'-dimethylpiperazine. Mixtures of salts are possible.
[0399] Compounds having both acidic and basic groups can form
internal salts.
[0400] For the purposes of isolation or purification, as well as in
the case of compounds that are used further as intermediates, it is
also possible to use pharmaceutically unacceptable salts, e.g. the
picrates. Only pharmaceutically acceptable, non-toxic salts may be
used for thera-peutic purposes, however, and those salts are
therefore preferred.
[0401] Such salts are formed, for example, as acid addition salts,
preferably with organic or inorganic acids, from compounds of
Formula (I) (or an exemplary formula thereof) with a basic nitrogen
atom, especially the pharmaceutically acceptable salts. Suitable
inorganic acids are, for example, halogen acids, such as
hydrochloric acid, sulfuric acid, or phosphoric acid. Suitable
organic acids are, for example, carboxylic, phosphonic, sulfonic or
sulfamic acids, for example acetic acid, propionic acid, octanoic
acid, decanoic acid, dodecanoic acid, glycolic acid, lactic acid,
fumaric acid, succinic acid, adipic acid, pimelic acid, suberic
acid, azelaic acid, malic acid, tartaric acid, citric acid, amino
acids, such as glutamic acid or aspartic acid, maleic acid,
hydroxymaleic acid, methylmaleic acid, cyclohexanecarboxylic acid,
adamantanecarboxylic acid, benzoic acid, salicylic acid,
4-aminosalicylic acid, phthalic acid, phenylacetic acid, mandelic
acid, cinnamic acid, methane- or ethane-sulfonic acid,
2-hydroxyethanesulfonic acid, ethane-1,2-disulfonic acid,
benzenesulfonic acid, 2-naphthalenesulfonic acid,
1,5-naphthalene-disulfonic acid, 2-, 3- or 4-methylbenzenesulfonic
acid, methylsulfuric acid, ethylsulfuric acid, dodecylsulfuric
acid, N-cyclohexylsulfamic acid, N-methyl-, N-ethyl- or
N-propyl-sulfamic acid, or other organic protonic acids, such as
ascorbic acid.
[0402] In the presence of negatively charged radicals, such as
carboxy or sulfo, salts may also be formed with bases, e.g. metal
or ammonium salts, such as alkali metal or alkaline earth metal
salts, for example sodium, potassium, magnesium or calcium salts,
or ammonium salts with ammonia or suitable organic amines, such as
tertiary monoamines, for example triethylamine or
tri(2-hydroxyethyl)amine, or heterocyclic bases, for example
N-ethyl-piperidine or N,N'-dimethylpiperazine.
[0403] When a basic group and an acid group are present in the same
molecule, a compound of Formula (I) (or an exemplary formula
thereof) may also form internal salts.
[0404] For isolation or purification purposes it is also possible
to use pharmaceutically unacceptable salts, for example picrates or
perchlorates. For therapeutic use, only pharmaceutically acceptable
salts or free compounds are employed (where applicable in the form
of pharmaceutical preparations), and these are therefore
preferred.
[0405] In view of the close relationship between the novel
compounds in free form and those in the form of their salts,
including those salts that can be used as intermediates, for
example in the purification or identification of the novel
compounds, any reference to the free compounds hereinbefore and
hereinafter is to be understood as referring also to the
corresponding salts, as appropriate and expedient.
[0406] The compounds of Formula (I) (or exemplary formulae thereof)
and N-oxides thereof have valuable pharmacological properties, as
described hereinbefore and hereinafter.
Biology
[0407] The efficacy of the compounds of the invention as inhibitors
of Bcr-Abl, EGF-R, VEGF-R2 (KDR) and FGFR3 (KDR) receptor tyrosine
kinase activity can be demonstrated as follows:
Test for Activity Against Bcr-Abl:
[0408] The murine myeloid progenitor cell line 32Dcl3 transfected
with the p210 Bcr-Abl expression vector pGDp210Bcr/Abl
(32D-bcr/abl) was obtained from J. Griffin (Dana Faber Cancer
Institue, Bosten, Mass., USA). The cells express the fusion Bcr-Abl
protein with a constitutively active abl kinase and proliferate
growth factor independent. The cells are expanded in RPMI 1640
(AMIMED), 10% fetal calf serum, 2 mM glutamine (Gibco) ("complete
medium"), and a working stock is prepared by freezing aliquots of
2.times.10.sup.6 cells per vial in freezing medium (95% FCS, 5%
DMSO (SIGMA)). After thawing, the cells are used during maximally
10-12 passages for the experiments. The antibody anti-abl SH3
domain cat. #06-466 from Upstate Biotechnology is used for the
ELISA. For detection of bcr-abl phosphorylation, the
anti-phosphotyrosine antibody Ab PY20, labelled with alkaline
phosphatase (PY10(AP)) from ZYMED (cat. #03-7722) is used. As
comparison and reference compound,
(N-{5-[4-(4-methyl-piperazino-methyl)-benzoylamido]-2-methylphenyl}-4-(3--
pyridyl)-2-pyrimidine-amine, in the form of the methane sulfonate
(monomesylate) salt (STI571) (marketed as Gleevec.RTM. or
Glivec.RTM., Novartis), is used. A stock solution of 10 mM is
prepared in DMSO and stored at -20.degree. C. For the cellular
assays, the stock solution is diluted in complete medium in two
steps (1:100 and 1:10) to yield a starting concentration of 10
.mu.M followed by preparation of serial threefold dilutions in
complete medium. No solubility problems are encountered using this
procedure. The test compounds are treated analogously. For the
assay, 200'000 32D-bcr/abl cells in 50 .mu.l are seeded per well in
96 well round bottom tissue culture plates. 50 .mu.l per well of
serial threefold dilutions of the test compound are added to the
cells in triplicates. The final concentration of the test compound
range e.g. from 5 .mu.M down to 0.01 .mu.M. Untreated cells are
used as control. The compound is incubated together with the cells
for 90 min at 37.degree. C., 5% CO.sub.2, followed by
centrifugation of the tissue culture plates at 1300 rpm (Beckman
GPR centrifuge) and removal of the supernatants by careful
aspiration taking care not to remove any of the pelleted cells. The
cell pellets are lysed by addition of 150 .mu.l lysis buffer (50 mM
Tris/HCl, pH 7.4, 150 mM sodium chloride, 5 mM EDTA, 1 mM EGTA, 1%
NP-40 (non-ionic detergent, Roche Diagnostics GmbH, Mannheim,
Germany), 2 mM sodium ortho-vanadate, 1 mM phenylmethyl
sulfonylfluoride, 50 .mu.g/ml aprotinin and 80 .mu.g/ml leupeptin)
and either used immediately for the ELISA or stored frozen at
-20.degree. C. until usage. The anti-abl SH3 domain antibody is
coated at 200 ng in 50 .mu.l PBS per well to black ELISA plates
(Packard HTRF-96 black plates; 6005207) overnight at 4.degree. C.
After washing 3.times. with 200 .mu.l/well PBS containing 0.05%
Tween 20 (PBST) and 0.5% TopBlock (Juro, Cat. #TB 232010), residual
protein binding sites are blocked with 200 .mu.l/well PBST, 3%
TopBlock for 4 h at room temperature, followed by incubation with
50 .mu.l lysates of untreated or test compound-treated cells (20
.mu.g total protein per well) for 3-4 h at 4.degree. C. After
3.times. washing, 50 .mu.l/well PY20(AP) (Zymed) diluted to 0.5
.mu.g/ml in blocking buffer is added and incubated overnight (4!C).
For all incubation steps, the plates are covered with plate sealers
(Costar, cat. #3095). Finally, the plates are washed another three
times with washing buffer and once with deionized water before
addition of 90 .mu.l/well of the AP substrate CPDStar RTU with
Emerald II. The plates now sealed with Packard Top Seal.TM.-A plate
sealers (cat. #6005185) are incubated for 45 min at room
temperature in the dark and luminescence is quantified by measuring
counts per second (CPS) with a Packard Top Count Microplate
Scintillation Counter (Top Count). For the final optimized version
of the ELISA, 50 .mu.l of the lysates of the cells grown, treated
and lysed in 96 well tissue culture plates, are transferred
directly from these plates to the ELISA plates that are precoated
with 50 ng/well of the rabbit poylclonal ant-abl-SH3 domain AB
06-466 from Upstate. The concentration of the anti-phosphotyrosine
AB PY20 (AP) can be reduced to 0.2 .mu.g/ml. Washing, blocking and
incubation with the luminescent substrate are as above. The
quantification is achieved as follows: The difference between the
ELISA readout (CPS) obtained for with the lysates of the untreated
32D-bcr/abl cells and the readout for the assay background (all
components, but without cell lysate) is calculated and taken as
100% reflecting the constitutively phosphorylated bcr-abl protein
present in these cells. The activity of the compound in the bcr-abl
kinase activity is expressed as percent reduction of the bcr-abl
phosphorylation. The values for the IC.sub.50 are determined from
the dose response curves by graphical inter- or extrapolation. The
compounds of the invention here preferably show IC.sub.50 values in
the range from 15 nM to 500 .mu.M, most preferably 15 nM to 200
.mu.M.
[0409] For cellular assays, compounds are dissolved in DMSO and
diluted with complete medium to yield a starting concentration of
10 .mu.M followed by preparation of serial 3-fold dilutions in
complete medium. 32D or Ba/F3 cells expressing either `wt`-Bcr-Abl
or Bcr-Abl mutants (e.g. T-315-I) were seeded at 200'000 cells in
50 .mu.L complete medium are seeded per well in 96 well round
bottom tissue culture plates. 50 .mu.L per well of serial 3-fold
dilutions of the test compound are added to the cells in
triplicates. Untreated cells are used as control. The compound is
incubated together with the cells for 90 min at 37.degree. C., 5%
CO.sub.2, followed by centrifugation of the tissue culture plates
at 1300 rpm (Beckmann GPR centrifuge) and removal of the
supernatants by careful aspiration taking care not to remove any of
the pelleted cells. The cell pellets are lysed by addition of 150
.mu.L lysis buffer (50 mM Tris/HCl, pH 7.4, 150 mM sodium chloride,
5 mM EDTA, 1 mM EGTA, 1% NP-40, 2 mM sodium ortho-vanadate, 1 mM
PMSF, 50 .mu.g/mL aprotinin and 80 .mu.g/mL leupeptin) and either
used immediately for the ELISA or stored frozen in the plates at
-20.degree. C. until usage.
[0410] The rabbit polyclonal anti-abl-SH3 domain Ab 06-466 from
Upstate was coated at 50 ng in 50 .mu.l PBS per well to black ELISA
plates (Packard HTRF-96 black plates; 6005207) over night at
4.degree. C. After washing 3 times with 200 .mu.L/well PBS
containing 0.05% Tween20 (PBST) and 0.5% TopBlock (Juro), residual
protein binding sites are blocked with 200 .mu.L/well PBST, 3%
TopBlock for 4 h at room temperature followed by incubation with 50
L lysates of untreated or compound-treated cells (20 .mu.g total
protein per well) for 3-4 h at 4.degree. C. After 3 washings, 50
.mu.L/well anti-phosphotyrosine Ab PY20(AP) labeled with alkaline
phosphatase (Zymed) diluted to 0.2 .mu.g/mL in blocking buffer is
added and incubated over night (4.degree. C.). For all incubation
steps the plates are covered with plate sealers (Costar). Finally,
the plates are washed another three times with washing buffer and
once with deionized water before addition of 90 .mu.L/well of the
AP-substrate CDPStar RTU with Emerald II. The plates, now sealed
with Packard TopSeal.TM.-A plate sealers, are incubated for 45 min
at room temperature in the dark and luminescence is quantified by
measuring counts per second (CPS) with a Packard Top Count
Microplate Scintillation Counter (Top Count).
[0411] The difference between the ELISA-readout (CPS) obtained for
with the lysates of the untreated 32D-Bcr/Abl cells and the readout
for the assay-background (all components, but without cell lysate)
is calculated and taken as 100% reflecting the constitutively
phosphorylated Bcr-Abl protein present in these cells. The activity
of the compound on the Bcr-Abl kinase activity is expressed as
percent reduction of the Bcr-Abl phosphorylation. The values for
the IC.sub.50 (and IC.sub.90) are determined from the dose response
curves by graphical extrapolation.
[0412] The compounds of the invention here preferably show
IC.sub.50 values below 500 nM for inhibition of autophosphorylation
and inhibition of IL-3 independent proliferation of Bcr-Abl mutants
in Ba/F3 transfected cells, in particular T315I.
[0413] The 32D cl3 cells were obtained from the American Type
Culture Collection (ATCC CRL11346) and the Ba/F3 cells from the
German Collection of Microorganisms and Cell Cultures (DSMZ,
Braunschweig and DSMZ No. ACC 300) [0414] Palacios et al., Nature,
309: 1984, 126, PubMed ID 6201749. [0415] Palacios et al., Cell,
41: 1985, 727, PubMed ID 3924409
[0416] The Ba/F3.p210 cells and the murine hematopoietic 32D
cl3cells, (32D p210 cells) were obtained by transfecting the
IL-3-dependent murine hematopoietic Ba/F3 cell line with a pGD
vector containing p210BCR-ABL (B2A2) cDNA [0417] Daley and
Baltimore, 1988; Sattler et al., 1996; Okuda et al., 1996. [0418]
Daley, G. Q., Baltimore, D. (1988) Transformation of an interleukin
3-dependent hematopoietic cell line by the chronic myeloid
leukemia-specific p210 BCR-ABL protein. PNAS 85, 9312-9316 [0419]
Sattler M, Salgia R, Okuda K, Uemura N, Durstin M A, Pisick E, et
al. (1996) The proto-oncogene product p120CBL and the adaptor
proteins CRKL and c-CRK link c-ABL, p190BCR-ABL and p210BCR-ABL to
the phosphatidylinositol-3' kinase pathway. Oncogene 12, 839-46.
[0420] Okuda K, Golub T R, Gilliland D G, Griffin J D. (1996)
p210BCR-ABL, p190BCR-ABL, and TEL/ABL activate similar signal
transduction pathways in hematopoietic cell lines. Oncogene 13,
1147-52. Test for Activity Against c-KIT
[0421] The baculovirus donor vector pFbacG01 GIBCO is used to
generate a recombinant baculovirus that expresses the amino acid
region amino acids 544-976 of the cytoplasmic kinase domains of
human c-Kit. The coding sequences for the cytoplasmic domain of
c-Kit is amplified by PCR from a human uterus c-DNA library
(Clontech). The amplified DNA fragment and the pFbacG01 vector are
made compatible for ligation by digestion with BamH1 and EcoRI.
Ligation of these DNA fragments results in the baculovirus donor
plasmid c-Kit. The production of the viruses, the expression of
proteins in Sf9 cells and the purification of the GST-fused
proteins are performed as follows:
Production of Virus:
[0422] Transfer vector pFbacG01-c-Kit containing the c-Kit kinase
domain is transfected into the DH10Bac cell line (GIBCO) and the
transfected cells are plated on selective agar plates. Colonies
without insertion of the fusion sequence into the viral genome
(carried by the bacteria) are blue. Single white colonies are
picked and viral DNA (bacmid) is isolated from the bacteria by
standard plasmid purification procedures. Sf9 cells or Sf21 cells
American Type Culture Collection are then transfected in 25
cm.sup.2 flasks with the viral DNA using Cellfectin reagent.
Determination of Small Scale Protein Expression in Sf9 Cells:
[0423] Virus containing media is collected from the transfected
cell culture and used for infection to increase its titer. Virus
containing media obtained after two rounds of infection is used for
large-scale protein expression. For large-scale protein expression
100 cm.sup.2 round tissue culture plates are seeded with
5.times.10.sup.7 cells/plate and infected with 1 mL of
virus-containing media (approx. 5 MOls). After 3 days the cells are
scraped off the plate and centrifuged at 500 rpm for 5 min. Cell
pellets from 10-20, 100 cm.sup.2 plates, are resuspended in 50 mL
of ice-cold lysis buffer (25 mM Tris-HCl, pH 7.5, 2 mM EDTA, 1%
NP-40, 1 mM DTT, 1 mM PMSF). The cells are stirred on ice for 15
min and then centrifuged at 5000 rpms for 20 min.
Purification of GST-tagged Protein:
[0424] The centrifuged cell lysate is loaded onto a 2 mL
glutathione-sepharose column (Pharmacia) and washed three times
with 10 mL of 25 mM Tris-HCl, pH 7.5, 2 mM EDTA, 1 mM DTT, 200 mM
NaCl. The GST-tagged protein is eluted by 10 applications (1 mL
each) of 25 mM Tris-HCl, pH 7.5, 10 mM reduced-glutathione, 100 mM
NaCl, 1 mM DTT, 10% Glycerol and stored at -70.degree. C.
Kinase Assay:
[0425] Tyrosine protein kinase assays with purified GST-c-Kit are
carried out in a final volume of 30 .mu.L containing 200-1800 ng of
enzyme protein (depending on the specific activity), 20 mM
Tris-HCl, pH 7.6, 3 mM MnCl.sub.2, 3 mM MgCl.sub.2, 1 mM DTT, 10
.mu.M Na.sub.3VO.sub.4, 5 .mu.g/mL poly(Glu,Tyr) 4:1, 1% DMSO, 1.0
.mu.M ATP and 0.1 .mu.Ci [.gamma..sup.33P] ATP. The activity is
assayed in the presence or absence of inhibitors, by measuring the
incorporation of .sup.33P from [.gamma..sup.33P] ATP into the
poly(Glu,Tyr) 4:1 substrate. The assay (30 .mu.L) is carried out in
96-well plates at ambient temperature for 20 min under conditions
described below and terminated by the addition of 20 .mu.L of 125
mM EDTA. Subsequently, 40 .mu.L of the reaction mixture is
transferred onto Immobilon-PVDF membrane (Millipore, Bedford,
Mass., USA) previously soaked for 5 min with methanol, rinsed with
water, then soaked for 5 min with 0.5% H.sub.3PO.sub.4 and mounted
on vacuum manifold with disconnected vacuum source. After spotting
all samples, vacuum is connected and each well rinsed with 200
.mu.L 0.5% H.sub.3PO.sub.4. Membranes are removed and washed
4.times. on a shaker with 1.0% H.sub.3PO.sub.4 and once with
ethanol. Membranes are counted after drying at ambient temperature,
mounting in Packard TopCount 96-well frame, and addition of 10
.mu.L/well of Microscint.TM. (Packard). IC.sub.50 values are
calculated by linear regression analysis of the percentage
inhibition of each compound in duplicate, at four concentrations
(usually 0.01, 0.1, 1 and 10 .mu.M). One unit of protein kinase
activity is defined as 1 nmole of .sup.33P ATP transferred from
[.gamma..sup.33P] ATP to the substrate protein per minute per mg of
protein at 37.degree. C.
Test for Activity Against EphB4
[0426] The efficacy of compounds of the formula I as inhibitors or
Ephrin B4 receptor (EphB4) kinases can be demonstrated as
follows:
[0427] Generation of Bac-to-Bac.TM. (Invitrogen Life Technologies,
Basel, Switzerland) GST-fusion expression vectors: Entire
cytoplasmatic coding regions of the EphB-class are amplified by PCR
from cDNA libraries derived from human placenta or brain,
respectively. Recombinant baculovirus are generated that express
the amino acid region 566-987 of the human EphB4 receptor
(SwissProt Database, Accession No. P54760). GST sequence is cloned
into pFastBac1.RTM. vector (Invitrogen Life Technologies, Basel,
Switzerland) and PCR amplified. cDNAs encoding EphB4-receptor
domains, respectively are cloned in frame 3' prime to the GST
sequence into this modified FastBac1 vector to generate
pBac-to-Bac.TM. donor vectors. Single colonies arising from the
transformation are inoculated to give overnight cultures for small
scale plasmid preparation. Restriction enzyme analysis of plasmid
DNA reveals several clones to contain inserts of the expected size.
By automated sequencing the inserts and approximately 50 bp of the
flanking vector sequences are confirmed on both strands.
[0428] Production of viruses: Viruses for each of the kinases are
made according to the protocol supplied by GIBCO if not stated
otherwise. In brief, transfer vectors containing the kinase domains
are transfected into the DH10Bac cell line (GIBCO) and plated on
selective agar plates. Colonies without insertion of the fusion
sequence into the viral genome (carried by the bacteria) are blue.
Single white colonies are picked and viral DNA (bacmid) isolated
from the bacteria by standard plasmid purification procedures. Sf9
cells or Sf21 cells are then transfected in 25 cm.sup.2 flasks with
the viral DNA using Cellfectin reagent according to the
protocol.
[0429] Purification of GST-tagged kinases: The centrifuged cell
lysate is loaded onto a 2 mL glutathione-sepharose column
(Pharmacia) and washed three times with 10 mL of 25 mM Tris-HCl, pH
7.5, 2 mM EDTA, 1 mM DTT, 200 mM NaCl. The GST-tagged proteins are
then eluted by 10 applications (1 mL each) of 25 mM Tris-HCl, pH
7.5, 10 mM reduced-glutathione, 100 mM NaCl, 1 mM DTT, 10% Glycerol
and stored at -70.degree. C.
[0430] Protein kinase assays: The activities of protein kinases are
assayed in the presence or absence of inhibitors, by measuring the
incorporation of .sup.33P from [.gamma..sup.33P]ATP into a polymer
of glutamic acid and tyrosine (poly(Glu,Tyr)) as a substrate. The
kinase assays with purified GST-EphB (30 ng) are carried out for
15-30 min at ambient temperature in a final volume of 30 .mu.L
containing 20 mM Tris.HCl , pH 7.5, 10 mM MgCl.sub.2, 3-50 mM
MnCl.sub.2, 0.01 mM Na.sub.3VO.sub.4, 1% DMSO, 1 mM DTT, 3 .mu.g/mL
poly(Glu,Tyr) 4:1 (Sigma; St. Louis, Mo., USA) and 2.0-3.0 .mu.M
ATP (.gamma.-[.sup.33P]-ATP 0.1 .mu.Ci). The assay is terminated by
the addition of 20 .mu.L of 125 mM EDTA. Subsequently, 40 .mu.l of
the reaction mixture are transferred onto Immobilon-PVDF membrane
(Millipore, Bedford, Mass., USA) previously soaked for 5 min with
methanol, rinsed with water, then soaked for 5 min with 0.5%
H.sub.3PO.sub.4 and mounted on vacuum manifold with disconnected
vacuum source. After spot-ting all samples, vacuum is connected and
each well rinsed with 200 .mu.l 0.5% H.sub.3PO.sub.4. Membra-nes
are removed and washed 4.times. on a shaker with 1.0%
H.sub.3PO.sub.4, once with ethanol. Membranes are counted after
drying at ambient temperature, mounting in Packard TopCount96-well
frame, and addition of 10 .mu.L/well of Microscint.TM. (Packard).
IC.sub.50 values are calculated by linear regression analysis of
the percentage inhibition of each compound in duplicate, at four
concentrations (usually 0.01, 0.1, 1 and 10 .mu.M). One unit of
protein kinase activity is defined as 1 nmole of .sup.33P ATP
transferred from [.gamma..sup.33P] ATP to the substrate protein per
minute per mg of protein at 37.degree. C.
Test for Activity Against EGF-R:
[0431] The inhibition of EGF-R tyrosine kinase activity can be
demonstrated using known methods, for example using the recombinant
intracellular domain of the EGF-receptor [EGF-R ICD; see, for
example, E. McGlynn et al., Europ. J. Biochem. 207, 265-275
(1992)]. Compared with the control without inhibitor, the compounds
of formula I inhibit the enzyme activity by 50% (IC.sub.50), for
example in a concentration of from 0.0005 to 0.5 .mu.M, especially
from 0.001 to 0.1 .mu.M.
[0432] As well as or instead of inhibiting EGF-R tyrosine kinase
activity, the compounds of formula I also inhibit other members of
this family of receptors, like ErbB-2. The inhibitory activity
(IC.sub.50) is approximately in the range of 0.001 to 0.5 .mu.M.
The inhibition of ErbB-2 tyrosine kinase (HER-2) can be determined,
for example, analogously to the method used for EGF-R protein
tyrosine kinase [see C. House et al., Europ. J. Biochem. 140,
363-367 (1984)]. The ErbB-2 kinase can be isolated, and its
activity determined, by means of protocols known per se, for
example in accordance with T. Akiyama et al., Science 232, 1644
(1986).
Test for Activity Against VEGF-R2 (KDR):
[0433] The inhibition of VEGF-induced receptor autophosphorylation
can be confirmed with a further in vitro experiments in cells such
as transfected CHO cells, which permanently express hu-man VEGF-R2
receptor (KDR), are seeded in complete culture medium (with 10%
fetal calf serum=FCS) in 6-well cell-culture plates and incubated
at 37.degree. C. under 5% CO.sub.2 until they show about 80%
confluency. The compounds to be tested are then diluted in culture
medium (without FCS, with 0.1% bovine serum albumin) and added to
the cells. (Controls comprise medium without test compounds). After
two hours of incubation at 37.degree. C., recombinant VEGF is
added; the final VEGF concentration is 20 ng/ml. After a further
five minutes incubation at 37.degree. C., the cells are washed
twice with ice-cold PBS (phosphate-buffered saline) and immediately
lysed in 100 .mu.l lysis buffer per well. The lysates are then
centrifuged to remove the cell nuclei, and the protein
concentrations of the supernatants are determined using a
commercial protein assay (BIORAD). The lysates can then either be
immediately used or, if necessary, stored at -20.degree. C.
[0434] A sandwich ELISA is carried out to measure the VEGF-R2
phosphorylation: a monoclonal antibody to VEGF-R2 (for example Mab
1495.12.14; prepared by H. Towbin, Novartis or comparable
monoclonal antibody) is immobilized on black ELISA plates
(OptiPlate.TM. HTRF-96 from Packard). The plates are then washed
and the remaining free protein-binding sites are saturated with 3%
TopBlock.RTM. (Juro, Cat. #TB232010) in phosphate buffered saline
with Tween 20.RTM. (polyoxyethylen(20)sorbitane monolaurate,
ICl/Uniquema) (PBST). The cell lysates (20 .mu.g protein per well)
are then incubated in these plates overnight at 4.degree. C.
together with an antiphosphotyrosine antibody coupled with alkaline
phosphatase (PY20:AP from Zymed). The (plates are washed again and
the) binding of the antiphosphotyrosine antibody to the captured
phosphorylated receptor is then demonstrated using a luminescent AP
sub-strate (CDP-Star, ready to use, with Emerald II; Applied
Biosystems). The luminescence is measured in a Packard Top Count
Microplate Scintillation Counter. The difference between the signal
of the positive control (stimulated with VEGF) and that of the
negative control (not stimulated with VEGF) corresponds to
VEGF-induced VEGF-R2 phosphorylation (=100%). The activity of the
tested substances is calculated as percent inhibition of
VEGF-induced VEGF-R2 phosphorylation, wherein the concentration of
substance that induces half the maximum inhibition is defined as
the IC.sub.50 (inhibitory dose for 50% inhibition).
Test for Activity Against Recombinant Protein Kinases Ret
(Ret-Men2A), Tie-2 (Tek) and FGFR3-K650E:
Cloning and Expression of Recombinant Protein Kinases:
[0435] (Ret); The Baculovirus donor vector pFB-GSTX3 was used to
generate a recombinant Baculovirus that expresses the amino acid
region 658-1072 of the intra-cytoplasmic kinase domain of human
Ret-Men2A which corresponds to the wild type kinase domain of Ret.
The coding sequence for the cytoplasmic domain of Ret was amplified
by PCR from the plasmid pBABEpuro RET-Men2A which was received from
Dr. James Fagin, College of Medicine, University of Cincinnati
(Novartis collaboration). The amplified DNA fragments and the
pFB-GSTX3 vector were made compatible for ligation by digestion
with SalI and KpnI. Ligation of these DNA fragments resulted in the
baculovirus donor plasmid pFB-GX3-Ret(-Men2A).
[0436] (Tie-2/Tek): The baculovirus donor vector pFbacG01 was used
to generate a recombinant baculovirus that expressed the amino acid
region amino acids 773-1124 of the cytoplasmic kinase domain of
human Tek, N-terminally fused to GST (Provided by Dr. Marme,
Institute of Molecular Medicine, Freiburg, Germany based on a
Research Collaboration). Tek was recloned into the pFbacG01
transfer vector by EcoRI excision and ligation into EcoRI digested
pFbacG01 (FBG-Tie2/Tek).
[0437] (FGFR-3-K650E): The baculovirus donor vector pFastBacGST2
was used to generate a recombinant baculovirus that expressed the
amino acid (aa) region amino acids 411-806 of the cytoplasmic
domain of human FGFR-3, N-terminally fused to GST (Provided by Dr.
Jim Griffin, Dana Farber Cancer Institute, Boston, USA based on a
Research Collaboration). DNA encoding amino acids 411-806 was
amplified by PCR, inserted into the pFastBac-GT2 vector to yield
pFB-GT2-FGFR3-wt. This plasmid was in turn used to generate a
vector encoding FGFR3(411-806) with a mutation at K650 using the
Stratagene XL-Site directed Mutagenesis Kit to produce
pFB-GT2-FGFR3-K650E. The production of the viruses, the expression
of proteins in Sf9 cells and the purification of the GST-fused
proteins were performed as described in the following sections.
Production of Virus:
[0438] Transfer vectors containing the kinase domains were
transfected into the DH10Bac cell line (GIBCO) and plated on
selective agar plates. Colonies without insertion of the fusion
sequence into the viral genome (carried by the bacteria) are blue.
Single white colonies were picked and viral DNA (bacmid) isolated
from the bacteria by standard plasmid purification procedures. Sf9
cells or Sf21 cells were then transfected in 25 cm.sup.2 flasks
with the viral DNA using Cellfectin reagent.
Determination of Small Scale Protein Expression in Sf9 Cells:
[0439] Virus containing media was collected from the transfected
cell culture and used for infection to increase its titer. Virus
containing media obtained after two rounds of infection was used
for large-scale protein expression. For large-scale protein
expression 100 cm.sup.2 round tissue culture plates were seeded
with 5.times.10.sup.7 cells/plate and infected with 1 mL of
virus-containing media (approx. 5 MOls). After 3 days the cells
were scraped off the plate and centrifuged at 500 rpm for 5 min.
Cell pellets from 10-20, 100 cm.sup.2 plates, were resuspended in
50 mL of ice-cold lysis buffer (25 mMTris-HCl, pH7.5, 2 mMEDTA, 1%
NP-40, 1 mM DTT, 1 mMP MSF).The cells were stirred on ice for 15
min and then centrifuged at 5000 rpms for 20 min.
Purification of GST-tagged Proteins:
[0440] The centrifuged cell lysate was loaded onto a 2 mL
glutathione-sepharose column and washed three times with 10 mL of
25 mM Tris-HCl, pH 7.5, 2 mM EDTA, 1 mM DTT, 200 mM NaCl. The
GST-tagged proteins were then eluted by 10 applications (1 mL each)
of 25 mM Tris-HCl, pH 7.5, 10 mM reduced-glutathione, 100 mM NaCl,
1 mM DTT, 10% Glycerol and stored at -70.degree. C.
Measure of Enzyme Activity:
[0441] Tyrosine protein kinase assays with either purified GST-Ret,
GST-Tek or GST-FGFR-3-K650E were carried out in a final volume of
30 .mu.L with final concentrations of the following components: Ret
included 15 ng of GST-Ret , 20 mM Tris-HCl, pH 7.5, 1 mM
MnCl.sub.2, 10 mM MgCl.sub.2, 1 mM DTT, 3 .mu.g/mL poly(Glu,Tyr)
4:1, 1% DMSO and 2.0 .mu.M ATP (.gamma.-[.sup.33P]-ATP 0.1 .mu.Ci).
Tek included 150 ng of GST-Tek , 20 mM Tris-HCl, pH 7.5, 3 mM
MnCl.sub.2, 3 mM MgCl.sub.2, 1 mM DTT, 0.01 mM Na.sub.3VO.sub.4,
250 .mu.g/mL PEG 20'000, 10 .mu.g/mL poly(Glu,Tyr) 4:1, 1% DMSO and
4.0 .mu.M ATP (.gamma.-[.sup.33P]-ATP 0.1 .mu.Ci). FGFR-3-K650E
included 10 ng of GST- FGFR-3-K650E , 20 mM Tris-HCl, pH 7.5, 3 mM
MnCl.sub.2, 3 mM MgCl.sub.2, 1 mM DTT, 0.01 mM PEG 20'000, 10
.mu.g/mL poly(Glu,Tyr) 4:1, 1% DMSO and 4.0 .mu.M ATP
(.gamma.-[.sup.33P]-ATP 0.1 .mu.Ci). The activity was assayed in
the presence or absence of inhibitors, by measuring the
incorporation of .sup.33P from [.gamma..sup.33P] ATP into
poly(Glu,Tyr) 4:1. The assay was carried out in 96-well plates at
ambient temperature for 30 min under conditions described below and
terminated by the addition of 50 .mu.L of 125 mM EDTA.
Subsequently, 60 .mu.L of the reaction mixture were transferred
onto Immobilon-PVDF membrane (Millipore) previously soaked for 5
min with methanol, rinsed with water, then soaked for 5 min with
0.5% H.sub.3PO.sub.4 and mounted on vacuum manifold with
disconnected vacuum source. After spotting all samples, vacuum was
connected and each well rinsed with 200 .mu.L 0.5% H.sub.3PO.sub.4.
Membranes were removed and washed 4.times. on a shaker with 1.0%
H.sub.3PO.sub.4, once with ethanol. Membranes were counted after
drying at ambient temperature, mounting in Packard TopCount 96-well
frame, and addition of 10 .mu.L/well of Microscint.TM. (Packard).
IC50 values were calculated by linear regression analysis of the
percentage inhibition of each compound in duplicate, at four
concentrations (usually 0.01, 0.1, 1 and 10 .mu.M). One unit of
protein kinase activity is defined as 1 nmole of .sup.33P ATP
transferred from [.gamma..sup.33P] ATP to the substrate protein per
minute per mg of protein at 37.degree. C.
[0442] On the basis of the inhibitory studies hereinbefore
described, a compound of Formula (I) or (I*) (or exemplary formula
thereof) according to the invention shows therapeutic efficacy
especially against disorders dependent on protein kinase,
especially proliferative diseases.
[0443] The heteroaryl aryl ureas useful according to the invention,
especially compounds of Formula (I) (or exemplary formula thereof),
that inhibit the protein kinase activities mentioned, especially
tyrosine protein kinases mentioned above and below, can therefore
be used in the treatment of protein kinase dependent diseases.
Protein kinase dependent diseases are especially proliferative
diseases, preferably benign or especially malignant tumours (for
example carcinoma of the kidneys, liver, adrenal glands, bladder,
breast, stomach, ovaries, colon, rectum, prostate, pancreas, lungs,
vagina or thyroid, sarcoma, glioblastomas and numerous tumours of
the neck and head, as well as leukemias). They are able to bring
about the regression of tumours and to prevent the formation of
tumour metastases and the growth of (also micro)metastases. In
addition they can be used in epidermal hyperproliferation (e.g.
psoriasis), in prostate hyperplasia, and in the treatment of
neoplasias, especially of epithelial character, for example mammary
carcinoma. It is also possible to use the compounds of Formula (I)
(or exemplary formula thereof) in the treatment of diseases of the
immune system insofar as several or, especially, individual
tyrosine protein kinases are involved; furthermore, the compounds
of Formula (I) (or exemplary formula thereof) can be used also in
the treatment of diseases of the central or peripheral nervous
system where signal transmission by at least one tyrosine protein
kinase, especially selected from those mentioned specifically, is
involved.
[0444] The expression of FGFR1 (also known as "Flg"), FGFR2 (also
known as "Bek") and the like belonging to a fibroblast growth
factor receptor family is reported to be found in various cancers
such as brain tumors, lung cancer, breast cancer, gastric cancer,
head and neck cancer, and prostatic cancer (Proc. Natl. Acad. Sci.
USA, 87: 5710-5714 (1990); Oncogene. 1997 Aug. 14; 15 (7): 817-26;
Cancer Res. 1994 Jan. 15; 54 (2): 523-30; Cancer Res. 1992 Feb. 1;
52 (3): 571-7). In particular, it is reported for gastric cancer
that overexpression of FGFR2 correlates with poor prognosis mainly
in poorly differentiated cancers such as scirrhus gastric cancers
(Clin Cancer Res. 1996 August; 2 (8): 1373-81; J Cancer Res Clin
Oncol. 2001 April; 127 (4): 207-16; Int Rev Cytol. 2001; 204:
49-95.). Further diseases associated with FGFR1 and FGFR4 are
diabetes and obesity.
[0445] Diseases related to FGFR1, FGFR2, FGFR3 and FGFR4 are
described previously herein under the heading "BACKGROUND", and as
inhibitors of these kinases the compounds of the invention may find
application in treating those diseases.
[0446] As inhibitors of VEGF-receptor tyrosine kinase activity, the
compounds of the invention may primarily inhibit the growth of
blood vessels and are thus, for example, effective against a number
of diseases associated with deregulated angiogenesis, especially
diseases caused by ocular neovascularisation, especially
retinopathies, such as diabetic retinopathy or age-related macula
degeneration, psoriasis, haemangioblastoma, such as haemangioma,
mesangial cell proliferative disorders, such as chronic or acute
renal diseases, e.g. diabetic nephropathy, malignant
nephrosclerosis, thrombotic microangiopathy syndromes or transplant
rejection, or especially inflammatory renal disease, such as
glomerulonephritis, especially mesangioproliferative
glomerulonephritis, haemolytic-uraemic syndrome, diabetic
nephropathy, hypertensive nephrosclerosis, atheroma, arterial
restenosis, autoimmune diseases, diabetes, endometriosis, chronic
asthma, and especially neoplastic diseases (solid tumors, but also
leukemias and other "liquid tumors", especially those expressing
KDR), such as especially breast cancer, cancer of the colon, lung
cancer (especially small-cell lung cancer), cancer of the prostate
or Kaposi's sarcoma. A compound of Formula (I) (or exemplary
formula thereof) (or an N-oxide thereof) inhibits the growth of
tumours and is especially suited to preventing the metastatic
spread of tumors and the growth of micrometastases.
[0447] Vascular endothelial growth factor receptor-2 (VEGF-R2; KDR)
is selectively expressed on the primary vascular endothelium and is
essential for normal vascular development. In order to grow beyond
minimal size, tumors must generate new vascular supply.
Angiogenesis, or the sprouting of new blood vessels, is a central
process in the growth of solid tumors. For many cancers, the extent
of vascularization of a tumor is a negative prognostic indicator
signifying aggressive disease and increased potential for
metastasis. Recent efforts to un-derstand the molecular basis of
tumor-associated angiogenesis have identified several po-tential
therapeutic targets, including the receptor tyrosine kinases for
the angiogenic factor vascular endothelial growth factor (VEGF)
(see Zeng et al., J. Biol. Chem. 276(35), 32714-32719 (2001)). The
heteroaryl aryl ureas according to the present invention,
especially the compounds of Formula (I) (or exemplary formula
thereof) for use as KDR inhibitors are thus especially appropriate
for the therapy of diseases related to VEGF receptor tyrosine
kinase overexpression. Among these diseases, especially
retinopathies, age-related macula degeneration, psoriasis,
haemangioblastoma, haemangioma, arteriosclerosis, inflammatory
diseases, such as rheumatoid or rheumatic inflammatory diseases,
especially arthritis, such as rheumatoid arthritis, or other
chronic inflammatory disorders, such as chronic asthma, arterial or
post-transplantational atherosclerosis, endometriosis, and
especially neoplastic diseases, for example so-called solid tumors
(especially cancers of the gastrointestinal tract, the pancreas,
breast, stomach, cervix, bladder, kidney, prostate, ovaries,
endometrium, lung, brain, melanoma, Kaposi's sarcoma, squamous cell
carcinoma of heand and neck, malignant pleural mesotherioma,
lymphoma or multiple myeloma) and liquid tumors (e.g. leukemias)
are especially important.
[0448] In particular, the present invention pertains to the use of
a compound of Formula I for the manufacture of a medicament for the
treatment of a proliferative disorder, a skeletal disorder, a
cancer, a solid tumour, especially an epithelial cancer, a T cell
mediated inflammatory or autoimmune disease.
[0449] In chronic myelogeous leukemia (CML), a reciprocally
balanced chromosomal translocation in hematopoietic stem cells
(HSCs) produces the BCR-ABL hybrid gene. The latter encodes the
oncogenic Bcr-Abl fusion protein. Whereas ABL encodes a tightly
regulated protein tyro-sine kinase, which plays a fundamental role
in regulating cell proliferation, adherence and apoptosis, the
BCR-ABL fusion gene encodes as constitutively activated kinase,
which trans-forms HSCs to produce a phenotype exhibiting
deregulated clonal proliferation, reduced capacity to adhere to the
bone marrow stroma and a reduces apoptotic response to mutagenic
stimuli, which enable it to accumulate progressively more malignant
transformations. The re-sulting granulocytes fail to develop into
mature lymphocytes and are released into the circu-lation, leading
to a deficiency in the mature cells and increased susceptibility to
infection. ATP-competitive inhibitors of Bcr-Abl have been
described which prevent the kinase from activating mitogenic and
anti-apoptotic pathways (e.g. P-3 kinase and STAT5), leading to the
death of the BCR-ABL phenotype cells and thereby providing an
effective therapy against CML. The heteroaryl aryl ureas useful
according to the present invention, especially the compounds of the
Formula (I) (or exemplary formula thereof) are thus especially
appropriate for the therapy of diseases related to its
overexpression, especially leukemias, such as leukemias, e.g. CML
or ALL.
[0450] Compounds of the Formula I*, II*, III*, IV*, V*, VI*, VII*,
VIII* or IX* (or exemplary formula thereof), in view of their
activity as PDGF receptor inhibitors, are also especially
appropriate in the treatment of proliferate diseases, especially
small lung cancer, atherosclerosis, thrombosis, psoriasis,
scleroderma or fibrosis.
[0451] There are also experiments to demonstrate the antitumor
activity of compounds of the Formula (I) (or exemplary formula
thereof) in vivo: The in vivo antitumor activity is tested, for
example, using breast carcinoma cell lines, such as the human
estrogen dependent breast carcinoma MCF-7 (ATCC: HTB22) or ZR-75-1
(ATCC: CRL1500), or the estrogen-independent breast carcinomas
MDA-MB468 (ATCC: HTB132) or MDA-MB231 (ATCC: HTB26); colon
carcinoma cell lines, such as the colon-carcinoma Cob 205 (ATCC:
CCL222); glioblastoma cell lines, such as the glioblastomas U-87MG
(ATCC: HTB14) or U-373MG (ATCC: HTB17); lung carcinoma cell lines,
such as the "small cell lung carcinomas" NCI-H69 (ATCC: HTB119) or
NCI-H209 (ATCC: HTB172), or the lung carcinoma NCI-H596 (ATCC:
HTB178); skin tumor cell lines, such as the melanomas Hs294T (ATCC:
HTB140) or A375 (ATCC: CRL1619); tumor cell lines from the
genitourinry systems, such as the ovarial carcinoma NIH-Ovcar3
(ATCC: HTB161), as well as the prostate carzinomas DU145 (ATCC:
HTB81) or PC-3 (ATCC: CRL1435), or the bladder carcinoma T24 (ATCC:
HTB4); epithelial carcinomas, such as the epithelial carcinoma
KB31; or (especially with regard to leukemias) K562 cells (American
Type Culture Collection, Mannassas, Va.) or human CFU-G cells
(CFU-G stands for granulocyte colony forming unit, and it
represents an early but committed granulocyte forming precursor
cell that circulates in the blood stream or bone marrow) each of
which is transplanted into female or male Balb/c nude mice. Other
cell lines include leukemic cell lines such as K-562, SUPB15,
MEG01, Ku812F, MOLM-13, BaF3, CEM/0, JURKAT/0 or U87MG.
[0452] Tumors are obtained after subcutaneous injection of the
respective cells (minimum 2.times.10.sup.6 cells in 100 ml
phosphate buffered physiological saline) into the carrier mice
(e.g. 4-8 mice per cell line). The resulting tumors are passed
serially through at least three subsequent transplantations before
treatment is started. Tumor fragments (about 25 mg each) are
in-jected s.c. into the left flank of the animals using a 13-gauge
Trocar needle under Forene narcosis (Abbott, Switzerland) for
implantation. Mice transplanted with estrogen-dependent tumor are,
in addition, supplied with an estrogen pellet (1.0 cm of a tube
with a quality appropriate for medical purposes, Dow Chemicals,
with 5 mg estradiole, Sigma). The treat-ment is started routinely
(that is at low or intermediate tumor burden), as soon as the tumor
has reached an average size of 100 mm.sup.3. Tumor growth is
determined once, twice or thrice weekly (depending on tumor growth
of the cell line) and 24 h after the last treatment by measurement
of the perpendicular diameter. In case of tumors, tumor volumes are
deter-mined according to the Formula L.times.D.times.p/6 (see
Evans, B. D., Smith, I. E., Shorthouse, A. J. and Millar, J. J.,
Brit. J. Cancer, 45: 466-468, 1982). The antitumor activity is
expressed as T/C % (average increase of the tumor volume of treated
animals divided by the average increase of tumor volume in control
animals multiplied by 100). Tumor regression (%) re-presents the
smallest mean tumor volume compared to the mean tumor volume at the
beginning of the treatment. Each animal in which the tumor reaches
a diameter of more than 1,5 to 2 cm.sup.3 is sacrificed. Leukemia
burden is assessed by examining both peripheral white blood count
and weight of spleen and thymus in animals tumored with leukemia
cell lines.
[0453] An exemplary (though not limiting) schedule for
administration of a heteroaryl aryl urea, es-pecially of Formula
(I) (or exemplary formula thereof), or a salt thereof, is daily
ad-ministration, with preferably 1 to 3 daily dosages for a longer
time, possibly until the disease is cured or, if only palliateive
treatment is achieved, for as long as required; alternatively,
treatment e.g. for 5 days, and/or administration at days 1, 4 and
9, with eventual repetition after a certain time without treatment
is possible. Alternatively, treatment several times a day (e.g. 2
to 5 times) or treatment by continuous administration (e.g.
infusion), e.g. at the time points indicated in the last sentence,
are possible. Generally, administration is orally or parenterally,
preferably orally. The test compounds are preferably diluted in
water or in sterile 0.9% saline.
[0454] All human tumor cell lines are obtained from the American
Type Culture Collection (ATCC, Rockville, Md., USA) if not
indicated otherwise and are cultivated in the suggested media with
the corresponding additives (ATCC culture conditions), if not
mentioned otherwise. The c-sis- and v-sis-transformed BALB/c 3T3
cells are obtained from Dr. C. Stiles (Dana Farber Cancer
Institute, Boston, Mass., USA). They are cultured in "Dulbecco's
modified Eagle's me-dium" (DMEM), that is supplemented with 10%
calf serum and Hygromycin B in a concen-tration of 0.2 mg/ml or
G418 in a concentration of 0.5 mg/ml. BALB/c AMuLV A.6R.1 cells
(ATCC) are kept in DMEM, supplemented with 10% fetal calf
serum.
[0455] The pharmacological activity of a heteroaryl aryl urea of
the Formula (I) (or exemplary formula thereof) may, for example, be
demonstrated in a clinical study or in a test procedure as
essentially described hereinafter.
[0456] Suitable clinical studies are, for example, open label
non-randomized, dose escalation stu-dies in patients with one of
the tumor diseases mentioned above. The beneficial effects on
proliferative diseases can be determined directly through the
results of these studies or by changes in the study design which
are known as such to a person skilled in the art. The effi-cacy of
the treatment can be determined in such studies, e.g., in case of
tumors after 18 or 24 weeks by radiologic evaluation of the tumors
every 6 weeks, in case of a leukemia e.g. by determination of the
count of aberrant white blood cells, and by staining mononuclear
cells and/or by means of determining minimum residual disease (MRD)
e.g. by FACS-LPC MRD or PCR.
[0457] Alternatively, a placebo-controlled, double blind study can
be used in order to prove the bene-fits of the heteroaryl aryl
ureas useful according to the invention, especially the compounds
of the Formula (I) (or exemplary formula thereof) mentioned
herein.
[0458] In a further embodiment, the present invention provides
compounds of Formula I** representing a sub-group of the compounds
of Formula I,
##STR00046## [0459] in which [0460] is selected from 0, 1 and 2;
[0461] s is selected from 0 and 1; [0462] X.sup.1 is selected from
O or S; [0463] X is CR.sub.6; [0464] Y and Z are both nitrogen;
[0465] R.sub.1 is selected from --X5NR.sub.7R.sub.8,
--X5NR.sub.7X5NR.sub.7R.sub.8, --X5NR.sub.7X5C(O)OR.sub.8,
--X5OR.sub.7, --X5R.sub.7 and --X5S(O).sub.0-2R.sub.7; wherein X5
is a bond or C.sub.1-4alkylene optionally substituted by 1 to 2
C.sub.1-6alkyl radicals; R.sub.7 is selected from hydrogen,
C.sub.1-6alkyl, C.sub.6-10aryl-C.sub.0-4alkyl,
C.sub.5-10heteroaryl-C.sub.0-4alkyl,
C.sub.3-10cycloalkyl-C.sub.0-4alkyl and
C.sub.3-10heterocycloalkyl-C.sub.0-4alkyl; and R.sub.6 is selected
from hydrogen and C.sub.1-6alkyl; or R.sub.7 and R.sub.8 together
with the nitrogen to which R.sub.7 and R.sub.8 are both attached
form heteroaryl or heterocycloalkyl; [0466] wherein any aryl,
heteroaryl, cycloalkyl and heterocycloalkyl of R.sub.7 or the
combination of R.sub.7 and R.sub.8 can be optionally substituted
with 1 to 3 radicals independently selected from halo, nitro,
cyano, hydroxy, C.sub.1-6alkyl, C.sub.1-6alkoxy,
halo-substituted-alkyl, halo-substituted-alkoxy,
--X5NR.sub.9R.sub.10, --X5OR.sub.9, --X5NR.sub.9S(O).sub.2R.sub.10,
--X5NR.sub.9S(O)R.sub.10, --X5NR.sub.9SR.sub.10,
--X5C(O)NR.sub.9R.sub.10, --X5NR.sub.9C(O)NR.sub.9R.sub.10,
--X5NR.sub.9C(O)R.sub.10, --X5NR.sub.9X5NR.sub.9R.sub.10,
--X5NR.sub.9X5OR.sub.9,
--X5NR.sub.9C(.dbd.NR.sub.9)NR.sub.9R.sub.10,
--X5S(O).sub.0-2R.sub.11, --X5NR.sub.9C(O)R.sub.10,
--X5NR.sub.9C(O)R.sub.11, --X5R.sub.11, --X5C(O)OR.sub.10,
--X5S(O).sub.2NR.sub.9R.sub.10, --X5S(O)NR.sub.9R.sub.10 and
--X5SNR.sub.9R.sub.10; wherein X5 is a bond or C.sub.1-4alkylene;
R.sub.9 and R.sub.10 are independently selected from hydrogen and
C.sub.1-4alkyl; and R.sub.11 is C.sub.3-10heterocycloalkyl
optionally substituted with 1 to 3 radicals selected from
C.sub.1-4alkyl, --X5NR.sub.9X5NR.sub.9R.sub.9, X5NR.sub.9X5OR.sub.9
and --X5OR.sub.9; [0467] R.sub.3 is selected from hydrogen,
C.sub.1-4alkyl, C.sub.6-10aryl-C.sub.0-4alkyl,
C.sub.5-10heteroaryl-C.sub.0-4-alkyl,
C.sub.3-10cycloalkyl-C.sub.0-4alkyl and
C.sub.3-10heterocycloalkyl-C.sub.0-4alkyl; wherein any alkyl, aryl,
heteroaryl, cycloalkyl or heterocycloalkyl of R.sub.3 is optionally
substituted by 1-3 radicals selected from halo, C.sub.1-4alkyl,
--X5S(O).sub.0-2NR.sub.9R.sub.10 and --X5OR.sub.9; wherein X5,
R.sub.9 and R.sub.10 are as described above; [0468] R.sub.45 is
selected from C.sub.6-10aryl-C.sub.0-4alkyl,
C.sub.5-10heteroaryl-C.sub.0-4alkyl,
C.sub.3-10cycloalkyl-C.sub.0-4alkyl and
C.sub.3-10heterocycloalkyl-C.sub.0-4alkyl; wherein any aryl,
heteroaryl, cycloalkyl or heterocycloalkyl of R.sub.45 is
optionally substituted with 1 to 3 radicals selected from halo,
hydroxy, C.sub.1-4alkyl, C.sub.1-4alkoxy,
halo-substituted-C.sub.1-4alkyl, halo-substituted-C.sub.1-4alkoxy
and C.sub.3-8heterocycloC.sub.0-4alkyl; wherein any
heterocycloalkyl substituent of R.sub.4 is optionally substituted
by 1 to 3 C.sub.1-4alkyl radicals; [0469] R.sub.2, R.sub.6 and
R.sub.35 are independently selected from halo, hydroxy,
C.sub.1-4alkyl, C.sub.1-4alkoxy, halo-substituted-C.sub.1-4alkyl
and halo-substituted-C.sub.1-4alkoxy; and the N-oxide derivatives,
prodrug derivatives, protected derivatives, individual isomers and
mixture of isomers thereof; and the pharmaceutically acceptable
salts and solvates (e.g. hydrates) of such compounds.
[0470] For the definition of the compound of Formula I**, the
following definitions apply:
[0471] "Alkyl" as a group and as a structural element of other
groups, for example halo-substituted-alkyl and alkoxy, can be
either straight-chained or branched. C.sub.1-4-alkoxy includes,
methoxy, ethoxy, and the like. Halo-substituted alkyl includes
trifluoromethyl, pentafluoroethyl, and the like.
[0472] "Aryl" means a monocyclic or fused bicyclic aromatic ring
assembly containing six to ten ring carbon atoms. For example, aryl
may be phenyl or naphthyl, preferably phenyl. "Arylene" means a
divalent radical derived from an aryl group.
[0473] "Heteroaryl" is as defined for aryl above where one or mom
of the ring members is a heteroatom. For example heteroaryl
includes pyridyl, indolyl, indazolyl, quinoxalinyl, quinolinyl,
benzofuranyl, benzopyranyl, benzothiopyranyl, benzo[1,3]dioxole,
imidazolyl, benzo-imidazolyl, pyrimidinyl, furanyl, oxazolyl,
isoxazolyl, triazolyl, tetrazolyl, pyrazolyl, thienyl, etc.
[0474] "Cycloalkyl" means a saturated or partially unsaturated,
monocyclic, fused bicyclic or bridged polycyclic ring assembly
containing the number of ring atoms indicated. For example,
C.sub.3-10cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, etc.
[0475] "Heterocycloalkyl" means cycloalkyl, as defined in this
application, provided that one or more of the ring carbons
indicated, are replaced by a moiety selected from --O--, --N.dbd.,
--NR--, --C(O)--, --S--, --S(O)-- or --S(O).sub.2--, wherein R is
hydrogen, C.sub.1-4alkyl or a nitrogen protecting group. For
example, C.sub.3-8heterocycloalkyl as used in this application to
describe compounds of the invention includes morpholino,
pyrrolidinyl, pyrrolidinyl-2-one, piperazinyl, piperidinyl,
piperidinylone, 1,4-dioxa-8-aza-spiro[4.5]clec-8-yl, etc.
[0476] "Halogen" (or halo) preferably represents chloro or fluoro,
but may also be bromo or iodo.
[0477] "Mutant forms of BCR-Abl" means single or multiple amino
acid changes from the wild-type sequence. Over 22 mutations have
been reported to date with the most common being G250E, E255V,
T315I, F317L and M351T.
[0478] "Treat", "treating" and "treatment" refer to a method of
alleviating or abating a disease and/or its attendant symptoms.
[0479] The fusion protein BCR-Abl is a result of a reciprocal
translocation that fuses the Abl proto-oncogene with the Bcr gene.
BCR-Abl is then capable of transforming B-cells through the
increase of mitogenic activity. This increase results in a
reduction of sensitivity to apoptosis, as well as altering the
adhesion and homing of CML progenitor cells. The present invention
provides compounds of Formula I**, compositions and methods for the
treatment of kinase related disease, particularly Abl, BCR-Abl,
BMX, FGFR35, Lck, JNK1, JNK2, CSK, RAF, MKK6 and P38kinase related
diseases. For example, leukemia and other proliferation disorders
related to BCR-Abl can be treated through the inhibition of wild
type and mutant forms of BCR-Abl.
[0480] With reference to compounds of Formula I**, preferably
r is selected from 0, 1 and 2; s is selected from 0 and 1; X.sub.1
is selected from O or S; R.sub.1 is selected from
--X5NR.sub.7R.sub.8, --X5NR.sub.7X5NR.sub.7R.sub.8,
--X5NR.sub.7X5C(O)OR.sub.8; wherein X5 is a bond or
C.sub.1-4alkylene optionally substituted by 1 to 2 C.sub.1-6alkyl
radicals; R.sub.7 is selected from hydrogen, C.sub.1-6alkyl,
C.sub.6-10aryl-C.sub.0-4alkyl, C.sub.5-10heteroaryl-C.sub.0-4alkyl,
C.sub.3-10cycloalkyl-C.sub.0-4alkyl and
C.sub.3-10heterocycloalkyl-C.sub.0-4alkyl; and R.sub.8 is selected
from hydrogen and C.sub.1-6alkyl; or R.sub.7 and R.sub.8 together
with the nitrogen to which R.sub.7 and R.sub.8 are both attached
form heteroaryl or heterocycloalkyl; [0481] wherein any aryl,
heteroaryl, cycloalkyl and heterocycloalkyl of R.sub.7 or the
combination of R.sub.7 and R.sub.8 can be optionally substituted
with 1 to 3 radicals independently selected from halo,
C.sub.1-6alkyl, C.sub.1-6alkoxy, halo-substituted-alkyl,
--X5NR.sub.9R.sub.10, --X5C(O)NR.sub.9R.sub.10,
--X5NR.sub.9C(O)R.sub.10, --X5S(O).sub.0-2R.sub.11, --X5R.sub.11;
R.sub.9 and R.sub.10 are independently selected from hydrogen and
C.sub.1-4alkyl; and R.sub.11 is C.sub.3-10heterocycloalkyl
optionally substituted with 1 to 3 C.sub.1-4alkyl radicals; [0482]
R.sub.3 is selected from hydrogen, C.sub.1-4alkyl,
C.sub.6-10aryl-C.sub.0-4alkyl, C.sub.5-10heteroaryl-C.sub.0-4alkyl,
C.sub.3-10cycloalkyl-C.sub.0-4alkyl and
C.sub.3-10heterocycloalkyl-C.sub.0-4alkyl; wherein any alkyl, aryl,
heteroaryl, cycloalkyl or heterocycloalkyl of R3 is optionally
substituted by 1-3 radicals selected from halo, C.sub.1-4alkyl,
--X5S(O).sub.0-2NR.sub.9R.sub.10 and --X5OR.sub.9; wherein X5,
R.sub.9 and R.sub.10 are as described above; [0483] R.sub.45 is
selected from C.sub.6-10aryl-C.sub.0-4alkyl optionally substituted
with 1 to 3 radicals selected from halo-substituted-C.sub.1-4alkyl
and C.sub.3-8heterocycloC.sub.0-4 alkyl; wherein any
heterocycloalkyl substituent of R45 is optionally substituted by 1
to 3 C.sub.1-4alkyl radicals; [0484] R.sub.35, R2 and R.sub.6 are
independently selected from halo, C.sub.1-4alkyl, C.sub.1-4alkoxy,
and halo-substituted-C.sub.1-4alkyl.
[0485] In another embodiment, the present invention provides a
compound of Formula I**, wherein R.sub.1 represents
NR.sub.7R.sub.8, in which:
R.sub.7 is selected from hydrogen, methyl, isopropyl,
carboxy-ethyl, amino-propyl, tetrahydro-furan-2-ylmethyl,
diisopropyl-amino-ethyl, benzo[1,3]dioxol-5-yl, phenyl,
furanyl-methyl, benzyl, 1-phenyl-ethyl, pyridinyl, phenethyl,
morpholino-propyl, 3-(2-oxo-pyrrolidin-1-yl)-propyl, cycloheptyl,
morpholino-ethyl, cyclopropyl, pyridinyl-ethyl; wherein any phenyl,
benzyl, pyridinyl, phenethyl, morpholino, cyclopropyl, cycloheptyl,
pyridinyl, furanyl and benzo-dioxolyl is optionally substituted by
1 to 2 radicals selected from methyl, dimethyl-amino,
methyl-carbonyl-amino, morpholino, morpholino-methyl,
morpholino-sulfonyl, methyl-piperazinyl, trifluoro-methyl, halo,
methoxy, methyl-amino-carbonyl, amino-carbonyl,
methyl-carbonyl-amino, [0486] R.sub.8 is hydrogen or R.sub.7 and
R.sub.8 together with the nitrogen atom to which R.sub.7 and
R.sub.8 are attached form morpholino, [0487] X.sub.1 is oxygen and
the other radicals and symbols have the same meanings as provided
for a compound of formula I** above.
[0488] In a further embodiment with respect to a compound of
formula I**, R.sub.3 is selected from hydrogen, methyl,
2-methoxy-1-methyl-ethyl, pyridinyl-methyl, pyridinyl-ethyl,
morpholino, pyrrolidinyl-ethyl, phenethyl, morpholino-ethyl,
morpholino-propyl, 3-(2-oxo-pyrrolidin-1-yl)-propyl, cycloheptyl,
3-(tetrahydro-furan-2-yl)-methyl, pyrrolidinyl-ethyl and
pyrazinyl-methyl; wherein any alkyl, aryl, heteroaryl, cycloalkyl
or heterocycloalkyl of R3 is optionally substituted by 1-3 radicals
selected from fluoro, methyl and amino-sulfonyl.
[0489] In another embodiment with respect to a compound of formula
I**, s and r are both 1; R.sub.35 is selected from methyl, methoxy
and fluoro; and R.sub.45 is selected from phenyl optionally
substituted by trifluoromethyl, piperazinyl-methyl; wherein any
piperazinyl substituent of R.sub.45 is optionally substituted by
methyl.
[0490] In another embodiment, r is 0; s is selected from 1 or 2;
and R.sub.35 is selected from methoxy and trifluoromethyl.
[0491] Preferred compounds of formula I** are selected from:
N-[4-Methyl-3-(3-methyl-3-{6-[(tetrahydro-furan-2-ylmethyl)-amino]-pyrimi-
din-4-yl}-ureido)-phenyl]-3-trifluoromethyl-benzamide;
N-(3-{3-[6-(Benzo[1,3]dioxol-5-ylamino)-pyrimidin-4-yl]-3-methyl-ureido}--
4-methyl-phenyl)-3-trifluoromethyl-benzamide;
N-(3-{3-[6-(3-Dimethylamino-phenylamino)-pyrimidin-4-yl]-3-methyl-ureido}-
-4-methyl-phenyl)-3-trifluoromethyl-benzamide;
N-(3-{3-[6-(3-Acetylamino-phenylamino)-pyrimidin-4-yl]-3-methyl-ureido}-4-
-methyl-phenyl)-3-trifluoromethyl-benzamide;
N-(4-Methyl-3-{3-methyl-3-[6-(4-morpholin-4-yl-phenylamino)-pyrimidin-4-y-
l]-ureido}-phenyl)-3-trifluoromethyl-benzamide;
N-[4-Methyl-3-(3-methyl-3-{6-[4-(4-methyl-piperazin-1-yl)-phenylamino]-py-
rimidin-4-yl}-ureido)-phenyl]-3-trifluoromethyl-benzamide;
N-{3-[3-(6-Amino-pyrimidin-4-yl)-3-(2-morpholin-4-yl-ethyl)-ureido]-4-met-
hyl-phenyl}-3-trifluoromethyl-benzamide;
N-(3-{3-(6-Amino-pyrimidin-4-yl)-3-[3-(2-oxo-pyrrolidin-1-yl)-propyl]-ure-
ido}-4-methyl-phenyl)-3-trifluoromethyl-benzamide;
N-(4-Fluoro-3-{3-[6-(4-trifluoromethyl-phenylamino)-pyrimidin-4-yl]-ureid-
o}-phenyl)-4-(4-methyl-piperazin-1-ylmethyl)-benzamide;
N-(3-{3-[6-(4-Chloro-benzylamino)-pyrimidin-4-yl]-3-methyl-ureido}-4-meth-
yl-phenyl)-3-trifluoromethyl-benzamide;
N-{4-Methyl-3-[3-methyl-3-(6-phenethylamino-pyrimidin-4-yl)-ureido]-pheny-
l}-3-trifluoromethyl-benzamide;
N-(3-{3-[6-(4-Methoxy-benzylamino)-pyrimidin-4-yl]-3-methyl-ureido}-4-met-
hyl-phenyl)-3-trifluoromethyl-benzamide;
N-[4-Methyl-3-(3-methyl-3-{6-[3-(2-oxo-pyrrolidin-1-yl)-propylamino]-pyri-
midin-4-yl}-ureido)-phenyl]-3-trifluoromethyl-benzamide;
N-{4-Methyl-3-[3-methyl-3-(6-methylamino-pyrimidin-4-yl)-ureido]-phenyl}--
3-trifluoromethyl-benzamide;
N-(4-Methyl-3-{3-methyl-3-[6-(1-phenyl-ethylamino)-pyrimidin-4-yl]-ureido-
}-phenyl)-3-trifluoromethyl-benzamide;
N-(4-Methyl-3-{3-methyl-3-[6-(3-morpholin-4-yl-propylamino)-pyrimidin-4-y-
l]-ureido}-phenyl)-3-trifluoromethyl-benzamide;
N-{3-[3-(6-Cyclopentylamino-pyrimidin-4-yl)-3-methyl-ureido]-4-methyl-phe-
nyl}-3-trifluoromethyl-benzamide;
N-(3-{3-[6-(2-Diisopropylamino-ethylamino)-pyrimidin-4-yl]-3-methyl-ureid-
o}-4-methyl-phenyl)-3-trifluoromethyl-benzamide;
N-(4-Methyl-3-{3-methyl-3-[6-(2-pyridin-2-yl-ethylamino)-pyrimidin-4-yl]--
ureido}-phenyl)-3-trifluoromethyl-benzamide;
N-{3-[3-(6-Isopropylamino-pyrimidin-4-yl)-3-methyl-ureido]-4-methyl-pheny-
l}-3-trifluoromethyl-benzamide;
N-[3-(3-{6-[(Furan-2-ylmethyl)-amino]-pyrimidin-4-yl}-3-methyl-ureido)-4--
methyl-phenyl]-3-trifluoromethyl-benzamide;
N-{3-[3-(6-Amino-pyrimidin-4-yl)-3-methyl-ureido]-4-methyl-phenyl}-3-trif-
luoromethyl-benzamide;
N-(3-{3-[6-(2-Amino-ethylamino)-pyrimidin-4-yl]-3-methyl-ureido}-4-methyl-
-phenyl)-3-trifluoromethyl-benzamide;
N-(3-(3-{6-[2-(4-Fluoro-phenyl)-ethylamino]-pyrimidin-4-yl}-3-methyl-urei-
do)-4-methyl-phenyl]-3-trifluoromethyl-benzamide;
N-(3-{3-[6-(4-Fluoro-benzylamino)-pyrimidin-4-yl]-3-methyl-ureido}-4-meth-
yl-phenyl)-3-trifluoromethyl-benzamide;
3-(6-{1-Methyl-3-[2-methyl-5-(3-trifluoromethyl-benzoylamino)-phenyl]-ure-
ido}-pyrimidin-4-ylamino)-propionic acid;
N-(3-{3-[6-(3-Amino-propylamino)-pyrimidin-4-yl]-3-methyl-ureido}-4-methy-
l-phenyl)-3-trifluoromethyl-benzamide;
N-[3-(3-{6-[2-(4-Methoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-3-methyl-ure-
ido)-4-methyl-phenyl]-3-trifluoromethyl-benzamide;
N-(3-{3-[6-(6-Methoxy-pyridin-3-ylamino)-pyrimidin-4-yl]-3-methyl-ureido}-
-4-methyl-phenyl)-3-trifluoromethyl-benzamide;
N-(4-Methyl-3-{3-methyl-3-[6-(2-trifluoromethyl-benzylamino)-pyrimidin-4--
yl]-ureido}-phenyl)-3-trifluoromethyl-benzamide;
N-[3-(3-{6-[(Benzo[1,3]dioxol-5-ylmethyl)-amino]-pyrimidin-4-yl}-3-methyl-
-ureido)-4-methyl-phenyl]-3-trifluoromethyl-benzamide;
N-{4-Methyl-3-[3-methyl-3-(6-morpholin-4-yl-pyrimidin-4-yl)-ureido]-pheny-
l}-3-trifluoromethyl-benzamide;
N-(4-Methyl-3-{3-methyl-3-[6-(2-morpholin-4-yl-ethylamino)-pyrimidin-4-yl-
]-ureido}-phenyl)-3-trifluoromethyl-benzamide;
N-(4-Methyl-3-{3-methyl-3-[6-((3-methyl-amino-carbonyl-phenyl)-amino)-pyr-
imidin-4-yl]-ureido}-phenyl)-3-trifluoromethyl-benzamide;
N-{3-[3-(6-Cyclopropylamino-pyrimidin-4-yl)-3-methyl-ureido]-4-methyl-phe-
nyl}-3-trifluoromethyl-benzamide;
N-(4-Methyl-3-{3-methyl-3-[6-((4-amino-carbonyl-phenyl)-amino)-pyrimidin--
4-yl]-ureido}-phenyl)-3-trifluoromethyl-benzamide;
N-(3-{3-[6-(4-Acetylamino-phenylamino)-pyrimidin-4-yl]-3-methyl-ureido}-4-
-methyl-phenyl)-3-trifluoromethyl-benzamide;
N-[4-Methyl-3-(3-methyl-3-{6-[4-(4-methyl-piperazin-1-ylmethyl)-phenylami-
no]-pyrimidin-4-yl}-ureido)-phenyl]-3-trifluoromethyl-benzamide;
N-(4-Methyl-3-{3-methyl-3-[6-(3-morpholin-4-ylmethyl-phenylamino)-pyrimid-
in-4-yl]-ureido}-phenyl)-3-trifluoromethyl-benzamide;
N-[4-Methyl-3-(3-methyl-3-{6-[3-(morpholine-4-sulfonyl)-phenylamino]-pyri-
midin-4-yl}-ureido)-phenyl]-3-trifluoromethyl-benzamide;
N-{3-[3-(6-Amino-pyrimidin-4-yl)-3-cyclopentyl-ureido]-4-methyl-phenyl}-3-
-trifluoromethyl-benzamide;
N-{3-[3-(6-Amino-pyrimidin-4-yl)-3-(tetrahydro-furan-2-ylmethyl)-ureido]--
4-methyl-phenyl}-3-trifluoromethyl-benzamide;
N-{3-[3-(6-Amino-pyrimidin-4-yl)-3-(2-pyrrolidin-1-yl-ethyl)-ureido]-4-me-
thyl-phenyl}-3-trifluoromethyl-benzamide;
N-{3-[3-(6-Amino-pyrimidin-4-yl)-3-(5-methyl-pyrazin-2-ylmethyl)-ureido]--
4-methyl-phenyl}-3-trifluoromethyl-benzamide;
N-{3-[3-(6-Amino-pyrimidin-4-yl)-3-(2-methoxy-1-methyl-ethyl)-ureido]-4-m-
ethyl-phenyl}-3-trifluoromethyl-benzamide;
N-{3-[3-(6-Amino-pyrimidin-4-yl)-3-pyridin-2-ylmethyl-ureido]-4-methyl-ph-
enyl}-3-trifluoromethyl-benzamide;
N-{3-[3-(6-Amino-pyrimidin-4-yl)-3-(2-pyridin-2-yl-ethyl)-ureido]-4-methy-
l-phenyl}-3-trifluoromethyl-benzamide;
N-{3-[3-(6-Amino-pyrimidin-4-yl)-3-morpholin-4-yl-ureido]-4-methyl-phenyl-
}-3-trifluoromethyl-benzamide;
N-(3-{3-(6-Amino-pyrimidin-4-yl)-3-[2-(1-methyl-pyrrolidin-2-yl)-ethyl]-u-
reido}-4-methyl-phenyl)-3-trifluoromethyl-benzamide;
N-(3-{3-(6-Amino-pyrimidin-4-yl)-3-[2-(4-sulfamoyl-phenyl)-ethyl]-ureido}-
-4-methyl-phenyl)-3-trifluoromethyl-benzamide;
N-{3-[3-(6-Amino-pyrimidin-4-yl)-3-(3-morpholin-4-yl-propyl)-ureido]-4-me-
thyl-phenyl}-3-trifluoromethyl-benzamide;
N-(3-{3-(6-Amino-pyrimidin-4-yl)-3-[2-(2-fluoro-phenyl)-ethyl]-ureido}-4--
methyl-phenyl)-3-trifluoromethyl-benzamide;
N-{3-[3-[6-(2,6-Dimethyl-pyridin-3-ylamino)-pyrimidin-4-yl]-3-(2-morpholi-
n-4-yl-ethyl)-ureido]-4-methyl-phenyl}-3-trifluoromethyl-benzamide;
N-{3-[3-[6-(4,6-Dimethyl-pyridin-3-ylamino)-pyrimidin-4-yl]-3-(2-morpholi-
n-4-yl-ethyl)-ureido]-4-methyl-phenyl}-3-trifluoromethyl-benzamide;
N-{3-[3-(6-Amino-5-methyl-pyrimidin-4-yl)-3-(2-morpholin-4-yl-ethyl)-urei-
do]-4-methyl-phenyl}-3-trifluoromethyl-benzamide;
N-{3-[3-(6-Amino-2-methyl-pyrimidin-4-yl)-3-(2-morpholin-4-yl-ethyl)-urei-
do]-4-methyl-phenyl}-3-trifluoromethyl-benzamide;
1-(6-Amino-pyrimidin-4-yl)-3-(2,4-dimethoxy-phenyl)-1-(2-morpholin-4-yl-e-
thyl)-urea;
1-(6-Amino-pyrimidin-4-yl)-3-(2,5-dimethoxy-phenyl)-1-(2-morpholin-4-yl-e-
thyl)-urea;
1-(6-Amino-pyrimidin-4-yl)-3-(3,4-dimethoxy-phenyl)-1-(2-morpholin-4-yl-e-
thyl)-urea;
1-(6-Amino-pyrimidin-4-yl)-3-(3,5-dimethoxy-phenyl)-1-(2-morpholin-4-yl-e-
thyl)-urea;
1-(6-Amino-pyrimidin-4-yl)-3-(3,5-bis-trifluoromethyl-phenyl)-1-(2-morpho-
lin-4-yl-ethyl)-urea; and
1-(6-Amino-pyrimidin-4-yl)-3-(3,5-bis-trifluoromethyl-phenyl)-1-(2-morpho-
lin-4-yl-ethyl)-thiourea.
[0492] Further preferred compounds of Formula I** are detailed in
the Examples and Table I, infra.
[0493] Compounds of Formula I** inhibit abl kinase, especially
v-abl kinase. The compounds of Formula I** also inhibit wild-type
BCR-Abl kinase and mutations of BCR-Abl kinase and are thus
suitable for the treatment of Bcr-abl-positive cancer and tumor
diseases, such as leukemias (especially chronic myeloid leukemia
and acute lymphoblastic leukemia, where especially apoptotic
mechanisms of action are found), and also shows effects on the
subgroup of leukemic stem cells as well as potential for the
purification of these cells in vitro after removal of said cells
(for example, bone marrow removal) and reimplantation of the cells
once they have been cleared of cancer cells (for example,
reimplantation of purified bone marrow cells).
[0494] PDGF (Platelet-derived Growth Factor) is a very commonly
occurring growth factor, which plays an important role both in
normal growth and also in pathological cell proliferation, such as
is seen in carcinogenesis and in diseases of the smooth-muscle
cells of blood vessels, for example in atherosclerosis and
thrombosis. Compounds of Formula I** can inhibit PDGF receptor
(PDGFR) activity and are, therefore, suitable for the treatment of
tumor diseases, such as gliomas, sarcomas, prostate tumors, and
tumors of the colon, breast, and ovary.
[0495] Compounds of Formula I** can be used not only as a
tumor-inhibiting substance, for example in small cell lung cancer,
but also as an agent to treat non-malignant proliferative
disorders, such as atherosclerosis, thrombosis, psoriasis,
scleroderma and fibrosis, as well as for the protection of stem
cells, for example to combat the hemotoxic effect of
chemotherapeutic agents, such as 5-fluoruracil, and in asthma.
Compounds of Formula I** can especially be used for the treatment
of diseases, which respond to an inhibition of the PDGF receptor
kinase.
[0496] Compounds of Formula I** show useful effects in the
treatment of disorders arising as a result of transplantation, for
example, allogenic transplantation, especially tissue rejection,
such as especially obliterative bronchiolitis (OB), i.e. a chronic
rejection of allogenic lung transplants. In contrast to patients
without OB, those with OB often show an elevated PDGF concentration
in bronchoalveolar lavage fluids.
[0497] Compounds of Formula I** are also effective in diseases
associated with vascular smooth-muscle cell migration and
proliferation (where PDGF and PDGF-R often also play a role), such
as restenosis and atherosclerosis. These effects and the
consequences thereof for the proliferation or migration of vascular
smooth-muscle cells in vitro and in vivo can be demonstrated by
administration of the compounds of the present invention, and also
by investigating its effect on the thickening of the vascular
intima following mechanical injury in vivo.
[0498] The compounds of Formula I** also inhibit cellular processes
involving stem-cell factor (SCF, also known as the c-kit ligand or
steel factor), such as inhibiting SCF receptor (kit)
autophosphorylation and SCF-stimulated activation of MAPK kinase
(mitogen-activated protein kinase). MO7e cells are a human
promegakaryocytic leukemia cell line, which depends on SCF for
proliferation. Compounds of the invention can inhibit the
autophosphorylation of SCF receptors.
[0499] The trk family of neurotrophin receptors (trkA, trkB, trkC)
promotes the survival, growth and differentiation of the neuronal
and non-neuronal tissues. The TrkB protein is expressed in
neuroendocrine-type cells in the small intestine and colon, in the
alpha cells of the pancreas, in the monocytes and macrophages of
the lymph nodes and of the spleen, and in the granular layers of
the epidermis (Shibayama and Koizumi, 1996). Expression of the TrkB
protein has been associated with an unfavorable progression of
Wilms tumors and of neuroblastomas. TkrB is, moreover, expressed in
cancerous prostate cells but not in normal cells. The signaling
pathway downstream of the trk receptors involves the cascade of
MAPK activation through the Shc, activated Ras, ERK-1 and ERK-2
genes, and the PLC-gammal transduction pathway (Sugimoto et al.,
2001).
[0500] The kinase, c-Src transmits oncogenic signals of many
receptors. For example, over-expression of EGFR or HER3/neu in
tumors leads to the constitutive activation of c-src, which is
characteristic for the malignant cell but absent from the normal
cell. On the other hand, mice deficient in the expression of c-src
exhibit an osteopetrotic phenotype, indicating a key participation
of c-src in osteoclast function and a possible involvement in
related disorders.
[0501] The Tec family kinase, Bmx, a non-receptor protein-tyrosine
kinase, controls the proliferation of mammary epithelial cancer
cells.
[0502] Fibroblast growth factor receptor 3 was shown to exert a
negative regulatory effect on bone growth and an inhibition of
chondrocyte proliferation. Thanatophoric dysplasia is caused by
different mutations in fibroblast growth factor receptor 3, and one
mutation, TDII FGFR35, has a constitutive tyrosine kinase activity
which activates the transcription factor Stat1, leading to
expression of a cell-cycle inhibitor, growth arrest and abnormal
bone development (Su et al., Nature, 1997, 386, 288-292). FGFR35 is
also often expressed in multiple myeloma-type cancers.
[0503] The activity of serum and glucocorticoid-regulated kinase
(SGK), is correlated to perturbed ion-channel activities, in
particular, those of sodium and/or potassium channels and compounds
of the invention can be useful for treating hypertension.
[0504] Lin et al (1997) J. Clin. Invest. 100, 8: 2072-2078 and P.
Lin (1998) PNAS 95, 8829-8834, have shown an inhibition of tumor
growth and vascularization and also a decrease in lung metastases
during adenoviral infections or during injections of the
extracellular domain of Tie-2 (Tek) in breast tumor and melanoma
xenograft models. Tie2 inhibitors can be used in situations where
neovascularization takes place inappropriately (i.e. in diabetic
retinopathy, chronic inflammation, psoriasis, Kaposi's sarcoma,
chronic neovascularization due to macular degeneration, rheumatoid
arthritis, infantile haemangioma and cancers).
[0505] Lck plays a role in T-cell signaling. Mice that lack the Lck
gene have a poor ability to develop thymocytes. The function of Lck
as a positive activator of T-cell signaling suggests that Lck
inhibitors may be useful for treating autoimmune disease such as
rheumatoid arthritis.
[0506] JNKs, along with other MAPKs, have been implicated in having
a role in mediating cellular response to cancer, thrombin-induced
platelet aggregation, immunodeficiency disorders, autoimmune
diseases, cell death, allergies, osteoporosis and heart disease.
The therapeutic targets related to activation of the JNK pathway
include chronic myelogenous leukemia (CML), rheumatoid arthritis,
asthma, osteoarthritis, ischemia, cancer and neurodegenerative
diseases. As a result of the importance of JNK activation
associated with liver disease or episodes of hepatic ischemia,
compounds of the invention may also be useful to treat various
hepatic disorders. A role for JNK in cardiovascular disease such as
myocardial infarction or congestive heart failure has also been
reported as it has been shown JNK mediates hypertrophic responses
to various forms of cardiac stress. It has been demonstrated that
the JNK cascade also plays a role in T-cell activation, including
activation of the IL-2 promoter.
[0507] Thus, inhibitors of JNK may have therapeutic value in
altering pathologic immune responses. A role for JNK activation in
various cancers has also been established, suggesting the potential
use of JNK inhibitors in cancer. For example, constitutively
activated JNK is associated with HTLV-1 mediated tumorigenesis
[Oncogene 13:135-42 (1996)]. JNK may play a role in Kaposi's
sarcoma (KS). Other proliferative effects of other cytokines
implicated in KS proliferation, such as vascular endothelial growth
factor (VEGF), IL-6 and INFO, may also be mediated by JNK. In
addition, regulation of the c-jun gene in p210 BCR-ABL transformed
cells corresponds with activity of JNK, suggesting a role for JNK
inhibitors in the treatment for chronic myelogenous leukemia (CML)
[Blood 92:2450-60 (1998)].
[0508] Certain abnormal proliferative conditions are believed to be
associated with raf expression and are, therefore, believed to be
responsive to inhibition of raf expression. Abnormally high levels
of expression of the raf protein are also implicated in
transformation and abnormal cell proliferation. These abnormal
proliferative conditions are also believed to be responsive to
inhibition of raf expression. For example, expression of the c-raf
protein is believed to play a role in abnormal cell proliferation
since it has been reported that 60% of all lung carcinoma cell
lines express unusually high levels of c-raf mRNA and protein.
Further examples of abnormal proliferative conditions are
hyper-proliferative disorders such as cancers, tumors, hyperplasia,
pulmonary fibrosis, angiogenesis, psoriasis, atherosclerosis and
smooth muscle cell proliferation in the blood vessels, such as
stenosis or restenosis following angioplasty. The cellular
signaling pathway of which raf is a part has also been implicated
in inflammatory disorders characterized by T-cell proliferation
(T-cell activation and growth), such as tissue graft rejection,
endotoxin shock, and glomerular nephritis, for example.
[0509] The stress activated protein kinases (SAPKs) are a family of
protein kinases that represent the penultimate step in signal
transduction pathways that result in activation of the c-jun
transcription factor and expression of genes regulated by c-jun. In
particular, c-jun is involved in the transcription of genes that
encode proteins involved in the repair of DNA that is damaged due
to genotoxic insults. Therefore, agents that inhibit SAPK activity
in a cell prevent DNA repair and sensitize the cell to agents that
induce DNA damage or inhibit DNA synthesis and induce apoptosis of
a cell or that inhibit cell proliferation.
[0510] Mitogen-activated protein kinases (MAPKs) are members of
conserved signal transduction pathways that activate transcription
factors, translation factors and other target molecules in response
to a variety of extracellular signals. MAPKs are activated by
phosphorylation at a dual phosphorylation motif having the sequence
Thr-X-Tyr by mitogen-activated protein kinase kinases (MKKs). In
higher eukaryotes, the physiological role of MAPK signaling has
been correlated with cellular events such as proliferation,
oncogenesis, development and differentiation. Accordingly, the
ability to regulate signal transduction via these pathways
(particularly via MKK4 and MKK6) could lead to the development of
treatments and preventive therapies for human diseases associated
with MAPK signaling, such as inflammatory diseases, autoimmune
diseases and cancer.
[0511] In accordance with the foregoing, the present invention
further provides a method for preventing or treating any of the
diseases or disorders described above in a subject in need of such
treatment, which method comprises administering to said subject a
therapeutically effective amount (See, "Administration and
Pharmaceutical Compositions", infra) of a compound of Formula I**
or a pharmaceutically acceptable salt thereof. For any of the above
uses, the required dosage will vary depending on the mode of
administration, the particular condition to be treated and the
effect desired.
[0512] In general, compounds of Formula I** will be administered in
therapeutically effective amounts via any of the usual and
acceptable modes known in the art, either singly or in combination
with one or more therapeutic agents. A therapeutically effective
amount may vary widely depending on the severity of the disease,
the age and relative health of the subject, the potency of the
compound used and other factors. In general, satisfactory results
are indicated to be obtained systemically at daily dosages of from
about 0.03 to 2.5 mg/kg per body weight. An indicated daily dosage
in the larger mammal, e.g. humans, is in the range from about 0.5
mg to about 100 mg, conveniently administered, e.g. in divided
doses up to four times a day or in retard form. Suitable unit
dosage forms for oral administration comprise from ca. 1 to 50 mg
active ingredient.
[0513] Compounds of Formula I** can be administered as
pharmaceutical compositions by any conventional route, in
particular enterally, e.g., orally, e.g., in the form of tablets or
capsules, or parenterally, e.g., in the form of injectable
solutions or suspensions, topically, e.g., in the form of lotions,
gels, ointments or creams, or in a nasal or suppository form.
Pharmaceutical compositions comprising a compound of the present
invention in free form or in a pharmaceutically acceptable salt
form in association with at least one pharmaceutically acceptable
carrier or diluent can be manufactured in a conventional manner by
mixing, granulating or coating methods. For example, oral
compositions can be tablets or gelatin capsules comprising the
active ingredient together with a) diluents, e.g., lactose,
dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine; b)
lubricants, e.g., silica, talcum, stearic acid, its magnesium or
calcium salt and/or polyethyleneglycol; for tablets also c)
binders, e.g., magnesium aluminum silicate, starch paste, gelatin,
tragacanth, methylcellulose, sodium carboxymethylcellulose and or
polyvinylpyrrolidone; if desired d) disintegrants, e.g., starches,
agar, alginic acid or its sodium salt, or effervescent mixtures;
and/or e) absorbents, colorants, flavors and sweeteners. Injectable
compositions can be aqueous isotonic solutions or suspensions, and
suppositories can be prepared from fatty emulsions or suspensions.
The compositions may be sterilized and/or contain adjuvants, such
as preserving, stabilizing, wetting or emulsifying agents, solution
promoters, salts for regulating the osmotic pressure and/or
buffers. In addition, they may also contain other therapeutically
valuable substances. Suitable formulations for transdermal
applications include an effective amount of a compound of the
present invention with a carrier. A carrier can include absorbable
pharmacologically acceptable solvents to assist passage through the
skin of the host. For example, transdermal devices are in the form
of a bandage comprising a backing member, a reservoir containing
the compound optionally with carriers, optionally a rate
controlling barrier to deliver the compound to the skin of the host
at a controlled and predetermined rate over a prolonged period of
time, and means to secure the device to the skin. Matrix
transdermal formulations may also be used. Suitable formulations
for topical application, e.g., to the skin and eyes, are preferably
aqueous solutions, ointments, creams or gels well-known in the art.
Such may contain solubilizers, stabilizers, tonicity enhancing
agents, buffers and preservatives.
[0514] Compounds of Formula I** can be administered in
therapeutically effective amounts in combination with one or more
therapeutic agents (pharmaceutical combinations). For example,
synergistic effects can occur with other immunomodulatory or
anti-inflammatory substances, for example when used in combination
with cyclosporin, rapamycin, or ascomycin, or immunosuppressant
analogues thereof, for example cyclosporin A (CsA), cyclosporin G,
FK-506, rapamycin, or comparable compounds, corticosteroids,
cyclophosphamide, azathioprine, methotrexate, brequinar,
leflunomide, mizoribine, mycophenolic acid, mycophenolate mofetil,
15-deoxyspergualin, immunosuppressant antibodies, especially
monoclonal antibodies for leukocyte receptors, for example MHC,
CD2, CD3, CD4, CD7, CD25, CD28, B7, CD45, CD58 or their ligands, or
other immunomodulatory compounds, such as CTLA41g. Where the
compounds of the invention are administered in conjunction with
other therapies, dosages of the co-administered compounds will of
course vary depending on the type of co-drug employed, on the
specific drug employed, on the condition being treated and so
forth.
[0515] The invention also provides for a pharmaceutical
combinations, e.g. a kit, comprising a) a first agent which is a
compound of Formula I** as disclosed herein, in free form or in
pharmaceutically acceptable salt form, and b) at least one
co-agent. The kit can comprise instructions for its
administration.
[0516] The terms "co-administration" or "combined administration"
or the like as utilized herein are meant to encompass
administration of the selected therapeutic agents to a single
patient, and are intended to include treatment regimens in which
the agents are not necessarily administered by the same route of
administration or at the same time.
[0517] The term "pharmaceutical combination" as used herein means a
product that results from the mixing or combining of more than one
active ingredient and includes both fixed and non-fixed
combinations of the active ingredients. The term "fixed
combination" means that the active ingredients, e.g. a compound of
Formula I** and a co-agent, are both administered to a patient
simultaneously in the form of a single entity or dosage. The term
"non-fixed combination" means that the active ingredients, e.g. a
compound of Formula I** and a co-agent, are both administered to a
patient as separate entities either simultaneously, concurrently or
sequentially with no specific time limits, wherein such
administration provides therapeutically effective levels of the 2
compounds in the body of the patient. The latter also applies to
cocktail therapy, e.g. the administration of 3 or more active
ingredients.
[0518] The present invention also includes processes for the
preparation of compounds of Formula I**. In the reactions described
herein, it can be necessary to protect reactive functional groups,
for example hydroxy, amino, imino, thio or carboxy groups, where
these are desired in the final product, to avoid their unwanted
participation in the reactions. Conventional protecting groups can
be used in accordance with standard practice, for example, see T.
W. Greene and P. G. M. Wuts in "Protective Groups in Organic
Chemistry", John Wiley and Sons, 1991.
[0519] Detailed examples of the synthesis of a compound of Formula
I** can be found in the Examples, infra. The examples include solid
phase synthesis of compounds of Formula I**.
[0520] A compound of Formula (I) (or exemplary formula thereof) can
be administered alone or in combination with one or more other
therapeutic agents, possible combination therapy taking the form of
fixed combinations or the administration of a compound of the
invention and one or more other therapeutic agents being staggered
or given independently of one another, or the combined
administration of fixed combinations and one or more other
therapeutic agents. A compound of Formula (I) (or exemplary formula
thereof) can besides or in addition be administered especially for
tumor therapy, such as leukaemia therapy, in combination with
chemotherapy, radiotherapy, immunotherapy, surgical intervention,
or a combination of these. Long-term therapy is equally possible as
is adjuvant therapy in the context of other treatment strategies,
as described above. Other possible treatments are therapy to
maintain the patient's status after tumor regression, or even
chemopreventive therapy, for example in patients at risk.
[0521] Therapeutic agents for possible combination are especially
one or more cytostatic or cytotoxic compounds, for example a
chemotherapeutic agent or several selected from the group
comprising indarubicin, cytarabine, interferon, hydroxyurea,
bisulfan, or an inhibitor of polyamine biosynthesis, an inhibitor
of protein kinase, especially of serine/threonine protein kinase,
such as protein kinase C, or of tyrosine protein kinase, such as
epidermal growth factor receptor tyrosine kinase, a cytokine, a
negative growth regulator, such as TGF-.beta. or IFN-.beta., an
aromatase inhibitor, a classical cytostatic, and an inhibitor of
the interaction of an SH2 domain with a phosphorylated protein. A
specific example of a combination agent is
(N-{5-[4-(4-methyl-piperazino-methyl)-benzoylamido]-2-methylphenyl}-4-(3--
pyridyl)-2-pyrimidine-amine (Glivec.RTM./Gleevec.RTM.).
[0522] A compound according to the invention is not only for the
(prophylactic and preferably therapeutic) management of humans, but
also for the treatment of other warm-blooded animals, for example
of commercially useful animals, for example rodents, such as mice,
rabbits or rats, or guinea-pigs. Such a compound may also be used
as a reference standard in the test systems described above to
permit a comparison with other compounds.
[0523] In general, the invention relates also to the use of a
compound of Formula (I) (or exemplary formula thereof) or a N-oxide
thereof for the inhibition of tyrosine kinase activity, either in
vitro or in vivo.
[0524] With the groups of preferred compounds of Formula (I) (or
exemplary formula thereof) and N-oxides thereof, definitions of
substituents from the general definitions mentioned hereinbefore
may reasonably be used, for example, to replace more general
definitions with more specific definitions or especially with
definitions characterized as being preferred.
[0525] Especially, the invention relates to the use of a compound
of Formula (I) (or exemplary formula thereof) or of a N-oxide or a
possible tautomer thereof or of a pharmaceutically acceptable salt
of such a compound for the preparation of a pharmaceutical
composition for the treatment of a disease which responds to an
inhibition of protein kinase activity, wherein the disease is a
neoplastic disease.
[0526] More particularly, the invention relates to the use of a
compound of theFormula (I) (or exemplary formula thereof) or of a
N-oxide or a possible tautomer thereof; or of a pharmaceutically
acceptable salt of such a compound for the preparation of a
pharmaceutical composition for the treatment of leukaemia which
responds to an inhibition of the Abl, Abl-Bcr, including mutant
forms thereof, and VEGF-R2 tyrosine kinase activity.
[0527] Particular active products are compounds named in the
examples and salts, esters, N-oxides or prodrugs thereof.
[0528] In addition, the invention provides a method for the
treatment of a disease which responds to an inhibition of protein
kinase activity, which comprises administering a compound of
Formula (I) (or exemplary formula thereof) or a N-oxide or a
pharmaceutically acceptable salt thereof, wherein the radicals and
symbols have the meanings as defined above, in a quantity effective
against said disease, to a warm-blooded animal requiring such
treatment.
[0529] A compound of the invention may be prepared by processes
that, though not applied hitherto for the new compounds of the
present invention, are known per se, where the compounds and
intermediates may also be present with functional groups in
protected form if necessary and/or in the form of salts, provided a
salt-forming group is present and the reaction in salt form is
possible;
any protecting groups in a protected derivative of a compound of
the Formula (I) (or exemplary formula thereof) are removed; and, if
so desired, an obtainable compound of Formula (I) (or exemplary
formula thereof) is converted into another compound of Formula (I)
(or exemplary formula thereof) or a N-oxide thereof, a free
compound of Formula (I) (or exemplary formula thereof) is converted
into a salt, an obtainable salt of a compound of Formula (I) (or
exemplary formula thereof) is converted into the free compound or
another salt, and/or a mixture of isomeric compounds of Formula (I)
(or exemplary formula thereof) is separated into the individual
isomers.
[0530] Compounds of the invention in unoxidized form can be
prepared from N-oxides of compounds of the invention by treating
with a reducing agent (e.g., sulfur, sulfur dioxide, triphenyl
phosphine, lithium borohydride, sodium borohydride, phosphorus
trichloride, tribromide, or the like) in a suitable inert organic
solvent (e.g. acetonitrile, ethanol, aqueous dioxane, or the like)
at 0 to 80.degree. C.
[0531] Prodrug derivatives of the compounds of the invention can be
prepared by methods known to those of ordinary skill in the art
(e.g., for further details see Saulnier et al., (1994), Bioorganic
and Medicinal Chemistry Letters, Vol. 4, p. 1985). For example,
appropriate prodrugs can be prepared by reacting a non-derivatized
compound of the invention with a suitable carbamylating agent
(e.g., 1,1-acyloxyalkylcarbanochloridate, para-nitrophenyl
carbonate, or the like).
[0532] Protected derivatives of the compounds of the invention can
be made by means known to those of ordinary skill in the art. A
detailed description of techniques applicable to the creation of
protecting groups and their removal can be found in T. W. Greene,
"Protecting Groups in Organic Chemistry", 3.sup.rd edition, John
Wiley and Sons, Inc., 1999.
[0533] Compounds of the present invention can be conveniently
prepared, or formed during the process of the invention, as
solvates (e.g., hydrates). Hydrates of compounds of the present
invention can be conveniently prepared by recrystallization from an
aqueous/organic solvent mixture, using organic solvents such as
dioxin, tetrahydrofuran or methanol.
[0534] Compounds of the invention can be prepared as their
individual stereoisomers by reacting a racemic mixture of the
compound with an optically active resolving agent to form a pair of
diastereoisomeric compounds, separating the diastereomers and
recovering the optically pure enantiomers. While resolution of
enantiomers can be carried out using covalent diastereomeric
derivatives of the compounds of the invention, dissociable
complexes are preferred (e.g., crystalline diastereomeric salts).
Diastereomers have distinct physical properties (e.g., melting
points, boiling points, solubilities, reactivity, etc.) and can be
readily separated by taking advantage of these dissimilarities. The
diastereomers can be separated by chromatography, or preferably, by
separation/resolution techniques based upon differences in
solubility. The optically pure enantiomer is then recovered, along
with the resolving agent, by any practical means that would not
result in racemization. A more detailed description of the
techniques applicable to the resolution of stereoisomers of
compounds from their racemic mixture can be found in Jean Jacques,
Andre Collet, Samuel H. Wilen, "Enantiomers, Racemates and
Resolutions", John Wiley And Sons, Inc., 1981.
[0535] Insofar as the production of the starting materials is not
particularly described, the compounds are known or can be prepared
analogously to methods known in the art or as disclosed in the
Examples hereinafter.
[0536] One of skill in the art will appreciate that the above
transformations are only representative of methods for preparation
of the compounds of the present invention, and that other well
known methods can similarly be used.
Protecting Groups
[0537] If one or more other functional groups, for example carboxy,
hydroxy, amino, or mercapto, are or need to be protected in a
compound of Formula (I) (or exemplary formula thereof)II, because
they should not take part in the reaction, these are such groups as
are usually used in the synthesis of amides, in particular peptide
compounds, and also of cephalosporins and penicillins, as well as
nucleic acid derivatives and sugars.
[0538] The protecting groups may already be present in precursors
and should protect the functional groups concerned against unwanted
secondary reactions, such as acylations, etherifications,
esterifications, oxidations, solvolysis, and similar reactions. It
is a characteristic of protecting groups that they lend themselves
readily, i.e. without undesired secondary reactions, to removal,
typically by solvolysis, reduction, photolysis or also by enzyme
activity, for example under conditions analogous to physiological
conditions, and that they are not present in the end-products. The
specialist knows, or can easily establish, which protecting groups
are suitable with the reactions mentioned hereinabove and
hereinafter.
[0539] The protection of such functional groups by such protecting
groups, the protecting groups themselves, and their removal
reactions are described for example in standard reference books for
peptide synthesis as cited hereinbefore, and in special books on
protective groups such as J. F. W. McOmie, "Protective Groups in
Organic Chemistry", Plenum Press, London and New York 1973, in
"Methoden der organischen Chemie" (Methods of organic chemistry),
Houben-Weyl, 4th edition, Volume 15/1, Georg Thieme Verlag,
Stuttgart 1974, and in T. W. Greene, "Protective Groups in Organic
Synthesis", Wiley, New York.
Pharmaceutical Preparations, Methods, and Uses
[0540] The present invention relates also to pharmaceutical
compositions that comprise a compound of Formula (I) (or exemplary
formula thereof) or a N-oxide thereof as active ingredient and that
can be used especially in the treatment of the aforementioned
diseases.
[0541] The pharmacologically acceptable compounds of the present
invention may be used, for ex-ample, for the preparation of
pharmaceutical compositions that comprise a pharmaceutically
effective amount of a compound of the Formula (I) (or exemplary
formula thereof), or a pharmaceutically acceptable salt thereof, as
active ingredient together or in admixture with a significant
amount of one or more inorganic or organic, solid or liquid,
pharmaceutically acceptable carriers.
[0542] The invention relates also to a pharmaceutical composition
that is suitable for administration to a warm-blooded animal,
especially a human (or to cells or cell lines derived from a
warm-blooded animal, especially a human, e.g. lymphocytes), for the
treatment or, in a broader aspect of the invention, prevention of
(=prophylaxis against) a disease that responds to inhibi-tion of
tyrosin protein kinase activity, especially one of the diseases
mentioned above as being preferred for use of a compound of Formula
(I) (or exemplary formula thereof), comprising an amount of a novel
compound of Formula (I) (or exemplary formula thereof), or a
pharmaceutically acceptable salt thereof, which is effective for
said inhibition, together with at least one pharmaceutically
acceptable carrier.
[0543] Compositions for enteral administration, such as nasal,
buccal, rectal or, especially, oral administration, and for
parenteral administration, such as intravenous, intramuscular or
subcutaneous administration, to warm-blooded animals, especially
humans, are especially preferred. The compositions comprise the
active ingredient alone or, preferably, together with a
pharmaceutically acceptable carrier. The dosage of the active
ingredient depends upon the disease to be treated and upon the
species, its age, weight, and individual condition, the individual
pharmacokinetic data, and the mode of administration.
[0544] The present invention relates especially to pharmaceutical
compositions that comprise a compound of Formula (I) (or exemplary
formula thereof), a tautomer, a N-oxide or a pharmaceutically
acceptable salt, or a hydrate or solvate thereof, and at least one
pharmaceutically acceptable carrier.
[0545] The invention relates also to pharmaceutical compositions
for use in a method for the pro-phylactic or especially therapeutic
management of the human or animal body, to a process for the
preparation thereof (especially in the form of compositions for the
treatment of tumors) and to a method of treating tumor diseases,
especially those mentioned hereinabove.
[0546] The invention relates also to processes and to the use of
compounds of Formula (I) (or exemplary formula thereof) or N-oxides
thereof for the preparation of pharmaceutical preparations which
comprise compounds of Formula (I) (or exemplary formula thereof) or
N-oxides thereof as active component (active ingredient).
[0547] The pharmaceutical compositions comprise from approximately
1% to approximately 95% active ingredient, single-dose
administration forms comprising in the preferred embodiment from
approximately 20% to approximately 90% active ingredient and forms
that are not of single-dose type comprising in the preferred
embodiment from approximately 5% to approximately 20% active
ingredient. Unit dose forms are, for example, coated and uncoated
tablets, ampoules, vials, suppositories, or capsules. Further
dosage forms are, for example, ointments, creams, pastes, foams,
tinctures, sprays, etc. Examples are capsules containing from about
0.05 g to about 1.0 g active ingredient.
[0548] The pharmaceutical compositions of the present invention are
prepared in a manner known per se, for example by means of
conventional mixing, granulating, coating, dissolving or
lyophilizing processes.
[0549] Preference is given to the use of solutions of the active
ingredient, and also suspensions or dispersions, especially
isotonic aqueous solutions, dispersions or suspensions which, for
example in the case of lyophilized compositions comprising the
active ingredient alone or together with a carrier can be made up
before use. The pharmaceutical compositions may be sterilized
and/or may comprise excipients, for example preservatives,
stabilizers, wetting agents and/or emulsifiers, solubilizers, salts
for regulating osmotic pressure and/or buffers and are prepared in
a manner known per se, for example by means of conventional
dissolving and lyophilizing processes. The said solutions or
suspensions may comprise viscosity-increasing agents or
solubilizers, such as sodium carboxymethylcellulose,
carboxy-methylcellulose, dextran, polyvinylpyrrolidone or
gelatin.
[0550] Suspensions in oil comprise as the oil component the
vegetable, synthetic or semi-synthetic oils customary for injection
purposes. There may be mentioned as such especially liquid fatty
acid esters that contain as the acid component a long-chained fatty
acid having from 8 to 22, especially from 12 to 22, carbon atoms,
for example lauric acid, tridecylic acid, myristic acid,
pentadecylic acid, palmitic acid, margaric acid, stearic acid,
arachidic acid, behenic acid or corresponding unsaturated acids,
for example oleic acid, elaidic acid, erucic acid, brasidic acid or
linoleic acid, if desired with the addition of antioxidants, for
example vitamin E, .beta.-carotene or
3,5-di-tert-butyl-4-hydroxytoluene. The alcohol component of those
fatty acid esters has a maximum of 6 carbon atoms and is a mono- or
poly-hydroxy, for example a mono-, di- or tri-hydroxy, alcohol, for
example methanol, ethanol, propanol, butanol or pentanol or the
isomers thereof, but especially glycol and glycerol. The following
examples of fatty acid esters are therefore to be mentioned: ethyl
oleate, isopropyl myristate, isopropyl palmitate, "Labrafil M 2375"
(polyoxyethylene glycerol trioleate, Gattefosse, Paris), "Miglyol
812" (tri-glyceride of saturated fatty acids with a chain length of
C.sub.8 to C.sub.12, Huls AG, Germany), but especially vegetable
oils, such as cottonseed oil, almond oil, olive oil, castor oil,
sesame oil, soybean oil and more especially groundnut oil.
[0551] Injection compositions are prepared in customary manner
under sterile conditions; the same applies also to introducing the
compositions into ampoules or vials and sealing the
con-tainers.
[0552] Pharmaceutical compositions for oral administration can be
obtained by combining the active ingredient with solid carriers, if
desired granulating a resulting mixture, and processing the
mixture, if desired or necessary, after the addition of appropriate
excipients, into tablets, dra-gee cores or capsules. It is also
possible for them to be incorporated into plastics carriers that
allow the active ingredients to diffuse or be released in measured
amounts.
[0553] Suitable carriers are especially fillers, such as sugars,
for example lactose, saccharose, mannitol or sorbitol, cellulose
preparations and/or calcium phosphates, for example trical-cium
phosphate or calcium hydrogen phosphate, and binders, such as
starch pastes using for example corn, wheat, rice or potato starch,
gelatin, tragacanth, methylcellulose,
hydro-xypropylmethylcellulose, sodium carboxymethylcellulose and/or
polyvinylpyrrolidone, and/or, if desired, disintegrators, such as
the above-mentioned starches, and/or carboxymethyl starch,
crosslinked polyvinylpyrrolidone, agar, alginic acid or a salt
thereof, such as sodium alginate. Excipients are especially flow
conditioners and lubricants, for example silicic acid, talc,
stearic acid or salts thereof, such as magnesium or calcium
stearate, and/or polyethyl-lene glycol. Dragee cores are provided
with suitable, optionally enteric, coatings, there being used,
inter alia, concentrated sugar solutions which may comprise gum
arabic, talc, polyvi-nylpyrrolidone, polyethylene glycol and/or
titanium dioxide, or coating solutions in suitable organic
solvents, or, for the preparation of enteric coatings, solutions of
suitable cellulose preparations, such as ethylcellulose phthalate
or hydroxypropylmethylcellulose phthalate. Capsules are dry-filled
capsules made of gelatin and soft sealed capsules made of gelatin
and a plasticiser, such as glycerol or sorbitol. The dry-filled
capsules may comprise the active ingredient in the form of
granules, for example with fillers, such as lactose, binders, such
as starches, and/or glidants, such as talc or magnesium stearate,
and if desired with stabili-sers. In soft capsules the active
ingredient is preferably dissolved or suspended in suitable oily
excipients, such as fatty oils, paraffin oil or liquid polyethylene
glycols, it being possible also for stabilisers and/or
antibacterial agents to be added. Dyes or pigments may be added to
the tablets or dragee coatings or the capsule casings, for example
for identification pur-poses or to indicate different doses of
active ingredient.
[0554] Tablet cores can be provided with suitable, optionally
enteric, coatings through the use of, inter alia, concentrated
sugar solutions which may comprise gum arabic, talc,
polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide,
or coating solutions in suitable organic solvents or solvent
mixtures, or, for the preparation of enteric coatings, solutions of
suitable cellulose preparations.
[0555] Pharmaceutical compositions for oral administration also
include hard capsules consisting of gelatin, and also soft, sealed
capsules consisting of gelatin and a plasticizer. The hard capsules
may contain the active ingredient in the form of granules, for
example in admixture with fillers, binders, and/or glidants, and
optionally stabilizers. In soft capsules, the active ingredient is
preferably dissolved or suspended in suitable liquid excipients, to
which stabilizers and detergents may also be added.
[0556] Pharmaceutical compositions suitable for rectal
administration are, for example, suppositories that consist of a
combination of the active ingredient and a suppository base.
[0557] For parenteral administration, aqueous solutions of an
active ingredient in water-soluble form, for example of a
water-soluble salt, or aqueous injection suspensions that contain
viscosity-increasing substances, for example sodium
carboxymethylcellulose, sorbitol and/or dextran, and, if desired,
stabilizers, are especially suitable. The active ingredient,
optionally together with excipients, can also be in the form of a
lyophilizate and can be made into a solution before parenteral
administration by the addition of suitable solvents.
[0558] Solutions such as are used, for example, for parenteral
administration can also be employed as infusion solutions.
[0559] The invention relates likewise to a process or a method for
the treatment of one of the pathological conditions mentioned
hereinabove, especially a disease which responds to an inhibition
of a tyrosine kinase, especially a corresponding neoplastic
disease. The compounds of Formula (I) (or exemplary formula
thereof) or N-oxides thereof can be administered as such or
especially in the form of pharmaceutical compositions,
prophylactically or therapeutically, preferably in an amount
effective against the said diseases, to a warm-blooded animal, for
example a human, requiring such treatment. In the case of an
individual having a bodyweight of about 70 kg the daily dose
administered is from approximately 0.05 g to approximately 5 g,
preferably from approximately 0.25 g to approximately 1.5 g, of a
compound of the present invention.
[0560] The invention also provides for a method of treating a
protein kinase dependent disease, comprising administering to a
warm-blooded animal, for example a human, one or more cytostatic or
cytotoxic compounds e.g. Glivec.RTM. in combination with a compound
of the invention, whether at the same time, or a separate time. The
term the same time is taken to mean in quick succession or
immediately after one another.
[0561] The present invention relates especially also to the use of
a compound of Formula (I) (or exemplary formula thereof) or
N-oxides thereof, or a pharmaceutically acceptable salt thereof,
especially a compound of Formula (I) (or exemplary formula thereof)
which is said to be preferred, or a pharmaceutically acceptable
salt thereof, as such or in the form of a pharmaceutical
formulation with at least one pharmaceutically acceptable carrier
for the therapeutic and also prophylactic management of one or more
of the diseases mentioned hereinabove, preferably a disease which
responds to an inhibition of a protein kinase, especially a
neoplastic disease, more especially leukaemia which responds to an
inhibition of the Abl tyrosine kinase.
[0562] The preferred dose quantity, composition, and preparation of
pharmaceutical formulations (medicines) which are to be used in
each case are described above.
[0563] A compound of the Formula (I) (or exemplary formula thereof)
may also be used to advantage in combination with other
antiproliferative agents. Such antiproliferative agents include,
but are not limited to aromatase inhibitors, antiestrogens,
topoisomerase I inhibitors, topoisomerase II inhibitors,
microtubule active agents, alkylating agents, histone deacetylase
inhibitors, farnesyl transferase inhibitors, COX-2 inhibitors, MMP
inhibitors, mTOR inhibitors, antineoplastic antimetabolites, platin
compounds, compounds decreasing the protein kinase activity and
further anti-angiogenic compounds, gonadorelin agonists,
anti-androgens, bengamides, bisphosphonates, antiproliferative
antibodies and temozolomide (TEMODAL.RTM.).
[0564] The term "aromatase inhibitors" as used herein relates to
compounds which inhibit the estrogen production, i.e. the
conversion of the substrates androstenedione and testosterone to
estrone and estradiol, respectively. The term includes, but is not
limited to steroids, especially exemestane and formestane and, in
particular, non-steroids, especially aminoglutethimide, vorozole,
fadrozole, anastrozole and, very especially, letrozole. Exemestane
can be administered, e.g., in the form as it is marketed, e.g.
under the trademark AROMASIN.TM.. Formestane can be administered,
e.g., in the form as it is marketed, e.g. under the trademark
LENTARON.TM.. Fadrozole can be administered, e.g., in the form as
it is marketed, e.g. under the trademark AFEMA.TM.. Anastrozole can
be administered, e.g., in the form as it is marketed, e.g. under
the trademark ARIMIDEX.TM.. Letrozole can be administered, e.g., in
the form as it is marketed, e.g. under the trademark FEMARA.TM. or
FEMAR.TM.. Aminoglutethimide can be administered, e.g., in the form
as it is marketed, e.g. under the trademark ORIMETEN.TM..
[0565] A combination of the invention comprising an antineoplastic
agent which is an aromatase inhibitor is particularly useful for
the treatment of hormone receptor positive breast tumors. The term
"antiestrogens" as used herein relates to compounds which
antagonize the effect of estrogens at the estrogen receptor level.
The term includes, but is not limited to tamoxifen, fulvestrant,
raloxifene and raloxifene hydrochloride. Tamoxifen can be
administered, e.g., in the form as it is marketed, e.g. under the
trademark NOLVADEX.TM.. Raloxifene hydrochloride can be
administered, e.g., in the form as it is marketed, e.g. under the
trademark EVISTA.TM.. Fulvestrant can be Formulated as disclosed in
U.S. Pat. No. 4,659,516 or it can be administered, e.g., in the
form as it is marketed, e.g. under the trademark FASLODEX.TM..
[0566] The term "topoisomerase I inhibitors" as used herein
includes, but is not limited to topotecan, irinotecan,
9-nitrocamptothecin and the macromolecular camptothecin conjugate
PNU-166148 (compound A1 in WO99/17804). Irinotecan can be
administered, e.g., in the form as it is marketed, e.g. under the
trademark CAMPTOSAR.TM.. Topotecan can be administered, e.g., in
the form as it is marketed, e.g. under the trademark
HYCAMTIN.TM..
[0567] The term "topoisomerase II inhibitors" as used herein
includes, but is not limited to the antracyclines doxorubicin
(including liposomal Formulation, e.g. CAELYX.TM.), epirubicin,
idarubicin and nemorubicin, the anthraquinones mitoxantrone and
losoxantrone, and the podophillotoxines etoposide and teniposide.
Etoposide can be administered, e.g., in the form as it is marketed,
e.g. under the trademark ETOPOPHOS.TM.. Teniposide can be
administered, e.g., in the form as it is marketed, e.g. under the
trademark VM 26-BRISTOL.TM.. Doxorubicin can be administered, e.g.,
in the form as it is marketed, e.g. under the trademark
ADRIBLASTIN.TM.. Epirubicin can be administered, e.g., in the form
as it is mar-keted, e.g. under the trademark FARMORUBICIN.TM..
Idarubicin can be administered, e.g., in the form as it is
marketed, e.g. under the trademark ZAVEDOS.TM.. Mitoxantrone can be
administered, e.g., in the form as it is marketed, e.g. under the
trademark NOVANTRON.TM..
[0568] The term "microtubule active agents" relates to microtubule
stabilizing and microtubule destabilizing agents including, but not
limited to the taxanes paclitaxel and docetaxel, the vinca
alkaloids, e.g., vinblastine, especially vinblastine sulfate,
vincristine especially vincristine sulfate, and vinorelbine,
discodermolide and epothilones, such as epothilone B and D.
Docetaxel can be administered, e.g., in the form as it is marketed,
e.g. under the trademark TAXOTERE.TM.. Vinblastine sulfate can be
administered, e.g., in the form as it is marketed, e.g. under the
trademark VINBLASTIN R.P..TM. Vincristine sulfate can be
administered, e.g., in the form as it is marketed, e.g. under the
trademark FARMISTIN.TM..
[0569] The term "alkylating agents" as used herein includes, but is
not limited to cyclophosphamide, ifosfamide and melphalan.
Cyclophosphamide can be administered, e.g., in the form as it is
marketed, e.g. under the trademark CYCLOSTIN.TM.. Ifosfamide can be
administered, e.g., in the form as it is marketed, e.g. under the
trademark HOLOXAN.TM..
[0570] The term "histone deacetylase inhibitors" relates to
compounds which inhibit the histone deacetylase and which possess
antiproliferative activity.
[0571] The term "farnesyl transferase inhibitors" relates to
compounds which inhibit the farnesyl transferase and which possess
antiproliferative activity.
[0572] The term "COX-2 inhibitors" relates to compounds which
inhibit the cyclooxygenase type 2 enyzme (COX-2) and which possess
antiproliferative activity such as celecoxib (Celebrex.RTM.),
rofecoxib (Vioxx.RTM.) and lumiracoxib (COX189).
[0573] The term "MMP inhibitors" relates to compounds which inhibit
the matrix metalloproteinase (MMP) and which possess
antiproliferative activity.
[0574] The term "mTOR inhibitors" relates to compounds which
inhibit the mammalian target of rapamycin (mTOR) and which possess
antiproliferative activity such as sirolimus (Rapamune.RTM.),
everolimus (Certican.TM.), CCI-779 and ABT578.
[0575] The term "antineoplastic antimetabolites" includes, but is
not limited to 5-fluorouracil, tegafur, capecitabine, cladribine,
cytarabine, fludarabine phosphate, fluorouridine, gemcitabine,
6-mercaptopurine, hydroxyurea, methotrexate, edatrexate and salts
of such compounds, and furthermore ZD 1694 (RALTITREXED.TM.),
LY231514 (ALIMTA.TM.), LY264618 (LOMOTREXOL.TM.) and OGT719.
[0576] The term "platin compounds" as used herein includes, but is
not limited to carboplatin, cis-platin and oxaliplatin. Carboplatin
can be administered, e.g., in the form as it is marketed, e.g.
under the trademark CARBOPLAT.TM.. Oxaliplatin can be administered,
e.g., in the form as it is marketed, e.g. under the trademark
ELOXATIN.TM..
[0577] The term "compounds decreasing the protein kinase activity
and further anti-angiogenic compounds" as used herein includes, but
is not limited to compounds which decrease the activity of e.g. the
Vascular Endothelial Growth Factor (VEGF), the Epidermal Growth
Factor (EGF), c-Src, protein kinase C, the Platelet-derived Growth
Factor (PDGF), Bcr-Abl, c-Kit, Flt-3, the Insulin-like Growth
Factor I Receptor (IGF-IR) and the Cyclin-dependent kinases (CDKs),
and anti-angiogenic compounds having another mechanism of action
than decreasing the protein kinase activity.
[0578] Compounds which decrease the activity of VEGF are especially
compounds which inhibit the VEGF receptor, especially the tyrosine
kinase activity of the VEGF receptor, and compounds binding to
VEGF, and are in particular those compounds, proteins and
monoclonal antibodies generically and specifically disclosed in WO
98/35958, WO 00/09495, WO 00/27820, WO 00/59509, WO 98/11223, WO
00/27819, WO 01/55114, WO 01/58899 and EP 0 769 947; those as
described by M. Prewett et al in Cancer Research 59 (1999)
5209-5218, by F. Yuan et al in Proc. Natl. Acad. Sci. USA, vol. 93,
pp. 14765-14770, December 1996, by Z. Zhu et al in Cancer Res. 58,
1998, 3209-3214, and by J. Mordenti et al in Toxicologic Pathology,
vol. 27, no. 1, pp 14-21, 1999; in WO 00/37502 and WO 94/10202;
Angiostatin.TM., described by M. S. O'Reilly et al, Cell 79, 1994,
315-328; and Endostatin.TM., described by M. S. O'Reilly et al,
Cell 88, 1997, 277-285;
compounds which decrease the activity of EGF are especially
compounds which inhibit the EGF receptor, especially the tyrosine
kinase activity of the EGF receptor, and compounds binding to EGF,
and are in particular those compounds generically and specifically
disclosed in WO 97/02266, EP 0 564 409, WO 99/03854, EP 0520722, EP
0 566 226, EP 0 787 722, EP 0 837 063, WO 98/10767, WO 97/30034, WO
97/49688, WO 97/38983 and, especially, WO 96/33980; compounds which
decrease the activity of c-Src include, but are not limited to,
compounds inhibiting the c-Src protein tyrosine kinase activity as
defined below and to SH2 interaction inhibitors such as those
disclosed in WO97/07131 and WO97/08193; compounds inhibiting the
c-Src protein tyrosine kinase activity include, but are not limited
to, compounds belonging to the structure classes of
pyrrolopyrimidines, especially pyrrolo[2,3-d]pyrimidines, purines,
pyrazopyrimidines, especially pyrazo[3,4-d]pyrimidines,
pyrazopyrimidines, especially pyrazo[3,4-d]pyrimidines and
pyridopyrimidines, especially pyrido[2,3-d]pyrimidines. Preferably,
the term relates to those compounds disclosed in WO 96/10028, WO
97/28161, WO97/32879 and WO97/49706; compounds which decreases the
activity of the protein kinase C are especially those staurosporine
derivatives disclosed in EP 0 296 110 (pharmaceutical preparation
described in WO 00/48571) which compounds are protein kinase C
inhibitors; further specific compounds that decrease protein kinase
activity and which may also be used in combination with the
compounds of the present invention are Imatinib
(Gleevec.RTM./Glivec.RTM.), PKC412, Iressa.TM. (ZD1839), PKI166,
PTK787, ZD6474, GW2016, CHIR-200131, CEP-7055/CEP-5214, CP-547632,
KRN-633 and SU5416; anti-angiogenic compounds having another
mechanism of action than decreasing the protein kinase activity
include, but are not limited to e.g. thalidomide (THALOMID),
celecoxib (Celebrex) and ZD6126.
[0579] The term "gonadorelin agonist" as used herein includes, but
is not limited to abarelix, goserelin and goserelin acetate.
Goserelin is disclosed in U.S. Pat. No. 4,100,274 and can be
administered, e.g., in the form as it is marketed, e.g. under the
trademark ZOLADEX.TM.. Abarelix can be Formulated, e.g. as
disclosed in U.S. Pat. No. 5,843,901.
[0580] The term "anti-androgens" as used herein includes, but is
not limited to bicalutamide (CASODEX.TM.), which can be Formulated,
e.g. as disclosed in U.S. Pat. No. 4,636,505.
[0581] The term "bengamides" relates to bengamides and derivatives
thereof having aniproliferative properties.
[0582] The term "bisphosphonates" as used herein includes, but is
not limited to etridonic acid, clodronic acid, tiludronic acid,
pamidronic acid, alendronic acid, ibandronic acid, risedronic acid
and zoledronic acid. "Etridonic acid" can be administered, e.g., in
the form as it is marketed, e.g. under the trademark DIDRONEL.TM..
"Clodronic acid" can be administered, e.g., in the form as it is
marketed, e.g. under the trademark BONEFOS.TM.. "Tiludronic acid"
can be administered, e.g., in the form as it is marketed, e.g.
under the trademark SKELID.TM.. "Pamidronic acid" can be
administered, e.g., in the form as it is marketed, e.g. under the
trademark AREDIA.TM.. "Alendronic acid" can be administered, e.g.,
in the form as it is marketed, e.g. under the trademark
FOSAMAX.TM.. "Ibandronic acid" can be administered, e.g., in the
form as it is marketed, e.g. under the trademark BONDRANAT.TM..
"Risedronic acid" can be administered, e.g., in the form as it is
marketed, e.g. under the trademark ACTONEL.TM.. "Zoledronic acid"
can be administered, e.g., in the form as it is marketed, e.g.
under the trademark ZOMETA.TM..
[0583] The term "antiproliferative antibodies" as used herein
includes, but is not limited to trastuzumab (Herceptin.TM.),
Trastuzumab-DM1, erlotinib (Tarceva.TM.), bevacizumab
(Avastin.TM.), rituximab (Rituxan.RTM.), PRO64553 (anti-CD40) and
2C4 Antibody.
[0584] For the treatment of acute myeloid leukemia (AML), compounds
of Formula (I) (or exemplary formula thereof) can be used in
combination with standard leukemia therapies, especially in
combination with therapies used for the treatment of AML. In
particular, compounds of Formula (I) (or exemplary formula thereof)
can be administered in combination with e.g. farnesyltransferase
inhibitors and/or other drugs useful for the treatment of AML, such
as Daunorubicin, Adriamycin, Ara-C, VP-16, Teniposide,
Mitoxantrone, Idarubicin, Carboplatinum and PKC412.
[0585] The structure of the active agents identified by code nos.,
generic or trade names may be taken from the actual edition of the
standard compendium "The Merck Index" or from databases, e.g.
Patents International (e.g. IMS World Publications).
[0586] The above-mentioned compounds, which can be used in
combination with a compound of the Formula (I) (or exemplary
formula thereof), can be prepared and administered as described in
the art such as in the documents cited above.
General Process Conditions
[0587] All process steps described here can be carried out under
known reaction conditions, preferably under those specifically
mentioned, in the absence of or usually in the presence of solvents
or diluents, preferably such as are inert to the reagents used and
able to dissolve these, in the absence or presence of catalysts,
condensing agents or neutralising agents, for example ion
exchangers, typically cation exchangers, for example in the H.sup.+
form, depending on the type of reaction and/or reactants at
reduced, normal, or elevated temperature, for example in the range
from -100.degree. C. to about 190.degree. C., preferably from about
-80.degree. C. to about 150.degree. C., for example at -80 to
-60.degree. C., at room temperature, at -20 to 40.degree. C. or at
the boiling point of the solvent used, under atmospheric pressure
or in a closed vessel, where appropriate under pressure, and/or in
an inert atmosphere, for example under argon or nitrogen.
[0588] It should be emphasized that reactions analogous to the
conversions mentioned in this chapter may also take place at the
level of appropriate intermediates.
DETAILED DESCRIPTION OF THE PROCESS
[0589] The heteroaryl aryl ureas of the present invention may be
prepared according to methods known in the art.
[0590] According to a general exemplary process, compounds of
having the structure of general formula (I), may be prepared by
reacting a heteroaryl amine of general Formula (VIII) with an aryl
isocyanate of general Formula (IX):
##STR00047##
[0591] The reaction may for example be carried out in an aprotic
solvent, such as toluene, for example. An exemplary procedure is
shown below:
##STR00048##
[0592] A preferred embodiment is as follows:
##STR00049##
[0593] According to a general exemplary process, compounds of
having the structure of general formula (I*), may be prepared by
reacting a heteroaryl amine of general Formula (VIIIp) with an aryl
isocyanate of general Formula (IXp):
##STR00050##
[0594] The reaction may for example be carried out in an aprotic
solvent, such as toluene, for example. An exemplary procedure is
shown below:
##STR00051##
[0595] A preferred embodiment is as follows:
##STR00052##
Additional Process Steps
[0596] In the additional process steps, carried out as desired,
functional groups of the starting compounds which should not take
part in the reaction may be present in unprotected form or may be
protected for example by one or more of the protecting groups
mentioned hereinabove under "protecting groups". The protecting
groups are then wholly or partly removed according to one of the
methods described there.
[0597] Salts of a compound of Formula (I) (or exemplary formula
thereof) with a salt-forming group may be prepared in a manner
known per se. Acid addition salts of compounds of Formula (I) (or
exemplary formula thereof) may thus be obtained by treatment with
an acid or with a suitable anion exchange reagent.
[0598] Salts can usually be converted to free compounds, e.g. by
treating with suitable basic agents, for example with alkali metal
carbonates, alkali metal hydrogencarbonates, or alkali metal
hydroxides, typically potassium carbonate or sodium hydroxide.
[0599] Stereoisomeric mixtures, e.g. mixtures of diastereomers, can
be separated into their corresponding isomers in a manner known per
se by means of suitable separation methods. Diastereomeric mixtures
for example may be separated into their individual diastereomers by
means of fractionated crystallization, chromatography, solvent
distribution, and similar procedures. This separation may take
place either at the level of a starting compound or in a compound
of Formula (I) (or exemplary formula thereof) itself. Enantiomers
may be separated through the formation of diastereomeric salts, for
example by salt formation with an enantiomer-pure chiral acid, or
by means of chromatography, for example by HPLC, using
chromatographic substrates with chiral ligands.
[0600] A compound of the invention, where hydrogen is present, can
be converted to the respective compound wherein R.sup.3 or R.sup.z
is lower alkyl by reaction e.g. with a diazo lower alkyl compound,
especially diazomethane, in an inert solvent, preferably in the
presence of a noble metal catalyst, especially in dispersed form,
e.g. copper, or a noble metal salt, e.g. copper(I)-chloride or
copper(II)-sulfate. Also reaction with lower alkylhalogenides is
possible, or with other leaving group carrying lower alkanes, e.g.
lower alkyl alcohols esterified by a strong organic sulfonic acid,
such as a lower alkanesulfonic acid (optionally substituted by
halogen, such as fluoro), an aromatic sulfonic acid, for example
unsubstituted or substituted benzenesulfonic acid, the substituents
preferably being selected from lower alkyl, such as methyl,
halogen, such as bromo, and/or nitro, e.g. esterified by
methanesulfonic acid, or p-toluene sulfonic acid. The alkylation
takes place under usual conditions for alkylation of amides,
especially in aqueous solution and/or in the presence of polar
solvents, typically alcohols, for example methanol, ethanol,
isopropanol, or ethylene glycol, or dipolar aprotic solvents, e.g.
tetrahydrofuran, dioxane, or dimethylformamide, where applicable in
the presence of acidic or basic catalysts, generally at
temperatures from about 0.degree. C. to the boiling temperature of
the corresponding reaction mixture, preferably between 20.degree.
C. and reflux temperature, if necessary under increased pressure,
e.g. in a sealed tube, and/or under inert gas, typically nitrogen
or argon.
[0601] Salts may be present in all starting compounds and
transients, if these contain salt-forming groups. Salts may also be
present during the reaction of such compounds, provided the
reaction is not thereby disturbed.
[0602] At all reaction stages, isomeric mixtures that occur can be
separated into their individual isomers, e.g. diastereomers or
enantiomers, or into any mixtures of isomers, e.g. racemates or
diastereomeric mixtures.
[0603] The invention relates also to those forms of the process in
which one starts from a compound obtainable at any stage as a
transient and carries out the missing steps, or breaks off the
process at any stage, or forms a starting material under the
reaction conditions, or uses said starting material in the form of
a reactive derivative or salt, or produces a compound obtainable by
means of the process according to the invention and processes the
said compound in situ. In the preferred embodiment, one starts from
those starting materials which lead to the compounds described
hereinabove as preferred, particularly as especially preferred,
primarily preferred, and/or preferred above all.
[0604] In the preferred embodiment, a compound of Formula (I) (or
exemplary formula thereof) is prepared according to or in analogy
to the processes and process steps defined in the Examples.
[0605] The compounds of Formula (I) (or exemplary formula thereof),
including their salts, are also obtainable in the form of hydrates,
or their crystals can include for example the solvent used for
crystallization (present as solvates).
EXAMPLES
[0606] The following Examples serve to illustrate the invention
without limiting the scope thereof.
[0607] Temperatures are measured in degrees Celsius. Unless
otherwise indicated, the reactions take place at room temperature
under N.sub.z-atmosphere.
[0608] The R.sub.f values which indicate the ratio of the distance
moved by each substance to the distance moved by the eluent front
are determined on silica gel thin-layer plates (Merck, Darmstadt,
Germany) by thin-layer chromatography using the respective named
solvent systems.
##STR00053##
[0609] Most respective anilines are described in WO 03/099771 or
can be prepared analogously to the therein exemplified derivatives.
All others are described elsewhere.
##STR00054##
HPLC Conditions
[0610] Gradient A: Performed on a Waters system equipped with a CTC
Analytics HTS PAL autosampler, 515 pumps, and a 996 DAD detector
operating at 210 nm. Column: CC70/3 Nucleosil 100-3 C.sub.18
(3.mu., 70.times.3 mm, Macherey-Nagel, order #721791.30),
temperature: 45.degree. C., flow: 1.2 mL min.sup.-1. Eluents: A:
Water+0.2% H.sub.3PO.sub.4 (85%, (Merck 100552)+2% Me.sub.4NOH,
(10%, Merck 108123), B: Acetonitrile+20% water+0.1% H3PO.sub.4
(85%)+1% Me.sub.4NOH (10%). Gradient: 0% B to 95% B within 6.6
min., then 95% B 4.4 min.
[0611] Gradient B: Linear gradient 20-100% CH.sub.3CN (0.1% TFA)
and H.sub.2O (0.1% TFA) in 7 min+2 min 100% CH.sub.3CN (0.1% TFA);
detection at 215 nm, flow rate 1 mL/min at 30.degree. C. Column:
Nucleosil 100-3 C18 (125.times.4.0 mm).
[0612] Gradient C: Column: (50.times.4.6 mm) packed with
reversed-phase material C18-Nucleosil (Interchrom UP30 DB-5QS,
Optisphere 3 .mu.M ODB). Detection by UV absorption at 215 nm. The
retention times (t.sub.R) are given in minutes. Flow rate: 2
ml/min. Gradient: 20% 100% a) in b) for 14 min+5 min 100% a). a):
Acetonitrile+0.1% TFA; b): water+0.1% TFA.
[0613] Gradient D: Column: (50.times.4.6 mm) packed with
reversed-phase material C18-Nucleosil (Interchrom UP30 DB-5QS,
Optisphere 3 .mu.M ODB). Detection by UV absorption at 215 nm. The
retention times (t.sub.R) are given in minutes. Flow rate: 2
ml/min. Gradient: 15% 100% a) in b) for 2.25 min+1.25 min 100% a).
a): Acetonitrile+0.1% TFA; b): water+0.1% TFA.
[0614] Gradient E: Column: (50.times.4.6 mm) packed with
reversed-phase material C18-Nucleosil (Interchrom UP30 DB-5QS,
Optisphere 3 .mu.M ODB). Detection by UV absorption at 215 nm. The
retention times (t.sub.R) are given in minutes. Flow rate: 2
ml/min.Gradient: 5% 60% a) in b) for 9 min+7 min 60% a). a):
Acetonitrile+0.1% TFA; b): water+0.1% TFA.
[0615] Gradient F: Column: (125.times.4 mm) packed with Nucleosil
100-5 C18 AB. Detection by UV absorption at 215 nm. The retention
times (t.sub.R) are given in minutes. Flow rate: 1.5 ml/min. Linear
gradient: 5%-100% CH.sub.3CN (0.1% TFA) and H.sub.2O (0.1% TFA) in
5 min, then 100% CH.sub.3CN (0.1% TFA) for 1 min.
[0616] Gradient G: Column: (125.times.4 mm) packed with Nucleosil
100-5 C18 AB. Detection by UV absorption at 215 nm. The retention
times (t.sub.R) are given in minutes. Flow rate: 1.5 ml/min. Linear
gradient: 10%-100% CH.sub.3CN (0.1% TFA) and H.sub.2O (0.1% TFA) in
5 min, then 100% CH.sub.3CN (0.1% TFA) for 1 min.
[0617] Gradient H: Column: (125.times.4 mm) packed with Nucleosil
100-5 C18 AB. Detection by UV absorption at 215 nm. The retention
times (t.sub.R) are given in minutes. Flow rate: 1.5 ml/min. Linear
gradient: 30%-100% CH.sub.3CN (0.1% TFA) and H.sub.2O (0.1% TFA) in
5 min, then 100% CH.sub.3CN (0.1% TFA) for 1 min.
[0618] Gradient I: Column: (250.times.4 mm) packed with Nucleosil
100-5 C18 AB. Detection by UV absorption at 215 nm. The retention
times (t.sub.R) are given in minutes. Flow rate: 2 ml/min. Linear
gradient: 2%-100% CH.sub.3CN (0.1% TFA) and H.sub.2O (0.1% TFA) in
10 min, then 100% CH.sub.3CN (0.1% TFA) for 3 min.
[0619] Gradient J: Linear gradient 20-100% CH.sub.3CN in 5 min+1.5
min 100% CH.sub.3CN (0.1% TFA); detection at 215 nm, flow rate 1
ml/min at 30.degree. C. Column: Nucleosil 100-3 C18 (70.times.4.0
mm).
Abbreviations
[0620] Ac=Acetyl [0621] AcCN=Acetonitrile [0622] Anal. elemental
analysis (for indicated atoms, difference between calculated and
measured value .ltoreq.0.4%) [0623] Brine=saturated aqueous
solution of sodium chloride conc. concentrated [0624] d day(s)
[0625] DCM=Dichloromethane [0626] DIPE diisopropyl-ether [0627]
DIPEA=N,N-Diisopropylethylamine [0628] DMAP dimethylaminopyridine
[0629] DMEU 1,3-dimethyl-2-imidazolidinone [0630] DMF dimethyl
formamide [0631] DMSO=Dimethylsulfoxide [0632] EE=Ethyl acetate
[0633] ESI-MS=Electro-spray ionization mass spectroscopy [0634]
Ether diethylether [0635] EtOAc ethyl acetate [0636] EtOH=Ethanol
[0637] Et.sub.3N triethylamine [0638] Ex. Example [0639] h hour(s)
[0640] HATU=O-(7-Azobenzotriazol-1-yl)-1,1,3,3-tetramethyluronium
hexafluorophosphate [0641] HPLC=High performance liquid
chromatography [0642] Hx=Hexanes [0643] L litre(s) [0644] Me methyl
[0645] MeOH=Methanol [0646] min minute(s) [0647] m.p.=Melting point
[0648] MPLC medium pressure liquid chromatography [0649] Combi
Flash system: normal phase SiO.sub.2 [0650] Gilson system: reversed
phase Nucleosil C18 (H.sub.2O/CH.sub.3CN+TFA), generally product
obtained as free base after neutralization with NaHCO.sub.3 [0651]
MS mass spectrum [0652] NEt.sub.3 triethylamine [0653]
NMP=N-methyl-pyrrolidinone [0654] NMR=Nuclear magnetic resonance
spectroscopy [0655]
Pd(PhCN).sub.2Cl.sub.2=Bis(benzonitrile)palladium (II) chloride
[0656] R.sub.f=Retention factor (TLC) [0657] RT=Room temperature
[0658] sat. saturated [0659] TBME=tert.-Butyl methyl ether [0660]
TFA=Trifluoroacetic acid [0661] THF=Tetrahydrofuran [0662] TLC=Thin
layer chromatography [0663] t.sub.R=Retention time (HPLC) [0664]
triphosgene bis(trichloromethyl) carbonate
PREPARATIONS
Preparation 1
2,6-Dichloro-3-methoxyisocyanate
[0665] To a solution of 2,6-dichloro-3-methoxyaniline (0.25 g, 1.30
mmol, 1.0 eq.) in dioxane (7.5 ml) is added a 20% phosgene solution
in toluene (0.69 ml, 1.30 mmol, 1.0 eq.) via a hypodermic syringe.
The light brown reaction mixture is stirred under nitrogen at room
temperature over night. The obtained clear solution is high vacuum
evaporated using a rotary evaporator at 45.degree. C. bath
temperature to afford a brown oil that solidifies upon standing:
400 MHz .sup.1H-NMR (CDCl.sub.3) .delta.: 3.90 (s, 3H, OMe), 6.72
(d, 1H, Ar--H4), 7.27 (d, 1H, Ar--H5).
2,6-Dichloro-3-methoxyaniline
[0666] To a solution of 2,4-dichloro-3-aminophenol hydrochloride
(GLSynthesis, 7.70 g, 35.9 mmol, 1.0 eq.) in acetone is added
powdered potassium hydroxide 85% (9.48 g, 143.6 mmol, 4.0 eq.) in
small portions. Then, dimethyl sulfate (5.13 ml, 53.9 mmol, 1.5
eq.) is added at such a rate that the internal temperature does not
rise above 30.degree. C. After 1 h stirring at room temperature
water (50 ml) is added and stirring is continued for another hour.
The solvent is evaporated and the residue is distributed between
ethyl acetate (150 ml) and water (100 ml). The organic layer is
isolated, dried over Na.sub.2SO.sub.4 and evaporated to give a
yellow oil. Kugelrohr distillation affords the desired product as a
colorless oil: b.p. 150.degree. C./0.3 mbar, HPLC: t.sub.R=5.61 min
(purity: 90%, gradient A), 400 MHz .sup.1H-NMR (CDCl.sub.3)
.delta.: 3.87 (s, 3H, OMe), 4.49 (br s, 2H, NH.sub.2), 6.30 (d, 1H,
Ar--H4), 7.11 (d, 1H, Ar--H5).
Preparation 2: 2,6-Dichloro-3,5-dimethoxyaniline
[0667] To a solution of N-(2-chloro-3,5-dimethoxy-phenyl)-acetamide
(6.72 g, 25.4 mmol) in ethanol (400 ml) is added 3M KOH (134 ml).
Then, the reaction mixture is refluxed for 90 h. After cooling
water (270 ml) is added dropwise with vigorous stirring. The
precipitate formed is filtered off, washed (1.times. EtOH/water
1:1, 50 ml, 1.times. water, 100 ml), and vacuum dried at 50.degree.
C. overnight. The title compound was obtained as colorless
crystals: HPLC: t.sub.R=5.43 min (purity: >99%, gradient A),
ESI-MS: 221.9/223.9/225.8 [MH].sup.+, 400 MHz .sup.1H-NMR
(CDCl.sub.3) .delta.: 3.89 (s, 6H, 2.times.OMe), 4.56 (br s, 2H,
NH.sub.2), 6.03 (s, 1H, Ar--H4).
N-(2-chloro-3,5-dimethoxy-phenyl)-acetamide
[0668] Sulfurylchloride (26.9 ml, 325 mmol, 1.93 eq.) is added (in
7 min) to a cold (0.degree. C.) suspension of
N-(3,5-dimethoxyphenyl)-acetamide (32.9 g, 169 mmol) in AcCN (500
ml), under an inert atmosphere. The resulting yellowish is allowed
to stir 30 min and quenched by dropwise addition of a saturated
aqueous solution of sodium bicarbonate (250 ml). The resulting
precipitate is collected by vacuum filtration, washed with water
(300 ml) and dried to afford 20 g of the desired product (batch 1).
The filtrate is diluted with a saturated aqueous solution of sodium
bicarbonate (300 ml) and extracted with EE (2.times.300 ml). The
organic phase is washed with water and brine, dried (sodium
sulphate), filtered and concentrated. The residue is purified by
silica gel column chromatography (EE/Hx, 1:1.fwdarw.2:1) to provide
8.8 g of product (batch 2). Batch 1 and 2 are combined and stirred
in hexane. The solid is collected by filtration, washed with hexane
and dried to afford 25.8 g of the title compound as a white solid.
ESI-MS: 264.0/266.0 [MH].sup.+.
Preparation 3:
N-(3-Amino-4-methyl-phenyl)-3-trifluoromethyl-benzamide
[0669] A suspension of
N-(4-methyl-3-nitro-phenyl)-3-trifluoromethyl-benzamide (9.91 g,
30.6 mmol) and 10% palladium on charcoal (990 mg) in ethanol (180
ml) is hydrogenated at atmospheric pressure and room temperature.
After 2 h the reaction is complete, the catalyst is removed by
filtration through Celite, and the filtrate is evaporated to
dryness. Recrystallization of the crude product from ethyl
acetate/hexanes followed by vacuum drying at 45.degree. C.
overnight affords the title compound as fluffy light grey needles:
HPLC: t.sub.R=5.38 min (purity: >99%, gradient A), ESI-MS: 295.3
[MH].sup.+
N-(4-methyl-3-nitro-phenyl)-3-trifluoromethyl-benzamide
[0670] To a solution of 4-methyl-3-nitroaniline (5 g, 32.2 mmol,
1.0 eq.) and triethylamine (5.38 ml, 38.6 mmol, 1.2 eq.) in
dichloromethane (100 ml) is added a solution of
3-tri-fluoromethylbenzoyl chloride 33.8 mmol, 1.05 eq.) within 30
min. The suspension formed is stirred for 1 h at room temperature.
Then, the reaction mixture is diluted with dichloromethane (800 ml)
and extracted with water (100 ml), 2M aqueous Na.sub.2CO.sub.3 (100
ml), 2M HCl (100 ml), water (100 ml). The organic layer is dried
over Na.sub.2SO.sub.4, evaporated to a volume of about 100 ml and
diluted with hexanes (100 ml). The precipitate is filtered off,
washed with hexanes /dichloromethane 1:1 and hexanes. Vacuum drying
over night at room temperatures gives light yellow fine needles:
HPLC: t.sub.R=6.72 min (purity: >99%, gradient A), ESI-MS: 325.2
[MH].sup.+
Preparation 4
4-(4-Methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-benzoic
acid
[0671] To a solution of ethyl
4-(4-methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-benzoate (7.23
g, 21.1 mmol, 1.0 eq.) in ethanol (40 ml) is added 1M NaOH (30.6
ml, 30.6 mmol, 1.4 eq.). After stirring for 2 h at room temperature
a clear pale yellow solution is obtained. The mixture is evaporated
to a volume of 30 ml. Then, the solution is adjusted to pH 7 by
addition of 1M HCl and the solvent is stripped off. The residue is
taken up three times in toluene (70 ml) and evaporated. The crude
material is dissolved in ethanol/THF 1:9 (150 ml), filtered,
evaporated, triturated with ethyl acetate, and vacuum dried at
60.degree. C. over night to afford a beige powder: HPLC:
t.sub.R=3.61 min (purity: >99%, gradient A), ESI-MS: 303.3
[MH].sup.+
Ethyl
4-(4-methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-benzoate
[0672] To a solution of N-methylpiperazine (5.8 g, 57.9 mmol, 1.0
eq.) in tetrahydrofuran (225 ml) containing anhydrous finely ground
potassium carbonate (10.4 g, 75.2 mmol, 1.3 eq.) is added a
solution of ethyl 4-bromomethyl-3-trifluoromethylbenzoate (18.0 g,
57.9 mmol, 1.0 eq.) in tetrahydrofuran with vigorous mechanical
stirring within 20 min. Stirring is continued at room temperature
for 20 h. The obtained suspension is filtered, and the filtrate is
evaporated to give a brown oil. The crude product is purified by
medium pressure chromatography (290 g silica gel, gradient: TBME to
EtOH/TBME 1:4 within 30 min, then 25% NH.sub.3/EtOH/TBME 1:19:80
for 60 min). The fractions containing the title compound are pooled
and evaporated to afford a yellow oil: HPLC: t.sub.R=4.75 min
(purity: >99%, gradient A), ESI-MS: 331.4 [MH].sup.+.
Ethyl 4-bromomethyl-3-trifluoromethyl-benzoate
[0673] A mixture of ethyl 4-methyl-3-trifluoromethylbenzoate (25.19
g, 108.5 mmol, 1.0 eq.), N-bromosuccinimide (19.94 g, 112.02 mmol,
1.03 eq.) and benzoyl peroxide (0.21 g, 0.83 mmol, 0.75 mol %) is
heated to reflux and illuminated by a 100 W daylight lamp for 7 h.
After cooling to room temperature the formed succinimide is
filtered off. The filtrate is evaporated to dryness giving a yellow
oil. Flash chromatography (TBME/hexanes) gives a colorless oil that
solidifies upon standing: HPLC: t.sub.R=7.17 min (purity: 97%,
gradient A), TLC: R.sub.f=0.30 (TBME/hexanes 1:9).
Ethyl 4-methyl-3-trifluoromethylbenzoate
[0674] A solution of commercially available
4-methyl-3-trifluoromethylbenzoic acid (24.5 g, 120 mmol) and conc.
sulfuric acid (6.5 ml) in dry ethanol (245 ml) is refluxed for 23
h. After reaching room temperature the solvent is evaporated and
the residue is neutralized by addition of saturated aqueous
NaHCO.sub.3 solution. The mixture is extracted with ethyl acetate
(3.times.40 ml). The organic extracts are combined, dried over
Na.sub.2SO.sub.4 and evaporated to dryness to afford a pale yellow
oil: HPLC: t.sub.R=7.15 min (purity: >96%, gradient A), ESI-MS:
233.3 [MH].sup.+.
Example 1
3-(2,6-Dichloro-3-methoxy-phenyl)-1-methyl-1-(6-[4-(4-methyl-piperazin-1-y-
l)-phenylamino]-pyrimidin-4-yl)-urea
##STR00055##
[0676] To a solution of 2,6-dichloro-3-methoxyphenylisocyanate
(preparation 1, 52.3 mg, 0.24 mmol, 1.2 eq.) in toluene (2.5 ml) is
added
N-methyl-N'-[4-(4-methyl-piperazin-1-yl)-phenyl]-pyrimidine-4,6-diamine
(59.7 mg, 0.2 mmol, 1.0 eq.). The obtained suspension is stirred
under argon at 110.degree. C. for 17 h. After cooling the crude
product is filtered off and purified by flash chromatography (100%
DCM to 5% MeOH in DCM within 35 min). Fractions containing the
product are pooled and evaporated to dryness. The residue is
triturated with ether (2 ml) and treated with ultra sound until a
homogeneous suspension is obtained. The precipitate is filtered off
and vacuum dried at 60.degree. C. over night to afford the title
compound as a colorless powder: m.p. 161.5-163.degree. C., HPLC:
t.sub.R=5.07 min (purity: >99%, gradient A), ESI-MS:
516.6/518.5/520.4 [MH].sup.+.
N-Methyl-N'-[4-(4-methyl-piperazin-1-yl)-phenyl]-pyrimidine-4,6-diamine
[0677] A solution of (6-chloro-pyrimidin-4-yl)-methyl-amine (1.65
g, 11.5 mmol, 1.1 eq.) and commercially available
4-(4-methylpiperazin-1-yl)-aniline (2.0 g, 10.5 mmol, 1.0 eq.) in a
mixture of water (4 ml) and glacial acetic acid (16 ml) is heated
to 100.degree. C. internal temperature for 16 h. After cooling the
solvent is evaporated.
[0678] The residue is taken up in methanol (50 ml) and made
alkaline by addition of 25% NH.sub.3 in water. To this silica gel
(11 g) is added and the solvent is evaporated. The silica adsorbed
crude product is purified by medium pressure liquid chromatography
(A: TBME; B: MeOH--NH.sub.3 99:1; gradient: 5% B->25% B in 180
min). The fractions containing the product are pooled and
evaporated to dryness. The residue is triturated with ether. The
product is filtered off, washed with ether, and vacuum dried at
50.degree. C. over night to give the title compound as pale yellow
powder: t.sub.R=3.04 min (purity: 97%, gradient A), ESI-MS: 299.3
[MH].sup.+.
(6-chloro-pyrimidin-4-yl)-methyl-amine
[0679] This material was prepared by a modified procedure published
in the literature (J. Appl. Chem. 1955, 5, 358): To a suspension of
commercially available 4,6-dichloropyrimidine (20 g, 131.6 mmol,
1.0 eq.) in isopropanol (60 ml) is added 33% methylamine in ethanol
(40.1 ml, 328.9 mmol, 2.5 eq.) at such a rate that the internal
temperature does not rise above 50.degree. C. After completion of
the addition the reaction mixture was stirred for 1 h at room
temperature. Then, water (50 ml) is added and the suspension formed
is chilled in an ice bath to 5.degree. C. The precipitated product
is filtered off, washed with cold isopropanol/water 2:1 (45 ml) and
water. The collected material is vacuum dried over night at
45.degree. C. to afford the title compound as colorless powder:
t.sub.R=3.57 min (purity: >99%, gradient A), ESI-MS: 144.3
/146.2 [MH].sup.+.
Example 2
3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-methyl-1-{6-[4-(4-methyl-piperazin-
-1-yl)-phenylamino]-pyrimidin-4-yl}-urea
##STR00056##
[0681] To a solution of 2,6-dichloro-3,5-dimethoxyaniline
(preparation 2, 74 mg, 0.34 mmol, 1.25 eq.) in dioxane is added 20%
phosgene solution in toluene (191 .mu.l, 0.36 mmol, 1.35 eq.) under
argon. The reaction mixture is stirred for further 6 h at room
temperature under argon. Then, the solvent is evaporated and the
colorless crystalline residue is taken up in dry toluene (2.5 ml).
After the addition of
N-methyl-N'-[4-(4-methyl-piperazin-1-yl)-phenyl]-pyrimidine-4,6-diamine
(see example 1, 80 mg, 0.27 mmol, 1.0 eq.) the suspension is
stirred at 70.degree. C. for 36 h under argon. After cooling the
precipitate is filtered off, washed with toluene, methanol/ether
1:1, and ether to give a beige powder. The crude product is
purified by flash chromatography (1% MeOH in DCM to 16% MeOH in DCM
within 30 min). The fractions containing the product are pooled,
evaporated, and triturated with ether. The precipitate is filtered
off, washed (1.times. cold methanol/ether 1:1, 1.times. ether), and
vacuum dried at 45.degree. C. over night to afford the title
compound as colorless powder: m.p. 221.degree. C. (dec.), ESI-MS:
546.1/548.0/550.0 [MH].sup.+.
[0682] By following the procedures of Examples 1 and 2 but using
the appropriate starting materials, examples 3--may be
prepared:
Example 3
3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-methyl-1-{6-[3-(4-methyl-piperazin-
-1-4-phenylamino]-pyrimidin-4-yl}-urea
##STR00057##
[0684] Colorless powder, m.p. 157-160.degree. C., ESI-MS:
546.1/547.8/549.9 [MH].sup.+.
Example 4
1-(2,6-Dichloro-phenyl)-3-{6-(4-(4-methyl-piperazin-1-yl)-phenylamino]-pyr-
imidin-4-yl}-urea
##STR00058##
[0686] Colorless powder, HPLC: t.sub.R=3.84 min (purity: >99%,
gradient B), ESI-MS: 472/474/476 [MH].sup.+.
Example 5
1-(2,6-Dichloro-phenyl)-3-{6-[3-(4-methyl-piperazin-1-yl)-phenylamino]-pyr-
imidin-4-yl}-urea
##STR00059##
[0688] Beige powder, m.p. 209-212.degree. C., TLC: R.sub.f=0.36
(DCM/MeOH/25% NH.sub.3 350:50:1), ESI-MS: 472/474/476
[MH].sup.+.
Example 6
1-(2-Chloro-6-methyl-phenyl)-3-{6-[4-(4-methyl-piperazin-1-yl)-phenyl-amin-
o]-pyrimidin-4-yl}-urea
##STR00060##
[0690] Colorless powder, TLC: R.sub.f=0.41 (DCM/MeOH/25% NH.sub.3
350:50:1), HPLC: t.sub.R=10.39 min (purity: 98%, Gradient C),
ESI-MS: 452/454 [MH].sup.+.
Example 7
1-(2-Chloro-6-methyl-phenyl)-3-(6-[3-(4-methyl-piperazin-1-yl)-phenyl-amin-
o]-pyrimidin-4-yl}-urea
##STR00061##
[0692] Colorless powder, TLC: R.sub.f=0.29 (DCM/MeOH/25% NH.sub.3
350:50:1), HPLC: t.sub.R=7.91 min (purity: 99%, Gradient C),
ESI-MS: 452/454 [MH].sup.+.
Example 8
1-(3-Methoxy-phenyl)-3-{6-[4-(4-methyl-Piperazin-1-yl)-phenylamino]-pyrimi-
din-4-yl}-urea
##STR00062##
[0694] Beige powder, HPLC: t.sub.R=4.52 min (purity: >99%,
gradient A), ESI-MS: 434.4 [MH].sup.+.
Example 9
1-(3-Methoxy-phenyl)-3-{6-[3-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimi-
din-4-yl}-urea
##STR00063##
[0696] Colorless powder, TLC: R.sub.f=0.20 (TBME/MeOH/NH.sub.3
90:9:1), HPLC: t.sub.R=4.67 min (purity: >99%, gradient A),
ESI-MS: 434.4 [MH].sup.+.
Example 10
1-(3,5-Dichloro-phenyl)-3-{6-[4-(4-methyl-piperazin-1-yl)-phenylamino]-pyr-
imidin-4-yl}-urea
##STR00064##
[0698] Colorless powder, HPLC: t.sub.R=5.62 min (purity: >99%,
gradient A), ESI-MS: 472.3/474.2 [MH].sup.+.
Example 11
1-(3,5-Dichloro-phenyl)-3-{6-[3-(4-methyl-piperazin-1-yl)-phenylamino]-pyr-
imidin-4-yl}-urea
##STR00065##
[0700] Colorless powder, HPLC: t.sub.R=5.71 min (purity: >99%,
gradient A), ESI-MS: 472.4/474.2 [MH].sup.+.
Example 12
1-(2,5-Dimethoxy-phenyl)-3-{6-[4-(4-methyl-piperazin-1-yl)-phenyl-amino]-p-
yrimidin-4-yl}-urea
##STR00066##
[0702] Colorless powder, TLC: R.sub.f=0.44 (TBME/MeOH/NH3 80:18:2),
HPLC: t.sub.R=4.76 min (purity: 90%, gradient A), ESI-MS: 464.4
[MH].sup.+.
Example 13
1-(2,5-Dimethoxy-phenyl)-3-{6-[3-(4-methyl-piperazin-1-yl)-phenyl-amino]-p-
yrimidin-4-yl}-urea
##STR00067##
[0704] Colorless powder, TLC: R.sub.f=0.27 (TBME/MeOH/NH.sub.3
80:18:2), HPLC: t.sub.R=4.90 min (purity: >99%, gradient A),
ESI-MS: 464.4 [MH].sup.+.
Example 14
1-{6-[4-(4-Methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-3-(3,4,5-tr-
imethoxy-phenyl)-urea
##STR00068##
[0706] Colorless powder, TLC: Rf=0.30 (TBME/MeOH/NH3 80:18:2),
HPLC: t.sub.R=4.36 min (purity: >99%, gradient A), ESI-MS: 494.5
[MH].sup.+.
Example 15
1-{6-[3-(4-Methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-3-(3,4,5-tr-
imethoxy-phenyl)-urea
##STR00069##
[0708] Colorless powder, HPLC: t.sub.R=4.72 min (purity: >99%,
gradient A), ESI-MS: 494.5 [MH].sup.+.
Example 16
1-(2,4-Dimethoxy-phenyl)-3-{6-[4-(4-methyl-piperazin-1-yl)-phenyl-amino]-p-
yrimidin-4-yl}-urea
##STR00070##
[0710] Colorless powder, TLC: Rf=0.24 (TBME/MeOH/NH3 80:18:2),
HPLC: t.sub.R=4.60 min (purity: >99%, gradient A), ESI-MS: 464.4
[MH].sup.+.
Example 17
1-(2,4-Dimethoxy-phenyl)-3-{6-[2-(4-methyl-piperazin-1-yl)-phenyl-amino]-p-
yrimidin-4-yl}-urea
##STR00071##
[0712] Colorless powder, HPLC: t.sub.R=4.75 min (purity: >95%,
gradient A), ESI-MS: 464.4 [MH].sup.+.
Example 18
1-(3,5-Dimethoxy-phenyl)-3-{6-[4-(4-methyl-piperazin-1-yl)-phenyl-amino]-p-
yrimidin-4-yl}-urea
##STR00072##
[0714] Colorless powder, TLC: Rf=0.19 (TBME/MeOH/NH3 80:18:2),
HPLC: t.sub.R=4.66 min (purity: >99%, gradient A), ESI-MS: 464.4
[MH].sup.+.
Example 19
1-(3,5-Dimethoxy-phenyl)-3-{6-[3-(4-methyl-piperazin-1-yl)-phenyl-amino]-p-
yrimidin-4-yl}-urea
##STR00073##
[0716] Colorless powder, HPLC: t.sub.R=4.78 min (purity: >99%,
gradient A), ESI-MS: 464.4 [MH].sup.+.
Example 20
1-(3,5-Bis-trifluoromethyl-phenyl)-3-{6-[4-(4-methyl-piperazin-1-yl)-pheny-
lamino]-pyrimidin-4-yl}-urea
##STR00074##
[0718] Colorless powder, HPLC: t.sub.R=5.86 min (purity: >99%,
gradient A), ESI-MS: 540.4 [MH].sup.+.
Example 21
1-(3,5-Bis-trifluoromethyl-phenyl)-3-{6-[3-(4-methyl-piperazin-1-yl)-pheny-
lamino]-pyrimidin-4-yl}-urea
##STR00075##
[0720] Colorless powder, HPLC: t.sub.R=5.98 min (purity: >99%,
gradient A), ESI-MS: 540.3 [MH].sup.+.
Example 22
1-(3,5-Dimethyl-phenyl)-3-{6-[4-(4-methyl-piperazin-1-yl)-phenyl-amino]-py-
rimidin-4-yl}-urea
##STR00076##
[0722] Colorless powder, TLC: R.sub.f=0.69 (TBME/MeOH/NH.sub.3
80:18:2), HPLC: t.sub.R=4.05 min (purity: >99%, gradient A),
ESI-MS: 432.4 [MH].sup.+.
Example 23
1-(3,5-Dimethyl-phenyl)-3-{6-[3-(4-methyl-piperazin-1-yl)-phenyl-amino]-py-
rimidin-4-yl}-urea
##STR00077##
[0724] Colorless powder, TLC: R.sub.f=0.31 (TBME/MeOH/NH.sub.3
90:9:1), HPLC: t.sub.R=5.33 min (purity: >99%, gradient A),
ESI-MS: 432.4 [MH].sup.+.
Example 24
1-(3-Chloro-4-methoxy-phenyl)-3-(6-[4-(4-methyl-piperazin-1-yl)-phenyl-ami-
no]-pyrimidin-4-yl}-urea
##STR00078##
[0726] Colorless powder, TLC: R.sub.f=0.17 (TBME/MeOH/NH3 80:18:2),
HPLC: t.sub.R=4.79 min (purity: >99%, gradient A), ESI-MS:
468.3/470.4 [MH].sup.+.
Example 25
1-(3-Chloro-4-methoxy-phenyl)-3-{6-[3-(4-methyl-piperazin-1-yl)-phenyl-ami-
no]-pyrimidin-4-yl}-urea
##STR00079##
[0728] Colorless powder, TLC: R.sub.f=0.57 (TBME/MeOH/NH.sub.3
90:9:1), HPLC: t.sub.R=4.96 min (purity: >99%, gradient A),
ESI-MS: 468.3/470.3 [MH].sup.+.
Example 26
1-(5-Methoxy-2-methyl-phenyl)-3-{6-[4-(4-methyl-piperazin-1-yl)-phenyl-ami-
no]-pyrimidin-4-yl}-urea
##STR00080##
[0730] Light grey powder, HPLC: t.sub.R=4.87 min (purity: >99%,
gradient A), ESI-MS: 448.4 [MH].sup.+.
Example 27
1-(5-Methoxy-2-methyl-phenyl)-3-{6-[3-(4-methyl-piperazin-1-yl)-phenyl-ami-
no]-pyrimidin-4-yl}-urea
##STR00081##
[0732] Colorless powder, TLC: R.sub.f=0.63 (TBME/MeOH/NH.sub.3
80:18:2), HPLC: t.sub.R=4.95 min (purity: >99%, gradient A),
ESI-MS: 448.5 [MH].sup.+.
Example 28
1-(2-Chloro-5-methoxy-phenyl)-3-{6-[4-(4-methyl-piperazin-1-yl)-phenyl-ami-
no]-pyrimidin-4-yl}-urea
##STR00082##
[0734] Colorless powder, HPLC: t.sub.R=5.35 min (purity: >99%,
gradient A), ESI-MS:468.3/470.4 [MH].sup.+.
Example 29
1-(2-Chloro-5-methoxy-phenyl)-3-{6-[3-(4-methyl-piperazin-1-yl)-phenyl-ami-
no]-pyrimidin-4-yl}-urea
##STR00083##
[0736] Colorless powder, HPLC: t.sub.R=5.33 min (purity: >99%,
gradient A), ESI-MS: 468.4/470.5 [MH].sup.+.
Example 30
1-(3,4-Dimethoxy-phenyl)-3-{6-[4-(4-methyl-piperazin-1-yl)-phenyl-amino]-p-
yrimidin-4-yl}-urea
##STR00084##
[0738] Pale yellow powder, TLC: R.sub.f=0.32 (TBME/MeOH/NH3
80:18:2), HPLC: t.sub.R=5.34 min (purity: 98%, gradient A), ESI-MS:
464.4 [MH].sup.+.
Example 31
1-(3,4-Dimethoxy-phenyl)-3-{6-[3-(4-methyl-piperazin-1-yl)-phenyl-amino]-p-
yrimidin-4-yl}-urea
##STR00085##
[0740] Colorless powder, TLC: R.sub.f=0.36 (TBME/MeOH/NH3 80:18:2),
HPLC: t.sub.R=4.62 min (purity: 98%, gradient A), ESI-MS: 464.4
[MH].sup.+.
Example 32
1-(4-Fluoro-3-methoxy-phenyl)-3-{6-[4-(4-methyl-piperazin-1-yl)-phenyl-ami-
no]-pyrimidin-4-yl}-urea
##STR00086##
[0742] Colorless powder, TLC: R.sub.f=0.63 (TBME/MeOH/NH3 70:27:3),
HPLC: t.sub.R=4.58 min (purity: >99%, gradient A), ESI-MS: 452.4
[MH].sup.+.
Example 33
1-(4-Fluoro-3-methoxy-phenyl)-3-{6-[3-(4-methyl-piperazin-1-yl)-phenyl-ami-
no]-pyrimidin-4-yl}-urea
##STR00087##
[0744] Pale yellow powder, TLC: R.sub.f=0.31 (TBME/MeOH/NH3
80:18:2), HPLC: t.sub.R=4.91 min (purity: >99%, gradient A),
ESI-MS: 452.4 [MH].sup.+.
Example 34
1-(4,5-Dimethoxy-2-methyl-phenyl)-3-{6-[4-(4-methyl-piperazin-1-yl)-phenyl-
-amino]-pyrimidin-4-yl}-urea
##STR00088##
[0746] Colorless powder, TLC: R.sub.f=0.27 (TBME/MeOH/NH3 70:27:3),
HPLC: t.sub.R=4.62 min (purity: >99%, gradient A), ESI-MS: 478.4
[MH].sup.+.
Example 35
1-(4,5-Dimethoxy-2-methyl-phenyl)-3-{6-[3-(4-methyl-piperazin-1-yl)-
##STR00089##
[0748] Pale yellow powder, TLC: R.sub.f=0.32 (TBME/MeOH/NH3
80:18:2), HPLC: t.sub.R=4.77 min (purity: >99%, gradient A),
ESI-MS: 478.4 [MH].sup.+.
Example 36
1-(2,6-Dichloro-3-methoxy-phenyl)-3-{6-[4-(4-methyl-piperazin-1-yl)-phenyl-
-amino]-pyrimidin-4-yl}-urea
##STR00090##
[0750] Colorless powder, TLC: R.sub.f=0.30 (DCM/MeOH 80:20), HPLC:
t.sub.R=4.83 min (purity: >100%, gradient A), ESI-MS:
502.6/504.4/506.4 [MH].sup.+.
Example 37
1-(2,6-Dichloro-3-methoxy-phenyl)-3-{6-[3-(2-morpholin-4-yl-ethoxy)-phenyl-
amino]-pyrimidin-4-yl}-urea
##STR00091##
[0752] Pale yellow powder, TLC: R.sub.f=0.63 (DCM/MeOH 80:20),
HPLC: t.sub.R=4.84 min (purity: 89%, gradient A), ESI-MS:
533.6/535.5/537.5 [MH].sup.+.
Example 38
1-(2-Chloro-3,5-dimethoxy-phenyl)-3-(6-methylamino-pyrimidin-4-yl)-urea
##STR00092##
[0754] Colorless powder, TLC: R.sub.f=0.47 (TBME/MeOH/NH3 90:9:1),
HPLC: t.sub.R=5.21 min (purity: >100%, gradient A), ESI-MS:
338.3/340.4 [MH].sup.+.
Example 39
1-(2-Chloro-3,5-dimethoxy-phenyl)-3-(6-phenylamino-pyrimidin-4-yl)-urea
##STR00093##
[0756] Colorless powder, HPLC: t.sub.R=6.60 min (purity: >99%,
gradient A), ESI-MS: 400.4/402.4 [MH].sup.+.
Example 40
1-(2-Chloro-3,5-dimethoxy-phenyl)-3-{6-[4-(4-methyl-piperazin-1-yl)-phenyl-
-amino]-pyrimidin-4-yl}-urea
##STR00094##
[0758] Colorless powder, TLC: R.sub.f=0.52 (TBME/MeOH/NH3 80:18:2),
HPLC: t.sub.R=5.27 min (purity: >99%, gradient A), ESI-MS:
498.4/500.2 [MH].sup.+.
Example 41
1-(2-Chloro-3,5-dimethoxy-2-methyl-phenyl)-3-{6-[3-(4-methyl-piperazin-1-y-
l)-phenyl-amino]-pyrimidin-4-yl}-urea
##STR00095##
[0760] Colorless powder, TLC: R.sub.f=0.47 (TBME/MeOH/NH3 80:18:2),
HPLC: t.sub.R=5.29 min (purity: >99%, gradient A), ESI-MS:
498.4/500.3 [MH].sup.+.
Example 42
1-(2-Chloro-3,5-dimethoxy-phenyl)-3-{6-[4-(2-diethylamino-ethoxy)-phenylam-
ino]-pyrimidin-4-yl}-urea
##STR00096##
[0762] Colorless powder, TLC: R.sub.f=0.60 (TBME/MeOH/NH3 80:18:2),
HPLC: t.sub.R=5.49 min (purity: >99%, gradient A), ESI-MS:
515.5/517.4 [MH].sup.+.
Example 43
1-(2-Chloro-3,5-dimethoxy-phenyl)-3-{6-[3-(2-dimethylamino-ethoxy)-phenyla-
mino]-pyrimidin-4-yl}-urea
##STR00097##
[0764] Colorless powder, TLC: R.sub.f=0.20 (TBME/MeOH 30:70), HPLC:
t.sub.R=5.38 min (purity: >99%, gradient A), ESI-MS: 487.4/489.4
[MH].sup.+.
Example 44
1-(2-Chloro-3,5-dimethoxy-phenyl)-3-{6-[4-(2-morpholin-4-yl-ethoxy)-phenyl-
amino]-pyrimidin-4-yl}-urea
##STR00098##
[0766] Colorless powder, HPLC: t.sub.R=5.30 min (purity: 96%,
gradient A), ESI-MS: 529.4/531.3 [MH].sup.+.
Example 45
1-(2-Chloro-3,5-dimethoxy-phenyl)-3-{6-[3-(2-morpholin-4-yl-ethoxy)-phenyl-
amino]-pyrimidin-4-yl}-urea
##STR00099##
[0768] Colorless powder, TLC: R.sub.f=0.40 (TBME/MeOH 75:25), HPLC:
t.sub.R=5.29 min (purity: >99%, gradient A), ESI-MS: 529.4/531.4
[MH].sup.+.
Example 46
3-(2,3-Dimethoxy-phenyl)-1-ethyl-1-{6-[4-(4-methyl-piperazin-1-yl)-phenyla-
mino]-pyrimidin-4-yl}-urea
##STR00100##
[0770] Colorless powder, TLC: R.sub.f=0.57 (DCM/MeOH 85:15), HPLC:
t.sub.R=5.29 min (purity: 98%, gradient A), ESI-MS: 492.2
[MH].sup.+.
Example 47
3-(3,5-Dimethoxy-phenyl)-1-methyl-1-{6-[4-(4-methyl-piperazin-1-yl)-phenyl-
amino]-pyrimidin-4-yl}-urea
##STR00101##
[0772] Pale yellow powder, TLC: R.sub.f=0.38 (TBME/MeOH/NH3
80:18:2), HPLC: t.sub.R=5.13 min (purity: 95%, gradient A), ESI-MS:
478.5 [MH].sup.+.
Example 48
3-(3,5-Dimethoxy-phenyl)-1-methyl-1-{6-[3-(4-methyl-piperazin-1-yl)-phenyl-
amino]-pyrimidin-4-yl}-urea
##STR00102##
[0774] Colorless powder, TLC: R.sub.f=0.48 (TBME/MeOH/NH3 80:18:2),
HPLC: t.sub.R=5.21 min (purity: 95%, gradient A), ESI-MS: 478.4
[MH].sup.+.
Example 49
3-(2-Chloro-3,5-dimethoxy-phenyl)-1-methyl-1-(6-phenylamino-pyrimidin-4-yl-
)-urea
##STR00103##
[0776] Colorless powder, HPLC: t.sub.R=7.38 min (purity: 96%,
gradient A), ESI-MS: 414.5/416.4 [MH].sup.+.
Example 50
3-(2-Chloro-3,5-dimethoxy-phenyl)-1-methyl-1-{6-[4-(4-methyl-piperazin-1-y-
l)-phenylamino]-pyrimidin-4-yl}-urea
##STR00104##
[0778] Colorless powder, HPLC: t.sub.R=5.65 min (purity: 95%,
gradient A), ESI-MS: 512.4/514.3 [MH].
Example 51
3-(2-Chloro-3,5-dimethoxy-phenyl)-1-methyl-1-{6-[3-(4-methyl-piperazin-1-y-
l)-phenylamino]-pyrimidin-4-yl}-urea
##STR00105##
[0780] Colorless powder, TLC: R.sub.f=0.53 (TBME/MeOH/NH3 80:18:2),
HPLC: t.sub.R=5.63 min (purity: >99%, gradient A), ESI-MS:
512.5/514.4 [MH].sup.+.
Example 52
3-(2-Chloro-3,5-dimethoxy-phenyl)-1-methyl-1-{6-[4-(4-methyl-piperazine-1--
carbonyl)-phenylamino]-pyrimidin-4-yl}-urea
##STR00106##
[0782] Colorless powder, TLC: R.sub.f=0.45 (DCM/MeOH 80:20), HPLC:
t.sub.R=5.33 min (purity: 90%, gradient A), ESI-MS: 540.5/542.4
[MH].sup.+.
Example 53
3-(2-Chloro-3,5-dimethoxy-phenyl)-1-{6-[4-(2-diethylamino-ethoxy)-phenylam-
ino]-pyrimidin-4-yl}-1-methyl-urea
##STR00107##
[0784] Colorless powder, TLC: R.sub.f=0.22 (TBME/MeOH 75:25), HPLC:
t.sub.R=5.74 min (purity: >99%, gradient A), ESI-MS: 529.4/531.3
[MH].sup.+.
Example 54
3-(2-Chloro-3,5-dimethoxy-phenyl)-1-{6-[3-(2-dimethylamino-ethoxy)-phenyla-
mino]-pyrimidin-4-yl}-1-methyl-urea
##STR00108##
[0786] Colorless powder, TLC: R.sub.f=0.34 (TBME/MeOH/NH3 80:18:2),
HPLC: t.sub.R=5.57 min (purity: >99%, gradient A), ESI-MS:
501.4/503.3 [MH].sup.+.
Example 55
3-(2-Chloro-3,5-dimethoxy-phenyl)-1-ethyl-1-{6-[4-(4-methyl-piperazin-1-yl-
)-phenylamino]-pyrimidin-4-yl}-urea
##STR00109##
[0788] Colorless powder, TLC: R.sub.f=0.26 (DCM/MeOH 90:10), HPLC:
t.sub.R=5.69 min (purity: >100%, gradient A), ESI-MS:
526.5/528.4 [MH].sup.+.
Example 56
3-(2-Chloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-methyl-piperazin-1-yl)-phenyl-
amino]-pyrimidin-4-yl}-1-thiophen-2-ylmethyl-urea
##STR00110##
[0790] Colorless powder, TLC: R.sub.f=0.36 (DCM/MeOH 90:10), HPLC:
t.sub.R=6.10 min (purity: >100%, gradient A), ESI-MS:
594.5/596.4 [MH].sup.+.
Example 57
3-(2-Chloro-3,5-dimethoxy-phenyl)-1-[2-(4-methyl-piperazin-1-yl)-ethyl]-1--
(6-phenylamino-pyrimidin-4-yl)-urea
##STR00111##
[0792] Colorless powder, TLC: R.sub.f=0.15 (TBME/MeOH 50:50), HPLC:
t.sub.R=5.82 min (purity: >100%, gradient A), ESI-MS:
526.5/528.4 [MH].sup.+.
Example 58
3-(2-Chloro-3,5-dimethoxy-phenyl)-1-(6-phenylamino-pyrimidin-4-yl)-1-(2-py-
ridin-2-yl-ethyl)-urea
##STR00112##
[0794] Colorless powder, HPLC: t.sub.R=7.30 min (purity: 95%,
gradient A), ESI-MS: 505.4/507.4 [MH].sup.+.
Example 59
3-(2,6-Dichloro-3-methoxy-phenyl)-1-ethyl-1-{6-[4-(4-methyl-piperazin-1-yl-
)-phenylamino]-pyrimidin-4-yl}-urea
##STR00113##
[0796] Yellow foam, TLC: R.sub.f=0.26 (TBME/MeOH 40:60), HPLC:
t.sub.R=5.37 min (purity: 96%, gradient A), ESI-MS:
530.1/532.0/534.0 [MH].sup.+.
Example 60
3-(2,6-Dichloro-3-methoxy-phenyl)-1-methyl-1-{6-[3-(4-methyl-piperazin-1-y-
l)-phenylamino]-pyrimidin-4-yl}-urea
##STR00114##
[0798] Colorless powder, TLC: R.sub.f=0.15 (TBME/MeOH 60:40), HPLC:
t.sub.R=5.31 min (purity: 97%, gradient A), ESI-MS:
516.1/518.0/520.1 [MH].sup.+.
Example 61
3-(2,6-Dichloro-3-methoxy-phenyl)-1-methyl-1-{6-[4-(4-methyl-piperazine-1--
carbonyl)-phenylamino]-pyrimidin-4-yl}-urea
##STR00115##
[0800] Colorless powder, TLC: R.sub.f=0.67 (DCM/MeOH 80:20), HPLC:
t.sub.R=5.11 min (purity: 91%, gradient A), ESI-MS:
544.4/546.3/548.4 [MH].sup.+.
Example 62
3-(2,6-Dichloro-3-methoxy-phenyl)-1-methyl-1-{6-[4-(4-methyl-piperazin-1-y-
lmethyl)-phenylamino]-pyrimidin-4-yl}-urea
##STR00116##
[0802] Beige powder, HPLC: t.sub.R=5.14 min (purity: 93%, gradient
A), ESI-MS: 529.2/531.0/533.1 [MH].sup.+.
Example 63
3-(2,6-Dichloro-3-methoxy-phenyl)-1-(6-methoxy-pyridin-3-ylmethyl)-1-{6-[4-
-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-urea
##STR00117##
[0804] Colorless powder, TLC: R.sub.f=0.56 (DCM/MeOH 80:20), HPLC:
t.sub.R=5.69 min (purity: >99%, gradient A), ESI-MS:
623.0/625.5/627.3 [MH].sup.+.
Example 64
3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-ethyl-1-{6-[4-(4-methyl-piperazine-
-1-carbonyl)-phenylamino]-pyrimidin-4-yl}-urea
##STR00118##
[0806] Colorless powder, TLC: R.sub.f=0.44 (DCM/MeOH 85:15), HPLC:
t.sub.R=5.23 min (purity: >99%, gradient A), ESI-MS:
588.5/590.1/592.2 [MH].sup.+.
Example 65
1-(2-Chloro-6-methyl-phenyl)-3-(6-isopropylamino-pyrimidin-4-4-urea
##STR00119##
[0808] Beige powder, m.p. 233-233.degree. C., TLC: R.sub.f=0.55
(DCM/MeOH/25% NH.sub.3 350:50:1), ESI-MS: 319/321 [MH].sup.+.
Example 66
(2,6-dichloro-phenyl)-carbamic acid
4-{6-[3-(2,6-dichloro-phenyl)-ureido]-pyrimidin-4-ylamino}-cyclohexyleste-
r
##STR00120##
[0810] Colorless powder, m.p. 222-224.degree. C., ESI-MS:
582/584/586 [MH].sup.+.
Example 67
1-(6-Isopropylamino-pyrimidin-4-yl)-3-(2,4,6-trichloro-phenyl)-urea
##STR00121##
[0812] Colorless powder, m.p. 218-220.degree. C., HPLC:
t.sub.R=9.92 min (purity: 100%, gradient C).
Example 68
1-(2,6-Dichloro-phenyl)-3-(6-isopropylamino-pyrimidin-4-yl)-urea
##STR00122##
[0814] Colorless powder, m.p. 203-204.degree. C., ESI-MS:
340/342/586 [MH].sup.+.
Example 69
1-{6-[4-(1-Methyl-piperidin-4-ylmethoxy)-phenylamino]-pyrimidin-4-yl}-3-(2-
,4,6-trichloro-phenyl)-urea
##STR00123##
[0816] Slightly yellow powder, m.p. 189-191.degree. C., ESI-MS:
535/537/539 [MH].sup.+.
Example 70
1-(2-Chloro-6-methyl-phenyl)-3-{6-[4-(1-methyl-piperidin-4-ylmethoxy)-phen-
ylamino]-pyrimidin-4-yl}-urea
##STR00124##
[0818] Slightly yellow powder, m.p. 178-180.degree. C., ESI-MS:
481/483 [MH].sup.+.
Example 71
1-(2,6-Dichloro-phenyl)-3-{6-[4-(1-methyl-piperidin-4-ylmethoxy)-phenylami-
no]-pyrimidin-4-yl}-urea
##STR00125##
[0820] Colorless powder, m.p. 183-185.degree. C., ESI-MS: 501/503
[MH].sup.+.
Example 72
1-(2,5-Dichloro-phenyl)-3-{6-[4-(4-methyl-piperazin-1-yl)-phenylamino]-pyr-
imidin-4-yl}-urea
##STR00126##
[0822] Colorless powder, m.p. 223-225.degree. C., ESI-MS: 472/474
[MH].sup.+.
Example 73
1-{6-[4-(4-Methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-3-(2,4,6-tr-
ichloro-phenyl)-urea
##STR00127##
[0824] Colorless powder, m.p. 209-211.degree. C., ESI-MS:
506/508/510 [MH].sup.+.
Example 74
1-{6-[4-(4-Methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-3-(2,4,5-tr-
ichloro-phenyl)-urea
##STR00128##
[0826] Colorless powder, m.p. 252-254.degree. C., ESI-MS:
506/508/510 [MH].sup.+.
Example 75
1-(3,4-Dichloro-phenyl)-3-{6-[4-(4-methyl-piperazin-1-yl-phenylamino]-pyri-
midin-4-yl}-urea
##STR00129##
[0828] Colorless powder, m.p. 260-262.degree. C., ESI-MS: 472/474
[MH].sup.+.
Example 76
1-(6-Amino-pyrimidin-4-yl}-3-(2,3-dichloro-phenyl)-1-[4-(4-methyl-piperazi-
n-1-yl)-phenyl]-urea
##STR00130##
[0830] Colorless powder, m.p. 280-282.degree. C., ESI-MS: 472/474
[MH].sup.+.
Example 77
1-(2,3-Dichloro-phenyl)-3-{6-[4-(4-methyl-piperazin-1-yl)-phenylamino]-pyr-
imidin-4-yl}-urea
##STR00131##
[0832] Colorless powder, m.p. 279-281.degree. C., ESI-MS: 472/474
[MH].sup.+.
Example 78
1-(5-Chloro-2-methoxy-phenyl)-3-{6-[4-(4-methyl-piperazin-1-yl)-phenylamin-
o]-pyrimidin-4-yl}-urea
##STR00132##
[0834] Colorless resin, TLC: R.sub.f 0.41 (DCM/MeOH/25% NH.sub.3
350:50:1), HPLC: t.sub.R=13.25 min (purity: 100%, gradient E),
ESI-MS: 468/470 [MH].sup.+.
Example 79
1-(2-Chloro-6-methyl-phenyl)-3-{6-[3-(1-methyl-piperidin-4-ylmethoxy)-phen-
ylamino]-pyrimidin-4-yl}-urea
##STR00133##
[0836] Colorless powder, m.p. 200-204.degree. C., ESI-MS: 481/483
[MH].sup.+.
Example 80
1-(2,6-Dichloro-phenyl)-3-{6-[3-(1-methyl-piperidin-4-ylmethoxy)-phenylami-
no]-pyrimidin-4-yl}-urea
##STR00134##
[0838] Colorless powder, m.p. 198-200.degree. C., ESI-MS: 501/503
[MH].sup.+.
Example 81
1-{6-[3-(1-Methyl-piperidin-4-ylmethoxy)-phenylamino]-pyrimidin-4-yl}-3-(2-
,4,6-trichloro-phenyl)-urea
##STR00135##
[0840] Colorless powder, m.p. 222-225.degree. C., ESI-MS:
535/537/539 [MH].sup.+.
Example 82
1-(2-Chloro-6-methyl-phenyl)-3-{6-[4-(4-methyl-piperazin-1-ylmethyl)-pheny-
lamino]-pyrimidin-4-yl}-urea
##STR00136##
[0842] Colorless powder, m.p. 199-201.degree. C., ESI-MS: 466/468
[MH].sup.+.
Example 83
1-(2,6-Dichloro-phenyl]-3-{6-[4-(4-methyl-piperazin-1-ylmethyl)-phenylamin-
o]-pyrimidin-4-yl}-urea
##STR00137##
[0844] Colorless powder, m.p. 199-201.degree. C., ESI-MS: 466/468
[MH].sup.+.
Example 84
1-{6-[4-(4-Methyl-piperazin-1-ylmethyl)-phenylamino]-pyrimidin-4-yl}-3-(2,-
4,6-trichloro-phenyl)-urea
##STR00138##
[0846] Yellowish powder, m.p. 194-196.degree. C., ESI-MS:
520/522/524 [MH].sup.+.
Example 85
1-{6-[4-(4-Methyl-piperazin-1-carbonyl)-phenylamino]-pyrimidin-4-yl}-3-(2,-
4,6-trichloro-phenyl)-urea
##STR00139##
[0848] Amorphous material, m.p. 165-175.degree. C., TLC:
R.sub.f=0.61 (DCM/MeOH/25% NH.sub.3 150:50:1), HPLC: t.sub.R=8.63
min (purity: 98.8%, gradient C), ESI-MS: 534/536/538
[MH].sup.+.
Example 86
1-{6-[3-(4-Methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-3-(2,4,6-tr-
ichloro-phenyl)-urea
##STR00140##
[0850] Yellowish amorphous material, m.p. 138-142.degree. C., TLC:
R.sub.f=0.41 (DCM/MeOH/25% NH.sub.3 350:50:1), HPLC: t.sub.R=8.92
min (purity: 99%, gradient C), ESI-MS: 506/508/510 [MH].sup.+.
Example 87
1-{6-[(trans)-4-(tert-Butyl-dimethyl-silanyloxy)-cyclohexylamino]-pyrimidi-
n-4-yl}-3-(2,4,6-trichloro-phenyl)-urea
##STR00141##
[0852] Colorless powder, m.p. 198-199.degree. C., ESI-MS:
570/572/574 [MH].sup.+.
Example 88
1-[6-((trans)-4-Hydroxy-cyclohexylamino)-pyrimidin-4-yl]-3-(2,4,6-trichlor-
o-phenyl)-urea
##STR00142##
[0854] Colorless powder, m.p. 171-173.degree. C., ESI-MS:
430/432/434 [MH].sup.+.
Example 89
1-[6-(trans)-4-(tert-Butyl-dimethyl-silanyloxy)-cyclohexylamino]-pyrimidin-
-4-yl]-3-(2-chloro-6-methyl-phenyl)-urea
##STR00143##
[0856] Beige powder, m.p. 218-220.degree. C., TLC: R.sub.f=0.74
(ethyl acetate/methanol 95:5), HPLC: t.sub.R=13.92 min (purity:
93.9%, gradient C), ESI-MS: 490/492 [MH].sup.+.
Example 90
1-(2-Chloro-6-methyl-phenyl)-3-[6-((trans)-4-hydroxy-cyclohexylamino)-pyri-
midin-4-yl]-urea
##STR00144##
[0858] Colorless powder, m.p. 149-152.degree. C., TLC: R.sub.f=0.22
(ethyl acetate/methanol 95:5), HPLC: t.sub.R=7.77 min (purity:
95.2%, gradient C), ESI-MS: 376/378 [MH].sup.+.
Example 91
1-{6-[(trans)-4-(tert-Butyl-dimethyl-silanyloxy)-cyclohexylamino]-pyrimidi-
n-4-yl}-3-(2,6-dichloro-phenyl)-urea
##STR00145##
[0860] Colorless powder, m.p. 211-212.degree. C., HPLC:
t.sub.R=2.63 min (purity: 97.9%, gradient D), ESI-MS: 510/512
[MH].sup.+.
Example 92
1-(2,6-Dichloro-phenyl)-3-[6-((trans)-4-hydroxy-cyclohexylamino)-pyrimidin-
-4-yl]-urea
##STR00146##
[0862] Amorphous material, TLC: R.sub.f=0.28 (ethyl
acetate/methanol 95:5), HPLC: t.sub.R=13.54 min (purity: 100%,
gradient C), ESI-MS: 396/398 [MH].sup.+.
Example 93
1-(2-Chloro-phenyl)-3-{6-[4-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimid-
in-4-yl}-urea
##STR00147##
[0864] Beige powder, HPLC: t.sub.R=4.17 min (purity: 100%, gradient
B), ESI-MS: 438/440 [MH].sup.+.
Example 94
1-(2-Bromo-phenyl)-3-{6-[4-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidi-
n-4-yl}-urea
##STR00148##
[0866] Colorless powder, HPLC: t.sub.R=4.23 min (purity: 100%,
gradient B), ESI-MS: 482/484 [MH].sup.+.
Example 95
1-(6-Amino-pyrimidin-4-yl]-3-(2-chloro-phenyl)-1-[4-(3-diethylamino-propox-
y)-phenyl]-urea
##STR00149##
[0868] Colorless powder, HPLC: t.sub.R=4.42 min (purity: 100%,
gradient B), ESI-MS: 469/471 [MH].sup.+.
Example 96
1-(2,6-Dichloro-phenyl)-3-1644-(2-morpholin-4-yl-ethoxy)-phenylamino]-pyri-
midin-4-yl}-urea
##STR00150##
[0870] Beige powder, HPLC: t.sub.R=3.93 min (purity: 100%, gradient
B), ESI-MS: 503/505 [MH].sup.+.
Example 97
1-(2-Bromo-phenyl)-3-{6-[4-(2-morpholin-4-yl-ethoxy)-phenylamino]-pyrimidi-
n-4-yl}-urea
##STR00151##
[0872] White powder, HPLC: t.sub.R=4.29 min (purity: 100%, gradient
B), ESI-MS: 513/515 [MH].sup.+.
Example 98
1-(2,6-Dichloro-phenyl)-3-1614-(3-morpholin-4-yl-propoxy)-phenylamino]-pyr-
imidin-4-yl}-urea
##STR00152##
[0874] Colorless powder, HPLC: t.sub.R=4.05 min (purity: 100%,
gradient B), ESI-MS: 517/519 [MH].sup.+.
Example 99
1-(2-Bromo-phenyl)-3-{6-[4-(3-morpholin-4-yl-propoxy)-phenylamino]-pyrimid-
in-4-yl}-urea
##STR00153##
[0876] Colorless powder, HPLC: t.sub.R=4.42 min (purity: 100%,
gradient B), ESI-MS: 527/529 [MH].sup.+.
Example 100
1-(2,6-Dichloro-phenyl)-3-{6-[4-(2-diethylamino-ethoxy)-phenylamino]-pyrim-
idin-4-yl}-urea
##STR00154##
[0878] Colorless powder, HPLC: t.sub.R=4.12 min (purity: 100%,
gradient B), ESI-MS: 489/491 [MH].sup.+.
Example 101
1-(2-Bromo-phenyl)-3-{6-[4-(2-diethylamino-ethoxy)-phenylamino]-pyrimidin--
4-yl}-urea
##STR00155##
[0880] Colorless powder, HPLC: t.sub.R=4.55 min (purity: 100%,
gradient B), ESI-MS: 499/501 [MH].sup.+.
Example 102
1-(2-Chloro-phenyl)-3-{6-[4-(3-diethylamino-propoxy)-phenylamino]-pyrimidi-
n-4-yl}-urea
##STR00156##
[0882] Colorless powder, HPLC: t.sub.R=4.58 min (purity: 100%,
gradient B), ESI-MS: 469/471 [MH].sup.+.
Example 103
1-(2,6-Dichloro-phenyl)-3-{6-[4-(3-diethylamino-propoxy)-phenylamino]-pyri-
midin-4-yl}-urea
##STR00157##
[0884] Colorless powder, HPLC: t.sub.R=4.26 min (purity: 100%,
gradient B), ESI-MS: 503/505 [MH].sup.+.
Example 104
1-(2-Bromo-phenyl)-3-{6-[4-(3-diethylamino-propoxy)-phenylamino]-pyrimidin-
-4-yl}-urea
##STR00158##
[0886] Colorless powder, HPLC: t.sub.R=4.62 min (purity: 100%,
gradient B), ESI-MS: 513/515 [MH].sup.+.
Example 105
1-[6-(4-Diethylamino-phenylamino)-pyrimidin-4-yl]-3-(2,6-difluoro-phenyl)--
urea
##STR00159##
[0887] A. N-(4-Diethylamino-phenyl)-pyrimidine-4,6-diamine
[0888] A mixture of 6-chloro-pyrimidin-4-ylamine (0.65 g, 5 mmol),
4-amino-N,N-diethylaniline (0.82 mL, 5 mmol), 2-propanol (5 mL) and
HCl conc. (0.225 mL, .about.2.5 mmol) is shaken for 36 h at
90.degree. C. After cooling to room temperature, the reaction
mixture is distributed between half-saturated
K.sub.2CO.sub.3-solution and ethyl acetate. The precipitate thus
formed is filtered off, washed with H.sub.2O and ethyl acetate and
dried in vacuo to afford the title compound. Greyish solid, HPLC:
t.sub.R=2.37 min (gradient F), ESI-MS: 258.3 [MH].sup.+.
B.
1-[6-(4-Diethylamino-phenylamino)-pyrimidin-4-yl]-3-(2,6-difluoro-pheny-
l)-urea
[0889] A mixture of
N-(4-diethylamino-phenyl)-pyrimidine-4,6-diamine (257.4 mg, 1
mmol), 2,6-difluorophenyl isocyanate (170.6 mg, 1.1 mmol) in dry
dioxane (4 mL) is shaken for 1.5 h at 80.degree. C. After
evaporation of the solvent in vacuo, the residue is distributed
between CH.sub.2Cl.sub.2 and half-saturated K.sub.2CO.sub.3
solution. The organic layer is dried over Na.sub.2SO.sub.4,
evaporated, and the residue purified by flash chromatography
(CH.sub.2Cl.sub.2/CH.sub.3OH). The combined pure fractions are
evaporated, the residue triturated with CH.sub.2Cl.sub.2 and the
solid filtered off and dried in vacuo to afford the title
compound.
[0890] White solid, HPLC: t.sub.R=3.35 min (purity:100%, gradient
F), ESI-MS: 413.4 [MH].sup.+.
Example 106
1-(2,6-Difluoro-phenyl)-3-[6-(3-dimethylamino-phenylamino)-pyrimidin-4-yl]-
-urea
##STR00160##
[0891] A. N-(3-Dimethylamino-phenyl)-pyrimidine-4,6-diamine
[0892] A mixture of N,N-dimethyl-m-phenylenediamine (1.36 g, 10
mmol), 6-chloro-pyrimidin-4-ylamine (1.30 g, 10 mmol), 2-propanol
(10 mL) and HCl conc. (0.45 mL, .about.5 mmol) is shaken for 16 h
at 90.degree. C. After cooling to room temperature, the reaction
mixture is distributed between half-concentrated Na.sub.2CO.sub.3
solution and ethyl acetate. The organic layer is dried over
Na.sub.2SO.sub.4, evaporated, and the residue purified by flash
chromatography (ethyl acetate /CH.sub.3OH). The combined pure
fractions are evaporated to afford the title compound.
[0893] Beige solid, HPLC: t.sub.R=1.53 min (gradient F), ESI-MS:
230.3 [MH].sup.+.
B.
1-(2,6-Difluoro-phenyl)-3-[6-(3-dimethylamino-phenylamino)-pyrimidin-4--
yl]-urea
[0894] A mixture of
N-(3-dimethylamino-phenyl)-pyrimidine-4,6-diamine (458.6 mg, 2
mmol), 2,6-difluorophenyl isocyanate (341.2 mg, 2.2 mmol) in dry
dioxane (5 mL) is shaken for 2.5 h at 80.degree. C. After cooling
down, the reaction mixture is treated with ethyl acetate. The
precipitate is filtered off and dried in vacuo to afford the title
compound.
[0895] White solid, HPLC: t.sub.R=3.39 min (purity: 100%, gradient
F), ESI-MS: 385.4 [MH].sup.+.
Example 107
1-(2,6-Dichloro-phenyl)-3-[6-(4-diethylamino-phenylamino)-pyrimidin-4-yl]--
urea
##STR00161##
[0897] The title compound is prepared analogously as described in
Example 105A from N-(4-diethylamino-phenyl)-pyrimidine-4,6-diamine
and 2,6-dichlorophenyl isocyanate.
[0898] White solid, HPLC: t.sub.R=3.61 min (purity: 100%, gradient
F), ESI-MS: 445.3/447.3 [MH].sup.+.
Example 108
1-(2,6-Dichloro-phenyl)-3-[6-(4-morpholin-4-yl-phenylamino)-pyrimidin-4-yl-
]-urea
##STR00162##
[0899] A. N-(4-Morpholin-4-yl-phenyl)-pyrimidine-4,6-diamine
[0900] The title compound is prepared analogously as described in
Example 105A from 6-chloro-pyrimidin-4-ylamine and
4-morpholinoaniline. The semi-solid reaction mixture received after
cooling to room temperature is dissolved in warm methanol, basified
with conc. aqueous ammonia solution and the mixture concentrated to
half of its volume. The precipitate obtained after addition of
H.sub.2O is filtered off, washed with H.sub.2O and dried in vacuo
to afford the title compound. Faintly violet solid, ESI-MS: 272.3
[MH].sup.+.
B.
1-(2,6-Dichloro-Phenyl)-3-[6-(4-morpholin-4-yl-phenylamino)-pyrimidin-4-
-yl]-urea
[0901] The title compound is prepared analogously as described in
Example 105B from
N-(4-morpholin-4-yl-phenyl)-pyrimidine-4,6-diamine and
2,6-dichlorophenyl isocyanate.
[0902] Faintly violet solid, HPLC: t.sub.R=3.74 min (purity: 100%,
gradient F), ESI-MS: 459.3/461.3 [MH].sup.+.
Example 109
1-(2,6-Difluoro-phenyl)-3-[6-(4-morpholin-4-yl-phenylamino)-pyrimidin-4-yl-
]-urea
##STR00163##
[0904] The title compound is prepared analogously as described in
Example 105B from
N-(4-morpholin-4-yl-phenyl)-pyrimidine-4,6-diamine and
2,6-difluorophenyl isocyanate.
[0905] Slightly pink solid, HPLC: t.sub.R=3.53 min (purity: 100%,
gradient F), ESI-MS: 427.4 [MH].sup.+.
Example 110
3-(2,6-Dichloro-phenyl)-1-[6-(4-diethylamino-phenylamino)-pyrimidin-4-yl]--
1-methyl-urea
##STR00164##
[0906] A.
N-(4-Diethylamino-phenyl)-N'-methyl-pyrimidine-4,6-diamine
##STR00165##
[0908] The title compound is prepared analogously as described in
Example 105A from (6-chloro-pyrimidin-4-yl)-methyl-amine and
4-amino-N,N-diethylaniline. The ethyl acetate layer is dried over
Na.sub.2SO.sub.4 and evaporated in vacuo. The residue is suspended
in CH.sub.2Cl.sub.2, filtered off and dried to afford the title
compound.
[0909] White solid, HPLC: t.sub.R=2.48 min (gradient F), ESI-MS:
272.3 [MH].sup.+.
B.
3-(2,6-Dichloro-phenyl)-1-[6-(4-diethylamino-phenylamino)-pyrimidin-4-y-
l]-1-methyl-urea
[0910] The title compound is prepared analogously as described in
Example 105B from
N-(4-diethylamino-phenyl)-N'-methyl-pyrimidine-4,6-diamine and
2,6-dichlorophenyl isocyanate.
[0911] White solid, HPLC: t.sub.R=2.46 min (purity: 95.6%, gradient
H), ESI-MS: 459.2/461.2 [MH].sup.+.
Example 111
3-(2,6-Dichloro-phenyl)-1-{6-[4-(1-hydroxy-1-methyl-ethyl)-phenylamino]-py-
rimidin-4-yl}-1-methyl-urea
##STR00166##
[0912] A.
1-[4-(6-Methylamino-pyrimidin-4-ylamino)-phenyl]ethanone
[0913] A mixture of (6-chloro-pyrimidin-4-yl)-methylamine (5.76 g,
40.1 mmol), 4-amino-acetophenone (5.40 g, 40 mmol), 2-propanol (40
mL) and conc. HCl (1.8 mL, .about.20 mmol) is stirred for 40 h at
90.degree. C. Conc. HCl (0.9 mL, .about.10 mmol) is added and
stirring is continued for 56 h. After addition of CH.sub.3OH the
reaction mixture is basified with conc. aqueous ammonia solution.
H.sub.2O is added and the precipitate is filtered off, washed with
H.sub.2O and dried in vacuo to afford the title compound. Yellow
solid, ESI-MS: 243.4 [MH].sup.+.
B.
1-[6-(4-Acetyl-phenylamino)-pyrimidin-4-yl]-3-(2,6-dichloro-phenyl)-1-m-
ethyl-urea
##STR00167##
[0915] A mixture of
1-[4-(6-methylamino-pyrimidin-4-ylamino)-phenyl]-ethanone (3.77 g,
15.56 mmol), 2,6-dichlorophenyl isocyanate (3.22 g, 17.12 mmol) in
dry dioxane (30 mL) is shaken for 16 h at 80.degree. C. After
evaporation of the solvent in vacuo, the residue is distributed
between ethyl acetate and half-saturated K.sub.2CO.sub.3 solution.
The precipitate is filtered off and washed with H.sub.2O and ethyl
acetate. The solid residue is suspended in methanol, heated to
reflux for several h and the hot yellow suspension filtered. This
procedure is repeated once. The residue obtained after the second
filtration is washed with CH.sub.3OH and dried in vacuo to afford
the title compound.
[0916] Yellowish solid, HPLC: t.sub.R=4.81 min (gradient G),
ESI-MS: 430.3/432.3 [MH].sup.+.
C.
3-(2,6-Dichloro-phenyl)-1-{6-[4-(1-hydroxy-1-methyl-ethyl)-phenylamino]-
-pyrimidin-4-yl}-1-methyl-urea
[0917] To a freshly prepared solution of methylmagnesium iodide in
diethyl ether (8 mL, .about.7 mmol) is added
1-[6-(4-acetyl-phenylamino)-pyrimidin-4-yl]-3-(2,6-dichloro-phenyl)-1-met-
hyl-urea (0.5 g, 1.16 mmol) in several portions. After stirring for
5 h, THF (4 mL) is added. After 16 h the reaction is quenched by
the addition of H.sub.2O and CH.sub.3OH and evaporated in vacuo.
The residue is co-evaporated twice with toluene and purified by
flash chromatography (CH.sub.2Cl.sub.2/CH.sub.3OH). The combined
pure fractions are evaporated to afford the title compound.
[0918] White solid, HPLC: t.sub.R=4.39 min (purity: 100%, gradient
G), ESI-MS: 446.4/448.4 [MH].sup.+.
Example 112
1-(2,6-Dichloro-phenyl)-3-[6-(6-methoxy-pyridin-3-ylamino)-pyrimidin-4-yl]-
-urea
##STR00168##
[0919] A. N-(6-Methoxy-pyridin-3-yl)-pyrimidine-4,6-diamine
[0920] A mixture of 6-chloro-pyrimidin-4-ylamine (0.65 g, 5 mmol),
5-amino-2-methoxypyridine (0.62 g, 5 mmol) and 2-propanol (5 mL) is
shaken for 36 h at 90.degree. C. After cooling to room temperature,
the reaction mixture is distributed between half-saturated
Na.sub.2CO.sub.3-solution and ethyl acetate. The organic layer is
dried over Na.sub.2SO.sub.4 and evaporated. The solid residue is
washed consecutively with CH.sub.3OH, ethyl acetate and
CH.sub.2Cl.sub.2 and dried in vacuo.
[0921] Pinkish solid, HPLC: t.sub.R=2.68 min (gradient F), ESI-MS:
218.3 [MH].sup.+.
B.
1-(2,6-Dichloro-phenyl)-3-[6-(6-methoxy-pyridin-3-ylamino)-pyrimidin-4--
yl]-urea
[0922] The title compound is prepared analogously as described in
Example 105B from N-(6-methoxy-pyridin-3-yl)-pyrimidine-4,6-diamine
and 2,6-dichlorophenyl isocyanate.
[0923] Slightly beige solid, HPLC: t.sub.R=4.01 min (purity: 100%,
gradient F), ESI-MS: 405.2/407.2 [MH].sup.+.
Example 113
3-(2,6-Dichloro-phenyl)-1-methyl-1-[6-(3-trifluoromethyl-phenylamino)-pyri-
midin-4-yl]-urea
##STR00169##
[0924] A.
(6-Chloro-pyrimidin-4-yl)-(3-trifluoromethyl-phenyl)-amine
[0925] A stirred mixture of 4,6-dichloropyrimidine (18.6 g, 125
mmol), 3-aminobenzotrifluoride (16.5 mL, 133 mmol), acetone (60 mL)
and H.sub.2O (90 mL) is kept at reflux for 3 h. Acetone is removed
in vacuo, the remaining aqueous layer is basified with conc.
aqueous ammonia solution and extracted with ethyl acetate. The
organic extract is dried over Na.sub.2SO.sub.4 and evaporated. The
residue is suspended in a small amount of acetone, filtered and the
filter cake dried in vacuo to afford the title compound.
[0926] White solid, HPLC: t.sub.R=4.82 min (gradient G), ESI-MS:
274.2/276.1 [MH].sup.+.
B.
N-Methyl-N'-(3-trifluoromethyl-phenyl)-pyrimidine-4,6-diamine
[0927] A solution of methylamine in ethanol (32 mL, 256 mmol) is
added to (6-chloro-pyrimidin-4-yl)-(3-trifluoromethyl-phenyl)-amine
(3.49 g, 12.8 mmol) and the mixture is stirred for 5 h at
100.degree. C. in a pressure bottle. The reaction mixture is
concentrated in vacuo, the residue diluted with CH.sub.3OH and
basified using conc. aqueous ammonia solution. The product is
filtered off, washed with H.sub.2O and CH.sub.3OH and dried in
vacuo.
[0928] Greyish solid, HPLC: t.sub.R=3.51 min (gradient G), ESI-MS:
269.2 [MH].sup.+.
C.
3-(2,6-Dichloro-phenyl)-1-methyl-1-[6-(3-trifluoromethyl-phenylamino)-p-
yrimidin-4-yl]-urea
[0929] A mixture of
N-methyl-N'-(3-trifluoromethyl-phenyl)-pyrimidine-4,6-diamine
(536.5 mg, 2 mmol), 2,6-dichlorophenyl isocyanate (413.6 mg, 2.2
mmol) in dry dioxane (5 mL) is shaken for 1 h at 80.degree. C.
After evaporation of the solvent in vacuo, the residue is
distributed between ethyl acetate and half-saturated
K.sub.2CO.sub.3 solution. The organic layer is dried over
Na.sub.2SO.sub.4, evaporated, and the residue recrystallized from
CH.sub.2Cl.sub.2/CH.sub.3OH. The solid residue is dried in vacuo to
afford the title compound.
[0930] White solid, HPLC: t.sub.R=5.08 min (purity: 100%, gradient
H), ESI-MS: 456.3/458.3 [MH].sup.+.
Example 114
1-[6-(3-Cyano-phenylamino)-pyrimidin-4-yl]-3-(2,6-dichloro-phenyl)-1-methy-
l-urea
##STR00170##
[0931] A. 3-(6-Methylamino-pyrimidin-4-ylamino)-benzonitrile
[0932] A mixture of (6-chloro-pyrimidin-4-yl)-methylamine (1.44 g,
10 mmol), 3-amino-benzonitrile. (1.18 g, 10 mmol), 2-propanol (10
mL) and conc. HCl (0.45 mL, .about.5 mmol) is stirred for 36 h at
90.degree. C. After cooling to room temperature, CH.sub.3OH is
added and the reaction mixture is basified with conc. aqueous
ammonia solution. The precipitate which forms upon addition of
H.sub.2O is filtered off, washed with H.sub.2O and dried in vacuo
to afford the title compound.
[0933] Beige solid, HPLC: t.sub.R=2.67 min (gradient G), ESI-MS:
226.2 [MH].sup.+.
B.
1-[6-(3-Cyano-phenylamino)-pyrimidin-4-yl]-3-(2,6-dichloro-phenyl)-1-me-
thyl-urea
[0934] A mixture of
3-(6-methylamino-pyrimidin-4-ylamino)-benzonitrile (450.5 mg, 2
mmol), 2,6-dichlorophenyl isocyanate (413.6 mg, 2.2 mmol) in dry
dioxane (5 mL) is shaken for 1.5 h at 80.degree. C. and then
evaporated in vacuo. The residue is suspended in half-concentrated
aqueous K.sub.2CO.sub.3 solution, filtered off, washed with
H.sub.2O and acetone and dried in vacuo to afford the title
compound.
[0935] Beige solid, HPLC: t.sub.R=4.34 min (purity: 100%, gradient
H), ESI-MS: 413.3/415.3 [MH].sup.+.
Example 115
1-(2,6-Dichloro-phenyl)-3-[6-(4-fluoro-phenylamino)-pyrimidin-4-yl]-urea
##STR00171##
[0936] A. N-(4-Fluoro-phenyl)-pyrimidine-4,6-diamine
[0937] The title compound is prepared analogously as described in
Example 114A from 6-chloro-pyrimidin-4-ylamine and
4-fluoroaniline.
[0938] Brownish solid, HPLC: t.sub.R=3.09 min (gradient F), ESI-MS:
205.2 [MH].sup.+.
B.
1-(2,6-Dichloro-phenyl)-346-(4-fluoro-phenylamino)-pyrimidin-4-yl]-urea
[0939] A suspension of N-(4-fluoro-phenyl)-pyrimidine-4,6-diamine
(408.4 mg, 2 mmol), 2,6-dichlorophenyl isocyanate (413.6 mg, 2.2
mmol) in dry dioxane (5 mL) is shaken for 14 h at 80.degree. C.
After cooling to 5.degree. C. the suspension is filtered, the
residue washed with half-saturated K.sub.2CO.sub.3 solution,
H.sub.2O and acetone and dried in vacuo.
[0940] Greyish solid, HPLC: t.sub.R=4.11 min (purity: 100%,
gradient G), ESI-MS: 392.3/394.3 [MH].sup.+.
Example 116
1-[6-(4-Fluoro-phenylamino)-pyrimidin-4-yl]-3-(4-methoxy-phenyl)-1-methyl--
urea
##STR00172##
[0942] A mixture of
N-(4-fluoro-phenyl)-N'-methyl-pyrimidine-4,6-diamine (2.18 g, 10
mmol), 4-methoxyphenyl isocyanate (1.29 mL, 10 mmol) and dibutyltin
diacetate (0.54 mL, 2 mmol) in dry dioxane (20 mL) is shaken for 6
h at 100.degree. C. After addition of a second portion of
4-methoxyphenyl isocyanate (0.9 mL, 7 mmol) stirring is continued
at 100.degree. C. for 9 h. The reaction mixture is treated with
ethyl acetate and half-saturated Na.sub.2CO.sub.3 solution. The
organic layer is filtered, dried over Na.sub.2SO.sub.4, evaporated,
and the residue purified by flash chromatography (hexane/ethyl
acetate). The combined pure fractions are evaporated, the residue
is suspended in hot CH.sub.3OH and the hot mixture filtered. This
procedure is repeated several times. The solid thus obtained is
dried in vacuo to afford the title compound.
[0943] White powder, HPLC: t.sub.R=4.54 min (purity: 100%, gradient
G), ESI-MS: 368.3 [MH].sup.+.
Example 117
3-(2,6-Dichloro-phenyl)-1-methyl-1-(6-(4-morpholin-4-yl-phenylamino)-pyrim-
idin-4-yl]-urea
##STR00173##
[0944] A.
N-Methyl-N'-(4-morpholin-4-yl-phenyl)-pyrimidine-4,6-diamine
##STR00174##
[0946] The title compound is prepared analogously as described in
Example 114A from (6-chloro-pyrimidin-4-yl)-methylamine and
4-morpholinoaniline.
[0947] Slightly violet solid, HPLC: t.sub.R=1.37 min (gradient G),
ESI-MS: 286.3 [MH].sup.+.
B.
3-(2,6-Dichloro-phenyl)-1-methyl-1-[6-(4-morpholin-4-yl-phenylamino)-py-
rimidin-4-yl]-urea
[0948] A mixture of
N-methyl-N'-(4-morpholin-4-yl-phenyl)-pyrimidine-4,6-diamine (428.0
mg, 1.5 mmol), 2,6-dichlorophenyl isocyanate (310.2 mg, 1.65 mmol)
in dry dioxane (5 mL) is shaken for 1.5 h at 80.degree. C. After
evaporation of the solvent in vacuo, the residue is purified by
flash chromatography (CH.sub.2Cl.sub.2/CH.sub.3OH). The combined
pure fractions are evaporated, the residue triturated with
CH.sub.2Cl.sub.2 and the solid filtered off and dried in vacuo to
afford the title compound.
[0949] White solid, HPLC: t.sub.R=2.79 min (purity: 100%, gradient
H), ESI-MS: 473.3/475.3 [MH].sup.+.
Example 118
3-(2,6-Dichloro-phenyl)-1-[6-(2,4-difluoro-phenylamino)-pyrimidin-4-yl]-1--
methyl-urea
##STR00175##
[0950] A.
N-(2,4-Difluoro-phenyl)-N'-methyl-pyrimidine-4,6-diamine
[0951] The title compound is prepared analogously as described in
Example 114A from (6-chloro-pyrimidin-4-yl)-methylamine and
2,4-difluoroaniline.
[0952] Pinkish solid, HPLC: t.sub.R=3.21 min (gradient F), ESI-MS:
237.2 [MH].sup.+.
B.
3-(2,6-Dichloro-phenyl)-1-[6-(2,4-difluoro-phenylamino)-pyrimidin-4-yl]-
-1-methyl-urea
[0953] The title compound is prepared analogously as described in
Example 105B from
N-(2,4-difluoro-phenyl)-N'-methyl-pyrimidine-4,6-diamine and
2,6-dichlorophenyl isocyanate.
[0954] White solid, HPLC: t.sub.R=4.41 min (purity: 100%, gradient
H), ESI-MS: 424.2/426.2 [MH].sup.+.
Example 119
1-(2,6-Dichloro-phenyl)-346-(3-dimethylamino-phenylamino)-pyrimidin-4-yl]--
urea
##STR00176##
[0956] The title compound is prepared analogously as described in
Example 105B from N-(3-dimethylamino-phenyl)-pyrimidine-4,6-diamine
and 2,6-dichlorophenyl isocyanate using ethyl acetate instead of
CH.sub.2Cl.sub.2 for the work-up procedure.
[0957] White solid, HPLC: t.sub.R=3.61 min (purity: 100%, gradient
F), ESI-MS: 417.3/419.2 [MH].sup.+.
Example 120
3-(2,6-Dichloro-phenyl)-1-[6-(3-dimethylamino-phenylamino)-pyrimidin-4-yl]-
-1
##STR00177##
[0958] A.
N-(3-Dimethylamino-phenyl)-N'-methyl-pyrimidine-4,6-diamine
[0959] The title compound is prepared analogously as described in
Example 105A from (6-chloro-pyrimidin-4-yl)-methylamine and
N,N-dimethyl-m-phenylenediamine. The crude product obtained after
evaporation of the ethyl acetate layer is purified by flash
chromatography (CH.sub.2Cl.sub.2/CH.sub.3OH).
[0960] Beige solid, HPLC: t.sub.R=2.45 min (gradient F), ESI-MS:
244.3 [MH].sup.+.
B.
3-(2,6-Dichloro-phenyl)-1-[6-(3-dimethylamino-phenylamino)-pyrimidin-4--
yl]-1-methyl-urea
[0961] A mixture of
N-(3-dimethylamino-phenyl)-N'-methyl-pyrimidine-4,6-diamine (243.3
mg, 1 mmol), 2,6-dichlorophenyl isocyanate (188 mg, 1 mmol) in dry
dimethylformamide (2.5 mL) is shaken for 14 h at 90.degree. C. Two
additional portions (188 mg, 1 mmol each) of 2,6-dichlorophenyl
isocyanate are added after 14 h and 26 h. After 38 h the reaction
mixture is evaporated in vacuo and the residue is distributed
between ethyl acetate and half-saturated K.sub.2CO.sub.3 solution.
The organic layer is dried over Na.sub.2SO.sub.4, evaporated, and
the residue purified by flash chromatography (hexane/ethyl
acetate). The combined pure fractions are evaporated, the residue
triturated with CH.sub.2Cl.sub.2 and the solid filtered off and
dried in vacuo to afford the title compound.
[0962] White solid, HPLC: t.sub.R=3.79 min (purity: 100%, gradient
G), ESI-MS: 431.1/433.1 [MH].sup.+.
Example 121
1-[6-(4-Fluoro-phenylamino)-pyrimidin-4-yl]-1-methyl-3-(3-trifluoro-methyl-
-phenyl)-urea
##STR00178##
[0964] A mixture of
N-(4-fluoro-phenyl)-N'-methyl-pyrimidine-4,6-diamine (218.2 mg, 1
mmol), 3-trifluoromethyl)phenyl isocyanate (165.20 L, 1.2 mmol) and
dibutyltin diacetate (53.7 .quadrature.L, 0.2 mmol) in dry dioxane
(2.5 mL) is shaken for 14 h at 100.degree. C. Two additional
portions (82.6 .quadrature.L, 0.6 mmol each) of
3-trifluoromethyl)phenyl isocyanate are added after 14 h and 20 h.
After 26 h the reaction mixture is distributed between ethyl
acetate and half-saturated Na.sub.2CO.sub.3 solution. The organic
layer is dried over Na.sub.2SO.sub.4, evaporated, and the residue
triturated with CH.sub.2Cl.sub.2. The solid is filtered off and the
filtrate purified by flash chromatography (hexane /ethyl acetate).
The combined pure fractions are evaporated, the residue
recrystallized from CH.sub.3OH/CH.sub.2Cl.sub.2 to afford the title
compound.
[0965] White solid, HPLC: t.sub.R=5.31 min (purity: 100%, gradient
G), ESI-MS: 406.3 [MH].sup.+.
Example 122
3-(3-Chloro-phenyl)-1-[6-(4-fluoro-phenylamino)-pyrimidin-4-yl]-1-methyl-u-
rea
##STR00179##
[0967] The title compound is prepared analogously as described in
Example 121 from
N-(4-fluoro-phenyl)-N'-methyl-pyrimidine-4,6-diamine and
3-chlorophenyl isocyanate.
[0968] White solid, HPLC: t.sub.R=5.25 min ((purity: 100%, gradient
G), ESI-MS: 372.2 [MH].sup.+.
Example 123
3-(2,6-Dichloro-phenyl)-1-[6-(4-fluoro-phenylamino)-pyrimidin-4-yl]-1-meth-
yl-urea
##STR00180##
[0970] A mixture of
N-(4-fluoro-phenyl)-N'-methyl-pyrimidine-4,6-diamine (218.2 mg, 1
mmol), 2,6-dichlorophenyl isocyanate (188 mg, 1 mmol) and
triethylamine (1.11 mL, 8 mmol) in dry dimethylformamide (2.5 mL)
is shaken for 14 h at 90.degree. C. The reaction mixture is
evaporated in vacuo and the residue is distributed between ethyl
acetate and half-saturated Na.sub.2CO.sub.3 solution. The organic
layer is dried over Na.sub.2SO.sub.4, evaporated, and the residue
purified by flash chromatography (CH.sub.2Cl.sub.2/CH.sub.3OH). The
combined pure fractions are evaporated, the residue triturated with
CH.sub.2Cl.sub.2 and the solid filtered off and dried in vacuo to
afford the title compound.
[0971] White solid, HPLC: t.sub.R=4.33 min (purity: 100%, gradient
H), ESI-MS: 406.1/408.1 [MH].sup.+.
Example 124
1-[6-(3-Chloro-phenylamino)-pyrimidin-4-yl]-3-(2,6-dichloro-phenyl)-1-meth-
yl-urea
##STR00181##
[0972] A. N-(3-Chloro-phenyl)-N'-methyl-pyrimidine-4,6-diamine
[0973] The title compound is prepared analogously as described in
Example 105A from (6-chloro-pyrimidin-4-yl)-methyl-amine and
3-chloroaniline. The ethyl acetate layer is dried over
Na.sub.2SO.sub.4 and evaporated. The solid residue is suspended in
CH.sub.2Cl.sub.2, filtered off and dried in vacuo to afford the
title compound.
[0974] White solid, HPLC: t.sub.R=3.23 min (gradient G), ESI-MS:
235.2 [MH].sup.+.
B.
1-[6-(3-Chloro-phenylamino)-pyrimidin-4-yl]-3-(2,6-dichloro-phenyl)-1-m-
ethyl-urea
[0975] The title compound is prepared analogously as described in
Example 105B from
N-(3-chloro-phenyl)-N'-methyl-pyrimidine-4,6-diamine and
2,6-dichloroaniline. The oily residue received after evaporation of
the CH.sub.2Cl.sub.2 layer is triturated with CH.sub.2Cl.sub.2 and
the crystals thus obtained were filtered off and dried in vacuo to
afford the title compound.
[0976] White solid, HPLC: t.sub.R=4.97 min (purity: 100%, gradient
H), ESI-MS: 422.3/424.3 [MH].sup.+.
Example 125
1-(2-Chloro-phenyl)-3-{6-[4-(3-morpholin-4-yl-propoxy)-phenylamino]-pyrimi-
din-4-yl}-urea bis-hydrochloride salt
##STR00182##
[0977] A. 1-(2-Chloro-phenyl)-3-(6-chloro-pyrimidin-4-yl)-urea
[0978] A solution of 6-chloro-pyrimidin-4-ylamine (997 mg, 7.7
mmol) and 2-chlorophenyl isocyanate (0.46 mL, 3.85 mmol) in THF (20
mL) is refluxed for 4 h. A further amount of 2-chlorophenyl
isocyanate (0.46 mL, 3.85 mmol) is added and the reaction mixture
is refluxed for 28 h. The reaction mixture is cooled to RT, the
precipitate is filtered to afford the title compound (1.9 g,
86%).
[0979] White powder. HPLC: t.sub.R=8.01 min (gradient I), ESI-MS:
281.1/283.1 [M-H].sup.+
B
1-(2-Chloro-phenyl)-3-{6-[4-(3-morpholin-4-yl-propoxy)-phenylamino]-pyri-
midin-4-yl}-urea
[0980] A solution of
1-(2-chloro-phenyl)-3-(6-chloro-pyrimidin-4-yl)-urea (99 mg, 0.35
mmol), 4-(3-morpholin-4-yl-propoxy)-phenylamine [Chabrier et al.
Bull. Soc. Chim. Fr. 1955; 1353] (83 mg, 0.35 mmol), and
concentrated HCl (0.1 ml, 1.4 mmol) in ethanol (5 ml) was refluxed
for 32 h. The reaction mixture is cooled to RT, and diluted with
water. The acidic solution is washed with ethyl acetate, basified
with aqueous ammoniac, and extracted with DCM. The combined organic
phases are dried over sodium sulfate, evaporated in vacuo, the
residue is crystallized from water/methanol/1 N HCl to afford the
title compound.
[0981] Brownish crystalline powder. HPLC: t.sub.R=5.92 min
(gradient I), ESI-MS: 483 [MH].sup.+
Example 126
1-(2-Chloro-phenyl)-3-{6-[4-(2-diethylamino-ethoxy)-phenylamino]-pyrimidin-
-4-yl}-urea
##STR00183##
[0983] The title compound is prepared analogously as described in
Example 125B using 4-(2-diethylamino-ethoxy)-phenylamine,
crystallization from DCM afford the title compound.
[0984] White powder. HPLC: t.sub.R=6.03 min (gradient I), ESI-MS:
455 [MH].sup.+
Example 127
1-[6-(3-Chloro-phenylamino)-pyrimidin-4-yl]-3-(2,6-dimethyl-phenyl)-1-meth-
yl-urea
##STR00184##
[0986] A solution of
N-(3-chloro-phenyl)-N'-methyl-pyrimidine-4,6-diamine (Example 124A,
94 mg, 0.4 mmol) and 2,6-dimethylphenyl isocyanate (74 mg, 0.52
mmol) in diglyme was stirred at 80.degree. C. for 18 h. The solvent
is evaporated in vacuo, and the residue is purified by column flash
chromatography on silica gel (ethyl acetate/hexane 1:2) to afford
title compound (29 mg, 19%).
[0987] White powder. HPLC: t.sub.R=9.60 min (gradient I), ESI-MS:
382.3 [MH].sup.+
Example 128
3-(2-Chloro-phenyl)-1-[6-(3-chloro-phenylamino)-pyrimidin-4-yl]-urea
##STR00185##
[0988] A. N-(3-Chloro-phenyl)-pyrimidine-4,6-diamine
[0989] The title compound is prepared analogously as described in
Example 105A from 6-chloro-pyrimidin-4-ylamine and
3-chloroaniline.
[0990] White powder. m.p. 171-172.degree. C., HPLC: t.sub.R=5.11
min (gradient I), ESI-MS: 221 [MH].sup.+
B.
3-(2-Chloro-phenyl)-1-[6-(3-chloro-phenylamino)-pyrimidin-4-yl]-urea
[0991] A solution of N-(3-chloro-phenyl)-pyrimidine-4,6-diamine
(110 mg, 0.5 mmol) and 2-chlorophenyl isocyanate (60 .mu.L, 0.5
mmol) in diglyme (1.5 mL) is stirred at 80.degree. C. for 18 h. The
precipitate which formed over time is filtered and washed with
hexane/ethyl acetate to afford the pure title compound (98 mg,
52%).
[0992] White powder. HPLC: t.sub.R=8.95 min (gradient I), ESI-MS:
374.1/376.1 [MH].sup.+
Example 129
1-(2-Bromo-Phenyl)-3-[6-(3-chloro-phenylamino)-pyrimidin-4-yl]-urea
##STR00186##
[0994] The title compound is prepared analogously as described in
Example 128 using 2-bromophenyl isocyanate.
[0995] White powder. HPLC: t.sub.R=9.03 min (gradient I), ESI-MS:
418.0/420.0 [MH].sup.+
Example 130
1-[6-(3-Chloro-phenylamino)-pyrimidin-4-yl]-3-(2-fluoro-phenyl)-urea
##STR00187##
[0997] The title compound is prepared analogously as described in
Example 128 using 2-fluorophenyl isocyanate.
[0998] White powder. HPLC: t.sub.R=8.24 min (gradient I), ESI-MS:
258.2 [MH].sup.+
Example 131
1-[6-(3-Chloro-phenylamino)-pyrimidin-4-yl]-3-(3-methoxy-phenyl)-urea
##STR00188##
[1000] The title compound is prepared analogously as described in
Example 128 using 3-methoxy-phenyl isocyanate.
[1001] White powder. HPLC: t.sub.R=7.90 min (gradient I), ESI-MS:
370.2 [MH].sup.+
Example 132
1-[6-(3-Chloro-phenylamino)-pyrimidin-4-yl]-3-(2,5-dimethoxy-phenyl)-urea
##STR00189##
[1003] The title compound is prepared analogously as described in
Example 127 from N-(3-chloro-phenyl)-pyrimidine-4,6-diamine and
2,5-dimethoxyphenyl isocyanate.
[1004] White powder. HPLC: t.sub.R=8.18 min (gradient I), ESI-MS:
400.2 [MH].sup.+
Example 133
1-[6-(3-Chloro-phenylamino)-pyrimidin-4-yl]-3-(2-trifluoromethyl-phenyl)-u-
rea
##STR00190##
[1006] The title compound is prepared analogously as described in
Example 128 using 3-trifluoromethylphenyl isocyanate.
[1007] White powder. HPLC: t.sub.R=8.94 min (gradient I), ESI-MS:
408.1 [MH].sup.+
Example 134
1-[6-(3-Chloro-phenylamino)-pyrimidin-4-yl]-3-(5-methoxy-2-methyl-phenyl)--
urea
##STR00191##
[1009] The title compound is prepared analogously as described in
Example 2 from 5-methoxy-2-methylaniline and
N-(3-chloro-phenyl)-pyrimidine-4,6-diamine.
[1010] White powder. HPLC: t.sub.R=8.38 min (gradient I), ESI-MS:
384.2 [MH].sup.+
Example 135
1-(3-Chloro-phenyl)-3-[6-(3-chloro-phenylamino)-pyrimidin-4-yl]-urea
##STR00192##
[1012] The title compound is prepared analogously as described in
Example 128 using 3-chlorophenyl isocyanate.
[1013] White powder. HPLC: t.sub.R=8.75 min (gradient I), ESI-MS:
374.1/376.1 [MH].sup.+
Example 136
1-[6-(3-Chloro-phenylamino)-pyrimidin-4-yl]-3-(3,4,5-trimethoxy-phenyl)-ur-
ea
##STR00193##
[1015] The title compound is prepared analogously as described in
Example 127 from N-(3-chloro-phenyl)-pyrimidine-4,6-diamine and
3,4,5-trimethoxyphenyl isocyanate.
[1016] White powder. HPLC: t.sub.R=7.60 min (gradient I), ESI-MS:
430.2 [MH].sup.+
Example 137
1-[6-(3-Chloro-phenylamino)-pyrimidin-4-yl]-3-(2,6-dichloro-phenyl)-urea
##STR00194##
[1018] The title compound is prepared analogously as described in
Example 127 from N-(3-chloro-phenyl)-pyrimidine-4,6-diamine and
2,6-dichlorophenyl isocyanate.
[1019] White powder. HPLC: t.sub.R=8.30 min (gradient I), ESI-MS:
410 [MH].sup.+
Example 138
1-(4-Chloro-phenyl)-3-[6-(3-chloro-phenylamino)-pyrimidin-4-yl]-urea
##STR00195##
[1021] The title compound is prepared analogously as described in
Example 128 using 4-chlorophenyl isocyanate.
[1022] White powder. HPLC: t.sub.R=8.63 min (gradient I), ESI-MS:
374.1/376.1 [MH].sup.+
Example 139
1-[6-(3-Chloro-phenylamino)-pyrimidin-4-yl]-3-(3,5-dimethoxy-phenyl)-urea
##STR00196##
[1024] The title compound is prepared analogously as described in
Example 128 using 3,5-dimethoxyphenyl isocyanate.
[1025] White powder. HPLC: t.sub.R=8.06 min (gradient I), ESI-MS:
400.2 [MH].sup.+
Example 140
1-[6-(3-Chloro-phenylamino)-pyrimidin-4-yl]-3-(2,6-dimethyl-phenyl)-urea
##STR00197##
[1027] The title compound is prepared analogously as described in
Example 127 from N-(3-chloro-phenyl)-pyrimidine-4,6-diamine and
2,6-dimethylphenyl isocyanate.
[1028] White powder. HPLC: t.sub.R=7.97 min (gradient I), ESI-MS:
368.2 [MH].sup.+
Example 141
1-[6-(3-Chloro-phenylamino)-pyrimidin-4-yl]-3-phenyl-urea
##STR00198##
[1030] The title compound is prepared analogously as described in
Example 128 using phenyl isocyanate.
[1031] White powder. HPLC: t.sub.R=7.83 min (gradient I), ESI-MS:
338 [MH].sup.+
Example 142
1-(2-Chloro-phenyl)-3-{6-[4-(2-morpholin-4-yl-ethoxy)-phenylamino]-pyrimid-
in-4-yl}-urea
##STR00199##
[1033] The title compound is prepared analogously as described in
Example 125B using 4-(2-morpholin-4-yl-ethoxy)-phenylamine,
crystallization from DCM afford the title compound.
[1034] White powder. HPLC: t.sub.R=5.82 min (gradient I), ESI-MS:
469 [MH].sup.+
Example 143
3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-ethyl-1-{6-[4-(4-methyl-piperazin--
1-yl)-phenylamino]-pyrimidin-4-yl}-urea
##STR00200##
[1036] To a solution of 2,6-dichloro-3-methoxyphenylisocyanate
(1.25 eq.) in toluene (1.9 ml) is added
N-ethyl-N'-[4-(4-methyl-piperazin-1-yl)-phenyl]-pyrimidine-4,6-diamine
(113 mg, 0.36 mmol), under an argon atmosphere. The resulting
mixture is stirred at 70.degree. C. for 18 h, allowed to cool to RT
and filtered. The recovered solid is washed with diethyl ether,
dried and further purified by MPLC (silica gel) (DCM/MeOH) to
afford 10 mg of the title compound as a white solid: ESI-MS:
559.9/561.9 [MH].sup.+; t.sub.R=3.53 min (purity: 100%, gradient
J); TLC: R.sub.f=0.28 (DCM/MeOH, 9:1).
A.
N-Ethyl-N'-[4-(4-methyl-piperazin-1-yl)-phenyl]-pyrimidine-4,6-diamine
##STR00201##
[1038] A mixture of (6-chloro-pyrimidin-4-yl)-ethyl-amine (363 mg,
2.30 mmol, 1.1 eq.) and 4-(4-methylpiperazin-1-yl)-aniline (400 mg,
2.09 mmol) in water (0.8 ml) and glacial acetic acid (3.2 ml) is
heated to 100.degree. C. 3 h. After solvent evaporation, the
residue is taken up in methanol, made alkaline by addition of 25%
NH.sub.3 in water and concentrated. The residue is purified by MPLC
(silica gel) (DCM/MeOH) to afford 395 mg of the title compound as a
white solid: ESI-MS: 313.2 [MI-1]'; t.sub.R=1.25 min (purity:
.about.90%, gradient J); TLC: R.sub.f=0.12 (DCM/MeOH, 9:1).
B. (6-Chloro-pyrimidin-4-yl)-ethyl-amine
[1039] Ethylamine (70% in water, 16 ml, 45.08 mmol, 2.5 eq.) is
added dropwise (15 min) to a suspension of 4,6-dichloropyrimidine
(12 g, 80.5 mmol) in EtOH (36 ml) at RT. The resulting yellowish
solution is allowed to stir for 1 h at RT and then cooled to
0.degree. C. The resulting white precipitate is collected by vacuum
filtration, washed with water and dried in vacuo to afford 12.4 g
of the title compound: ESI-MS: 157.9 [MH].sup.+; single peak at
t.sub.R=2.02 min (purity: 100%, gradient J).
Example 144
3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-[6-(3-dimethylaminomethyl-phenylam-
ino)-pyrimidin-4-yl]-1-methyl-urea
##STR00202##
[1041] 2,6-dichloro-3,5-dimethoxyphenylisocyanate (1.25 eq.) is
added to a solution of
N-(3-dimethylaminomethyl-phenyl)-N'-methyl-pyrimidine-4,6-diamine
(93 mg, 0.36 mmol, 1 eq.) in toluene (3 ml), at 70.degree. C. and
under an argon atmosphere. The resulting mixture is stirred at
70.degree. C. for 18 h, allowed to cool to RT, and diluted with DCM
and a saturated aqueous solution of sodium bicarbonate. The aqueous
layer is separated and extracted with DCM. The organic phase is
washed with brine, dried (sodium sulfate), filtered and
concentrated. Purification of the crude product by silica gel
column chromatography (DCM/MeOH+1% NH.sub.3.sup.aq, 9:1) affords
121 mg of the title compound as a white solid: ESI-MS: 504.9/506.9
[MH].sup.+; t.sub.R=3.64 min (purity: 100%, gradient J); TLC:
R.sub.f=0.12 (DCM/MeOH+1% NH.sub.3.sup.aq, 9:1).
A.
N-(3-Dimethylaminomethyl-phenyl)-N'-methyl-pyrimidine-4,6-diamine
[1042] A mixture of (6-chloro-pyrimidin-4-yl)-methyl-amine (Example
1) (750 mg, 5.2 mmol), 3-dimethylaminomethyl-phenylamine (787 mg,
5.2 mmol) and 4N HCl in dioxane (15 ml) is heated in a sealed tube
to 150.degree. C. for 5 h. The reaction mixture is concentrated,
diluted with DCM and a saturated aqueous solution of sodium
bicarbonate. The aqueous layer is separated and extracted with DCM.
The organic phase is washed with brine, dried (sodium sulfate),
filtered and concentrated. Purification of the residue by silica
gel column chromatography (DCM/MeOH+1% NH.sub.3.sup.aq, 9:1)
affords 800 mg of the title compound as a white solid: ESI-MS:
258.1 [MH].sup.+; t.sub.R=1.00 min (purity: 100%, gradient J); TLC:
R.sub.f=0.14 (DCM/MeOH+1% NH.sub.3.sup.aq, 9:1).
Example 145
3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-ethyl-piperazin-1-yl)-phe-
nylamino]-pyrimidin-4-yl}-1-methyl-urea
##STR00203##
[1044] The title compound is prepared as described in Example 144
but using
N-[4-(4-ethyl-piperazin-1-yl)-phenyl]-N-methyl-pyrimidine-4,6-diami-
ne (2.39 g, 7.7 mmol, 1 eq.) and stirring the reaction mixture for
1.5 h at reflux. Purification of the crude product by silica gel
column chromatography (DCM/MeOH+1% NH.sub.3.sup.aq, 95:5) affords
the title compound as a white solid: ESI-MS: 560.0/561.9
[MH].sup.+; t.sub.R=3.54 min (purity: 100%, gradient J); TLC:
R.sub.f=0.28 (DCM/MeOH+1% NH.sub.3.sup.aq, 95:5).
A.
N-[4-(4-ethyl-piperazin-1-yl)-phenyl]-N'-methyl-pyrimidine-4,6-diamine
[1045] The title compound is prepared as described in Example 144A
but using 4-(4-ethylpiperazin-1-yl)-aniline (1 g, 4.88 mmol) and
(6-chloro-pyrimidin-4-yl)-methyl-amine (Example 1) (771 1.81 g,
12.68 mmol, 1.3 eq.). Purification of the residue by silica gel
column chromatography (DCM/MeOH, 93:7) followed by trituration in
diethyl ether affords the title compound as a white solid: ESI-MS:
313.2 [MH].sup.+; t.sub.R=1.10 min (gradient J); TLC: R.sub.f=0.21
(DCM/MeOH, 93:7).
B. 4-(4-Ethylpiperazin-1-yl)-aniline
[1046] A suspension of 1-ethyl-4-(4-nitro-phenyl)-piperazine (6.2
g, 26.35 mmol) and Raney Nickel (2 g) in MeOH (120 mL) is stirred
for 7 h at RT, under a hydrogen atmosphere. The reaction mixture is
filtered through a pad of celite and concentrated to afford 5.3 g
of the title compound as a violet solid: ESI-MS: 206.1 [MH].sup.+;
TLC: R.sub.f=0.15 (DCM/MeOH+1% NH.sub.3.sup.aq, 9:1).
C. 1-Ethyl-4-(4-nitro-phenyl)-piperazine
[1047] A mixture of 1-bromo-4-nitrobenzene (6 g, 29.7 mmol) and
1-ethylpiperazine (7.6 ml, 59.4 mmol, 2 eq.) is heated to
80.degree. C. for 15 h. After cooling to RT, the reaction mixture
is diluted with water and DCM/MeOH, 9:1. The aqueous layer is
separated and extracted with DCM/MeOH, 9:1. The organic phase is
washed with brine, dried (sodium sulfate), filtered and
concentrated. Purification of the residue by silica gel column
chromatography (DCM/MeOH+1% NH.sub.3.sup.aq, 9:1) affords 6.2 g of
the title compound as a yellow solid: ESI-MS: 236.0 [MH].sup.+;
t.sub.R=2.35 min (purity: 100%, gradient J); TLC: R.sub.f=0.50
(DCM/MeOH+1% NH.sub.3.sup.aq, 9:1).
Example 146
3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-methyl-1-(6-{4-[3-(4-methyl-pipera-
zin-1-yl)-propoxy]-phenylamino}-pyrimidin-4-yl)-urea
##STR00204##
[1049] The title compound is prepared as described in Example 144
but using
N-methyl-N'-{4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-pyrimi-
dine-4,6-diamine (93 mg, 0.26 mmol, 1 eq.). Purification of the
crude product by silica gel column chromatography (DCM/MeOH+1%
NH.sub.3.sup.aq, 95:5) affords 86 mg of the title compound as a
white solid: ESI-MS: 603.9/605.9 [MH].sup.+; t.sub.R=3.21 min
(purity: 100%, gradient J); TLC: R.sub.f=0.19 (DCM/MeOH+1%
NH.sub.3.sup.aq, 95:5).
A.
N-Methyl-N'-{4-[3-(4-methyl-Piperazin-1-yl)-propoxy]-phenyl}-pyrimidine-
-4,6-diamine
[1050] The title compound is prepared as described in Example 143A
but using 4-[3-(4-methylpiperazin-1-yl)-propoxy]-phenylamine (383
mg, 1.50 mmol, 1.1 eq.) and stirring the reaction mixture for 18 h
at 100.degree. C. The reaction mixture is allowed to cool to RT,
poured onto a saturated aqueous solution of sodium bicarbonate, and
extracted with EE and DCM. The organic phase is dried (sodium
sulfate), filtered and concentrated.
[1051] The residue is triturated in diethyl ether to provide 115 mg
of the title compound as a white solid: ESI-MS: 357.1 [MH].sup.+;
t.sub.R=1.10 min (gradient J); purity: 100%, gradient J); TLC:
R.sub.f=0.08 (DCM/MeOH, 9:1).
B. 4-[3-(4-Methylpiperazin-1-yl)-propoxyl]-phenylamine
##STR00205##
[1053] 1-(3-Chloro-propyl)-4-methyl-piperazine hydrochloride (1.7
g, 9.6 mmol, 1.2 eq.) is added in one portion to a mixture of
4-aminophenol (893 mg, 8.0 mmol) and finely powdered sodium
hydroxide (808 mg, 20 mmol, 2.5 eq.) in DMF (27 ml). The reaction
mixture is stirred for 17 h at RT. The resulting dark suspension is
filtered. The filtrate is diluted with DCM (200 ml) and washed with
brine (2.times.50 ml). The aqueous layer is back-extracted with
DCM. The organic phase is dried (sodium sulfate), filtered and
concentrated. Purification of the residue by silica gel column
chromatography (DCM/MeOH, 7:3) provides 1.86 g of the title
compound as a yellow-brown oil: ESI-MS: 250.2 [MH].sup.+, TLC:
R.sub.f=0.31 (DCM/MeOH, 7:3).
Example 147
3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(3-dimethylamino-propyl)-phe-
nylamino]-pyrimidin-4-yl}-1-methyl-urea
##STR00206##
[1055] The title compound is prepared as described in Example 144
but using
N-K-(3-dimethylamino-propyl)-phenyl]-N'-pyrimidine-4,6-diamine (206
mg, 0.72 mmol, 1 eq.). Purification of the crude product by silica
gel column chromatography (DCM/MeOH+1% NH.sub.3.sup.aq, 93:7)
affords 84 mg of the title compound as a white solid: ESI-MS:
532.9/534.9 [MH].sup.+; t.sub.R=3.70 min (purity: 100%, gradient
J); TLC: R.sub.f=0.15 (DCM/MeOH+1% NH.sub.3.sup.aq, 93:7).
A.
N-[4-(3-Dimethylamino-propyl)-phenyl]-N'-pyrimidine-4,6-diamine
[1056] The title compound is prepared as described in Example 144A
but using 4-(3-dimethylamino-propyl-phenylamine (311 mg, 1.7 mmol).
Purification of the residue by silica gel column chromatography
(DCM/MeOH+1% NH.sub.3.sup.aq, 9:1), followed by trituration of the
resulting solid in diethyl ether, affords 213 mg of the title
compound as a white solid: ESI-MS: 286.1 [MH].sup.+; t.sub.R=1.20
min (gradient J); purity: 100%, gradient J); TLC: R.sub.f 0.08
(DCM/MeOH+1% NH.sub.3.sup.aq, 9:1).
B. 4-(3-Dimethylamino-propyl-phenylamine
[1057] A mixture of dimethyl-[3-(4-nitro-phenyl)-prop-2-ynyl]-amine
(1.35 g, 6.6 mmol), 10% palladium on carbon (140 mg), and EtOH (25
ml) is stirred for 22 h at RT, under a hydrogen atmosphere. The
reaction mixture is filtered through a pad of celite and
concentrated. Purification of the residue by silica gel column
chromatography (DCM/MeOH+1.degree. A) NH.sub.3.sup.aq, 95:5)
affords 797 mg of the title compound as a brown oil: ESI-MS: 179.0
[MH].sup.+; TLC: R.sub.f=0.14 (DCM/MeOH+1% NH.sub.3.sup.aq,
95:5).
C. Dimethyl-[3-(4-nitro-phenyl)-prop-2-ynyl]-amine
[1058] Tri-t-butylphosphine (0.25 M in dioxane, 11.9 ml, 3.0 mmol,
0.2 eq.), 3-dimethylamino-1-propyne (2.2 ml, 20.8 mmol, 1.4 eq.),
and diisopropylamine (2.7 ml, 19.3 mmol, 1.3 eq.) are added
sequentially to a mixture of 4-bromonitrobenzene (3 g, 14.9 mmol),
copper (I) iodide (198 mg, 1.0 mmol, 0.07 eq.), and
Pd(PhCN).sub.2Cl.sub.2 (570 mg, 1.5 mmol, 0.1 eq.) in dioxane (20
ml), under an argon atmosphere. The resulting mixture is stirred
for 22 h at RT and concentrated. The residue is dissolved in EE and
water and filtered through a pad of celite. The aqueous layer is
separated and extracted with EE. The organic phase is washed with
brine, dried (sodium sulfate), filtered and concentrated.
Purification of the residue by silica gel column chromatography
(DCM/MeOH+1% NH.sub.3.sup.aq, 95:5) affords 2.72 g of the title
compound as a brown oil: ESI-MS: 205.0 [MH].sup.+; t.sub.R=2.51 min
(purity: 100%, gradient J); TLC: R.sub.f=0.41 (DCM/MeOH+1%
NH.sub.3.sup.aq, 95:5).
Example 148
3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-methyl-1-{6-[4-(2-pyrrolidin-1-yl--
ethoxy)-phenylamino]-pyrimidin-4-yl}-urea
##STR00207##
[1060] The title compound is prepared as described in Example 144
but using
N-methyl-N'-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-pyrimidine-4,6-di-
amine (227 mg, 0.72 mmol, 1 eq.). Purification of the crude product
by silica gel column chromatography (DCM/MeOH+1% NH.sub.3.sup.aq,
92:8) affords 156 mg of the title compound as a white solid:
ESI-MS: 560.9/562.9 [MH].sup.+; t.sub.R=3.64 min (purity: 100%,
gradient J); TLC: R.sub.f=0.42 (DCM/MeOH+1% NH.sub.3.sup.aq,
92:8).
A.
N-Methyl-N'-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-pyrimidine-4,6-diamin-
e
[1061] The title compound is prepared as described in Example 143A
but using 4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine (360 mg, 1.70
mmol, 1 eq.) and stirring the reaction mixture for 18 h at
150.degree. C. The reaction mixture is allowed to cool to RT and
the top phase is discarded. The gluey bottom residue is diluted
with a saturated aqueous solution of sodium bicarbonate and DCM.
The aqueous layer is separated and extracted with DCM. The organic
phase is dried (sodium sulfate), filtered and concentrated.
Purification of the crude product by silica gel column
chromatography (DCM/MeOH+1% NH.sub.3.sup.aq, 9:1), followed by
trituration of the resulting solid in diethyl ether, affords 402 mg
of the title compound as a grey solid: ESI-MS: 314.1 [MH].sup.+;
t.sub.R=1.15 min (gradient J); purity: 100%, gradient J); TLC:
R=0.15 (DCM/MeOH+1% NH.sub.3.sup.aq, 9:1).
B. 4-(2-Pyrrolidin-1-yl-ethoxy)-phenylamine
[1062] The title compound is prepared as described in Example 146B
but using 1-(2-chloroethyl)-pyrrolidine hydrochloride (7.6 g, 44.9
mmol, 1.2 eq.) and stirring the reaction mixture for 2 h at
75.degree. C. Purification of the residue by silica gel column
chromatography (DCM/MeOH, 1:1) affords 7.7 g of the title compound
as a brown oil: ESI-MS: 207.1 [MH].sup.+; TLC: R.sub.f=0.22
(DCM/MeOH, 1:1).
Example 149
3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-ethyl-piperazin-1-ylmethy-
l)-phenylamino]-pyrimidin-4-yl}-1-methyl-urea
##STR00208##
[1064] The title compound is prepared as described in Example 144
but using
N-[4-(4-ethyl-piperazin-1-ylmethyl)-phenyl]-N'-methyl-pyrimidine-4,-
6-diamine (140 mg, 0.43 mmol, 1 eq.). Purification of the crude
product by MPLC (silica gel) (DCM/MeOH+1% NH.sub.3.sup.aq, 95:5)
affords 24 mg of the title compound: ESI-MS: 573.9/575.9
[MH].sup.+; t.sub.R=3.25 min (purity: 90%, gradient J); TLC:
R.sub.f=0.09 (DCM/MeOH+1% NH.sub.3.sup.aq, 9:1).
A.
N-[4-(4-Ethyl-piperazin-1-ylmethyl)-phenyl]-N'-methyl-pyrimidine-4,6-di-
amine
[1065] The title compound is prepared as described in Example 143A
but using 4-(4-ethyl-piperazin-1-ylmethyl)-phenylamine (500 mg,
2.28 mmol, 1 eq.) and stirring the reaction mixture for 18 h at
150.degree. C. Purification of the crude product by MPLC (silica
gel) (DCM/MeOH+1% NH.sub.3.sup.aq, 9:1) affords 140 mg of impure
product which is used without further purification.
B. 4-(4-Ethyl-piperazin-1-ylmethyl)-phenylamine
[1066] A suspension of 1-ethyl-4-(4-nitro-benzyl)-piperazine (7.2
g, 29.14 mmol) and Raney Nickel (1.5 g) in MeOH (100 mL) is stirred
for 6 h at RT, under a hydrogen atmosphere. The reaction mixture is
filtered through a pad of celite and concentrated to afford 6.3 g
of the title compound as a yellow solid: ESI-MS: 220.1 [MH].sup.+;
TLC: R.sub.f=0.08 (DCM/MeOH+1% NH.sub.3.sup.aq, 9:1).
C. 1-Ethyl-4-(4-nitro-benzyl)-piperazine
[1067] A mixture of 4-nitrobenzylchloride (5 g, 29.14 mmol),
N-ethylpiperazine (4.4 ml, 34.97 mmol, 1.2 eq.), potassium
carbonate (8 g, 58.28, 2 eq.), and acetone (100 ml) is stirred for
15 h at reflux. The reaction mixture is allowed to cool to RT,
filtered and concentrated to afford 7.2 g of the title compound as
a brow oil: ESI-MS: 250.1 [MH].sup.+; TLC: R.sub.f=0.31
(DCM/MeOH+1% NH.sub.3.sup.aq, 9:1).
Example 150
3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-{6-[3-(4-ethyl-piperazin-1-ylmethy-
l)-phenylamino]-pyrimidin-4-yl}-1-methyl-urea
##STR00209##
[1069] The title compound is prepared as described in Example 144
but using
N-[3-(4-ethyl-piperazin-1-ylmethyl)-phenyl]-N'-methyl-pyrimidine-4,-
6-diamine (306 mg, 0.94 mmol, 1 eq.). Purification of the crude
product by MPLC (silica gel) (DCM/MeOH+1% NH.sub.3.sup.aq, 95:5)
affords 207 mg of the title compound: ESI-MS: 573.9/575.9
[MH].sup.+; t.sub.R=3.28 min (purity: 100%, gradient J); TLC:
R.sub.f=0.24 (DCM/MeOH+1% NH.sub.3.sup.aq, 95:5).
A.
N-[3-(4-Ethyl-piperazin-1-ylmethyl)-phenyl]-N'-methyl-pyrimidine-4,6-di-
amine
[1070] The title compound is prepared as described in Example 143A
but using 3-(4-ethyl-piperazin-1-ylmethyl)-phenylamine (500 mg,
2.28 mmol, 1 eq.) and stirring the reaction mixture for 15 h at
150.degree. C. Purification of the crude product by MPLC (silica
gel) (DCM/MeOH+1% NH.sub.3.sup.aq, 9:1) affords 306 mg of the title
compound as a beige solid: ESI-MS: 327.2 [MH].sup.+; TLC:
R.sub.f=0.05 (DCM/MeOH+1% NH.sub.3.sup.aq, 9:1).
B. 3-(4-Ethyl-piperazin-1-ylmethyl)-phenylamine
[1071] The title compound is prepared as described in Example 149B:
ESI-MS: 220.1 [MH].sup.+; t.sub.R=0.79 min (purity: 100%, gradient
J).
C. 1-Ethyl-4-(3-nitro-benzyl)-piperazine
[1072] The title compound is prepared as described in Example 149C:
ESI-MS: 250.1 [MH].sup.+; t.sub.R=1.50 min (purity: 100%, gradient
J); TLC: R.sub.f=0.32 (DCM/MeOH+1% NH.sub.3.sup.aq, 9:1).
Example 151
3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-[6-(3-dimethylaminomethyl-phenylam-
ino)-pyrimidin-4-yl]-1-ethyl-urea
##STR00210##
[1074] A suspension of 2,6-dichloro-3-methoxyphenylisocyanate (2
eq.) in toluene (3 ml) is added to a refluxing solution of
N-(3-dimethylaminomethyl-phenyl)-N'-methyl-pyrimidine-4,6-diamine
(216 mg, 0.80 mmol, 1 eq.) in toluene (3 ml), under an argon
atmosphere. The resulting mixture is stirred at reflux for 2 h and
allowed to cool to RT. The reaction mixture is diluted with EE and
a saturated aqueous solution of sodium bicarbonate. The aqueous
layer is separated and extracted with EE. The organic phase is
washed with brine, dried (sodium sulfate), filtered and
concentrated. Purification of the residue by silica gel column
chromatography (DCM/MeOH+1% NH.sub.3.sup.aq, 95:5), followed by
reversed phase MPLC purification (AcCN/H.sub.2O/TFA) of the
resulting product, affords 161 mg of the title compound as a white
solid: ESI-MS: 518.9/520.9 [MH].sup.+; t.sub.R=3.76 min (purity:
100%, gradient J); TLC: R.sub.f 0.21 (DCM/MeOH+1% NH.sub.3.sup.aq,
95:5).
A.
N-(3-Dimethylaminomethyl-phenyl)-N'-ethyl-pyrimidine-4,6-diamine
[1075] The title compound is prepared as described in Example 143A
but using 3-dimethylaminomethyl-phenylamine (334 mg, 2.20 mmol, 1
eq.), (6-chloro-pyrimidin-4-yl)-ethyl-amine (Example 143B) and
stirring the reaction mixture for 3 h at 160.degree. C.
Purification of the crude product by silica gel column
chromatography (DCM/MeOH+1% NH.sub.3.sup.aq, 9:1), followed by
trituration of the resulting solid in diethyl ether, affords 335 mg
of the title compound as a beige solid: ESI-MS: 272.1 [MH].sup.+;
t.sub.R=1.18 min (purity: 100%, gradient J); TLC: R.sub.f 0.16
(DCM/MeOH+1% NH.sub.3.sup.aq, 9:1).
Example 152
3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(2-diethylamino-ethoxy)-phen-
ylamino]-pyrimidin-4-yl}-1-methyl-urea
##STR00211##
[1077] The title compound is prepared as described in Example 151
but using
N-[4-(2-diethylamino-ethoxy)-phenyl]-N'-methyl-pyrimidine-4,6-diami-
ne (255 mg, 0.81 mmol, 1 eq.). Purification of the crude product by
silica gel column chromatography (DCM/MeOH+1% NH.sub.3.sup.aq,
95:5), followed by trituration of the resulting solid in MeOH,
affords 220 mg of the title compound as a white solid: ESI-MS:
562.9/564.9 [MH].sup.+; t.sub.R=3.70 min (purity: 93%, gradient J);
TLC: R.sub.f=0.21 (DCM/MeOH+1% NH.sub.3.sup.aq, 95:5).
A.
N-[4-(2-Diethylamino-ethoxy)-phenyl]-N'-methyl-pyrimidine-4,6-diamine
[1078] The title compound is prepared as described in Example 143A
but using 4-(2-diethylamino-ethoxy)-phenylamine (271 mg, 1.3 mmol,
1 eq.) and stirring the reaction mixture for 18 h at 150.degree. C.
The reaction mixture is allowed to cool to RT and the top phase is
discarded. The gluey bottom residue is diluted with a saturated
aqueous solution of sodium bicarbonate and DCM. The aqueous layer
is separated and extracted with DCM. The organic phase is dried
(sodium sulfate), filtered and concentrated. Purification of the
crude product by silica gel column chromatography (DCM/MeOH+1%
NH.sub.3.sup.aq, 92:8) provides 261 mg of the title compound as a
grey solid: ESI-MS: 316.1 [MH].sup.+; t.sub.R=1.25 min (purity:
100%, gradient J); TLC: R.sub.f=0.19 (DCM/MeOH+1% NH.sub.3.sup.aq,
92:8).
B. 4-(2-Diethylamino-ethoxy)-phenylamine
[1079] The title compound is prepared as described in Example 146B
but using 1-(2-chloroethyl)-diethylamine hydrochloride (1.9 g, 11
mmol, 1.2 eq.) and stirring the reaction mixture for 1 h at RT.
Purification of the residue by silica gel column chromatography
(DCM/MeOH, 4:1.fwdarw.7:3) affords 1.52 g of the title compound as
a brown oil: ESI-MS: 209.1 [MH].sup.+; TLC: R.sub.f=0.12 (DCM/MeOH,
7:3).
Example 153
3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-[6-(2,6-dimethyl-pyridin-3-ylamino-
)-pyrimidin-4-yl]-1-methyl-urea
##STR00212##
[1081] The title compound is prepared as described in Example 151
but using
N-(2,6-dimethyl-pyridin-3-yl)-N'-methyl-pyrimidine-4,6-diamine.
[1082] ESI-MS: 476.9/478.9 [MH].sup.+; t.sub.R=3.44 min (purity:
100%, gradient J); TLC: R.sub.f=0.40 (DCM/MeOH+1% NH.sub.3.sup.aq,
9:1).
A.
N-(2,6-Dimethyl-pyridin-3-yl)-N'-methyl-pyrimidine-4,6-diamine
[1083] The title compound is prepared as described in Example 152A
but using 3-amino-2,6-dimethylpyrimidine and stirring the reaction
mixture for 24 h at 150.degree. C.
[1084] ESI-MS: 230.1 [MH].sup.+; TLC: R.sub.f=0.22 (DCM/MeOH,
9:1).
Example 154
3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-methyl-1-[6-(6-trifluoromethyl-pyr-
idin-3-ylamino)-pyrimidin-4-yl]-urea
##STR00213##
[1086] The title compound is prepared as described in Example 151
but using
N-methyl-N'-(6-trifluoromethyl-pyridin-3-yl)-pyrimidine-4,6-diamine-
.
[1087] ESI-MS: 514.8/516.8 [MH].sup.-; t.sub.R=5.27 min (purity:
100%, gradient J); TLC: R.sub.f=0.49 (DCM/MeOH, 9:1).
A.
N-Methyl-N'-(6-trifluoromethyl-pyridin-3-yl)-pyrimidine-4,6-diamine
[1088] The title compound is prepared as described in Example 152A
but using 3-amino-6-(trifluoromethyl)pyridine and stirring the
reaction mixture for 24 h at 150.degree. C.
[1089] ESI-MS: 270.0 [MH].sup.+; t.sub.R=2.63 min (purity: 100%,
gradient J); TLC: R.sub.f=0.32 (DCM/MeOH, 9:1).
Example 155
1-(2,6-Dichloro-3,5-dimethoxy-phenyl)-3-{6-[4-(2-pyrrolidin-1-yl-ethoxy)-p-
henylamino]-pyrimidin-4-yl}-urea
##STR00214##
[1091] The title compound is prepared as described in Example 151
but using
N-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-pyrimidine-4,6-diamine.
[1092] ESI-MS: 546.9/548.8 [MH]; t.sub.R=3.15 min (purity: 100%,
gradient J); TLC: R.sub.f=0.49 (DCM/MeOH+1% NH.sub.3.sup.aq,
95:5).
A.
N-[4-(2-Pyrrolidin-1-yl-ethoxy)-phenyl]-pyrimidine-4,6-diamine
[1093] The title compound is prepared as described in Example 152A
but using 6-chloro-pyrimidin-4-ylamine,
4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine (Example 148B), and
stirring the reaction mixture for 2 h at 150.degree. C.
[1094] ESI-MS: 300.1 [MH].sup.+; t.sub.R=1.10 min (purity: 100%,
gradient J).
Example 156
3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-ethyl-1-{6-[4-(2-pyrrolidin-1-yl-e-
thoxy)-phenylamino]-pyrimidin-4-yl}-urea
##STR00215##
[1096] The title compound is prepared as described in Example 151
but using
N-ethyl-N'-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-pyrimidine-4,6-dia-
mine.
[1097] ESI-MS: 575.2/577.2 [MH].sup.+; t.sub.R=3.74 min (purity:
100%, gradient J); TLC: R.sub.f=0.42 (DCM/MeOH+1% NH.sub.3.sup.aq,
95:5).
A.
N-Ethyl-N'-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-pyrimidine-4,6-diamine
[1098] The title compound is prepared as described in Example 152A
but using 6-chloro-pyrimidin-4-yl)-ethyl-amine,
4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine (Example 148B), and
stirring the reaction mixture for 6 h at 150.degree. C. The crude
product is purified by trituration in diethyl ether.
[1099] ESI-MS: 326.1 [MH].sup.-; t.sub.R=1.45 min (purity: 95%,
gradient J).
Example 157
1-(2,6-Dichloro-3,5-dimethoxy-phenyl)-3-[6-(3-dimethylaminomethyl-phenylam-
ino)-pyrimidin-4-yl]-urea
##STR00216##
[1101] The title compound is prepared as described in Example 151
but using
N-(3-dimethylaminomethyl-phenyl)-pyrimidine-4,6-diamine.
[1102] ESI-MS: 491.0/493.0 [MH].sup.+; t.sub.R=3.17 min (purity:
97%, gradient J); TLC: R.sub.f=0.25 (DCM/MeOH+1% NH.sub.3.sup.aq,
92:8).
A. N-(3-Dimethylaminomethyl-phenyl)-pyrimidine-4,6-diamine
[1103] The title compound is prepared as described in Example 152A
but using 3-dimethylaminomethyl-phenylamine,
6-chloro-pyrimidin-4-ylamine, and stirring the reaction mixture for
2 h at 150.degree. C. The crude product is purified by trituration
in diethyl ether followed by silica gel column chromatography
(DCM/MeOH+1% NH.sub.3.sup.aq, 92:8) of the resulting beige solid to
afford the title compound as a white solid. ESI-MS: 242.1
[MH].sup.-; t.sub.R=0.95 min (purity: 100%, gradient J); TLC:
R.sub.f=0.11 (DCM/MeOH+1% NH.sub.3.sup.aq, 92:8).
Example 158
1-(2,6-Dichloro-3,5-dimethoxy-phenyl)-3-(6-{4-[2-(4-methyl-piperazin-1-yl)-
-ethoxy]-phenylamino}-pyrimidin-4-yl)-urea
##STR00217##
[1105] The title compound is prepared as described in Example 151
but using
N-(3-dimethylaminomethyl-phenyl)-pyrimidine-4,6-diamine.
[1106] ESI-MS: 575.9/577.9 [MH].sup.+; t.sub.R=2.83 min (purity:
100%, gradient J); TLC: R.sub.f=0.03 (DCM/MeOH+1% NH.sub.3.sup.aq,
95:5).
A.
N-{4-[2-(4-Methyl-piperazin-1-yl)-ethoxy]-phenyl}-pyrimidine-4,6-diamin-
e
[1107] The title compound is prepared as described in Example 152A
but using 4-[2-(4-methyl-piperazin-1-yl)-ethoxy]-phenylamine (300
mg, 1.28 mmol, 1 eq.), 6-chloro-pyrimidin-4-ylamine, water (0.5
ml), and stirring the reaction mixture for 2 h at 150.degree. C.
The crude product is purified by trituration in diethyl ether to
afford the title compound as a white solid. ESI-MS: 329.1
[MH].sup.+; t.sub.R=0.98 min (purity: 100%, gradient J).
Example 159
1-(2,6-Dichloro-3,5-dimethoxy-phenyl)-3-[6-(4-dimethylaminomethyl-3-triflu-
oromethyl-phenylamino)-pyrimidin-4-yl]-urea
##STR00218##
[1109] The title compound is prepared as described in Example 151
but using
N-(4-dimethylaminomethyl-3-trifluoromethyl-phenyl)-pyrimidine-4,6-d-
iamine.
[1110] ESI-MS: 558.9/560.9 [MH].sup.+; t.sub.R=3.69 min (purity:
100%, gradient J); TLC: R.sub.f=0.21 (DCM/MeOH+1% NH.sub.3.sup.aq,
95:5).
A.
N-(4-Dimethylaminomethyl-3-trifluoromethyl-phenyl)-pyrimidine-4,6-diami-
ne
[1111] The title compound is prepared as described in Example 152A
but using 4-dimethylaminomethyl-3-trifluoromethyl-phenylamine (218
mg, 1.46 mmol, 1 eq.), 6-chloro-pyrimidin-4-ylamine, and stirring
the reaction mixture for 5 h at 150.degree. C. The crude product is
purified by silica gel column chromatography (DCM/MeOH+1%
NH.sub.3.sup.aq, 92:8) to afford the title compound as a white
solid. ESI-MS: 312.1 [MH].sup.+; t.sub.R=1.20 min (purity: 100%,
gradient J); TLC: R.sub.f=0.16 (DCM/MeOH+1% NH.sub.3.sup.aq,
92:8).
B.
4-(4-(N,N-Dimethylamino-methyl)-3-trifluoromethyl-phenyl-amine
[1112]
N-(4-Dimethylaminomethyl-3-trifluoromethyl-phenyl)-pyrimidine-4,6-d-
iamine (359 mg, 1.2 mmol) is dissolved in MeOH (12 mL) and treated
with K.sub.2CO.sub.3 (6 mL of a 1N aqueous solution) at RT. The
reaction is heated to reflux for 1.5 h until completion, cooled
back to RT and concentrated. The residual oil is taken up in EtOAc
and washed with brine. The organic layers are dried over
Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure.
Drying under high vacuum gives the title compound as a yellow oil.
ESI-MS: 219 [MH].sup.+.
C.
N-(4-Dimethylaminomethyl-3-trifluoromethyl-phenyl)-pyrimidine-4,6-diami-
ne
[1113] 501 mg (1.5 mmol)
N-(4-bromomethyl-3-trifluoromethyl-phenyl)-2,2,2-trifluoro-acetamide
(Step 14.2) is added to 5 ml of a solution of dimethyl amine in
EtOH (33%) at RT. The reaction is stirred at ambient temperature
for 0.5 h until completion. It is concentrated and the residual
crude product is purified by flash chromatography (SiO.sub.2;
CH.sub.2Cl.sub.2/MeOH, gradient 0-5% MeOH) to give the title
compound as a yellow oil. ESI-MS: 315 [MH].sup.+.
D.
N-(4-Bromomethyl-3-trifluoromethyl-phenyl)-2,2,2-trifluoro-acetamide
[1114] To a solution of 60.9 g (224.6 mmol) of
N-(4-methyl-3-trifluoromethyl-phenyl)-2,2,2-trifluoro-acetamide in
830 ml n-butyl acetate under a nitrogen atmosphere, 44 g (247 mmol)
N-bromosuccinimide and 830 mg (5 mmol) azo-iso-butyronitrile are
added. The suspension is heated up to 60.degree. C. and then
illuminated for 30 min by a Phillips low-voltage lamp (500 W; 10500
lm), whereby the temperature rises to 70-75.degree. C. and a clear
brown solution is formed. There is still remaining educt
detectable, therefore another 22 g N-bromosuccinimide are added in
3 portions. After totally 6 h illumination, the resulting solid is
filtered off and discarded and the filtrate concentrated. The
residue is distributed between 2 l CH.sub.2Cl.sub.2 and 1 l
H.sub.2O and the aqueous layer extracted with 1 l CH.sub.2Cl.sub.2.
The organic phases are washed 4 times with 1 l H.sub.2O, 0.5 l
brine, dried (Na.sub.2SO.sub.4) and concentrated. Column
chromatography (SiO.sub.2; hexane/CH.sub.2Cl.sub.2 2:1.fwdarw.1:1)
and crystallization from CH.sub.2Cl.sub.2/hexane yields the title
compound: m.p.: 119-120.degree. C.
E.
N-(4-Methyl-3-trifluoromethyl-phenyl)-2,2,2-trifluoro-acetamide
[1115] To an ice-cooled solution of 320 g (1.827 Mol) of
5-amino-2-methylbenzotrifluoride and 1.47 l (18.27 mol) pyridine in
4.5 l of CH.sub.2Cl.sub.2 under N.sub.2-atmosphere, 284 ml (2.01
Mol) of trifluoroacetic acid anhydride are added dropwise. After 50
min, the mixture is diluted with 5 l ice-cooled 2 N HCl. The
organic phases are separated off and washed two times with 2 l cold
2 N HCl, then 1 l 2 N HCl and finally with 2 l brine. The aqueous
layers are extracted twice with CH.sub.2Cl.sub.2, the organic
phases dried (Na.sub.2SO.sub.4) and concentrated partially.
Crystallization by addition of hexane yields the title compound:
m.p.: 72-73.degree. C.
Example 160
1-(2,6-Dichloro-3,5-dimethoxy-phenyl)-3-{6-[4-(4-ethyl-piperazin-1-yl)-phe-
nylamino]-pyrimidin-4-yl}-urea
##STR00219##
[1117] 2,6-dichloro-3,5-dimethoxyphenylisocyanate (1.2 eq.) is
added to a solution of
N-[4-(4-ethyl-piperazin-1-yl)-phenyl]-pyrimidine-4,6-diamine (350
mg, 1.18 mmol) in NMP (2 ml), at 70.degree. C. and under an argon
atmosphere. The resulting mixture is stirred at 70.degree. C. for 2
h, allowed to cool to RT and concentrated. The residue is diluted
with DCM and a saturated aqueous solution of sodium bicarbonate.
The aqueous layer is separated and extracted with DCM. The organic
phase is washed with brine, dried (sodium sulfate), filtered and
concentrated. Purification of the crude product by trituration in
MeOH followed by silica gel column chromatography (DCM/MeOH+1%
NH.sub.3.sup.aq, 97:3) affords the title compound as a white solid:
ESI-MS: 545.9/547.9 [MH].sup.+; t.sub.R=3.10 min (purity: 100%,
gradient J); TLC: R.sub.f=0.18 (DCM/MeOH+1% NH.sub.3.sup.aq,
95:5).
A. N-(4-(4-Ethyl-piperazin-1-yl)-phenyl]-pyrimidine-4,6-diamine
[1118] A mixture of 6-chloro-pyrimidin-4-yl)-amine (500 mg, 3.87
mmol, 1.3 eq.) and 4-(4-ethylpiperazin-1-yl)-aniline (611 mg, 2.98
mmol) in water (3.0 ml) and glacial acetic acid (10 ml) is heated
to 100.degree. C. for 15 h. The reaction mixture is diluted with
DCM and brine. The aqueous layer is made basic by addition of
sodium bicarbonate. The aqueous layer is separated and extracted
with DCM. The organic phase is washed with brine, dried (sodium
sulfate), filtered and concentrated. Purification of the crude
product by trituration in EE affords the title compound: ESI-MS:
299.2 [MH].sup.+; t.sub.R=1.05 min (gradient J).
Example 161
3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-{6-[3-(4-isopropyl-piperazin-1-ylm-
ethyl)-phenylamino]-pyrimidin-4-yl}-1-methyl-urea
##STR00220##
[1120] The title compound is prepared as described in Example 151
but using
N-[3-(4-isopropyl-piperazin-1-ylmethyl)-phenyl]-N'-methyl-pyrimidin-
e-4,6-diamine. Purification of the crude product by MPLC (silica
gel) (DCM/MeOH+1% NH.sub.3.sup.aq, 95:5) affords the title compound
as a white solid: ESI-MS: 587.9/589.9 [MH].sup.+; t.sub.R=3.35 min
(purity: 100%, gradient J); TLC: R.sub.f=0.17 (DCM/MeOH+1%
NH.sub.3.sup.aq, 9:1).
A.
N-[3-(4-Isopropyl-piperazin-1-ylmethyl)-phenyl]-N'-methyl-pyrimidine-4,-
6-diamine
[1121] The title compound is prepared as described in Example 152A
but using 3-(4-isopropyl-piperazin-1-ylmethyl)-phenylamine and
stirring the reaction mixture for 17.5 h at 150.degree. C. The
crude product is purified by MPLC (silica gel) (DCM/MeOH+1%
NH.sub.3.sup.aq, 95:5) to afford the title compound as a light
yellow solid. ESI-MS: 341.2 [MH].sup.+; t.sub.R=1.05 min (purity:
100%, gradient J); TLC: R.sub.f=0.10 (DCM/MeOH+1% NH.sub.3.sup.aq,
9:1).
B. 3-(4-Isopropyl-Piperazin-1-ylmethyl)-phenylamine
[1122] The title compound is prepared as described in Example 149B:
ESI-MS: 234.2 [MH].sup.+.
C. 1-Isopropyl-4-(3-nitro-benzyl)-piperazine
[1123] The title compound is prepared as described in Example 149C.
Purification of the crude product by silica gel column
chromatography (DCM/MeOH+1% NH.sub.3.sup.aq, 9:1) affords the title
compound as a yellow solid: ESI-MS: 264.1 [MH].sup.+; t.sub.R=1.64
min (purity: 96.5%, gradient J); TLC: R.sub.f=0.35 (DCM/MeOH+1%
NH.sub.3.sup.aq, 9:1).
Example 162
3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-[6-(3-{[(2-dimethylamino-ethyl)-me-
thyl-amino]-methyl}-phenylamino)-pyrimidin-4-yl]-1-methyl-urea
##STR00221##
[1125] The title compound is prepared as described in Example 151
but using
N-(3-{[(2-dimethylamino-ethyl)-methyl-amino]-methyl}-phenyl)-N'-met-
hyl-pyrimidine-4,6-diamine. Purification of the crude product by
MPLC (silica gel) (DCM/MeOH+1% NH.sub.3.sup.aq, 95:5) affords the
title compound as a white solid: ESI-MS: 561.9/563.9 [MH].sup.+;
t.sub.R=3.24 min (purity: 100%, gradient J); TLC: R.sub.f=0.10
(DCM/MeOH+1% NH.sub.3.sup.aq, 9:1).
A.
N-(3-{[(2-Dimethylamino-ethyl)-methyl-amino]-methyl}-phenyl)-N'-methyl--
pyrimidine-4,6-diamine
[1126] The title compound is prepared as described in Example 152A
but using N-(3-amino-benzyl)-N,N',N'-trimethyl-ethane-1,2-diamine
and stirring the reaction mixture for 17.5 h at 150.degree. C. The
crude product is purified by MPLC (silica gel) (DCM/MeOH+1%
NH.sub.3.sup.aq, 95:5) to afford the title compound as a beige
solid. ESI-MS: 315.2 [MH].sup.+; TLC: R.sub.f=0.05 (DCM/MeOH+1
NH.sub.3.sup.aq, 9:1).
B. N-(3-Amino-benzyl)-N,N',N'-trimethyl-ethane-1,2-diamine
[1127] The title compound is prepared as described in Example 149B:
ESI-MS: 208.2 [MH].sup.+.
C. N,N',N'-Trimethyl-N'-(3-nitro-benzyl)-ethane-1,2-diamine
[1128] The title compound is prepared as described in Example 149C.
Purification of the crude product by silica gel column
chromatography (DCM.fwdarw.DCM/MeOH+1% NH.sub.3.sup.aq, 9:1)
affords the title compound as a brown oil: ESI-MS: 238.1
[MH].sup.+; t.sub.R=1.15 min (purity: 96.5%, gradient J); TLC:
R.sub.f=0.10 (DCM/MeOH, 9:1).
Example 163
3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-isopropyl-piperazin-1-yl)-
-phenylamino]-pyrimidin-4-yl}-1-methyl-urea
##STR00222##
[1130] The title compound is prepared as described in Example 151
but using
N-[4-(4-isopropyl-piperazin-1-yl)-phenyl]-N'-methyl-pyrimidine-4,6--
diamine.
[1131] ESI-MS: 573.9/575.9 [MH].sup.+; t.sub.R=3.65 min (purity:
97%, gradient J); TLC: R.sub.f=0.10 (DCM/MeOH+1% NH.sub.3.sup.aq,
97:3).
A.
N-[4-(4-Isopropyl-piperazin-1-yl)-phenyl]-N'-methyl-pyrimidine-4,6-diam-
ine
[1132] The title compound is prepared as described in Example 152A
but using N-(3-amino-benzyl)-N,N',N'-trimethyl-ethane-1,2-diamine
and stirring the reaction mixture for 4 h at 150.degree. C. The
crude product is purified by silica gel column chromatography
(DCM/MeOH+1% NH.sub.3.sup.aq, 92:8) to afford the title compound as
a white solid. ESI-MS: 327.2 [MH].sup.+; TLC: R.sub.f=0.26
(DCM/MeOH+1% NH.sub.3.sup.aq, 92:8).
B. 4-(4-Isopropyl-piperazin-1-yl)-phenylamine
[1133] The title compound is prepared as described in Example 149B:
ESI-MS: 220.1 [MH].sup.+.
C. 1-Isopropyl-4-(4-nitro-phenyl)-piperazine
[1134] The title compound is prepared as described in Example 149C.
Purification of the crude product by silica gel column
chromatography (DCM/MeOH, 95:5) affords the title compound as a
yellow solid: ESI-MS: 238.1 [MH].sup.+; t.sub.R=2.57 min (purity:
100%, gradient J); TLC: R.sub.f=0.16 (DCM/MeOH, 95:5).
Example 164
1-(2,6-Dichloro-3,5-dimethoxy-phenyl)-3-{6-[4-(1-methyl-piperidin-4-yloxy)-
-phenylamino]-pyrimidin-4-yl}-urea
##STR00223##
[1135] Example 165
3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-methyl-{6-[4-(1-methyl-piperidin-4-
-yloxy)-phenylamino]-pyrimidin-4-yl}-urea
##STR00224##
[1136] Example 166
3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-ethyl-{6-[4-(1-methyl-piperidin-4--
yloxy)-phenylamino]-pyrimidin-4-yl}-urea
##STR00225##
[1137] Example 167
3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-[6-(4-dimethylaminomethyl-3-triflu-
oromethyl-phenylamino)-pyrimidin-4-yl]-1-methyl-urea
##STR00226##
[1138] Example 168
1-(2,6-Dichloro-3,5-dimethoxy-phenyl)-3-{6-[4-(4-ethyl-piperazin-1-ylmethy-
l)-3-trifluoromethyl-phenylamino]-pyrimidin-4-yl}-urea
##STR00227##
[1139] Example 169
3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-ethyl-piperazin-1-ylmethy-
l)-3-trifluoromethyl-phenylamino]-pyrimidin-4-yl}-1-methyl-urea
##STR00228##
[1140] Example 170
In Vitro Enzymatic Data
[1141] The compounds of Examples 1 to 169 were tested under the
protocols as hereinbefore described for their inhibitory activity
against KDR, FGFR3 and TEK. Measurements are made as described in
the aforementioned methods in the general description. For KDR
67-100% inhibition at 10 .mu.M, for FGFR3 (K650E) 27-100%
inhibition at 10 .mu.M and for Tek 12-100% inhibition at 10 .mu.M
is observed.
Method A
Examples 171-193
Example 171
N-[4-Methyl-3-(3-methyl-3-{6-[4-(4-methyl-piperazin-1-yl)-phenyl-amino]-py-
rimidin-4-yl}-ureido)-phenyl]-3-trifluoromethyl-benzamide
[1142] To a solution of
N-(3-Amino-4-methyl-phenyl)-3-trifluoromethyl-benzamide
(preparation 3, 62 mg, 0.21 mmol, 1.25 eq.) in dioxane is added 20%
phosgene solution in toluene (110 .mu.l, 0.21 mmol, 1.25 eq.) under
argon. The reaction mixture is stirred for further 22 h at room
temperature under argon. Then, the solvent is evaporated and the
residue is taken up in dry toluene (2 ml). After the addition of
N-Methyl-N'-[4-(4-methyl-piperazin-1-yl)-phenyl]-pyrimidine-4,6-diamine
(50 mg, 0.168 mmol, 1.0 eq.) the suspension is refluxed for 24 h
under argon. After cooling ether (2 ml) is added and the mixture is
stirred for 30 min. The precipitated product is filtered off,
washed (1.times. toluene/ether 1:1, 1.times. ether) and vacuum
dried at 60.degree. C. overnight to afford the title compound as
colorless crystals: M.p. 189.5-191.degree. C., HPLC: t.sub.R=6.02
min (purity: >99%, gradient A), ESI-MS: 619.6 [MH].sup.+.
N-Methyl-N'-[4-(4-methyl-piperazin-1-yl)-phenyl]-pyrimidine-4,6-diamine
[1143] A solution of (6-chloro-pyrimidin-4-yl)-methyl-amine (1.65
g, 11.5 mmol, 1.1 eq.) and commercially available
4-(4-methylpiperazin-1-yl)-aniline (2.0 g, 10.5 mmol, 1.0 eq.) in a
mixture of water (4 ml) and glacial acetic acid (16 ml) is heated
to 100.degree. C. internal temperature for 16 h. After cooling the
solvent is evaporated.
[1144] The residue is taken up in methanol (50 ml) and made
alkaline by addition of 25% NH.sub.3 in water. To this silica gel
(11 g) is added and the solvent is evaporated. The silica adsorbed
crude product is purified by medium pressure liquid chromatography
(A: TBME; B: MeOH--NH.sub.3 99:1; gradient: 5% B->25% B in 180
min). The fractions containing the product are pooled and
evaporated to dryness. The residue is triturated with ether. The
product is filtered off, washed with ether, and vacuum dried at
50.degree. C. over night to give the title compound as pale yellow
powder: t.sub.R=3.04 min (purity: 97%, gradient A), ESI-MS: 299.3
[MH].sup.+.
(6-chloro-pyrimidin-4-yl)-methyl-amine
[1145] This material was prepared by a modified procedure published
in the literature (J. Appl. Chem. 1955, 5, 358): To a suspension of
commercially available 4,6-dichloropyrimidine (20 g, 131.6 mmol,
1.0 eq.) in isopropanol (60 ml) is added 33% methylamine in ethanol
(40.1 ml, 328.9 mmol, 2.5 eq.) at such a rate that the internal
temperature does not rise above 50.degree. C. After completion of
the addition the reaction mixture was stirred for 1 h at room
temperature. Then, water (50 ml) is added and the suspension formed
is chilled in an ice bath to 5.degree. C. The precipitated product
is filtered off, washed with cold isopropanol/water 2:1 (45 ml) and
water. The collected material is vacuum dried over night at
45.degree. C. to afford the title compound as colorless crystals:
t.sub.R=3.57 min (purity: >99%, gradient A), ESI-MS: 144.3/146.2
[MH].sup.+.
[1146] By following the procedure of Example 171 but using the
appropriate starting materials, examples 172-193 may be
prepared:
Example 172
N-{4-Methyl-3-[3-(6-methylamino-pyrimidin-4-yl)-ureido]-phenyl}-3-trifluor-
omethyl-benzamide
[1147] Colorless crystals, TLC: R.sub.f=0.40 (TBME/MeOH/NH3
90:9:1), HPLC: t.sub.R=5.88 min (purity: 85%, gradient A), ESI-MS:
445.4 [MH].sup.+.
Example 173
N-{4-Methyl-3-[3-(6-phenylamino-pyrimidin-4-yl)-ureido]-phenyl}-3-trifluor-
omethyl-benzamide
[1148] Colorless crystals, HPLC: t.sub.R=6.94 min (purity: >99%,
gradient A), ESI-MS: 507.4 [MH].sup.+.
Example 174
N-[4-Methyl-3-(3-{6-[4-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4--
yl}-ureido)-phenyl]-3-trifluoromethyl-benzamide
[1149] Colorless crystals, TLC: R.sub.f=0.53 (TBME/MeOH/NH3
80:18:2), HPLC: t.sub.R=5.79 min (purity: >99%, gradient A),
ESI-MS: 605.5 [MH].sup.+.
Example 175
N-[4-Methyl-3-(3-{6-[3-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4--
yl}-ureido)-phenyl]-3-trifluoromethyl-benzamide
##STR00229##
[1151] Colorless crystals, TLC: R.sub.f=0.34 (TBME/MeOH/NH3
80:18:2), HPLC: t.sub.R=5.72 min (purity: >99%, gradient A),
ESI-MS: 605.5 [MH].sup.+.
Example 176
N-[2-(3-{6-[4-(2-Diethylamino-ethoxy)-phenylamino]-pyrimidin-4-yl}-ureido)-
-4-methyl-phenyl]-3-trifluoromethyl-benzamide
##STR00230##
[1153] Colorless crystals, TLC: R.sub.f=0.63 (TBME/MeOH/NH3
80:18:2), HPLC: t.sub.R=5.84 min (purity: >99%, gradient A),
ESI-MS: 622.4 [MH].sup.+.
Example 177
N-[3-(3-{6-[4-(3-Dimethylamino-propoxy)-phenylamino]-pyrimidin-4-yl}-ureid-
o]-4-methyl-phenyl]-3-trifluoromethyl-benzamide
##STR00231##
[1155] Colorless crystals, HPLC: t.sub.R=5.75 min (purity: >99%,
gradient A), ESI-MS: 608.4 [MH].sup.+.
Example 178
N-[3-(3-{6-[3-(2-Dimethylamino-ethoxy)-phenylamino]-pyrimidin-4-yl}-ureido-
)-4-methyl-phenyl]-3-trifluoromethyl-benzamide
##STR00232##
[1157] Colorless crystals, TLC: R.sub.f=0.17 (TBME/MeOH 30:70),
HPLC: t.sub.R=5.72 min (purity: 95%, gradient A), ESI-MS: 594.5
[MH].sup.+.
Example 179
N-[4-Methyl-3-(3-{6-[4-(2-morpholin-4-yl-ethoxy)-phenylamino]-pyrimidin-4--
yl}-ureido)-phenyl]-3-trifluoromethyl-benzamide
##STR00233##
[1159] Colorless crystals, TLC: R.sub.f=0.31 (TBME/MeOH 80:20),
HPLC: t.sub.R=5.66 min (purity: >99%, gradient A), ESI-MS:
636.5.4 [MH].sup.+.
Example 180
N-[4-Methyl-3-(3-{6-[3-(2-morpholin-4-yl-ethoxy)-phenylamino]-pyrimidin-4--
yl}-ureido)-phenyl]-3-trifluoromethyl-benzamide
##STR00234##
[1161] Colorless crystals, TLC: R.sub.f=0.42 (TBME/MeOH 75:25),
HPLC: t.sub.R=5.86 min (purity: >99%, gradient A), ESI-MS: 636.6
[MH].sup.+.
Example 181
N-{4-Methyl-3-[3-methyl-3-(6-phenylamino-pyrimidin-4-yl)-ureido]-phenyl}-3-
-trifluoromethyl-benzamide
##STR00235##
[1163] Colorless crystals, TLC: R.sub.f=0.69 (TBME/MeOH90:10),
HPLC: t.sub.R=7.67 min (purity: >99%, gradient A), ESI-MS: 521.4
[MH].sup.+.
Example 182
N-[3-(3-{6-[3-(2-Dimethylamino-ethoxy)-phenylamino]-pyrimidin-4-yl}-3-meth-
yl-ureido)-4-methyl-phenyl]-3-trifluoromethyl-benzamide
##STR00236##
[1165] Colorless crystals, TLC: R.sub.f=0.51 (TBME/MeOH/NH3
80:18:2), HPLC: t.sub.R=6.02 min (purity: >99%, gradient A),
ESI-MS: 608.4 [MH].sup.+.
Example 183
N-[3-(3-{6-[4-(2-Diethylamino-ethoxy)-phenylamino]-pyrimidin-4-yl}-3-methy-
l-ureido)-4-methyl-phenyl]-3-trifluoromethyl-benzamide
##STR00237##
[1167] Colorless crystals, TLC: R.sub.f=0.24 (TBME/MeOH 75:25),
HPLC: t.sub.R=6.23 min (purity: 94%, gradient A), ESI-MS: 636.5
[MH].sup.+.
Example 184
N-{4-Methyl-3-[3-methyl-3-(6-{4-[2-(4-methyl-piperazin-1-yl)-ethoxy]-pheny-
lamino}-pyrimidin-4-yl)-ureido]-phenyl}-3-trifluoromethyl-benzamide
##STR00238##
[1169] Colorless crystals, TLC: R.sub.f=0.21 (DCM/MeOH 80:20),
HPLC: t.sub.R=6.07 min (purity: 88%, gradient A), ESI-MS: 633.2
[MH].sup.+.
Example 185
N-{4-Methyl-3-[3-methyl-3-(6-{3-[2-(4-methyl-piperazin-1-yl)-ethoxy]-pheny-
lamino}-pyrimidin-4-yl)-ureido]-phenyl}-3-trifluoromethyl-benzamide
##STR00239##
[1171] Colorless crystals, HPLC: t.sub.R=6.15 min (purity: 92%,
gradient A), ESI-MS: 633.3 [MH].sup.+.
Example 186
4-Methyl-3-(3-methyl-3-{6-[4-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimi-
din-4-yl}-ureido)-N-(3-trifluoromethyl-phenyl)-benzamide
##STR00240##
[1173] Colorless powder, HPLC: t.sub.R=6.19 min (purity: 96%,
gradient A), ESI-MS: 619.3 [MH].sup.+.
Example 187
N-[4-Methyl-3-(3-methyl-3-{6-[4-(4-methyl-piperazine-1-carbonyl)-phenylami-
no]-pyrimidin-4-yl}-ureido)-phenyl]-3-trifluoromethyl-benzamide
##STR00241##
[1175] Colorless crystals, TLC: R.sub.f=0.50 (DCM/MeOH 80:20),
HPLC: t.sub.R=5.82 min (purity: 88%, gradient A), ESI-MS: 647.6
[MH].sup.+.
Example 188
N-[4-Methyl-3-(3-methyl-3-{6-[3-(4-methyl-piperazin-1-yl)-phenylamino]-pyr-
imidin-4-yl}-ureido)-phenyl]-3-trifluoromethyl-benzamide
##STR00242##
[1177] Pale yellow crystals, TLC: R.sub.f=0.50 (TBME/MeOH/NH3
80:18:2), HPLC: t.sub.R=6.14 min (purity: 95%, gradient A), ESI-MS:
619.5 [MH].sup.+.
Example 189
N-{4-Methyl-3-[3-[2-(4-methyl-piperazin-1-yl)-ethyl]-3-(6-phenylamino-pyri-
midin-4-yl)-ureido]-phenyl}-3-trifluoromethyl-benzamide
##STR00243##
[1179] Colorless crystals, TLC: R.sub.f=0.04 (TBME/MeOH 90:10),
HPLC: t.sub.R=6.26 min (purity: >100%, gradient A), ESI-MS:
633.5 [MH].sup.+.
Example 190
N-{4-Methyl-3-[3-(6-phenylamino-pyrimidin-4-yl)-3-(2-pyridin-2-yl-ethyl)-u-
reido]-phenyl}-3-trifluoromethyl-benzamide
##STR00244##
[1181] Colorless crystals, HPLC: t.sub.R=7.58 min (purity:
>100%, gradient A), ESI-MS: 612.4 [MH].sup.+.
Example 191
N-{4-Methyl-3-[3-{6-[4-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimid-in-4-
-yl}-3-(2-pyridin-2-yl-ethyl)-ureido]-phenyl}-3-trifluoromethyl-benzamide
##STR00245##
[1183] Pink crystals, TLC: R.sub.f=0.54 (DCM/MeOH 80:20), HPLC:
t.sub.R=5.87 min (purity: 92%, gradient A), ESI-MS: 710.6
[MH].sup.+.
Example 192
N-[3-(3-Ethyl-3-{6-[4-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-y-
l}-ureido)-4-methyl-phenyl]-3-trifluoromethyl-benzamide
##STR00246##
[1185] Colorless crystals, TLC: R.sub.f=0.45 (DCM/MeOH 80:20),
HPLC: t.sub.R=6.18 min (purity: >100%, gradient A), ESI-MS:
633.6 [MH].sup.+.
Example 193
N-[4-Methyl-3-(3-{6-[4-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimid-in-4-
-yl}-3-thiophen-2-ylmethyl-ureido)-phenyl]-3-trifluoromethyl-benzamide
##STR00247##
[1187] Colorless crystals, TLC: R.sub.f=0.26 (DCM/MeOH 90:10),
HPLC: t.sub.R=6.51 min (purity: >100%, gradient A), ESI-MS:
701.5 [MH].sup.+.
Method B
Examples 194-201
Example 194
N-{3-[3-(6-Amino-pyrimidin-4-yl)-3-methyl-ureido]-4-methyl-phenyl}-4-(4-me-
thyl-piperazin-1-ylmethyl)-3-trifluoromethyl-benzamide
##STR00248##
[1189] To tert-butyl
[6-(1-Methyl-3-{2-methyl-5-[4-(4-methyl-piperazin-1-ylmethyl)-3-trifluoro-
-methyl-benzoylamino]-phenyl}-ureido)-pyrimidin-4-yl]-carbamate (50
mg, 0.076 mmol) is added trifluoroacetic acid/DCM 2:3 (2 ml). The
clear reaction mixture is stirred for 1 h at room temperature.
Then, methanol/DCM 1:9 (20 ml) is added. The solution is washed
with 50% aqueous K.sub.2CO.sub.3, dried over MgSO.sub.4 and
evaporated to give the title compound as a beige powder: M.p.
191.5-193.degree. C., HPLC: t.sub.R=5.27 min (purity: >99%,
gradient A), ESI-MS: 557.3 [MH].sup.+, 400 MHz .sup.1H-NMR
(DMSO-d.sub.6) .delta.: 2.19 (s, 3H, NMe), 2.30 (s, 3H, ArMe),
2.24-2.62 (br m, 8H, piperazine), 3.32 (s, 3H, urea-NMe), 3.69 (s,
2H, ArCH.sub.2N), 6.09 (s, 1H, pyrimidine-H5), 7.02 (s, 2H,
NH.sub.2), 7.19 (d, 1H, Ar--H5), 7.50 (dd, 1H, Ar--H4), 7.91 (d,
1H, Ar'--H5), 8.23 (dd, 1H, Ar'--H6), 8.26 (d, 1H, Ar--H2), 8.30
(s, 1H, pyrimidine-H2), 8.41 (d, 1H, Ar'--H2), 10.41 (s, 1H,
amide-NH).
tert-Butyl
[6-(1-Methyl-3-{2-methyl-5-[4-(4-methyl-piperazin-1-ylmethyl)-3-
-trifluoro-methyl-benzoylamino]-phenyl}-ureido)-pyrimidin-4-yl]-carbamate
[1190] To a solution of
4-(4-Methyl-piperazin-1-ylmethyl)-2-trifluoromethyl-benzoic acid
(Preparation 2, 80 mg, 0.27 mmol, 1.1 eq.) in DMA is added HATU
(138 mg, 0.36 mmol, 1.5 eq.) and diisopropylethylamine (83 .mu.l,
0.48 mmol, 2.0 eq.) after 10 min stirring at room temperature
tert-butyl
{6-[3-(5-Amino-2-methyl-phenyl)-1-methyl-ureido]-pyrimidin-4-yl}-carbamat-
e is added. The reaction mixture is sonicated for 5 min. After
stirring at room temperature over night a grey suspension is
formed. The precipitate is filtered off, washed with DMA and ether.
Vacuum drying at 60.degree. C. over night afforded a gray powder:
HPLC: t.sub.R=6.30 min (purity: >99%, gradient A), ESI-MS: 657.4
[MH].sup.+.
tert-Butyl
{6-[3-(5-Amino-2-methyl-phenyl)-1-methyl-ureido]-pyrimidin-4-yl-
}-carbamate
[1191] A solution of tert-butyl
{6-[3-(2-methyl-5-nitro-phenyl)-1-methyl-ureido]-pyrimidin-4-yl}-carbamat-
e (330 mg, 0.82 mmol) in a mixture of methanol (20 ml) and DMF (50
ml) is hydrogenated in the presence of 10% palladium on charcoal
(500 mg) at atmospheric pressure. After 20 h the hydrogenation is
complete and the catalyst is filtered off. The filtrate is
evaporated to dryness. The residue obtained is triturated with
ether, filtered off, and vacuum dried to afford a gray powder:
HPLC: t.sub.R=5.38 min (purity: 97%, gradient A), ESI-MS: 373.4
[MH].sup.+.
tert-Butyl
{6-[3-(2-methyl-5-nitro-phenyl)-1-methyl-ureido]-pyrimidin-4-yl-
}-carbamate
[1192] A solution of tert-butyl
(6-Methylamino-pyrimidin-4-yl)-carbamate (240 mg, 1.07 mmol, 1.0
eq.), commercially available 2-methyl-5-nitrophenylisocyanate (210
mg, 1.18 mmol, 1.1 eq.), and DMAP (26 mg, 0.21 mmol, 0.2 eq.) in
toluene (10 ml) is stirred at 80.degree. C. for 24 h. After cooling
to room temperature methanol (10 ml) is added and the suspension
formed is stirred for 10 min at 50.degree. C. The precipitate is
filtered off and washed with methanol (2.times.10 ml). After drying
in vacuo an extremely insoluble colorless powder is obtained: HPLC:
t.sub.R=8.09 min (purity: 85%, gradient A), ESI-MS: 403.5
[MH].sup.+.
tert-Butyl (6-Methylamino-pyrimidin-4-yl)-carbamate
[1193] A solution of
bis(tert-butyl)-(6-chloro-4-pyrimidinyl)-imidodicarboxylate (1 g,
3.03 mmol, 1.0 eq.) in 33% methylamine in ethanol (5.63 ml, 45.5
mmol, 15 eq.) is heated to 80.degree. C. in a sealed tube for 2 h
and then allowed to reach room temperature. The precipitated
product is filtered off, washed with cold ethanol and vacuum dried
at 60.degree. C. over night. The title compound is obtained as
colorless crystals: HPLC: t.sub.R=3.82 min (purity: 99%, gradient
A), ESI-MS: 225.1 [MH].sup.+ (weak), 169.1 [MH-tBu].sup.+.
[1194] Bis(tert-butyl)-(6-chloro-4-pyrimidinyl)-imidodicarboxylate
may be prepared according to a procedure published in the
literature: J. M. Lehn et al., Eur. J. Chem. 2001, 1515-1521.
[1195] By following the procedure of Example 194 but using the
appropriate starting materials, examples 195-201 may be
prepared:
Example 195
N-{4-Methyl-3-[3-methyl-3-(6-phenylamino-pyrimidin-4-yl)-ureido]-phenyl}-4-
-(4-methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-benzamide
##STR00249##
[1197] Beige crystals, HPLC: t.sub.R=6.33 min (purity: 96%,
gradient A), ESI-MS: 633.8 [MH].sup.+.
Example 196
3-(5-Amino-2-methoxy-phenyl)-1-methyl-1-{6-[4-(4-methyl-piperazin-1-yl)-ph-
enylamino]-pyrimidin-4-yl}-urea
##STR00250##
[1199] Beige crystals, TLC: R.sub.f=0.19 (DCM/MeOH 85:15), HPLC:
t.sub.R=3.72 min (purity: >100%, gradient A), ESI-MS: 463.6
[MH].sup.+.
Example 197
N-[4-Methoxy-3-(3-methyl-3-{6-[4-(4-methyl-piperazin-1-yl)-phenyl
amino]-pyrimidin-4-yl}-ureido)-phenyl]-3-trifluoromethyl-benzamide
##STR00251##
[1201] Pale yellow crystals, TLC: R.sub.f=0.21 (TBME/MeOH 60:40),
HPLC: t.sub.R=5.94 min (purity: 97%, gradient A), ESI-MS: 635.2
[MH].sup.+.
Example 198
N-[4-Methoxy-3-(3-methyl-3-{6-[4-(4-methyl-piperazin-1-yl)-phenyl-amino]-p-
yrimidin-4-yl}-ureido)-phenyl]-4-(4-methyl-piperazin-1-ylmethyl)-3-trifluo-
ro-methyl-benzamide
##STR00252##
[1203] Pale yellow crystals, TLC: R.sub.f=0.19 (TBME/MeOH/NEt3
50:50:1.5), HPLC: t.sub.R=5.07 min (purity: 96%, gradient A),
ESI-MS: 747.4 [MH].sup.+.
Example 199
N-{3-[3-(6-Amino-pyrimidin-4-yl)-3-methyl-ureido]-5-methoxy-phenyl}-4-(4-m-
ethyl-piperazin-1-ylmethyl)-3-trifluoromethyl-benzamide
##STR00253##
[1205] Colorless crystals, HPLC: t.sub.R=5.12 min (purity: 97%,
gradient A), ESI-MS: 573.2 [MH].sup.+.
Example 200
N-{3-Methoxy-5-[3-methyl-3-(6-phenylamino-pyrimidin-4-yl)-ureido]-phenyl}--
4-(4-methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-benzamide
##STR00254##
[1207] Yellow resin, HPLC: t.sub.R=6.20 min (purity: 99%, gradient
A), ESI-MS: 649.4 [MH].sup.+.
Example 201
N-[3-Methoxy-5-(3-methyl-3-{6-[4-(4-methyl-piperazin-1-yl)-phenyl-amino]-p-
yrimidin-4-yl}-ureido)-phenyl]-4-methyl-3-trifluoromethyl-benzamide
##STR00255##
[1209] Beige crystals, TLC: R.sub.f=0.39 (DCM/MeOH 85:15), HPLC:
t.sub.R=6.17 min (purity: >100%, gradient A), ESI-MS: 649.7
[MH].sup.+.
Example 202
N-[3-[3-(6-Acetylaminopyrimidin-4-yl)-3-methylureido]-4-methylphenyL]-4-(4-
-methylpiperazin-1-ylmethyl)-3-trifluoromethylbenzamide
##STR00256##
[1211] colourless crystalline solid, TLC: R.sub.f=0.24
(DCM/EtOH/NH3 90:9:1), HPLC: t.sub.R=10.57 min (purity: 100%,
gradient B), ESI-MS: 599 [MH].sup.+.
Example 203
[6-(1-Methyl-3-{2-methyl-5-[4-(4-methyl-piperazin-1-ylmethyl)-3-trifluorom-
ethyl-benzoylamino]-phenyl}-ureido)-pyrimidin-4-yl]-carbamic acid
methyl ester
##STR00257##
[1213] Colourless powder, TLC: R.sub.f=0.20 (DCM/EtOH/NH3 90:9:1),
HPLC: t.sub.R=11.25 min (purity: 100%, gradient B), ESI-MS: 615
[MH].sup.+.
Example 204
[6-(1-Methyl-3-{2-methyl-5-[4-(4-methyl-piperazin-1-ylmethyl)-3-trifluorom-
ethyl-phenylcarbamoyl]-phenyl}-ureido)-pyrimidin-4-yl]-carbamic
acid methyl ester
##STR00258##
[1215] Colourless powder, TLC: R.sub.f=0.33 (DCM/EtOH/NH3 90:9:1),
HPLC: t.sub.R=10.97 min (purity: 100%, gradient B), ESI-MS: 615
[MH].sup.+.
Example 205
3-[3-(6-Acetylamino-pyrimidin-4-yl)-3-methyl-ureido]-4-methyl-N-[4-(4-meth-
yl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenyl]-benzamide
##STR00259##
[1216] Example 206
3-[3-(6-Amino-pyrimidin-4-yl)-3-methyl-ureido]-4-methyl-N-[4-(4-methyl-pip-
erazin-1-ylmethyl)-3-trifluoromethyl-phenyl]-benzamide
##STR00260##
[1217] Example 207
In Vitro Inhibition Data
[1218] The compounds of Examples 171 to 206 were tested under the
protocols as hereinbefore described for their inhibitory activity
against c-Abl, KDR and FGFR3. For c-Abl 79-100% inhibition at 10
.mu.M, for KDR 87-100% inhibition at 10 .mu.M and for FGFR3 56-98%
inhibition at 10 .mu.M is observed.
Example 208
N-[4-Methyl-3-(3-methyl-3-{6-[(tetrahydro-furan-2-ylmethyl)-amino]-pyrimid-
in-4-yl}-ureido)-phenyl]-3-trifluoromethyl-benzamide
##STR00261##
[1220] Pal-resin bearing C-(Tetrahydro-furan-2-yl)-methylamine (1
g, 1 mmol), DIEA (0.52 mL, 3 mmol), and 4,6-dichloropyrimidine (300
mg, 2 mmol) are mixed in n-BuOH (15 mL). The reaction vial is put
into a heating shaker and heated up at 80.degree. C. for 16 hours.
The resultant mixture is filtered and the resin is washed with DMF
(3.times.20 mL), MeOH (3.times.20 mL), CH.sub.2Cl.sub.2 (3.times.20
mL), and dried under vacuum. 10 mgs of the resin is treated with
TFA/CH.sub.2Cl.sub.2/H.sub.2O (45/50/5) (200 .mu.L) for 1 hour.
LC-MS revealed only one major peak: observed MS (M+H.sup.+) is
214.2;
##STR00262##
[1221] Pal-resin bearing (6-Chloro-pyrimidin-4 yl)
(tetrahydro-furan-2-ylmethyl)-amine (1 mmol), 40% methylamine water
solution (1.95 mL, 25 mmol), 15 mL n-BuOH are mixed together in a
sealed tube. The reaction vial is put into a heating shaker and
heated up at 100.degree. C. for 12 hours. After cooling, another
1.95 mL of 40% methylamine water solution is added into the
reaction vial. The reaction is heated to 100.degree. C. for 12
hours. The resultant mixture is filtered and the resin is washed
with DMF (3.times.20 mL), MeOH (3.times.20 mL), CH.sub.2Cl.sub.2
(3.times.20 mL), and dried under vacuum. 10 mgs of the resin is
treated with TFA/CH.sub.2Cl.sub.2/H.sub.2O (45/50/5) (200 .mu.L)
for 1 hour. LC-MS revealed only one major peak: observed MS
(M+H.sup.+) is 209.2.
##STR00263##
[1222] Pal-resin bearing
N-Methyl-N'-(tetrahydro-furan-2-ylmethyl)-pyrimidine-4,6-diamine (1
mmol), 2-methyl-5-nitrophenyl-isocyanate (540 mg, 3 mmol), DIEA
(0.52 mL, 3 mmol), 15 mL anhydrous DMF are mixed together. The
reaction vial is heated with shaking to 60.degree. C. for 14 hours.
The resultant mixture is filtered and the resin is washed with DMF
(3.times.20 mL), MeOH (3.times.20 mL), CH.sub.2Cl.sub.2 (3.times.20
mL), and dried under vacuum. 10 mgs of the resin is treated with
TFA/CH.sub.2Cl.sub.2/H.sub.2O (45/50/5) (2004) for 1 hour. LC-MS
revealed only one major peak: observed MS (M+H) is 387.2.
##STR00264##
[1223] Pal-resin bearing 1-Methyl 3 (2
methyl-5-nitro-phenyl)-1-{6-[(tetrahydro-furan-2-ylmethyl)-amino]-pyrimid-
in-4-yl}-urea (1 mmol), tin(II) chloride (1.55 g, 8 mmol), 15 mL
NMP are mixed together. The reaction vial is shaken at room
temperature for 16 hours. The resultant mixture is filtered and the
resin is washed with DMF (3.times.20 mL), MeOH (3.times.20 mL),
CH.sub.2Cl.sub.2 (3.times.20 mL), and dried under vacuum. 10 mgs of
the resin is treated with TFA/CH.sub.2Cl.sub.2/H.sub.2O (45/50/5)
(200 .mu.L) for 1 hour. LC-MS revealed only one major peak:
observed MS (M+H.sup.+) is 357.3.
##STR00265##
[1224] Pal-resin bearing
3-(5-Amino-2-methyl-phenyl)-1-methyl-1-{6-[(tetrahydro-furan-2-ylmethyl)--
amino]-pyrimidin-4-yl}-urea (1 mmol), 3-trifluoromethyl-benzoyl
chloride (630 mg, 3 mmol), DIEA (0.52 mL, 3 mmol) and 15 mL
anhydrous DMF are mixed together. The reaction vial is shaking in
room temperature for 16 hours. The resultant mixture is filtered
and the resin is washed with DMF (3.times.20 mL), MeOH (3.times.20
mL), CH.sub.2Cl.sub.2 (3.times.20 mL), and dried under vacuum. 10
mgs of the resin is treated with TFA/CH.sub.2Cl.sub.2/H.sub.2O
(45/50/5) (2004) for 1 hour. LC-MS revealed only one major peak:
observed MS (M+H.sup.+) is 529.3.
[1225] All of the pal resin is treated with
TFA/CH.sub.2Cl.sub.2/H.sub.2O (45/50/5) (10 mL) for 2 hours. After
removing the solvent under the vacuum, the crude product is
dissolved in DMSO and purified by reverse phase preparative HPLC to
give the final product N-[4-Methyl 3 (3
methyl-3-{6-[(tetrahydro-furan-2-ylmethyl)-amino]-pyrimidin-4-yl}-ureido)-
-phenyl]-3-trifluoromethyl-benzamide as the white solid, 241 mg. A
summary of the procedure is described in the flow diagram below.
The solid spheres indicate a solid support (Pal resin); .sup.1H NMR
(600 MHz, DMSO-d.sub.6) .delta. 12.84 (s, 1H), 10.44 (s, 1H), 8.41
(s, 1H), 8.34 (s, 1H), 8.28 (s, 1H), 8.27 (d, J=7.9 Hz, 1H), 7.96
(d, J=8.0 Hz, 1H), 7.78 (t, J=7.4 Hz, 1H), 7.60 (s, 1H), 7.51 (d,
J=8.2 Hz, 1H), 7.20 (d, J=8.0 Hz, 1H), 6.16 (s, 1H), 3.92-3.79 (m,
3H), 3.64-3.62 (m, 2H), 3.34 (s, 3H), 2.31 (s, 3H), 1.85-1.82 (m,
4H); ESIMS m/z 529.3 (M.sup.++1).
##STR00266##
Example 209
N-(3-{3-[6-(Benzo[1,3]dioxol-5-ylamino)-pyrimidin-4-yl]-3-methyl-ureido}-4-
-methyl-phenyl)-3-trifluoromethyl-benzamide
##STR00267##
[1227] The general procedure is as same as example 208, except the
Pal-resin is attached to benzo[1,3]dioxol-5-ylamine. All of the pal
resin is treated with TFA/CH.sub.2Cl.sub.2/H.sub.2O (45/50/5) (10
mL) for 2 hours. After removing the solvent under the vacuum, the
crude product is dissolved into DMSO and purified by reverse phase
preparative HPLC to give the final product
N-(3-{3-[6-(Benzo[1,3]dioxol-5-ylamino)-pyrimidin-4-yl]-3-methyl-ureido}--
4-methyl-phenyl)-3-trifluoromethyl-benzamide as the white solid;
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 12.70 (s, 1H), 10.44
(s, 1H), 9.58 (s, 1H), 8.49 (s, 1H), 8.40 (d, J=11.8 Hz, 2H), 8.30
(s, 1H), 8.27 (d, J=7.8 Hz, 1H), 7.95 (d, J=7.6 Hz, 1H), 7.78 (t,
J=7.8 Hz, 1H), 7.51 (d, J=8.4 Hz, 1H), 7.37 (t, J=8.1 Hz, 1H), 7.25
(d, J=8.8 Hz, 1H), 6.88 (d, J=8.3 Hz, 1H), 6.35 (s, 1H), 6.00 (s,
2H), 3.33 (s, 3H), 2.32 (s, 3H); ESIMS m/z 565.3 (M.sup.++1).
##STR00268##
[1228] in which R represents an R.sub.7 substituent as defined in
the Summary of the Invention.
Example 210
N-(3-{3-[6-(3-Dimethylamino-phenylamino)-pyrimidin-4-yl]-3-methyl-ureido}--
4-methyl-phenyl]-3-trifluoromethyl-benzamide
##STR00269##
[1230] A reaction scheme for this protocol is shown above.
4,6-dichloropyrimidine (1.0 g, 6.75 mmol), 2.0M methylamine in MeOH
(3.38 mL, 6.75 mmol) and DIEA (1.76 mL, 10.13 mmol) are dissolved
in 30 mL ethanol. The reaction is heated to 70.degree. C. for 4
hours. After removing the solvent, the crude product is purified by
flash chromatography using EA/Hexane (3:7) to get the final product
(6-Chloro-pyrimidin-4-yl)-methyl-amine as the white solid.
[1231] (6-Chloro-pyrimidin 4 yl)methyl-amine (940 mg, 6.57 mmol),
2-methyl-5-nitrophenyl-isocyanate (1.23 g, 6.90 mmol), DIEA (2.30
mL, 13.15 mmol) are dissolved in 30 mL anhydrous DMF. The reaction
is stirred in room temperature for 14 hours. After removing the
solvent, the crude product is purified by flash chromatography
using EA/Hexane (4:6) to get the final product
1-(6-Chloro-pyrimidin-4-yl)-1-methyl-3-(2
methyl-5-nitro-phenyl)-urea as the white solid.
[1232] 1-(6-Chloro-pyrimidin-4-yl)-1-methyl-3-(2
methyl-5-nitro-phenyl)-urea (100 mg, 0.31 mmol),
N,N-Dimethyl-benzene-1,3-diamine HCl salt (82 mg, 0.47 mmol) are
dissolved in 6 mL n-BuOH. The reaction is heated up to 90.degree.
C. for 16 hours. After removing the solvent, the crude product is
purified by flash chromatography using EA/Hexane (1:1) to get the
final product
1-[6-(3-dimethylamino-phenylamino)-pyrimidin-4-yl]-1-methyl-3-(2-methyl-5-
-nitro-phenyl)-urea as white solid.
[1233]
1-[6-(3-Dimethylamino-phenylamino)-pyrimidin-4-yl]-1-methyl-3-(2-me-
thyl-5-nitro-phenyl)-urea (110 mg, 0.26 mmol) and 10 mg 10%
palladium carbon powder are mixed in 20 mL EtOH under hydrogen
environment. The reaction is stirred at 50.degree. C. for 4 hours.
The reaction mixture is passed through a celite plug and washed by
methanol. After removing the solvent under the vacuum, the crude
product
3-(5-Amino-2-methyl-phenyl)-1-[6-(3-dimethylamino-phenylamino)-pyrimidin--
4-yl]-1-methyl-urea is used for next step reaction without
purification.
[1234]
3-(5-Amino-2-methyl-phenyl)-1-[6-(3-dimethylamino-phenylamino)-pyri-
midin-4-yl]-1-methyl-urea (0.26 mmol), 3-trifluoromethyl-benzoyl
chloride (57 mg, 0.27 mmol) and DIEA (68 uL, 0.39 mmol) are
dissolved in 10 mL anhydrous DMF. The reaction is stirred in the
room temperature for 4 hours. After removing the solvent, the crude
product is dissolved into DMSO and purified by reverse phase
preparative HPLC to give the final product
N-(3-{3-[6-(3-Dimethylamino-phenylamino)-pyrimidin-4-yl]-3-methyl-
-ureido}-4-methyl-phenyl)-3-trifluoromethyl-benzamide as the white
solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) .delta. 12.67 (s, 1H),
10.44 (s, 1H), 9.84 (s, 1H), 8.56 (s, 1H), 8.40 (d, J=11.8 Hz, 2H),
8.28 (s, 1H), 8.24 (d, J=8.2 Hz, 1H), 7.94 (d, J=7.7 Hz, 1H), 7.76
(t, J=7.8 Hz, 1H), 7.48 (d, J=8.4 Hz, 1H), 7.35 (t, J=8.1 Hz, 1H),
7.22 (d, J=8.8 Hz, 1H), 6.81 (d, J=7.5 Hz, 1H), 6.64 (s, 1H), 6.59
(d, J=8.2 Hz, 1H), 3.35 (s, 3H), 2.92 (s, 6H), 2.35 (s, 3H); ESIMS
m/z 565.3 (M.sup.++1).
Example 211
N-(3-{3-[6-(3-Acetylamino-phenylamino)-pyrimidin-4-yl]-3-methyl-ureido}-4--
methyl-phenyl)-3-trifluoromethyl-benzamide
##STR00270##
[1236] The general procedure is as same as example 3, except
N-(3-Amino-phenyl)-acetamide (71 mg, 0.47 mmol) and 0.12 mL 4M HCl
in dioxane solution are added in the reaction. The final product
N-(3-{3-[6-(3-Acetylamino-phenylamino)-pyrimidin-4-yl]-3-methyl-ureido}-4-
-methyl-phenyl)-3-trifluoromethyl-benzamide is purified by reverse
phase preparative HPLC to give the white solid; .sup.1H NMR (600
MHz, DMSO-d.sub.6) .delta. 12.67 (s, 1H), 10.44 (s, 1H), 9.84 (s,
1H), 8.56 (s, 1H), 8.40-8.36 (m, 2H), 8.31 (s, 1H), 8.28 (d, J=7.8
Hz, 1H), 8.07 (s, 1H), 7.95 (d, J=7.7 Hz, 1H), 7.84 (d, J=6.6 Hz,
1H), 7.78 (t, J=7.8 Hz, 1H), 7.52 (d, J=6.6 Hz, 1H), 7.47 (d, J=7.8
Hz, 1H), 7.41 (t, J=7.8 Hz, 1H), 7.22 (d, J=8.4 Hz, 1H), 6.48 (s,
1H), 3.37 (s, 3H), 2.79 (d, J=4.2, 3H), 2.34 (s, 3H); ESIMS m/z
578.3 (M.sup.++1).
##STR00271##
Example 212
N-(4-Methyl-3-{3-methyl-3-[6-(4-morpholin-4-yl-phenylamino)-pyrimidin-4-yl-
]-ureido}-phenyl)-3-trifluoromethyl-benzamide
##STR00272##
[1238] 4-methyl-3-nitroaniline (3.0 g, 20 mmol) is dissolved in 100
ml methylene chloride. 3 ml triethylamine (22 mmol) is added, the
solution is cooled to 0.degree. C., and 3-trifluorobenzioc chloride
(4.1 g; 20 mmol) is added slowly to the above mixture while
stirring. The reaction mixture was allowed raised to room
temperature and the reaction was completed in 1 hr. The reaction
mixture was washed with 10% NaHCO.sub.3 solution, brine and dried
over Na.sub.2SO.sub.4. The final product (3)
N-(4-Methyl-3-nitro-phenyl)-3-trifluoromethyl-benzamide is a yellow
solid, 6.28 g.
[1239] N-(4-Methyl-3-nitro-phenyl)-3-trifluoromethyl-benzamide (6.2
g, 19 mmol) was dissolved in 80 ml ethanol and 600 mg Pd/C was
added to the solution. The mixture was stirred under hydrogen at
room temperature for 4 hours. The Pd/C was removed by filtration.
The crude product was recrystallized in ethyl acetate. The final
product (4) N-(3-Amino-4-methyl-phenyl)-3-trifluoromethyl-benzamide
is dark solid, 5.5 g. 4,6-dichloro-pyrimidine (10 g, 67 mmol) was
dissolved in 50 ml methanol. Then 37 ml 2M methylamine THF solution
was added to it. The reaction was stirred for 10 hours at room
temperature. The solvent was removed by rotary evaporation and the
crude product was recrystallized in methanol. The final product (5)
(6-Chloro-pyrimidin-4-yl)methylamine was light yellow solid, 8.2
g.
[1240] (6-Chloro-pyrimidin-4-yl)methyl-amine (1.43 g 10 mmol) was
dissolved in 20 ml dioxane and mixed with 1.7 ml DIEA (15 mmol),
then 1.2 g triphosgene was added to the solution. The reaction
mixture was stirred at 85.degree. C. for 3 hours. The reaction
mixture was cooled down to room temperature. To this reaction
mixture, 1.7 ml DIEA and 2.94 g
N-(3-Amino-4-methyl-phenyl)-3-trifluoromethyl-benzamide (4) were
added. The reaction was stirred at room temperature for 3 hours.
The crude product was recrystallized in ethyl acetate. The final
product (8)
N-{3-[3-(6-Chloro-pyrimidin-4-yl)-3-methyl-ureido]-4-methyl-phenyl}-3-tri-
fluoromethyl-benzamide is light yellow solid, 3.9 g.
[1241]
N-{3-[3-(6-Chloro-pyrimidin-4-yl)-3-methyl-ureido]-4-methyl-phenyl}-
-3-trifluoromethyl-benzamide (50 mg, 0.107 mmol) and
p-toluenesulfonic acid (20 mg, 0.105 mmol) were mixed and dissolved
in 1 ml DMF. Then 4-Morpholin-4-yl-phenylamine (22 mg, 0.11 mmol)
was added to it. The reaction was stirred at 80.degree. C. for 10
hours. The crude product was purified by reverse phase HPLC to give
final product
N-(4-Methyl-3-{3-methyl-3-[6-(4-morpholin-4-yl-phenylamino)-pyrimidin-4-y-
l]-ureido}-phenyl)-3-trifluoromethyl-benzamide as grey solid, 48
mg; .sup.1H NMR 600 MHz (DMSO) .delta. 12.74 (s, 1H), 10.46 (s,
1H), 9.53 (s, 1H), 8.47 (s, 1H), 8.41 (m, 1H), 8.31 (s, 1H), 8.28
(d, 1H, J=7.8 Hz), 7.97 (d, 1H, J=7.2 Hz), 7.79 (t, 1H, J=4.2 Hz),
7.52 (d, 1H, J=7.8 Hz), 7.47 (d, 2H, J=8.4 Hz), 7.22 (d, 1H, J=8.4
Hz), 6.99 (s, 1H), 6.98 (s, 1H), 6.34 (s, 1H), 4.15 (m, 4H), 3.76
(m, 4H), 3.10 (m, 3H), 2.32 (s, 3H); MS m/z 606.2 (M+1).
Example 213
N-[4-Methyl-3-(3-methyl-3-{6-[4-(4-methyl-piperazin-1-yl)-phenylamino]-pyr-
imidin-4-yl}-ureido)-phenyl]-3-trifluoromethyl-benzamide
##STR00273##
[1243] This compound was made using the same procedure as above,
except that the 4-(4-Methyl-piperazin-1-yl)-phenylamine was used
instead of 4-Morpholin-4-yl phenylamine. The final compound
N-[4-Methyl-3-(3-methyl-3-{6-[4-(4-methyl-piperazin-1-yl)-phenylamino]-py-
rimidin-4-yl}-ureido)-phenyl]-3-trifluoromethyl-benzamide is white
solid, 43 mg; .sup.1H NMR 600 MHz (DMSO) .delta. 12.75 (s, 1H),
10.47 (s, 1H), 9.64 (s, 1H), 9.55 (s, 1H), 8.47 (s, 1H), 8.41 (m,
1H), 8.31 (s, 1H), 8.28 (d, 1H, J=7.8 Hz), 7.97 (d, 1H, J=7.2 Hz),
7.79 (t, 1H, J=4.2 Hz), 7.52 (d, 1H, J=7.8 Hz), 7.47 (d, 2H, J=8.4
Hz), 7.22 (d, 1H, J=8.4 Hz), 6.99 (s, 1H), 6.98 (s, 1H), 6.34 (s,
1H), 3.79 (m, 2H), 3.56 (m, 4H), 3.18 (m, 3H), 2.95 (m, 2H), 2.87
(s, 3H), 2.33 (s, 3H); MS m/z 620.2 (M+1).
##STR00274##
Example 214
N-{3-[3-(6-Amino-pyrimidin-4-yl)-3-(2-morpholin-4-yl-ethyl)-ureido]-4-meth-
yl-phenyl}-3-trifluoromethyl-benzamide
##STR00275##
[1245] Rink resin with free amino group (50 g, 53 mmol) is mixed
with 4,6-dichloropyrimidine (23 g, 159 mmol) in 60 ml butanol and
28 ml DIEA. The reaction mixture was shaken on heating block at
50.degree. C. for 10 hours. The resin was washed with DMF, methanol
and methylene chloride. Then to 1 g of the resin is added 3
equivalent amine and 3 ml butanol, the reaction was shaken at
90.degree. C. for 10 hours. The resin was washed with DMF, methanol
and methylene chloride.
[1246] N-(3-Amino-4-methyl-phenyl)-3-trifluoromethyl-benzamide (880
mg, 3 mmol) was dissolved in 8 ml dioxane with 0.52 ml DIEA added.
Then triphosgene (357 mg, 1.2 mmol) was added to this solution. The
reaction was stirred at room temperature for 1 hour. This reaction
mixture was then added to the above resin. The reaction was shaken
at 60.degree. C. for 10 hours. The resin was washed with DMF,
methanol and methylene chloride. The resin was cleaved with TFA at
room temperature for 1 hour. The crude product was purified by
RP-HPLC.
[1247] Example 214 is prepared using 2-morpholin-4-yl-ethylamine as
amine in the procedure above. The final product
N-{3-[3-(6-Amino-pyrimidin-4-yl)-3-(2-morpholin-4-yl-ethyl)-ureido]-4-met-
hyl-phenyl}-3-trifluoromethyl-benzamide was white solid, 63 mg;
.sup.1H NMR 600 MHz (DMSO) .delta. 12.95 (s, 1H), 10.46 (s, 1H),
8.41 (s, 1H), 8.31 (s, 1H), 8.28 (s, 1H), 8.27 (s, 1H), 7.95 (d,
1H, J=7.7 Hz), 7.77 (t, 1H, J=7.8 Hz), 7.54 (d, 1H, J=6.8 Hz), 7.20
(d, 2H, J=8.3 Hz), 7.03 (s, 2H), 6.99 (s, 1H), 6.17 (s, 1H), 3.98
(s, 2H), 3.59 (s, 4H), 3.35 (m, 2H), 2.50 (m, 4H), 2.30 (s, 3H); MS
m/z 544.2 (M+1).
Example 215
N-(3-{3-(6-Amino-pyrimidin-4-yl)-3-[3-(2-oxo-pyrrolidin-1-yl)-propyl]-urei-
do}-4-methyl-phenyl)-3-trifluoromethyl-benzamide
##STR00276##
[1249] This compound was prepared using
1-(3-Amino-propyl)-pyrrolidin-2-one as amine in the procedure
above. The final product
N-(3-{3-(6-Amino-pyrimidin-4-yl)-3-[3-(2-oxo-pyrrolidin-1-yl)-propyl]-ure-
ido}-4-methyl-phenyl)-3-trifluoromethyl-benzamide is white solid,
14 mg; .sup.1H NMR 600 MHz (DMSO) .delta. 12.51 (s, 1H), 10.40 (s,
1H), 8.38 (s, 1H), 8.31 (s, 1H), 8.28 (s, 1H), 8.27 (s, 1H), 7.95
(d, 1H, J=7.7 Hz), 7.77 (t, 1H, J=7.8 Hz), 7.54 (d, 1H, J=6.8 Hz),
7.20 (d, 2H, J=8.3 Hz), 7.03 (s, 2H), 6.99 (s, 1H), 6.17 (s, 1H),
3.70 (m, 2H), 3.31 (t, 2H, J=7.2 Hz), 3.24 (t, 2H, J=7.2 Hz), 2.23
(s, 3H), 2.16 (t, 2H, J=8.4 Hz), 1.87 (m, 2H), 1.74 (m, 2H); MS m/z
556.2 (M+1).
Example 216
[1250] By repeating the procedures described in the above examples
208 to 215, using appropriate starting materials, the following
compounds of Formula I, as identified in Table 1, are obtained.
TABLE-US-00003 TABLE 1 Compound Number Structure Physical Data 1
##STR00277## .sup.1H NMR (400 MHz, CD.sub.3OH-d.sub.4) .delta. 9.92
(d, J = 5.1 Hz, 1H), 9.80 (s, 1H), 9.20 (d, J = 8.1 Hz, 2H), 8.93
(d, J = 8.5 Hz, 2H), 8.85 (d, J = 8.6 Hz, 2H), 8.79 (d, J = 5.0 Hz,
2H), 8.76 (d, J = 8.0 Hz, 2H), 8.75 (s, 1H), 8.46 (t, J = 9.0 Hz,
1H), 8.08 (s, 1H), 4.92 (s, 2H), 4.71 (s, 2H), 3.66 (m, 6H); ESIMS
m/z 623.20 (M.sup.+ + 1). 2 ##STR00278## .sup.1H NMR (600 MHz,
DMSO- d.sub.6) .delta. 12.82 (s, 1H), 10.44 (s, 1H), 8.40 (s, 1H),
8.36 (s, 1H), 8.31 (s, 1H), 8.28 (d, J = 7.9 Hz, 1H), 7.96 (d, J =
7.8 Hz, 1H), 7.78 (t, 7.8 Hz, 1H), 7.50 (d, J = 8.2 Hz, 1H), 7.40
(d, J = 8.1 Hz, 2H), 7.38 (d, J = 8.1 Hz, 2H), 7.20 (d, J = 8.1 Hz,
1H), 6.21 (s, 1H), 4.57 (s, 2H), 3.18 (s, 3H), 2.39 (s, 3H); ESIMS
m/z 569.10 (M.sup.+ + 1). 3 ##STR00279## .sup.1H NMR (600 MHz,
DMSO- d.sub.6) .delta. 12.85 (s, 1H), 10.44 (s, 1H), 8.41 (s, 1H),
8.34 (s, 1H), 8.31 (s, 1H), 8.28 (d, J = 7.4 Hz, 1H), 7.96 (d, J =
7.7 Hz, 1H), 7.78 (t, J = 7.9 Hz, 1H), 7.62 (s, 1H), 7.51 (d, J =
8.1 Hz, 1H), 7.33 (s, 1H), 7.31 (d, J = 7.1 Hz, 1H), 7.28 (s, 1H),
7.27 (s, 1H), 7.22 (d, J = 9.2 Hz, 1H), 7.20 (d, J = 8.6 Hz, 1H),
6.15 (s, 1H), 3.30 (m, 2H), 3.18 (s, 3H), 2.86 (t, J = 6.7 Hz, 2H),
2.24 (s, 3H); ESIMS m/z 549.20 (M.sup.+ + 1). 4 ##STR00280##
.sup.1H NMR (600 MHz, DMSO- d.sub.6) .delta. 12.83 (s, 1H), 10.44
(s, 1H), 8.40 (s, 1H), 8.36 (s, 1H), 8.31 (s, 1H), 8.27 (d, J = 7.9
Hz, 1H), 7.99 (s, 1H), 7.96 (d, J = 7.5 Hz, 1H), 7.78 (t, J = 7.7
Hz, 1H), 7.50 (d, J = 8.2 Hz, 1H), 7.28 (s, 1H), 7.27 (s, 1H), 7.20
(d, J = 8.4 Hz, 1H), 6.91 (s, 1H), 6.90 (s, 1H), 6.15 (s, 1H), 4.50
(s, 2H), 3.73 (s, 3H), 3.29 (s, 3H), 2.20 (3H); ESIMS m/z 565.20
(M.sup.+ + 1). 5 ##STR00281## .sup.1H NMR (600 MHz, DMSO- d.sub.6)
.delta. 12.86 (s, 1H), 10.44 (s, 1H), 8.41 (s, 1H), 8.35 (br, 1H),
8.31 (s, 1H), 8.28 (d, J = 7.8 Hz, 1H), 7.96 (d, J = 7.9 Hz, 1H),
7.78 (t, J = 7.8 Hz, 1H), 7.54 (s, 1H), 7.51 (d, J = 8.2 Hz, 1H),
7.20 (d, J = 8.3 Hz, 2H), 6.12 (s, 1H), 3.34 (s, 3H), 3.31 (t, J =
7.0 Hz, 2H), 3.25 (t, J = 7.0 Hz, 4H), 2.31 (s, 3H), 2.22 (t, J =
8.1 Hz, 2H), 1.93 (dt, J = 7.6, 14.1 Hz, 2H), 1.73 (m, 2H); ESIMS
m/z 570.20 (M.sup.+ + 1). 6 ##STR00282## ESIMS m/z 559.10 (M.sup.+
+ 1). 7 ##STR00283## ESIMS m/z 549.20 (M.sup.+ + 1). 8 ##STR00284##
ESIMS m/z 572.30 (M.sup.+ + 1). 9 ##STR00285## ESIMS m/z 513.20
(M.sup.+ + 1). 10 ##STR00286## ESIMS m/z 572.30 (M.sup.+ + 1). 11
##STR00287## ESIMS m/z 550.20 (M.sup.+ + 1). 12 ##STR00288## ESIMS
m/z 487.20 (M.sup.+ + 1). 13 ##STR00289## ESIMS m/z 525.20 (M.sup.+
+ 1). 14 ##STR00290## .sup.1H NMR (400 MHz, DMSO- d.sub.6) .delta.
10.47 (s, 1H), 8.40 (d, J = 2.1 Hz, 1H), 8.33 (s, 1H), 8.31-8.25
(m, 2H), ), 7.96 (t, J = 7.8 Hz, 1H), 7.78 (t, J = 7.8 Hz, 1H),
7.54 (d, J = 6.0, 1H), 7.52 (d, J = 8.2 Hz, 1H), 7.21 (d, J = 8.3
Hz, 2H) 6.13 (s, 1H), 3.31 (s, 3H), 2.31 (s, 3H), 2.17 (s, 2H);
ESIMS m/z 445.10 (M.sup.+ + 1). 15 ##STR00291## ESIMS m/z 488.10
(M.sup.+ + 1). 16 ##STR00292## ESIMS m/z 567.10 (M.sup.+ + 1). 17
##STR00293## ESIMS m/z 553.10 (M.sup.+ + 1). 18 ##STR00294## ESIMS
m/z 517.10 (M.sup.+ + 1). 19 ##STR00295## ESIMS m/z 502.20 (M.sup.+
+ 1). 20 ##STR00296## ESIMS m/z 579.20 (M.sup.+ + 1). 21
##STR00297## ESIMS m/z 552.10 (M.sup.+ + 1). 22 ##STR00298## ESIMS
m/z 603.10 (M.sup.+ + 1). 23 ##STR00299## ESIMS m/z 579.15 (M.sup.+
+ 1). 24 ##STR00300## ESIMS m/z 578.30 (M.sup.+ + 1). 25
##STR00301## ESIMS m/z 515.20 (M.sup.+ + 1). 26 ##STR00302## ESIMS
m/z 558.30 (M.sup.+ + 1). 27 ##STR00303## ESIMS m/z 485.20 (M.sup.+
+ 1). 28 ##STR00304## ESIMS m/z 564.20 (M.sup.+ + 1). 29
##STR00305## ESIMS m/z 578.20 (M.sup.+ + 1). 30 ##STR00306## ESIMS
m/z 633.30 (M.sup.+ + 1). 31 ##STR00307## ESIMS m/z 620.30 (M.sup.+
+ 1). 32 ##STR00308## ESIMS m/z 670.30 (M.sup.+ + 1). 33
##STR00309## ESIMS m/z 499.2 (M.sup.+ + 1). 34 ##STR00310## ESIMS
m/z 515.2 (M.sup.+ + 1). 35 ##STR00311## ESIMS m/z 528.3 (M.sup.+ +
1). 36 ##STR00312## ESIMS m/z 537.2 (M.sup.+ + 1). 37 ##STR00313##
ESIMS m/z 503.2 (M.sup.+ + 1). 38 ##STR00314## ESIMS m/z 522.2
(M.sup.+ + 1). 39 ##STR00315## ESIMS m/z 536.2 (M.sup.+ + 1). 40
##STR00316## ESIMS m/z 516.2 (M.sup.+ + 1). 41 ##STR00317## ESIMS
m/z 542.30 (M.sup.+ + 1). 42 ##STR00318## ESIMS m/z 614.30 (M.sup.+
+ 1). 43 ##STR00319## ESIMS m/z 558.30 (M.sup.+ + 1). 44
##STR00320## ESIMS m/z 553.30 (M.sup.+ + 1). 45 ##STR00321## ESIMS
m/z 649.30 (M.sup.+ + 1). 46 ##STR00322## ESIMS m/z 649.30 (M.sup.+
+ 1). 47 ##STR00323## ESIMS m/z 558.30 (M.sup.+ + 1). 48
##STR00324## ESIMS m/z 558.30 (M.sup.+ + 1). 49 ##STR00325## ESIMS
m/z 403.30 (M.sup.+ + 1). 50 ##STR00326## ESIMS m/z 403.30 (M.sup.+
+ 1). 51 ##STR00327## ESIMS m/z 403.30 (M.sup.+ + 1). 52
##STR00328## ESIMS m/z 403.30 (M.sup.+ + 1). 53 ##STR00329## ESIMS
m/z 495.3 (M.sup.+ + 1). 54 ##STR00330## ESIMS m/z 479.30 (M.sup.+
+ 1).
1. Assays
[1251] Compounds of Examples 208 to 216 are assayed to measure
their capacity to selectively inhibit cell proliferation of 32D
cells expressing BCR-Abl (32D-p210) compared with parental 32D
cells. Compounds selectively inhibiting the proliferation of these
BCR-Abl transformed cells are tested for anti-proliferative
activity on Ba/F3 cells expressing either wild type or the mutant
forms of Bcr-abl. In addition, compounds are assayed to measure
their capacity to inhibit FGFR35 (in an enzyme and cellular assay),
FLT3, PDGFR13, trkB, c-SRC, BMX, SGK, Tie2, Lck, JNK2a2, MKK4,
c-RAF, MKK6, SAPK2a and SAPK213 kinases.
Inhibition of Cellular BCR-Abl Dependent Proliferation (High
Throughput Method)
[1252] The murine cell line used is the 32D hemopoietic progenitor
cell line transformed with BCR-Abl cDNA (32D-p210). These cells are
maintained in RPMI/10% fetal calf serum (RPMI/FCS) supplemented
with penicillin 50 .mu.g/mL, streptomycin 50 .mu.g/mL and
L-glutamine 200 mM. Untransformed 32D cells are similarly
maintained with the addition of 15% of WEHI conditioned medium as a
source of IL3.
[1253] 50 .mu.l of a 32D or 32D-p210 cells suspension are plated in
Greiner 384 well microplates (black) at a density of 5000 cells per
well. 50n1 of test compound (1 mM in DMSO stock solution) is added
to each well (STI571 is included as a positive control). The cells
are incubated for 72 hours at 37.degree. C., 5% CO.sub.2. 10 .mu.l
of a 60% Alamar Blue solution (Tek diagnostics) is added to each
well and the cells are incubated for an additional 24 hours. The
fluorescence intensity (Excitation at 530 nm, Emission at 580 nm)
is quantified using the Acquest.TM. system (Molecular Devices).
Inhibition of Cellular BCR-Abl Dependent Proliferation
[1254] 32D-p210 cells are plated into 96 well TC plates at a
density of 15,000 cells per well. 50 .mu.L of two fold serial
dilutions of the test compound (C.sub.max is 40 .mu.M) are added to
each well (STI571 is included as a positive control). After
incubating the cells for 48 hours at 37.degree. C., 5% CO.sub.2, 15
.mu.L of MTT (Promega) is added to each well and the cells are
incubated for an additional 5 hours. The optical density at 570 nm
is quantified spectrophotometrically and IC.sub.50 values, the
concentration of compound required for 50% inhibition, determined
from a dose response curve.
Effect on Cell Cycle Distribution
[1255] 32D and 32D-p210 cells are plated into 6 well TC plates at
2.5.times.10.sup.6 cells per well in 5 ml of medium and test
compound at 1 or 10 .mu.M is added (STI571 is included as a
control). The cells are then incubated for 24 or 48 hours at
37.degree. C., 5% CO.sub.2. 2 ml of cell suspension is washed with
PBS, fixed in 70% EtOH for 1 hour and treated with PBS/EDTA/RNase A
for 30 minutes. Propidium iodide (Cf=10 .mu.g/ml) is added and the
fluorescence intensity is quantified by flow cytometry on the
FACScalibur.TM. system (BD Biosciences). Test compounds of the
present invention demonstrate an apoptotic effect on the 32D-p210
cells but do not induce apoptosis in the 32D parental cells.
Effect on Cellular BCR-Abl Autophosphorylation
[1256] BCR-Abl autophosphorylation is quantified with capture Elisa
using a c-abl specific capture antibody and an antiphosphotyrosine
antibody. 32D-p210 cells are plated in 96 well TC plates at
2.times.10.sup.5 cells per well in 50 .mu.L of medium. 50 .mu.L of
two fold serial dilutions of test compounds (C.sub.max is 10 .mu.M)
are added to each well (STI571 is included as a positive control).
The cells are incubated for 90 minutes at 37.degree. C., 5%
CO.sub.2. The cells are then treated for 1 hour on ice with 150
.mu.L of lysis buffer (50 mM Tris-HCl, pH 7.4, 150 mM NaCl, 5 mM
EDTA, 1 mM EGTA and 1% NP-40) containing protease and phosphatase
inhibitors. 50 .mu.L of cell lysate is added to 96 well optiplates
previously coated with anti-abl specific antibody and blocked. The
plates are incubated for 4 hours at 4.degree. C. After washing with
TBS-Tween 20 buffer, 50 .mu.L of alkaline-phosphatase conjugated
anti-phosphotyrosine antibody is added and the plate is further
incubated overnight at 4.degree. C. After washing with TBS-Tween 20
buffer, 90 .mu.L of a luminescent substrate are added and the
luminescence is quantified using the Acquest.TM. system (Molecular
Devices). Test compounds of the invention that inhibit the
proliferation of the BCR-Abl expressing cells, inhibit the cellular
BCR-Abl autophosphorylation in a dose-dependent manner.
Effect on Proliferation of Cells Expressing Mutant Forms of
Bcr-abl
[1257] Compounds of the invention are tested for their
antiproliferative effect on Ba/F3 cells expressing either wild type
or the mutant forms of BCR-Abl (G250E, E255V, T315I, F317L, M351T)
that confers resistance or diminished sensitivity to STI571. The
antiproliferative effect of these compounds on the mutant-BCR-Abl
expressing cells and on the non transformed cells were tested at
10, 3.3, 1.1 and 0.37 .mu.M as described above (in media lacking
IL3). The IC.sub.50 values of the compounds lacking toxicity on the
untransformed cells were determined from the dose response curves
obtained as describe above.
FGFR35 (Enzymatic Assay)
[1258] Kinase activity assay with purified FGFR35 (Upstate) is
carried out in a final volume of 104 containing 0.25 .mu.g/mL of
enzyme in kinase buffer (30 mM Tris-HCl pH7.5, 15 mM MgCl.sub.2,
4.5 mM MnCl.sub.2, 15 .mu.M Na.sub.3VO.sub.4 and 50 .mu.g/mL BSA),
and substrates (5 .mu.g/mL biotin-poly-EY(Glu, Tyr) (CIS-US, Inc.)
and 304 ATP). Two solutions are made: the first solution of 5 .mu.l
contains the FGFR35 enzyme in kinase buffer was first dispensed
into 384-format ProxiPlate.RTM. (Perkin-Elmer) followed by adding
50 mL of compounds dissolved in DMSO, then 5 .mu.l of second
solution contains the substrate (poly-EY) and ATP in kinase buffer
was added to each wells. The reactions are incubated at room
temperature for one hour, stopped by adding 10 .mu.L of HTRF
detection mixture, which contains 30 mM Tris-HCl pH7.5, 0.5 M KF,
50 mM ETDA, 0.2 mg/mL BSA, 15 .mu.g/mL streptavidin-XL665 (CIS-US,
Inc.) and 150 ng/mL cryptate conjugated anti-phosphotyrosine
antibody (CIS-US, Inc.). After one hour of room temperature
incubation to allow for streptavidin-biotin interaction, time
resolved florescent signals are read on Analyst GT (Molecular
Devices Corp.). IC.sub.50 values are calculated by linear
regression analysis of the percentage inhibition of each compound
at 12 concentrations (1:3 dilution from 50 .mu.M to 0.28 nM). In
this assay, compounds of the invention have an IC.sub.50 in the
range of 10 nM to 2 .mu.M.
FGFR35 (Cellular Assay)
[1259] Compounds of the invention are tested for their ability to
inhibit transformed Ba/F3-TEL-FGFR35 cells proliferation, which is
depended on FGFR35 cellular kinase activity. Ba/F3-TEL-FGFR35 are
cultured up to 800,000 cells/mL in suspension, with RPMI 1640
supplemented with 10% fetal bovine serum as the culture medium.
Cells are dispensed into 384-well format plate at 5000 cell/well in
50 .mu.L culture medium. Compounds of the invention are dissolved
and diluted in dimethylsufoxide (DMSO). Twelve points 1:3 serial
dilutions are made into DMSO to create concentrations gradient
ranging typically from 10 mM to 0.05 .mu.M. Cells are added with 50
nL of diluted compounds and incubated for 48 hours in cell culture
incubator. AlamarBlue.RTM. (TREK Diagnostic Systems), which can be
used to monitor the reducing environment created by proliferating
cells, are added to cells at final concentration of 10%. After
additional four hours of incubation in a 37.degree. C. cell culture
incubator, fluorescence signals from reduced AlamarBlue.RTM.
(Excitation at 530 nm, Emission at 580 nm) are quantified on
Analyst GT (Molecular Devices Corp.). IC.sub.50 values are
calculated by linear regression analysis of the percentage
inhibition of each compound at 12 concentrations.
Upstate KinaseProfiler.TM.--Radio-enzymatic Filter Binding
Assay
[1260] Compounds of the invention are assessed for their ability to
inhibit individual members of a panel of kinases (a partial,
non-limiting list of kinases includes: Abl, BCR-Abl, BMX, FGFR35,
Lck, JNK1, JNK2, CSK, RAF, MKK6 and P38). The compounds are tested
in duplicates at a final concentration of 10 .mu.M following this
generic protocol. Note that the kinase buffer composition and the
substrates vary for the different kinases included in the "Upstate
KinaseProfiler.TM." panel. The compounds are tested in duplicates
at a final concentration of 10 .mu.M following this generic
protocol. Note that the kinase buffer composition and the
substrates vary for the different kinases included in the "Upstate
KinaseProfiler.TM." panel. Kinase buffer (2.5 .mu.L,
10.times.-containing MnCl.sub.2 when required), active kinase
(0.001-0.01 Units; 2.5 .mu.L), specific or Poly(Glu4-Tyr) peptide
(5-500 .mu.M or 0.01 mg/ml) in kinase buffer and kinase buffer (50
.mu.M; 5 .mu.L) are mixed in an eppendorf on ice. A Mg/ATP mix (10
.mu.L; 67.5 (or 33.75) mM MgCl.sub.2, 450 (or 225) .mu.M ATP and 1
.mu.Ci/.mu.l [.gamma.-.sup.32P]-ATP (3000Ci/mmol)) is added and the
reaction is incubated at about 30.degree. C. for about 10 minutes.
The reaction mixture is spotted (20 .mu.L) onto a 2 cm.times.2 cm
P81 (phosphocellulose, for positively charged peptide substrates)
or Whatman No. 1 (for Poly (Glu-4-Tyr) peptide substrate) paper
square. The assay squares are washed 4 times, for 5 minutes each,
with 0.75% phosphoric acid and washed once with acetone for 5
minutes. The assay squares are transferred to a scintillation vial,
5 ml scintillation cocktail are added and .sup.32P incorporation
(cpm) to the peptide substrate is quantified with a Beckman
scintillation counter. Percentage inhibition is calculated for each
reaction.
[1261] Compounds of Formula I**, in free form or in
pharmaceutically acceptable salt form, exhibit valuable
pharmacological properties, for example, as indicated by the in
vitro tests described in this application. For example, compounds
of Formula I** preferably show an IC.sub.50 in the range of
1.times.10.sup.-10 to 1.times.10.sup.-5M, preferably less than 50
nM for wild type BCR-Abl and G250E, E255V, T315I, F317L and M351T
BCR-Abl mutants. Compounds of Formula I** preferably, at a
concentration of 10 mM, preferably show a percentage inhibition of
greater than 50%, preferably greater than about 70%, against Abl,
Bcr-abl, c-RAF, c-SRC, JNK2.alpha.2, lck, MKK6, PDGFR.alpha.,
SAPK2.alpha., SAPK2.beta., Tie2 and TrkB kinases. For example:
N-(3-{3-[6-(3-Acetylamino-phenylamino)-pyrimidin-4-yl]-3-methyl-ureido}-4-
-methyl-phenyl)-3-trifluoromethyl-benzamide (Example 4) has an
IC.sub.50 of <0.5 nM, 38 nM, 44 nM, 41 nM, <0.5 nM and
<0.5 nM for wild type, G250E, E255V, T315I, F317L and M351T
Bcr-abl, respectively;
[1262] b).
N-{3-[3-(6-Amino-pyrimidin-4-yl)-3-(2-morpholin-4-yl-ethyl)-ure-
ido]-4-methyl-phenyl}-3-trifluoromethyl-benzamide (Example 214) has
an IC50 of 65 nM and 49 nM for the FGFR35 enzyme and cellular
assays, respectively, and 14.9 nM and 0.4 nM for Bcr-abl wild type
and PDGFR.beta., respectively;
[1263] c). N-(3-{3-(6-Amino-pyrimidin-4-yl)-3-[3-(2 oxo
pyrrolidin-1-yl)-propyl]-ureido}-4-methyl-phenyl)-3-trifluoromethyl-benza-
mide (Example 215) has an IC50 of 16 nM and 15 nM for the FGFR35
enzyme and cellular assays, respectively, and 10 nM and 2 nM for
Bcr-abl wild type and PDGFR.beta., respectively;
[1264] d).
N-(3-{3-(6-Amino-pyrimidin-4-yl)-3-[3-(2-oxo-pyrrolidin-1-yl)-p-
ropyl]-ureido}-4-methyl-phenyl)-3-trifluoromethyl-benzamide
(Example 215), at a concentration of 10 .mu.M, inhibits the
following kinases by the percentage shown in brackets (for example,
100% means complete inhibition, 0% means no inhibition): wild-type
Abl (99%), c-RAF (99%), CSK (97%), c-SRC (100%), FGFR35 (99%), INK2
cc2 (93%), lck (100%), MKK6 (88%), p70S6K (81%), ROS (95%),
SAPK2.alpha. (99%), SAPK2.beta. (99%), Tie2 (100%) and TrkB (99%).
It is understood that the examples and embodiments described herein
are for illustrative purposes only and that various modifications
or changes in light thereof will be suggested to persons skilled in
the art and are to be included within the spirit and purview of
this application and scope of the appended claims. All
publications, patents, and patent applications cited herein are
hereby incorporated by reference for all purposes.
Example 217
1-(2,6-Dichloro-3,5-dimethoxy-Phenyl)-3-{6-[4-(4-isopropyl-piperazin-1-yl)-
-phenylamino]-pyrimidin-4-yl}-urea
##STR00331##
[1266] The title compound is prepared as described in Example 160
but using
N-[4-(4-isopropyl-piperazin-1-yl)-phenyl]-pyrimidine-4,6-diamine
(385 mg, 1.23 mmol, 1 eq.), and stirring the reaction mixture for
0.5 h at 70.degree. C. The title compound: ESI-MS: 560.0/562.0
[MH].sup.+; t.sub.R=3.17 min (purity: 98%, gradient J); TLC:
R.sub.f=0.31 (DCM/MeOH+1% NH.sub.3.sup.aq, 95:5).
A.
N-[4-(4-Isopropyl-piperazin-1-yl)-phenyl]-pyrimidine-4,6-diamine
[1267] The title compound is prepared as described in Example 144A
but using 4-(4-isopropyl-piperazin-1-yl)-phenylamine (400 mg, 1.83
mmol, 1 eq.), 6-chloro-pyrimidin-4-yl)-amine (1.3 eq.), and
stirring the reaction mixture at 150.degree. C. for 18 h.
Purification of the crude product by trituration in diethyl ether
affords the title compound as a white solid: ESI-MS: 313.2
[MH].sup.+; t.sub.R=1.00 min (gradient J).
B. 4-(4-Isopropylpiperazin-1-yl)-aniline
[1268] A suspension of 1-isopropyl-4-(4-nitro-phenyl)-piperazine
(5.18 g, 20.80 mmol) and Palladium (5%) on carbon (0.5 g) in MeOH
(100 mL) is stirred for 2.7 h at RT, under a hydrogen atmosphere.
The reaction mixture is filtered through a pad of celite and
concentrated to afford the title compound as a violet solid:
ESI-MS: 220.1 [MH].sup.+; t.sub.R=0.95 min (gradient J).
C. 1-Isopropyl-4-(4-nitro-phenyl)-piperazine
[1269] A mixture of 1-bromo-4-nitrobenzene (6 g, 29.7 mmol) and
1-ethylpiperazine (7.6 ml, 59.4 mmol, 2 eq.) is heated to
80.degree. C. for 15 h. After cooling to RT, the reaction mixture
is concentrated. Purification of the residue by silica gel column
chromatography (DCM/MeOH , 95:5) affords 5.18 g of the title
compound as a yellow solid: ESI-MS: 250.1 [MH].degree.;
t.sub.R=2.57 min (purity: 100%, gradient J); TLC: R.sub.f=0.16
(DCM/MeOH , 95:5).
Example 218
3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-methyl-1-(6-{4-[2-(4-methyl-pipera-
zin-1-yl)-ethoxy]-phenylamino}-pyrimidin-4-yl)-urea
##STR00332##
[1271] The title compound is prepared as described in Example 144
but using
N-{4-[2-(4-methyl-piperazin-1-yl)-ethoxy]-phenyl}-pyrimidine-4,6-di-
amine (227 mg, 1.23 mmol, 1 eq.), and stirring the reaction mixture
for 18 h at 70.degree. C. Purification of the crude product by
silica gel column chromatography (DCM/MeOH+1% NH.sub.3.sup.aq,
95:5) affords the title compound as a white solid: ESI-MS:
589.9/591.9 [MH].sup.+; t.sub.R=3.11 min (purity: 100%, gradient
J); TLC: R.sub.f=0.12 (DCM/MeOH+1% NH.sub.3.sup.aq, 95:5).
A.
N-Methyl-N'-{4-[2-(4-methyl-piperazin-1-yl)-ethoxy]-phenyl}-pyrimidine--
4,6-diamine
[1272] The title compound is prepared as described in Example 160A
but using 4-[2-(4-methyl-piperazin-1-yl)-ethoxy]-phenylamine (500
mg, 2.13 mmol, 1 eq.), (6-chloro-pyrimidin-4-yl)-ethyl-amine and
stirring the reaction mixture at 150.degree. C. for 20 h.
Purification of the crude product by silica gel column
chromatography (DCM/MeOH+1% NH.sub.3.sup.aq, 9:1) followed by
trituration in diethyl ether affords 250 mg of the title compound
as a white solid: ESI-MS: 343.2 [MH].sup.+; t.sub.R=1.00 min
(gradient J); TLC: R.sub.f=0.23 (DCM/MeOH+1% NH.sub.3.sup.aq,
9:1).
Example 219
3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-isopropyl-Piperazin-1-yl)-
-phenylamino]-pyrimidin-4-yl}-1-methyl-urea
##STR00333##
[1274] The title compound is prepared as described in Example 144
but using
N-[4-(4-isopropyl-piperazin-1-yl)-phenyl]-N'-methyl-pyrimidine-4,6--
diamine (1.71 g, 5.25 mmol, 1 eq.) and performing the reaction
mixture for 45 min at reflux. Purification of the crude product by
trituration in MeOH followed by silica gel column chromatography
(DCM/MeOH+1% NH.sub.3.sup.aq, 97:3) affords the title compound as a
white solid: ESI-MS: 573.9/575.9 [MH].sup.+: t.sub.R=3.65 min
(purity: 100%, gradient J); TLC: R.sub.f 0.10 (DCM/MeOH+1%
NH.sub.3.sup.aq, 97:3).
A.
N-[4-(4-Isopropyl-piperazin-1-yl)-phenyl]-N'-methyl-pyrimidine-4,6-diam-
ine
[1275] The title compound is prepared as described in Example 144A
but using 4-(4-isopropylpiperazin-1-yl)-aniline (Example 2178) (2.6
g, 11.9 mmol). Purification of the residue by silica gel column
chromatography (DCM/MeOH, 93:7) affords 1.71 g of the title
compound as a white solid: ESI-MS: 327.2 [MH].sup.+; t.sub.R=1.30
min (gradient J); TLC: R.sub.f 0.26 (DCM/MeOH, 93:7).
Example 220
1-(2,6-Dichloro-3,5-dimethoxy-phenyl)-3-[6-(4-dimethylaminomethyl-3-triflu-
oromethyl-phenylamino)-pyrimidin-4-yl]-urea
##STR00334##
[1277] The title compound is prepared as described in Example 144
but using
N-(4-dimethylaminomethyl-3-trifluoromethyl-phenyl)-pyrimidine-4,6-d-
iamine (250 mg, 0.80 mmol, 1 eq.), 2 eq. of isocyanate, and
performing the reaction mixture for 30 min at reflux. Purification
of the crude product by silica gel column chromatography
(DCM/MeOH+1% NH.sub.3.sup.aq, 95:5) affords the title compound as a
white solid: ESI-MS: 558.9/560.9 [MH].sup.+; t.sub.R=3.69 min
(purity: 100%, gradient J); TLC: R.sub.f=0.21 (DCM/MeOH+1%
NH.sub.3.sup.aq, 95:5).
A.
N-(4-Dimethylaminomethyl-3-trifluoromethyl-phenyl)-pyrimidine-4,6-diami-
ne
[1278] The title compound is prepared as described in Example 144A
but using 4-dimethylaminomethyl-3-trifluoromethyl-phenylamine (300
mg, 1.46 mmol) and 6-chloro-pyrimidin-4-yl)-amine (1.3 eq.).
Purification of the crude product by silica gel column
chromatography (DCM/MeOH, 93:7) affords the title compound as a
white solid: ESI-MS: 312.1 [MH].sup.+; TLC: R.sub.f=0.16 (DCM/MeOH,
93:7).
Example 164
3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-[6-(4-dimethylaminomethyl-3-triflu-
oromethyl-phenylamino)-pyrimidin-4-yl]-1-methyl-urea
##STR00335##
[1280] The title compound is prepared as described in Example 144
but using
N-(4-dimethylaminomethyl-3-trifluoromethyl-phenyl)-N'-methyl-pyrimi-
dine-4,6-diamine (200 mg, 0.62 mmol, 1 eq.), and performing the
reaction mixture for 1 h at reflux. Purification of the crude
product by trituration in MeOH followed by silica gel column
chromatography (DCM/MeOH+1% NH.sub.3.sup.aq, 95:5) affords the
title compound as a white solid: ESI-MS: 572.8 /574.8 [MH].sup.+;
t.sub.R=4.14 min (purity: 100%, gradient J); TLC: R.sub.f=0.24
(DCM/MeOH+1% NH.sub.3.sup.aq, 95:5).
A.
N-(4-Dimethylaminomethyl-3-trifluoromethyl-phenyl)-N'-methyl-pyrimidine-
-4,6-diamine
[1281] The title compound is prepared as described in Example 144A
but using 4-dimethylaminomethyl-3-trifluoromethyl-phenylamine (300
mg, 1.46 mmol) and 1.3 eq. of
6-chloro-pyrimidin-4-yl)-methyl-amine. Purification of the crude
product by silica gel column chromatography (DCM/MeOH, 93:7)
affords the title compound as a white solid: ESI-MS: 326.1
[MH].sup.+; TLC: R.sub.f=0.27 (DCM/MeOH, 93:7).
Example 222
3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-(6-(3-{[(2-dimethylamino-ethyl)-me-
thyl-amino]-methyl}-phenylamino)-pyrimidin-4-yl]-1-methyl-urea
##STR00336##
[1283] The title compound is prepared as described in Example 144
but using
N-(3-{[(2-dimethylamino-ethyl)-methyl-amino]-methyl}-phenyl)-pyrimi-
dine-4,6-diamine (250 mg, 0.80 mmol, 1 eq.), 1.5 eq. of isocynaze,
and performing the reaction mixture for 6 h at reflux. Purification
of the crude product by MPLC (by silica gel) (DCM/MeOH+1%
NH.sub.3.sup.aq, 95:5) followed by trituration in diethyl ether
affords the title compound as a white solid: ESI-MS: 561.9/563.9
[MH].sup.+; t.sub.R=3.24 min (purity: 100%, gradient J); TLC:
R.sub.f=0.10 (DCM/MeOH+1% NH.sub.3.sup.aq, 9:1).
A.
N-(3-{[(2-Dimethylamino-ethyl)-methyl-amino]-methyl}-phenyl)-N'-methyl--
pyrimidine-4,6-diamine
[1284] The title compound is prepared as described in Example 144A
but using N-(3-amino-benzyl)-N,N',N'-trimethyl-ethane-1,2-diamine
(500 mg, 2.41 mmol), 1.1 eq. of
6-chloro-pyrimidin-4-yl)-methyl-amine, and stirring the reaction
mixture for 17.5 h. Purification of the crude product by silica gel
column chromatography (DCM/MeOH+1% NH.sub.3.sup.aq, 95:5) affords
the title compound as a beige solid: ESI-MS: 315.2 [MH].sup.+; TLC:
R.sub.f=0.05 (DCM/MeOH+1% NH.sub.3.sup.aq, 9:1).
B. N-(3-Amino-benzyl)-N,N',N'-trimethyl-ethane-1,2-diamine
[1285] A suspension of
N,N',N'-trimethyl-N'-(3-nitro-benzyl)-ethane-1,2-diamine (4.5 g,
18.96 mmol) and Raney Nickel (1.2 g) in MeOH (100 mL) is stirred
for 2 h at RT, under a hydrogen atmosphere. The reaction mixture is
filtered through a pad of celite and concentrated to afford the
title compound as a yellow oil: ESI-MS: 208.2.
C. N,N',N'-Trimethyl-N'-(3-nitro-benzyl)-ethane-1,2-diamine
[1286] A mixture of 3-nitrobenzylchloride (4.5 g, 26.23 mmol),
N,N,N-trimethylethylendiamine (4.1 ml, 31.47 mmol, 1.2 eq.),
potassium carbonate (7.3 g, 52.46, 2 eq.), and acetone (90 ml) is
stirred for 19 h at 80.degree. C. The reaction mixture is allowed
to cool to RT, filtered and concentrated. Purification of the crude
product by silica gel column chromatography (DCM/MeOH+1%
NH.sub.3.sup.aq, 9:1) affords the title compound as a brown oil:
ESI-MS: 238.1 [MH].sup.+; t.sub.R=1.10 min (gradient J); TLC:
R.sub.f=0.10 (DCM/MeOH+1% NH.sub.3.sup.aq, 9:1).
Example 223
3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-{6-[3-(4-isopropyl-piperazin-1-ylm-
ethyl)-phenylamino]-pyrimidin-4-yl}-1-methyl-urea
##STR00337##
[1288] The title compound is prepared as described in Example 144
but using
N-[3-(4-isopropyl-piperazin-1-ylmethyl)-phenyl]-N'-methyl-pyrimidin-
e-4,6-diamine (250 mg, 0.73 mmol, 1 eq.). Purification of the crude
product by MPLC (silica gel) (DCM/MeOH+1% NH.sub.3.sup.aq, 95:5)
followed by trituration in diethyl ether affords the title compound
as a white solid: ESI-MS: 587.9/589.9 [MH].sup.+; t.sub.R=3.35 min
(purity: 100%, gradient J); TLC: R.sub.f=0.17 (DCM/MeOH+1%
NH.sub.3.sup.aq, 9:1).
A.
N-[3-(4-Isopropyl-piperazin-1-ylmethyl)-phenyl]-N'-methyl-pyrimidine-4,-
6-diamine
[1289] The title compound is prepared as described in Example 143A
but using 3-(4-isopropyl-piperazin-1-ylmethyl)-phenylamine (500 mg,
2.14 mmol, 1 eq.) and stirring the reaction mixture for 17.5 h at
150.degree. C. Purification of the crude product by MPLC (silica
gel) (DCM/MeOH+1% NH.sub.3.sup.aq, 95:5) affords the title compound
as a light yellow solid: TLC: R.sub.f=0.10 (DCM/MeOH+1%
NH.sub.3.sup.aq, 9:1).
B. 3-(4-Isopropyl-piperazin-1-ylmethyl)-phenylamine
[1290] The title compound is prepared as described in Example 149B:
ESI-MS: 234.1 [MH].sup.+; t.sub.R=0.95 min (gradient J).
C. 1-Isopropyl-4-(3-nitro-benzyl)-piperazine
[1291] The title compound is prepared as described in Example 222C:
ESI-MS: 264.1 [MH].sup.+; TLC: R.sub.f=0.35 (DCM/MeOH+1%
NH.sub.3.sup.aq, 9:1).
Example 224
1-(2,6-Dichloro-3,5-dimethoxy-phenyl)-3-{6-[3-(1-methyl-piperidin-4-yloxy)-
-phenylamino]-pyrimidin-4-yl}-urea
##STR00338##
[1293] The title compound is prepared as described in Example 160
but using
N-[3-(1-methyl-piperidin-4-yloxy)-phenyl]-pyrimidine-4,6-diamine
(205 mg, 0.69 mmol, 1 eq.). Purification of the crude product by
silica gel column chromatography (DCM/MeOH+1% NH.sub.3.sup.aq,
95:5) followed by trituration in MeOH affords the title compound as
a white solid: ESI-MS: 546.9 /548.9 [MH].sup.+; t.sub.R=3.14 min
(purity: 100%, gradient J); TLC: R.sub.f=0.13 (DCM/MeOH+1%
NH.sub.3.sup.aq, 95:5).
A.
N-[3-(1-Methyl-piperidin-4-yloxy)-phenyl]-pyrimidine-4,6-diamine
[1294] The title compound is prepared as described in Example 160A
but using 3-(1-methyl-piperidin-4-yloxy)-phenylamine (500 mg, 2.43
mmol, 1 eq.) and stirring the reaction mixture for 20 h at
100.degree. C. Trituration of the crude product in EE affords the
title compound as a red solid: ESI-MS: 300.2 [MH].sup.+;
t.sub.R=0.85 min (gradient J).
B. 3-(1-Methyl-piperidin-4-yloxy)-phenylamine
[1295] The title compound is prepared as described in Example 217B:
ESI-MS: 207.1 [MH].sup.+.
C. 1-Methyl-4-(3-nitro-phenoxy)-piperidine
[1296] A mixture of 4-fluoro-nitrobenzene (10 g, 71.0 mmol),
4-hydroxy-1-methyl-piperidine (16.6 ml, 141.8 mmol, 2 eq.),
tetrabutylammonium bromide (4.6 g, 14.2 mmol, 0.2 eq.), toluene (50
ml) and a 25% aqueous solution of potassium hydroxide (50 ml) is
stirred for 15 h at 60.degree. C. The reaction mixture is cooled to
RT and poured onto ice/water. The resulting suspension is filtered
and the filtrate is extracted with EE. The organic phase is washed
with 0.5 N HCl, brine, then dried (sodium sulfate), filtered, and
concentrated to afford 6 g of the title compound. The aqueous layer
is made neutral by addition of sodium bicarbonate and extracted
with EE. The organic phase is washed with brine, dried (sodium
sulfate), filtered, and concentrated to afford additional 10 g of
the title compound: ESI-MS: 237.0 [MH].sup.+; t.sub.R=2.61 min
(purity: 90%, gradient J).
Example 225
3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-methyl-{6-[3-(1-methyl-piperidin-4-
-yloxy)-phenylamino]-pyrimidin-4-yl}-urea
##STR00339##
[1298] The title compound is prepared as described in Example 144
but using
N-methyl-N'-[3-(1-methyl-piperidin-4-yloxy)-phenyl]-pyrimidine-4,6--
diamine (130 mg, 0.41 mmol, 1 eq.). Purification of the crude
product by silica gel column chromatography (DCM/MeOH+1%
NH.sub.3.sup.aq, 95:5) followed by trituration in MeOH affords the
title compound as a white solid: ESI-MS: 561.0/563.0 [MH].sup.+;
t.sub.R=3.66 min (purity: 97%, gradient J).
A.
N-Methyl-N'-[3-(1-methyl-piperidin-4-yloxy)-phenyl]-pyrimidine-4,6-diam-
ine
[1299] The title compound is prepared as described in Example 160A
but using 3-(1-methyl-piperidin-4-yloxy)-phenylamine (Example
224B). The title compound as a red solid: ESI-MS: 314.2 [MH].sup.+;
TLC: R.sub.f=0.16 (DCM/MeOH+1% NH.sub.3.sup.aq, 9:1).
Example 226
3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-[6-(3-diethylaminomethyl-phenylami-
no)-pyrimidin-4-yl]-1-methyl-urea
##STR00340##
[1301] The title compound is prepared as described in Example 144
but using
N-(3-diethylaminomethyl-phenyl)-N'-methyl-pyrimidine-4,6-diamine
(128 mg, 0.45 mmol, 1 eq.). The title compound: ESI-MS: 533.0/535.0
[MH].sup.+; t.sub.R=3.94 min (purity: 100%, gradient J); TLC:
R.sub.f=0.37 (DCM/MeOH+1% NH.sub.3.sup.aq, 92:8).
A.
N-(3-Diethylaminomethyl-phenyl)-N'-methyl-pyrimidine-4,6-diamine
[1302] The title compound is prepared as described in Example 144A
but using 3-diethylaminomethyl-phenylamine. The title compound:
ESI-MS: 286.1 [MH].sup.+; TLC: R.sub.f=0.05 (DCM/MeOH+1%
NH.sub.3.sup.aq, 9:1).
B. 3-Diethylaminomethyl-phenylamine
[1303] The title compound is prepared as described in Example 149B
but using diethyl-(3-nitrobenzyl)-amine. The title compound
contains 30% of 3-methyl-aniline and is used as a crude impure
material.
C. Diethyl-(3-nitrobenzyl)-amine
[1304] The title compound is prepared as described in Example 149C
but using diethylamine. The title compound: t.sub.R=1.83 min
(purity: 100%, gradient J); TLC: R.sub.f=0.38 (DCM/MeOH, 9:1).
Example 227
3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-methyl-1-{4-[4-(4-methyl-piperazin-
-1-yl)-phenylamino]-[1,3,5]triazin-2-yl}-urea
##STR00341##
[1306] To a solution of 2,6-dichloro-3,5-dimethoxy-aniline (124 mg
, 0.56 mmol; Preparation 2) in 2 ml of dioxane under a nitrogene
atmosphere, phosgene (0.52 ml 20% in toluene, 0.98 mmol) is added.
The mixture is stirred for 70 min at 100.degree. C., cooled to RT
and concentrated in vacuo, yielding
2,6-dichloro-3,5-dimethoxyphenylisocyanate.
[1307] The resulting solid is added portion-wise to a boiling
solution of
N-methyl-N'-[4-(4-methyl-piperazin-1-yl)-phenyl]-[1,3,5]triazine-2,4-diam-
ine (140 mg, 0.47 mmol) in 8 ml of toluene during 20 min. After 3
h, another 2 eq of 2,6-dichloro-3,5-dimethoxyphenylisocyanate are
added and stirring is continued for totally 5 h. Then the reaction
mixture is diluted with DCM and a saturated aqueous solution of
NaHCO.sub.3. The aqueous layer is separated and extracted twice
with DCM. The organic phases are washed with water and brine, dried
(Na.sub.2SO.sub.4) and concentrated. Column chromatography
(SiO.sub.2; DCM/MeOH/NH.sub.3.sup.aq 97:3:0.2) gives the title
compound: ESI-MS: 547/549 [MH].sup.+; t.sub.R=3.5 min (purity:
100%, gradient J); TLC: R.sub.f=0.40 (DCM/MeOH+1% NH.sub.3.sup.aq,
95:5).
A.
N-Methyl-N'-[4-(4-methyl-piperazin-1-yl)-phenyl]-[1,3,5]triazine-2,4-di-
amine
[1308] A solution of (4-chloro-[1,3,5]triazin-2-yl)methyl-amine
(290 mg, 2.00 mmol) and 4-(4-methylpiperazin-1-yl)-aniline (570 mg,
3.0 mmol) in EtOH (20 ml) and N-ethyl-diisopropyl amine (530 .mu.l,
3.1 mmol) is heated to 80.degree. C. for 2 h under a nitrogen
atmosphere. The reaction mixture is concentrated and the residue
re-dissolved in EE and water. The separated off aqueous phase is
extracted twice with EE, the organic layer washed with water and
brine, dried (Na.sub.2SO.sub.4) and concentrated. Column
chromatography (SiO.sub.2; DCM/MeOH/NH.sub.3.sup.aq 95:5:0.2) gives
the title compound: TLC: R.sub.f=0.07 (DCM/MeOH+1 NH.sub.3.sup.aq,
95:5).
B. (4-Chloro-[1,3,5]triazin-2-yl)-methyl-amine
[1309] To an ice cooled solution of 2,4-dichlor-[1,3,5]triazine
(2.25 g, 15 mmol; WO 2004/072063, Expl. 9) in 20 ml of THF,
MeNH.sub.2 (15 ml of 2 M solution in THF) is added. After 1 h the
mixture is diluted with 15 ml of water and concentrated partially
in vacuo. The precipitated title compound can be filtered off,
washed with ice-water and dried: ESI-MS: 143 [M-H.
Example 228
3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-methyl-1-{4-[4-(4-ethyl-piperazin--
1-yl)-phenylamino]-[1,3,5]triazin-2-yl}-urea
##STR00342##
[1311] To a solution of 2,6-dichloro-3,5-dimethoxy-anilin (133 mg ,
0.60 mmol; Preparation 2) in 2 ml of dioxane under a nitrogen
atmosphere, phosgene (0.54 ml 20% in toluene, 1.0 mmol) is added.
The mixture is stirred for 60 min at 100.degree. C., cooled to RT
and concentrated in vacuo, yielding
2,6-dichloro-3,5-dimethoxyphenylisocyanate. The resulting solid is
added portion-wise to a boiling solution of
N-methyl-N'-[4-(4-ethyl-piperazin-1-yl)-phenyl]-[1,3,5]triazine-2,4-diami-
ne (156 mg, 0.50 mmol) in 7 ml of toluene during 15 min. After 5 h,
the reaction mixture is diluted with DCM and a saturated aqueous
solution of NaHCO.sub.3. The aqueous layer is separated and
extracted twice with DCM. The organic phases are washed with water
and brine, dried (Na.sub.2SO.sub.4) and concentrated. Column
chromatography (SiO.sub.2; DCM/MeOH/NH.sub.3.sup.aq 95:5:0.2) gives
the title compound: ESI-MS: 561 /563 [MH].sup.+; t.sub.R=3.6 min
(gradient J); TLC: R.sub.f=0.4 (DCM/MeOH+1% NH.sub.3.sup.aq,
95:5).
A.
N-Methyl-N'-[4-(4-ethyl-piperazin-1-yl)-phenyl]-[1,3,5]triazine-2,4-dia-
mine
[1312] A mixture of (4-chloro-[1,3,5]triazin-2-yl)-methyl-amine
(290 mg, 2.00 mmol), NaI (28 mg) and
4-(4-ethylpiperazin-1-yl)-aniline (410 mg, 2.0 mmol) in EtOH (20
ml) and N-ethyl-diisopropyl amine (350 .mu.l, 2.0 mmol) is heated
to 80.degree. C. for 3 h under a nitrogen atmosphere. The reaction
mixture is cooled to RT, concentrated partially in vacuo and
diluted with hexane at 0.degree. C. The precipitate is filtered
off, washed with Et.sub.2O and re-dissolved in EE and water. The
separated off aqueous phase is extracted twice with EE, the organic
layer washed with water and brine, dried (Na.sub.2SO.sub.4) and
concentrated, yielding the title compound: ESI-MS: 314 [MH].sup.+;
TLC: R.sub.f=0.10 (DCM/MeOH 9:1).
Example 229
3-(4-Fluoro-3-trifluoromethyl-phenyl)-1-methyl-1-{4-[4-(4-ethyl-piperazin--
1-yl)-phenylamino]-[1,3,5]triazin-2-yl}-urea
##STR00343##
[1314] To a solution of
N-methyl-N'-[4-(4-ethyl-piperazin-1-yl)-phenyl]-[1,3,5]triazine-2,4-diami-
ne (24 mg, 0.077 mmol) in 1.5 ml THF and 2.5 ml toluene,
4-fluoro-3-trifluoromethyl-phenyl-isocyanate (25 .mu.l, 0.17 mmol)
is added and the mixture is stirred for 5 h at 100.degree. C.
Workup analogously as described in Example 171 gives the title
compound: ESI-MS: 519 [MH].sup.+; t.sub.R=4.3 min (purity: 100%,
gradient J); TLC: R.sub.f=0.43 (DCM/MeOH 9).
Example 230
3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-methyl-1-{4-[4-(4-isopropyl-pipera-
zin-1-yl)-phenylamino]-[1,3,5]triazin-2-yl}-urea
##STR00344##
[1316] As described in Example 230,
2,6-dichloro-3,5-dimethoxy-aniline (133 mg , 0.60 mmol; Preparation
2) and
N-methyl-N'-[4-(4-isopropyl-piperazin-1-yl)-phenyl]-[1,3,5]triazine-2,4-d-
iamine (163 mg, 0.50 mmol) are converted to the title compound:
ESI-MS: 575/577 [MH].sup.+; t.sub.R=3.7 min (gradient J); TLC:
R.sub.f=0.32 (DCM/MeOH+1% NH.sub.3.sup.aq, 95:5).
A.
N-Methyl-N'-[4-(4-isopropyl-piperazin-1-yl)-phenyl]-[1,3,5]triazine-2,4-
-diamine
[1317] A mixture of (4-chloro-[1,3,5]triazin-2-yl)methyl-amine (290
mg, 2.00 mmol), NaI (28 mg) and 4-(4-propylpiperazin-1-yl)-aniline
(500 mg, 2.0 mmol) in EtOH (20 ml) and N-ethyl-diisopropyl amine
(350 .mu.l, 2.0 mmol) is heated to 80.degree. C. for 3 h under a
nitrogen atmosphere. Workup as described in Example 228A gives the
title compound: ESI-MS: 328 [MH].sup.+; TLC: R.sub.f=0.14
(DCM/MeOH, 9:1).
Example 231
3-(2,6-Dichloro-3-trifluoromethyl-phenyl)-1-{6-[4-(4-ethyl-piperazin-1-yl)-
-phenylamino]-pyrimidin-4-yl}-1-methyl-urea
##STR00345##
[1319] To a solution of 2,6-dichloro-3-trifluoromethyl-aniline (138
mg , 0.60 mmol) in 2 ml of dioxane under a nitrogen atmosphere,
phosgene (0.54 ml 20% in toluene, 1.0 mmol) is added. The mixture
is stirred for 2 h at 100.degree. C., cooled to rt and concentrated
in vacuo, yielding
2,6-dichloro-3-trifluoromethyl-phenylisocyanate.
[1320] This oil is re-dissolved in 2 ml of toluene and added
portion-wise to a boiling solution of
N-[4-(4-ethyl-piperazin-1-yl)-phenyl]-N'-methyl-pyrimidine-4,6-diamine
(156 mg, 0.50 mmol; Example 145A) in 6 ml of toluene during 10 min.
After 1.5 h, another 2 eq of
2,6-dichloro-3-trifluoromethyl-phenylisocyanate are added and
stirring is continued for totally 2 h. Then the reaction mixture is
diluted with DCM and a saturated aqueous solution of NaHCO.sub.3.
The aqueous layer is separated and extracted twice with DCM. The
organic phases are washed with water and brine, dried
(Na.sub.2SO.sub.4) and concentrated. Column chromatography
(SiO.sub.2; CH.sub.2Cl.sub.2/MeOH/NH.sub.3.sup.aq 95:5:0.5) gives
the title compound: ESI-MS: 568/570 [MH].sup.+; t.sub.R=4.1 min
(gradient J); TLC: R.sub.f=0.3 (DCM/MeOH+1% NH.sub.3.sup.aq,
95:5).
A. 2,6-Dichloro-3-trifluoromethyl-anilin
[1321] Hydrogenation of 2,4-dichloro-3-nitro-benzotrifluorid (5.0
g, 19.2 mmol; ABCR, Karlsruhe/Germany) in 100 ml MeOH in the
presence of 1 g Raney-nickel, filtration and concentration of the
filtrate gives the title compound: TLC: R.sub.f=0.67 (EE).
* * * * *