U.S. patent application number 11/291007 was filed with the patent office on 2006-04-06 for cysteine protease inhibitors with 2-cyano-4-amino-pyrimidine structure and cathepsin k inhibitory activity for the treatment of inflammations and other diseases.
Invention is credited to Eva Altmann, Kenji Hayakawa, Genji Iwasaki.
Application Number | 20060074092 11/291007 |
Document ID | / |
Family ID | 26246490 |
Filed Date | 2006-04-06 |
United States Patent
Application |
20060074092 |
Kind Code |
A1 |
Altmann; Eva ; et
al. |
April 6, 2006 |
Cysteine protease inhibitors with 2-cyano-4-amino-pyrimidine
structure and cathepsin K inhibitory activity for the treatment of
inflammations and other diseases
Abstract
The invention provides compounds of formula I ##STR1## or a
pharmaceutically acceptable salt or ester thereof (I), wherein the
symbols have meaning as defined, which are inhibitors of cathepsin
K and find use pharmaceutically for treatment of diseases and
medical conditions in which cathepsin K is implicated, e.g.,
various disorders including inflammation, rheumatoid arthritis,
osteoarthritis, osteoporosis and tumors.
Inventors: |
Altmann; Eva; (Reinach,
CH) ; Hayakawa; Kenji; (Hyogo Pref., JP) ;
Iwasaki; Genji; (Ibaraki Pref., JP) |
Correspondence
Address: |
NOVARTIS;CORPORATE INTELLECTUAL PROPERTY
ONE HEALTH PLAZA 104/3
EAST HANOVER
NJ
07936-1080
US
|
Family ID: |
26246490 |
Appl. No.: |
11/291007 |
Filed: |
November 30, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10487741 |
Feb 24, 2004 |
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PCT/EP02/09661 |
Aug 29, 2002 |
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11291007 |
Nov 30, 2005 |
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Current U.S.
Class: |
514/256 ;
544/329 |
Current CPC
Class: |
A61P 33/00 20180101;
A61P 43/00 20180101; A61P 21/04 20180101; A61P 37/02 20180101; A61P
19/02 20180101; A61P 9/10 20180101; C07D 401/12 20130101; A61P
19/10 20180101; A61P 19/08 20180101; C07D 239/42 20130101; A61P
11/00 20180101; A61P 33/12 20180101; C07D 403/12 20130101; A61P
35/00 20180101; A61P 33/06 20180101; A61P 19/00 20180101; A61P 1/02
20180101; A61P 29/00 20180101 |
Class at
Publication: |
514/256 ;
544/329 |
International
Class: |
C07D 239/42 20060101
C07D239/42; A61K 31/505 20060101 A61K031/505 |
Foreign Application Data
Date |
Code |
Application Number |
Aug 30, 2001 |
GB |
0121026.9 |
Aug 30, 2001 |
GB |
0121024.4 |
Claims
1. A method for treating a patient suffering from or susceptible to
a disease or medical condition in which cathepsin K is implicated,
comprising administering an effective amount of a compound of
formula I, or a pharmaceutically acceptable salt or ester thereof
##STR149## wherein R is H, --R4, --OR4 or NR3R4, wherein R3 is H,
lower alkyl or C.sub.3 to C.sub.10 cycloalkyl, and R4 is lower
alkyl or C.sub.3 to C.sub.10 cycloalkyl, wherein R3 and R4 are
independently, optionally substituted by halo, hydroxy, lower
alkoxy, CN, NO.sub.2, or optionally mono- or di-lower alkyl
substituted amino; R1 is --CO--NR5R6, --NH--CO--R5,
--CH.sub.2--NH--C(O)--R5, --CO--R5, --S(O)--R5, --S(O).sub.2--R5,
--CH.sub.2--CO--R5 or --CH.sub.2--NR5R6, wherein R5 is aryl,
aryl-lower alkyl, C.sub.3-C.sub.10cycloalkyl,
C.sub.3-C.sub.10cycloalkyl-lower alkyl, heterocyclyl or
heterocyclyl-lower alkyl, R6 is H, aryl, aryl-lower alkyl,
aryl-lower-alkenyl, C.sub.3-C.sub.10cycloalkyl,
C.sub.3-C.sub.10cycloalkyl-lower alkyl, heterocyclyl or
heterocyclyl-lower alkyl, or wherein R5 and R6 together with the
nitrogen atom to which they attached are joined to form an
N-heterocyclyl group, wherein N-heterocyclyl denotes a saturated,
partially unsaturated or aromatic nitrogen containing heterocyclic
moiety attached via a nitrogen atom thereof having from 3 to 8 ring
atoms optionally containing a further 1, 2 or 3 heteroatoms
selected from N, NR7, O, S, S(O) or S(O).sub.2 wherein R7 is H or
optionally substituted (lower alkyl, carboxy, acyl (including both
lower alkyl acyl, e.g. formyl, acetyl or propionyl, or aryl acyl,
e.g. benzoyl), amido, aryl, S(O) or S(O).sub.2), and wherein the
N-heterocyclyl is optionally fused in a bicyclic structure, e.g.
with a benzene or pyridine ring, and wherein the N-heterocyclyl is
optionally linked in a spiro structure with a 3 to 8 membered
cycloalkyl or heterocyclic ring wherein the heterocyclic ring has
from 3 to 10 ring members and contains from 1 to 3 heteroatoms
selected from N. NR6, O, S, S(O) or S(O).sub.2 wherein R6 is as
defined above), and wherein heterocyclyl denotes a ring having from
3 to 10 ring members and containing from 1 to 3 heteroatoms
selected from N, NR7, O, S, S(O) or S(O).sub.2 wherein R7 is as
defined above), and wherein R5 and R6 are independently, optionally
substituted by one or more groups, e.g. 1-3 groups, selected from
halo, hydroxy, oxo, lower alkoxy, CN or NO.sub.2, or optionally
substituted (optionally mono- or di-lower alkyl substituted amino,
lower alkoxy, aryl, aryl-lower alkyl, N-heterocyclyl or
N-heterocyclyl-lower alkyl) wherein the optional substitution
comprises from 1 to 3 substituents selected from halo, hydroxy,
lower alkoxy, lower alkoxy-lower alkyl, lower alkoxy-carbonyl CN,
NO.sub.2, optionally mono- or di-lower alkyl substituted amino,
N-heterocyclyl or N-heterocyclyl-lower alkyl or optionally mono- or
di-lower alkyl substituted amino; R2 is is independently H, or
optionally substituted (lower alkyl, aryl, aryl-lower alkyl,
C.sub.3-C.sub.10cycloalkyl, C.sub.3-C.sub.10cycloalkyl-lower alkyl,
heterocyclyl or heterocyclyl-lower alkyl), and wherein R2 is
optionally substituted by halo, hydroxy, oxo, lower alkoxy, CN,
NO.sub.2, or optionally mono- or di-lower alkyl substituted
amino.
2-12. (canceled)
Description
[0001] This invention relates to inhibitors of cysteine proteases,
in particular to heteroaryl nitrile cathepsin K inhibitors and to
their pharmaceutical use for the treatment or prophylaxis of
diseases or medical conditions in which cathepsin K is
implicated.
[0002] Cathepsin K is a member of the family of lysosomal cysteine
cathepsin enzymes, e.g. cathepsins B, K, L and S, which are
implicated in various disorders including inflammation, rheumatoid
arthritis, osteoarthritis, osteoporosis, tumors (especially tumor
invasion and tumor metastasis), coronary disease, atherosclerosis
(including atherosclerotic plaque rupture and destabilization),
autoimmune diseases, respiratory diseases, infectious diseases and
immunologically mediated diseases (including transplant
rejection).
[0003] Accordingly the present invention provides a compound of
formula I, or a pharmaceutically acceptable salt or ester thereof
##STR2## wherein [0004] R is H, --R4, --OR4 or NR3R4, [0005]
wherein R3 is H, lower alkyl or C.sub.3 to C.sub.10 cycloalkyl, and
[0006] R4 is lower alkyl or C.sub.3 to C.sub.10 cycloalkyl, and
[0007] wherein R3 and R4 are independently, optionally substituted
by halo, hydroxy, lower alkoxy, CN, NO.sub.2, or optionally mono-
or di-lower alkyl substituted amino; [0008] R1 is --CO--NR5R6,
--NH--CO--R5, --CH.sub.2--NH--C(O)--R5, --CO--R5, --S(O)--R5,
--S(O).sub.2--R5, --CH.sub.2--CO--R5 or --CH.sub.2--NR5R6, wherein
[0009] R5 is aryl, aryl-lower alkyl, C.sub.3-C.sub.10cycloalkyl,
C.sub.3-C.sub.10cycloalkyl-4-lower alkyl, heterocyclyl or
heterocyclyl-lower alkyl, [0010] R6 is H, aryl, aryl-lower alkyl,
aryl-lower-alkenyl, C.sub.3-C.sub.10cycloalkyl,
C.sub.3-C.sub.10cycloalkyl-lower alkyl, heterocyclyl or
heterocyclyl-lower alkyl, or [0011] wherein R5 and R6 together with
the nitrogen atom to which they attached are joined to form an
N-heterocyclyl group, [0012] wherein N-heterocyclyl denotes a
saturated, partially unsaturated or aromatic nitrogen containing
heterocyclic moiety attached via a nitrogen atom thereof having
from 3 to 8 ring atoms optionally containing a further 1, 2 or 3
heteroatoms selected from N, NR7, O, S, S(O) or S(O).sub.2 wherein
R7 is H or optionally substituted (lower alkyl, carboxy, acyl
(including both lower alkyl acyl, e.g. formyl, acetyl or propionyl,
or aryl acyl, e.g. benzoyl), amido, aryl, S(O) or S(O).sub.2), and
wherein the N-heterocyclyl is optionally fused in a bicyclic
structure, e.g. with a benzene or pyridine ring, and wherein the
N-heterocyclyl is optionally linked in a spiro structure with a 3
to 8 membered cycloalkyl or heterocyclic ring wherein the
heterocyclic ring has from 3 to 10 ring members and contains from 1
to 3 heteroatoms selected from N, NR6, O, S, S(O) or S(O).sub.2
wherein R6 is as defined above), and [0013] wherein heterocyclyl
denotes a ring having from 3 to 10 ring members and containing from
1 to 3 heteroatoms selected from N, NR7, O, S, S(O) or S(O).sub.2
wherein R7 is as defined above), and [0014] wherein R5 and R6 are
independently, optionally substituted by one or more groups, e.g.
1-3 groups, selected from halo, hydroxy, oxo, lower alkoxy, CN or
NO.sub.2, or optionally substituted (optionally mono- or di-lower
alkyl substituted amino, lower-alkoxy, aryl, aryl-lower alkyl,
N-heterocyclyl or N-heterocyclyl-lower alkyl (wherein the optional
substitution comprises from 1 to 3 substituents selected from halo,
hydroxy, lower alkoxy, lower alkoxy-lower alkyl, lower
alkoxy-carbonyl, CN, NO.sub.2, N-heterocyclyl or
N-heterocyclyl-lower alkyl, or optionally mono- or di-lower alkyl
substituted amino; [0015] R2 is is independently H, or optionally
substituted (lower alkyl, aryl, aryl-lower alkyl,
C.sub.3-C.sub.10cycloalkyl, C.sub.3-C.sub.10cycloalkyl-lower alkyl,
heterocyclyl or heterocyclyl-lower alkyl), and [0016] wherein R2 is
optionally substituted by halo, hydroxy, oxo, lower alkoxy, CN,
NO.sub.2, or optionally mono- or di-lower alkyl substituted
amino.
[0017] Above and elsewhere in the present description the following
terms have the following meanings.
Halo or halogen denote I, Br, Cl or F.
[0018] The term "lower" referred to above and hereinafter in
connection with organic radicals or compounds respectively defines
such as branched or unbranched with up to and including 7,
preferably up to and including 5 and advantageously one, two or
three carbon atoms. A lower alkyl group is branched or unbranched
and contains 1 to 7 carbon atoms, preferably 1-5 carbon atoms.
Lower alkyl represents; for example, methyl, ethyl, propyl, butyl,
isopropyl isobutyl, tertiary butyl or neopentyl
(2,2-dimethylpropyl). Halo-substituted lower alkyl is
C.sub.1-C.sub.7lower alkyl substituted by up to 6 halo atoms. A
lower alkoxy group is branched or unbranched and contains 1 to 7
carbon atoms, preferably 1-4 carbon atoms. Lower alkoxy represents
for example methoxy, ethoxy, propoxy, butoxy, isopropoxy, isobutoxy
or tertiary butoxy.
[0019] A lower alkene, alkenyl or alkenyloxy group is branched or
unbranched and contains 2 to 7 carbon atoms, preferably 2-4 carbon
atoms and contains at least one carbon-carbon double bond. Lower
alkene lower alkenyl or lower alkenyloxy represents for example
vinyl, prop-1-enyl, allyl, butenyl, isopropenyl or isobutenyl and
the oxy equivalents thereof.
[0020] A lower alkyne, alkynyl or alkynyloxy group is branched or
unbranched and contains 2 to 7 carbon atoms, preferably 2-4 carbon
atoms and contains at least one carbon-carbon triple bond. Lower
alkyne or alkynyl represents for example ethynyl, prop-1-ynyl,
propargyl, butynyl, isopropynyl or isobutynyl and the oxy
equivalents thereof.
In the present description, oxygen containing substituents, e.g.
alkoxy, alkenyloxy, alkynyloxy, carbonyl, etc. encompass their
sulphur containing homologues, e.g. thioalkoxy, thioalkenyloxy,
thioalkynyloxy, thiocarbonyl, sulphone, sulphoxide etc.
[0021] Aryl represents carbocyclic or heterocyclic aryl.
[0022] Carbocyclic aryl represents monocyclic, bicyclic or
tricyclic aryl, for example phenyl or phenyl mono-, di- or
tri-substituted by one, two or three radicals selected from lower
alkyl, lower alkoxy, aryl, hydroxy, halogen, cyano,
trifluoromethyl, lower alkylenedioxy and
oxy-C.sub.2-C.sub.3-alkylene and other substituents, for instance
as described in the examples; or 1- or 2-naphthyl; or 1- or
2-phenanthrenyl. Lower alkylenedioxy is a divalent substituent
attached to two adjacent carbon atoms of phenyl, e.g.
methylenedioxy or ethylenedioxy. Oxy-C.sub.2-C.sub.3-alkylene is
also a divalent substituent attached to two adjacent carbon atoms
of phenyl, e.g. oxyethylene or oxypropylene. An example for
oxy-C.sub.2-C.sub.3-alkylene-phenyl is
2,3-dihydrobenzofuran-5-yl.
[0023] Preferred as carbocyclic aryl is naphthyl, phenyl or phenyl
optionally substituted, for instance, as described in the examples,
e.g. mono- or disubstituted by lower alkoxy, phenyl, halogen, lower
alkyl or trifluoromethyl.
[0024] Heterocyclic aryl represents monocyclic or bicyclic
heteroaryl, for example pyridyl, indolyl, quinoxalinyl, quinolinyl,
isoquinolinyl, benzothienyl, benzofuranyl, benzopyranyl,
benzothiopyranyl, furanyl, pyrrolyl, thiazolyl, oxazolyl,
isoxazolyl, triazolyl, tetrazolyl, pyrazolyl, imidazolyl, thienyl,
or any said radical substituted, especially mono- or di-substituted
as defined above.
[0025] Preferably, heterocyclic aryl is pyridyl, indolyl,
quinolinyl, pyrrolyl, thiazolyl, isoxazolyl, triazolyl, tetrazolyl,
pyrazolyl, imidazolyl, thienyl, or any said radical substituted,
especially mono- or di-substituted as defined above.
[0026] Cycloalkyl represents a saturated cyclic hydrocarbon
optionally substituted by lower alkyl which contains 3 to 10 ring
carbons and is advantageously cyclopropyl, cyclopentyl, cyclohexyl,
cycloheptyl or cyclooctyl optionally substituted by lower
alkyl.
[0027] N-heterocyclyl is as defined above. Preferred N-heterocyclic
substituents are optionally substituted pyrrolidine, pyrrole,
diazole, triazole, tetrazole, imidazole, oxazole, thiazole,
pyridine, pyrimidine, triazine, piperidine, piperazine, morpholine,
phthalimde, hydantoin, oxazolidinone or 2,6-dioxo-piperazine and,
for example, as hereinafter described in the examples.
[0028] In a further embodiment the invention provides a compound of
formula IIa, or a pharmaceutically-acceptable salt or ester thereof
##STR3## wherein R2 is as defined above and R5''' and R6''' are as
defined above for R5 and R6 respectively.
[0029] R2 is preferably R2' which is lower alkyl, e.g. straight
chain or more preferably branched-chain C.sub.1-C.sub.6 alkyl, e.g.
especially 2-ethylbutyl, isobutyl, or 2,2-dimethylpropyl; or
C.sub.3-C.sub.6cycloalkyl, especially cyclopropyl, cyclopentyl or
cyclohexyl.
[0030] R5''' and R6''' may be such that R5''' and R6''' together
with the nitrogen atom to which they are joined to form an
N-heterocyclyl group
[0031] R5''' is preferably optionally substituted
(aryl-lower-alkyl, heterocyclyl-aryl, N-heterocyclyl-aryl or
aryl-N-heterocyclyl (where N-heterocyclyl is as defined above).
[0032] R5''' is preferably optionally substituted by from 1-4
substituents selected from halo, hydroxy, nitro, cyano,
lower-alkyl, lower-alkoxy or lower-alkoxy-lower-akyl.
[0033] For example, R5''' is 4-methoxy-benzyl, 3-methoxy-benzyl,
4-(4-methyl-piperazin-1-yl)-benzyl,
4-[4-(2-ethoxy-ethyl)-piperazin-1-yl]-benzyl,
1-methyl-1-phenyl-ethyl, 2-(4-methoxy-phenyl)-1,1-dimethyl-ethyl,
2-(4-fluoro-phenyl)-1,1-dimethyl-ethyl,
4-(4-methyl-piperazin-1-yl)-phenyl)-ethyl,
2-[4-(4-isopropyl-piperazin-1-yl)-phenyl]-1,1-dimethyl-ethyl,
2-{4-[4-(2-methoxy-ethyl)-piperazin-1-yl]-phenyl}-1,1-dimethyl-ethyl,
2-{3-[4-(2-ethoxy-ethyl)-piperazin-1-yl]-phenyl}-1,1-dimethyl-ethyl,
2-[3-(4-ethyl-piperazin-1-yl)-phenyl]-1,1-dimethyl-ethyl,
2-[3-(4-isopropyl-piperazin-1-yl)-phenyl]-1,1-dimethyl-ethyl,
1,1-dimethyl-2-(3-pyrrolidin-1-yl-phenyl)-ethyl,
2-{3-[4-(2-methoxy-ethyl)-piperazin-1-yl]-phenyl}-1,1-dimethyl-ethyl,
2-(4-methoxy-phenyl)-ethyl
2-[4-(4-methyl-piperazin-1-yl)-phenyl]-ethyl,
2-[4-(4-isopropyl-piperazin-1-yl)-phenyl]-ethyl,
2-{4-[4-(2-methoxy-ethyl)-piperazin-1-yl]-phenyl}-ethyl,
2-(3-methoxy-phenyl)-ethyl,
2-[3-(4-methyl-piperazin-1-yl)-phenyl]-ethyl,
2-[4-(4-isopropyl-piperazin-1-yl)-phenyl]-ethyl,
2-pyrrol-1-yl-ethyl, 3-piperidin-1-yl-propyl
2-(4-methoxy-phenyl)-2-methyl-propyl,
2-methyl-2-[4-(4-methyl-piperazin-1-yl)-phenyl]-propyl,
2-[4-(4-isopropyl-piperazin-1-yl)-phenyl]-2-methyl-propyl,
2-{4-[4-(2-ethoxy-ethyl)-piperazin-1-yl]-phenyl}-2-methyl-propyl,
2-{4-[pyrimidin-1-yl]-phenyl}-2-methyl-propyl,
4-(3-methoxy-phenyl)-piperazin-1-yl-methyl,
4-(4-methoxy-phenyl)-piperazin-1-yl-methyl,
1-methyl-1-(1-phenyl-cyclopropyl)-ethyl,
[0034] For example, R5''' and R6''' together with the nitrogen atom
to which they are joined to form an N-heterocyclyl group is
4-(2-pyridin-4-yl-ethyl)-piperazin-1-yl,
[4-(2-pyridin-2-yl-ethyl)piperazin-1-yl,
4-pyridin-4-ylmethyl-piperazin-1-yl,
4-(2-piperidin-1-yl-ethyl)-piperazin-1-yl,
4-(2-pyrrolidin-1-yl-ethyl)-piperazin-1-yl,
4-(2-Diethylamino-ethyl)-piperazin-1-yl,
4-(3-Diethylamino-propyl)piperazin-1-yl,
4-(1-methyl-piperidin-4-yl)-piperazin-1-yl,
4-pyrrolidin-1-yl-piperidin-1-yl,
4-(2-methoxy-ethyl)-piperazin-1-yl
[0035] In a preferred embodiment the invention provides a compound
of formula II, or a pharmaceutically acceptable salt or ester
thereof ##STR4## wherein R2 is as defined above and R5' is as
defined above for R5.
[0036] R2 is preferably R2' which is lower alkyl, e.g. straight
chain or more preferably branched-chain C.sub.1-C.sub.6 alkyl, e.g.
especially 2-ethylbutyl, isobutyl, or 2,2-dimethylpropyl; or
C.sub.3-C.sub.6cycloalkyl, especially cyclopropyl, cyclopentyl or
cyclohexyl.
[0037] R5' is preferably optionally substituted (aryl-lower-alkyl,
heterocyclyl-aryl, N-heterocyclyl-aryl or aryl-N-heterocyclyl
(where N-heterocyclyl is as defined above).
[0038] R5' is preferably optionally substituted by from 14
substituents selected from halo, hydroxy, nitro, cyano,
lower-alkyl, lower-alkoxy, lower-alkoxy-carbonyl or
lower-alkoxy-lower-akyl.
[0039] For example, R5' is 4-methoxy-phenyl,
4-(1-propyl-piperidin-4-yl)-phenyl,
4-(4-methyl-piperazin-1-yl)-phenyl,
4-[1-(2-methoxy-ethyl)-piperidin-4-yl]-phenyl,
4-(4-propyl-piperazin-1-yl)-phenyl,
3-[4-(4-methyl-piperazin-1-yl)-phenyl]-propionyl,
3-[3-(4-methyl-piperazin-1-yl)-phenyl]-propionyl,
4-(4-ethyl-piperazin-1-yl)phenyl,
4-(4-isopropyl-piperazin-1-yl)-phenyl,
4-[4-(2-ethoxy-ethyl)-piperazin-1-yl]-phenyl,
4-[4-(2-methoxy-ethyl)-piperazin-1-yl]-phenyl,
4-piperazin-1-yl-phenyl, 4-[4-(carboxylic acid tert-butyl ester)
piperazino-1-yl-]-phenyl, 3-[4-(carboxylic acid tert-butyl ester)
piperazino-1-yl-]-phenyl, 3-(4-methyl-piperazin-1-yl)-phenyl,
3-(4-ethyl-piperazin-1-yl)-phenyl,
3-(4-isopropyl-piperazin-1-yl)-phenyl,
3-[4-(2-methoxy-ethyl)-piperazin-1-yl]-phenyl,
3-[4-(2-ethoxy-ethyl)-piperazin-1-yl]-phenyl,
3-(2-pyrrolidin-1-yl-ethoxy)-phenyl,
3-(2-dimethylamino-ethoxy)-4-methoxy-phenyl,
4-dimethylaminomethyl-phenyl,
4-(4-methyl-piperazin-1-ylmethyl)phenyl,
4-[1-(2-methoxy-ethyl)piperidin-4-ylmethyl]-phenyl,
4-methoxy-3-(2-piperidin-1-yl-ethoxy)-phenyl,
3-[4-(4-ethyl-piperazin-1-yl)-phenyl]-2,2-dimethyl-propionyl,
3-[4-(4-propyl-piperazin-1-yl)-phenyl]-propionyl,
3-(4-pyrrolidin-1-yl-phenyl)-propionyl,
3-[3-(4-ethyl-piperazin-1-yl)-phenyl]-2,2-dimethyl-propionyl,
3-{3-[4-(2-methoxy-ethyl)-piperazin-1-yl]-phenyl}-2,2-dimethyl-propionyl,
3-{3-[4-(2-ethoxy-ethyl)-piperazin-1-yl]-phenyl}-2,2-dimethyl-propionyl,
3-(3-pyrrolidin-1-yl-phenyl)-propionyl,
2-[4-(4-methyl-piperazin-1-yl)-phenyl]-isobutyl,
2-(4-methoxy-phenyl)-acetyl, 2-(3-methoxy-phenyl)-acetyl,
2-[4-(4-methyl-piperazin-1-yl)phenyl]-acetyl,
2-[4-(4-ethyl-piperazin-1-yl)-phenyl]-acetyl,
2-[4-(4-isopropyl-piperazin-1-yl)-phenyl]-acetyl,
2-(4-pyrrolidin-1-yl-phenyl)-acetyl,
2-[4-(2-diethylamino-ethylamino)-phenyl]-isobutyl,
2-(4-pyrrolidin-1-yl-phenyl)-isobutyl.
[0040] In a further preferred embodiment the invention provides a
compound of formula III or a pharmaceutically acceptable salt or
ester thereof ##STR5## wherein R2 is as defined above and R5'' is
as defined above for R5.
[0041] R2 is preferably R2'' which is lower alkyl, e.g. straight
chain or more preferably branched-chain C.sub.1-C.sub.6 alkyl, e.g.
especially 2-ethylbutyl, isobutyl, or 2,2-dimethylpropyl; or
C.sub.3-C.sub.6cycloalkyl, especially cyclopropyl, cyclopentyl or
cyclohexyl.
[0042] R5'' is preferably optionally substituted (aryl-loweralkyl,
aryl-aryl, N-heterocyclyl-aryl or aryl-N-heterocyclyl (where
N-heterocyclyl is as defined above).
[0043] R5'' is preferably optionally substituted by from 1-4
substituents selected from halo, hydroxy, nitro, cyano, optionally
mono- or di-loweralkyl substituted amino, oxo, lower-alkyl,
lower-alkenyl, lower-alkynyl, C.sub.3-C.sub.10cycloalkyl or
C.sub.3-C.sub.10cycloalkyl-lower-alkyl.
[0044] For example, R5'' is 4-methoxybenzyl,
5-methyl-2-phenyl-2.H.-pyrazol-3-yl, 4-chlorobenzyl,
4-dimethylaminobenzyl, benzyl, 2-phenyl-2.H.-pyrazol-3-yl,
2-phenyl-phenyl, 2-pyrrol-1-yl-phenyl, 2-imidazol-1-yl-phenyl,
5-methyl-2-(4-chlorophenyl)-2.H.-pyrazol-3-yl,
5-methyl-2-(2-chlorophenyl)-2.H.-pyrazol-3-yl and
5-methyl-2-(2,4-dichlorophenyl)-2.H.-pyrazol-3-yl,
2-(4-methoxy-phenyl)-1,1-dimethyl-ethyl,
1,1-dimethyl-2-[3-(4-methyl-piperazin-1-yl)-phenyl]-ethyl,
1,1-dimethyl-2-[4-(4-methyl-piperazin-1-yl)-phenyl]-ethyl,
1,1-dimethyl-2-[3-(2-pyrrolidin-1-yl-ethylamino)-phenyl]-ethyl,
2-{3-[4-(2-ethoxy-ethyl)-piperazin-1-yl]-phenyl}-1,1-dimethyl-ethyl,
2-(4-difluoromethoxy-phenyl)-ethyl,
2-[3-(4-methyl-piperazin-1-yl)-phenyl]-ethyl.
[0045] Particularly preferred compounds of the invention are the
compounds of formula II, IIa and III as described in the
examples.
[0046] Compounds of formula II, or pharmaceutically acceptable
salts or ester thereofs ##STR6## wherein R2 and R5' are as defined
above, may be prepared by cyanation of a 2-chloro precursor of
formula IV ##STR7## wherein R2 and R5' are as defined above; for
instance, substantially as described in the examples.
[0047] The above cyanation reactions may be carried out under
various conditions and in the presence of solvents and other
reagents as required, including catalysts and co-factors as known
in the art and for instance, as hereinafter described in the
examples.
[0048] The starting materials may be prepared and the coupled and
cyclised products may be converted into other compounds of formula
II and salts and esters thereof using methods and procedures known
in the art, and as hereinafter described in the examples.
[0049] Accordingly the present invention further provides a process
for the preparation of a compound of Formula II or a
pharmaceutically acceptable salt or ester thereof ##STR8## wherein
R2 and R5' are as defined above, comprising cyanation of a 2-chloro
precursor of formula IV ##STR9## wherein R2 and R5' are as defined
above, and thereafter, if desired, converting the product obtained
into a further compound of formula II, or into a salt or ester
thereof. Compounds of Formula IIa or a pharmaceutically acceptable
salt or ester thereof ##STR10## wherein R2, R5'' and R6''' are as
defined above, comprising cyanation of a 2-chloro precursor of
formula IVa ##STR11## wherein R2, R5'' and R6''' are as defined
above, and thereafter, if desired, converting the product obtained
into a further compound of formula IIa, or into a salt or ester
thereof.
[0050] Compounds of formula III or pharmaceutically acceptable
salts or esters thereof ##STR12## wherein R2 and R5'' are as
defined above, may be prepared either by cyanation of a 2-chloro
precursor of formula V ##STR13## or coupling of a carboxylic acid
precursor of formula VI with a corresponding amine of formula VII
##STR14## wherein the R2 and R5'' are as defined above; for
instance, substantially as described in the examples.
[0051] The above coupling and cyanation reactions may be carried
out under various conditions and in the presence of solvents and
other reagents as required, including catalysts and co-factors as
known in the art and for instance, as hereinafter described in the
examples.
[0052] The starting materials may be prepared and the coupled and
cyclised products may be converted into other compounds of formula
III and salts and esters thereof using methods and procedures known
in the art, and as hereinafter described in the examples.
[0053] Accordingly the present invention further provides a process
for the preparation of a compound of Formula III or a
pharmaceutically acceptable salt or ester thereof ##STR15## wherein
R2 and R3 are as defined above, comprising either cyanation of a
2-chloro precursor of formula V ##STR16## or coupling of a
catboxylic acid precursor of formula VI with a corresponding amine
of formula VII ##STR17## wherein the R2 and R5'' are as defined
above, and thereafter, if desired, converting the product obtained
into a further compound of formula III, or into a salt or ester
thereof.
[0054] Compounda of formula I, II and III as defined above and the
compounds of the Examples are hereinafter referred to as Compounds
of the Invention.
[0055] Compounds of the invention are either obtained in the free
form, or as a salt thereof if salt forming groups are present.
[0056] Compounds of the Invention having basic groups can be
converted into acid addition salts, especially pharmaceutically
acceptable salts. These are formed, for example, with inorganic
acids, such as mineral acids, for example sulfuric acid, a
phosphoric or hydrohalic acid, or with organic carboxylic acids,
such as (C.sub.1-C.sub.4)alkanecarboxylic acids which, for example,
are unsubstituted or substituted by halogen, for example acetic
acid, such as saturated or unsaturated dicarboxylic acids, for
example oxalic, succinic, maleic or fumaric acid, such as
hydroxycarboxylic acids, for example glycolic, lactic, malic,
tartaric or citric acid, such as amino acids, for example aspartic
or glutamic acid, or with organic sulfonic acids, such as
(C.sub.1-C.sub.4)-alkylsulfonic acids (for example methanesulfonic
acid) or arylsulfonic acids which are unsubstituted or substituted
(for example by halogen). Preferred are salts formed with
hydrochloric acid, methanesulfonic acid and maleic acid.
[0057] In view of the close relationship between the free compounds
and the compounds in the form of their salts, whenever a compound
is referred to in this context, a corresponding salt is also
intended, provided such is possible or appropriate under the
circumstances.
[0058] The compounds, including their salts, can also be obtained
in the form of their hydrates, or include other solvents used for
their crystallization.
[0059] The compounds of the invention exhibit valuable
pharmacological properties in mammals and are particularly useful
as inhibitors of cathepsin K.
[0060] The cathepsin K inhibitory effects of the compound of the
invention can be demonstrated in vitro by measuring the inhibition
of e.g. recombinant human cathepsin K.
The in vitro assay is carried out as follows:
[0061] For cathepsin K:
[0062] The assay is performed in 96 well microtiter plates at
ambient temperature using recombinant human cathepsin K. Inhibition
of cathepsin K is assayed at a constant enzyme (0.16 nM) and
substrate concentration (54 mM Z-Phe-Arg-AMCA--Peptide Institute
Inc. Osaka, Japan) in 100 mM sodium phosphate buffer, pH 7.0,
containing 2 mM dithiothreitol, 20 mM Tween 80 and 1 mM EDTA.
Cathepsin K is preincubated with the inhibitors for 30 min, and the
reaction is initiated by the addition of substrate. After 30 min
incubation the reaction is stopped by the addition of E-64 (2 mM),
and fluorescence intensity is read on a multi-well plate reader at
excitation and emission wavelengths of 360 and 460 nm,
respectively. Compounds of the Invention typically have IC.sub.50s
for inhibition of human cathepsin K of less than about 100 nM down
to about 1 nM or less, preferably of about 5 nM or less, e.g. about
1 nM. Thus for example, the compounds of Examples I-22 and I-23
have IC.sub.50s for inhibition of human cathepsin K of 3 nM and 1.5
nM respectively.
[0063] In view of their activity as inhibitors of cathepsin K,
Compounds of the Invention are particularly useful in mammals as
agents for treatment and prophylaxis of diseases and medical
conditions involving elevated levels of cathepsin K. Such diseases
include diseases involving infection by organisms such as
pneumocystis carinii, trypsanoma cruzi, trypsanoma brucei,
crithidia fusiculata, as well as parasitic diseases such as
schistosomiasis and malaria, tumours (tumour invasion and tumour
metastasis), and other diseases such as metachromatic
leukodystrophy, muscular dystrophy, amytrophy and similar
diseases.
[0064] Cathepsin K, has been implicated in diseases of excessive
bone loss, and thus the Compounds of the Invention may be used for
treatment and prophylaxis of such diseases, including osteoporosis,
gingival diseases such as gingivitis and periodontitis, Paget's
disease, hypercalcemia of malignancy, e.g. tumour-induced
hypercalcemia and metabolic bone disease. Also the Compounds of the
Invention may be use for treatment or prophylaxis of diseases of
excessive cartilage or matrix degradation, including osteoarthritis
and rheumatoid arthritis as well as certain neoplastic diseases
involving expression of high levels of proteolytic enzymes and
matrix degradation.
[0065] Compounds of the Invention, are also indicated for
preventing or treating coronary disease, atherosclerosis (including
atherosclerotic plaque rupture and destabilization), autoimmune
diseases, respiratory diseases and immunologically mediated
diseases (including transplant rejection).
[0066] Compounds of the Invention are particularly indicated for
preventing or treating osteoporosis of various genesis (e.g.
juvenile, menopausal, post-menopausal, post-traumatic, caused by
old age or by cortico-steroid therapy or inactivity).
[0067] Beneficial effects are evaluated in in vitro and in vivo
pharmacological tests generally known in the art, and as
illustrated herein.
[0068] The above cited properties are demonstrable in in vitro and
in vivo tests, using advantageously mammals, e.g. rats, mice, dogs,
rabbits, monkeys or isolated organs and tissues, as well as
mammalian enzyme preparations, either natural or prepared by e.g.
recombinant technology. Compounds of the Invention can be applied
in vitro in the form of solutions, e.g. preferably aqueous
solutions or suspensions, and in vivo either enterally or
parenterally, advantageously orally, e.g. as a suspension or in
aqueous solution, or as a solid capsule or tablet formulation. The
dosage in vitro may range between about 10.sup.-5 molar and
10.sup.-9 molar concentrations. The dosage in vivo may range,
depending on the route of administration, between about 0.1 and 100
mg/kg.
[0069] The antiarthritic efficacy of the Compounds of the Invention
for the treatment of rheumatoid arthritis can be determined using
models such as or similar to the rat model of adjuvant arthritis,
as described previously (R. E. Esser, et. al. J. Rheumatology,
1993, 20, 1176.)
[0070] The efficacy of the compounds of the invention for the
treatment of osteoarthritis can be determined using models such as
or similar to the rabbit partial lateral meniscectomy model, as
described previously (Colombo et al. Arth. Rheum. 1993 26,
875-886). The efficacy of the compounds in the model can be
quantified using histological scoring methods, as described
previously (O'Byrne et al. Inflamm Res 1995, 44, S117-S118).
[0071] The efficacy of the compounds of the invention for the
treatment of osteoporosis can be determined using an animal model
such as the ovariectomised rat or other similar species, e.g.
rabbit or monkey, in which test compounds are administered to the
animal and the presence of markers of bone resorption are measured
in urine or serum (e.g. as described in Osteoporos Int (1997)
7:539-543).
[0072] Accordingly in further aspects the invention provides:
[0073] A Compound of the Invention for use as a pharmaceutical;
[0074] a pharmaceutical composition comprising a Compound of the
Invention as an active ingredient; [0075] a method of treating a
patient suffering from or susceptible to a disease or medical
condition in which cathepsin K is implicated, comprising
administering an effective amount of a Compound of the Invention to
the patient, and [0076] the use of a Compound of the Invention for
the preparation of a medicament for therapeutic or prophylactic
treatment of a disease or medical condition in which cathepsin K is
implicated.
[0077] The present invention relates to methods of using Compounds
of the Invention and their pharmaceutically acceptable salts, or
pharmaceutical compositions thereof, in mammals for inhibiting
cathepsin K, and for the treatment of cathepsin K dependent
conditions, such as the cathepsin K dependent conditions, described
herein, e.g. inflammation, osteoporosis, rheumatoid arthritis and
osteoarthritis.
[0078] Particularly the present invention relates to a method of
selectively inhibiting cathepsin K activity in a mammal which
comprises administering to a mammal in need thereof an effective
cathepsin K inhibiting amount of a Compound of the Invention.
[0079] More specifically such relates to a method of treating
osteoporosis, rheumatoid arthritis, osteoarthritis, and
inflammation (and other diseases as identified above) in mammals
comprises administering to a mammal in need thereof a
correspondingly effective amount of a Compound of the
Invention.
[0080] The following examples are intended to illustrate the
invention and are not to be construed as being limitations thereon.
Temperatures are given in degrees Centigrade. If not mentioned
otherwise, all evaporations are performed under reduced pressure,
preferably between about 15 and 100 mm Hg (=20-133 mbar). The
structure of final products, intermediates and starting materials
is confirmed by standard analytical methods, e.g. microanalysis and
spectroscopic characteristics (e.g. MS, IR, NMR). Abbreviations
used are those conventional in the art.
EXAMPLES
[0081] Example I describes the preparation of
2-Cyano-Pyrimidine-5-ylmethyl-amides
1.
N-[2-Cyano-4-(2,2-dimethyl-propylamino)-Pyrimidin-5-ylmethyl]-2-(4-meth-
oxy phenyl)-acetamide
[0082] ##STR18##
A. 2,4-Dichloro-5-choromethyl-pyrimidine
[0083] ##STR19##
[0084] To 50 ml of POCl.sub.3 is added 21.5 g (103.5 mmol) of
PCl.sub.5 and 4.0 g (27.6 mmol) of 5-(hydroxymethyl)-uracil. The
resulting reaction mixture is stirred at 115.degree. C. for 15 h.
The reaction mixture is then cooled to r.t. and distilled, to yield
2,4-dichloro-5-choromethyl-pyrimidine as a colourless liquid,
boiling point 74.degree. C. (0.01 mbar).
[0085] .sup.1H-NMR (300 MHz, CDCl.sub.3): 8.64 (s, 1H), 4.62 (s,
2H).
B.
(2-Chloro-5-chloromethyl-pyrimidin-4-yl)-(2,2-dimethyl-propyl)-amine
[0086] ##STR20##
[0087] A solution of 3.47 g (17.57 mmol) of
2,4-dichloro-5-choromethyl-pyrimidine and 2.9 ml (21.08 mmol)
triethylamine in 29 ml of THF is cooled to -5.degree. C. and 2.2 ml
(17.57 mmol) 2,2-dimethyl-propylamin is added over a period of 15
minutes. The reaction mixture is stirred at -5.degree. C. for
additional 2 h, then diluted with ethyl acetate and extracted once
with brine. The organic layer is separated and dried over
Na.sub.2SO.sub.4. Purification of the crude product by flash
chromatography (hexanes/ethyl acetate) yields
(2-chloro-5-chloromethyl-pyrimidin-4-yl)(2,2-dimethyl-propyl)-amin-
e as white crystalls.
[0088] MS (ES+): 249 (M+H).sup.+
[0089] .sup.1H-NMR (300 MHz, CDCl.sub.3): 7.94 (s, 1H), 5.4 (m
(broad), 1H), 4.47 (s, 2H), 3.4 (d, 2H), 1.02 (s, 9H).
C. (5-Azidomethyl-2-chloro-pyrimidin
4-yl)-(2,2-dimethyl-propyl)-amine
[0090] ##STR21##
[0091] A solution of 1.47 g (5.92 mmol) of
(2-chloro-5-chloromethyl-pyrimidinyl)-(2,2-dimethyl-propyl)-amine
and 0.46 g (7.1 mmol) NaN.sub.3 is dissolved in 6 ml of DMF and was
stirred at 30.degree. C. for 2.5 hours. Then the reaction mixture
is cooled to r.t., diluted with ethyl acetate and twice extracted
with H.sub.2O. The organic layer is separated and dried over
Na.sub.2SO.sub.4. Evaporation of the ethyl acetate yielded
(5-azidomethyl-2-chloro-pyrimidin-4-yl)-(2,2-dimethyl-propyl)-amine
as white crystalls.
[0092] Mp.: 133-136.degree. C.
[0093] MS (ES+): 255 (M+H).sup.+
[0094] .sup.1H-NMR (300 MHz, CDCl.sub.3): 7.92 (s, 1H), 5.49 (t
(broad), 1H), 4.2 (s, 2H), 3.37 (d, 2H), 1 (s, 9H).
D.
(5-Aminomethyl-2-chloro-pyrimidin-4-yl)-(2,2-dimethyl-propyl)-amine
[0095] ##STR22##
[0096] A solution of 1.47 g (15.77 mmol)
(5-azidomethyl-2-chloro-pyrimidin-4-yl)-(2,2-dimethyl-propyl)-amine
and 1.67 g (6.35 mmol) of triphenylphosphine in 20 ml of THF and
0.08 ml of H.sub.2O is stirred at r.t. for 24 h. Then the solvent
is removed and the residue dissolved in 40 ml EtOH and 17 ml
NH.sub.3 (25%). This reaction mixture is stirred for 48 h at r.t.
and again the solvent is removed. The residue is dissolved in
diethylether and twice extracted with 25 ml of 1N HCl. Both acidic
extracts were combined and once more extracted with diethylether,
then the acidic layer is evaporated under vacuo. The solid residue
was triturated with diethylether yielding
(5-Aminomethyl-2-chloro-pyrimidin-4-yl)-(2,2-dimethyl-propyl)-amine
2HCl as slightly yellow crystalls.
[0097] MS (ES+): 229 (M+H).sup.+
[0098] .sup.1H-NMR (300 MHz, CD.sub.3OD): 8.27 (s, 1H), 4.19 (s,
2H), 3.57 (s, 2H), 1.01 (s, 9H).
E.
N-[2-Chloro-4-(2,2-dimethyl-propylamino)-pyrimidin-5-ylmethyl]-2-(4-met-
hoxy-phenyl)acetamide
[0099] ##STR23##
[0100] To a solution of 0.089 g (0.38 mmol) of
(5-aminomethyl-2-chloro-pyrimidin-4-yl)(2,2-dimethyl-propyl)-amine
and 0.27 ml (1.6 mmol) DIEA in 2.5 ml of DMF 0.063 g (0.38 mmol) of
(4-methoxy-phenyl)-acetic acid is added and the reaction mixture is
stirred at r.t for 16 h. The reaction mixture is then diluted with
ethyl acetate and twice washed with H.sub.2O, the organic layer is
separated and dried over Na.sub.2SO.sub.4 and then concentrated
under reduced pressure. Flash chromatography (ethyl acetate/hexanes
1:1) of the residue provided
N-[2-chloro-4-(2,2-dimethyl-propylamino)-pyrimidin-5-ylmethyl]-2-
-(4-methoxy-phenyl)acetamide as white crystalls.
[0101] MS (ES+): 377 (M+H).sup.+
[0102] .sup.1H-NMR (300 MHz, CDCl.sub.3): 7.55 (s, 1H), 7.11 (m,
3H), 6.85 (d, 2H), 6.22 (t, 1H), 4.2 (d, 2H), 3.79 (s, 3H), 3.53
(s, 2H), 3.3 (d, 2H), 0.98 (s, 9H).
F.
N-[2-Cyano-4-(2,2-dimethyl-propylamino)-pyrimidin-5-ylmethyl]-2-(4-meth-
oxy-phenyl)-acetamide
[0103] ##STR24##
[0104] A solution of 0.036 g (0.096 mmol) of
N-[2-chloro-4-(2,2-dimethyl-propylamino)-pyrimidin-5-ylmethyl]-2-(4-metho-
xy-phenyl)acetamide, 0.013 g (0.192 mmol) of KCN and 0.011 g (0.096
mmol) of 1.4-diazabicyclo[2.2.2]octan in 1 ml of DMSO/H.sub.2O
(85:15) is stirred for 45 minutes at 60.degree. C. The reaction
mixture is cooled to r.t. and subjected to preparative HPLC.
N-[2-cyano-4-(2,2-dimethyl-propylamino)-pyrimidin-5-ylmethyl]-2-(4-methox-
y-phenyl)-acetamide is obtained as a white solid.
[0105] MS (ES+): 368 (M+H).sup.+
[0106] .sup.1H-NMR (300 MHz, CDCl.sub.3): 7.81 (s, 1H), 7.28 (t,
2H), 7.13 (d, 2H), 6.88 (d, 2H), 5.85 (t, 1H), 4.25 (d, 2H), 3.8
(s, 3H), 3.54 (s, 2H, 3.32 (d, 2H), 1.0 (s, 9H).
[0107] By repeating the procedure described above in example 1,
using the appropraite starting materials and conditions the
following compounds of formula 2-7 are obtained as identified below
in table. TABLE-US-00001 ##STR25## MS (ES+) Ex. R (M + H).sup.+
.sup.1H-NMR I-1 N-[2-Cyano-4-(2,2- dimethyl-propylamino)-
pyrimidin-5-ylmethyl]-4- (1-propyl-piperidin-4-yl)- benzamide
##STR26## 449 (300 MHz, CDCl.sub.3): 7.95(s, 1H), 7.72(d, 2H),
7.5(t, 1H), 7.32(d, 2H), 6.8(t, 1H), 4.51(d, 2H), 3.32(d, 2H),
3.08(d, 2H), 2.58(m, 1H), 2.39(m, 2H), 2.08(m, 2H), 1.82 (m, 4H),
1.59(q, 2H), 0.98 (s, 9H), 0.91(t, 3H). I-2 N-[2-Cyano-4-(2,2-
dimethyl-propylamino)- pyrimidin-5-ylnethyl]-4-
(4-inethyl-piperazin-1-yl)- benzamide ##STR27## 422 (300 MHz,
CDCl.sub.3): 7.9(s, 1H), 7.69(d, 2H), 7.6(t, 1H), 6.89(d, 2H),
6.68(t, 1H), 4.5(d, 2H), 3.33(m, 6H), 2.59(m, 4H), 2.38(s, 3H),
0.99(s, 9H). I-3 N-[2-Cyano-4-(2,2- dimethyl-propylamino)-
pyrimidin-5-ylmethyl]-4- [1-(2-inethoxy-ethyl)-
piperidin-4-yl]-benzamide ##STR28## 465 (300 MHz, CDCl.sub.3):
7.94(s, 1H), 7.72(d, 2H), 7.5(t, 1H), 7.29(d, 2H), 6.8(t, 1H),
4.52(d, 2H), 3.55(t, 2H), 3.38(s, 3H), 3.36(d, 2H), 3.13(m, 2H),
2.65(t, 2H), 2.6(t, 3H), 2.17(m, 2H), 1.82(m, 4H), 0.99(s, 9H). I-4
N-[2-Cyano-4-(2,2- dimethyl-propylamino)- pyrimidin-5-ylmethyl]-4-
(4-propyl-piperazin-1-yl)- benzamide ##STR29## 450 (300 MHz,
CDCl.sub.3): 7.9(s, 1H), 7.69(d, 2H), 7.6(t, 1H), 6.87(d, 2H),
6.59(t, 1H), 4.5(d, 2H), 3.34(m, 6H), 2.6(m, 4H), 2.35(t, 2H),
2.45(m, 2H), 0.99(s, 9H), 0.98(t, 3H). I-5 N-[2-Cyano-4-(2,2-
dimethyl-propylamino)- pyrimidin-5-ylmethyl]-2,2-
diinethyl-3-[4-(4-methyl- piperazin-1-yl)-phenyl]- propionamide
##STR30## 478 (300 MHz, CDCl.sub.3): 7.72(s, 1H), 7.62(t, 1H),
6.88(d, 2H), 6.69(d, 2H), 5.8(m, 1H), 4.19(d, 2H), 3.38(d, 2H),
3.18(m, 4H), 2.71(s, 2H), 2.65(m, 4H), 2.39(s, 3H), 1.1(s, 6H),
1.01(s, 9H). I-6 N-[2-Cyano-4-(2,2- dimethyl-propylamino)-
pyrimidin-5-ylmethyl]-2,2- dimethyl-3-[3-(4-methyl-
piperazin-1-yl)-phenyl]- propionamide ##STR31## 478 (300 MHz,
CDCl.sub.3): 7.8(s, 1H), 7.51(t, 1H), 7.04(t, 1H), 6.69(d, 1H),
6.61(s, 1H), 6.52(d, 1H), 5.85(m, 1H), 4.19(d, 2H), 3.35(d, 2H),
3.19(m, 4H), 2.79(s, 2H), 2.63(m, 4H), 2.4(s, 3H), 1.1(s, 6H),
1.01(s, 9H). I-7 N-[2-Cyano-4-(2,2- dimethyl-propylamino)-
pyrimidin-5-ylmethyl]-4- (4-ethyl-piperazin-1-yl)- benzamide
##STR32## 436 (300 MHz, CDCl.sub.3): 7.92(s, 1H), 7.68(d, 2H),
7.58(t, 1H), 6.86(d, 2H), 6.56(t, 1H), 4.49(d, 2H), 3.32(m, 6H),
2.60(mm, 6H)2.4(q, 2H) 1.12(t, 3H), 0.98(s, 9H). I-8
N-[2-Cyano-4-(2,2- dimethyl-propylamino)- pyrimidin-5-ylmethyl]-4-
(4-isopropyl-piperazin-1- yl)-benzamide ##STR33## 450 (300 MHz,
CDCl.sub.3): 7.92(s, 1H), 7.65(d, 2H), 7.54(t, 1H), 6.88(d, 2H),
6,46(t, 1H), 4.51(d, 2H), 3.32(m, 6H), 2.74(m, 1H), 2.68(m, 4H),
1.10(d, 6H), 0.98(s, 9H). I-9 N-[2-Cyano-4-(2,2-
dimethyl-propylamino)- pyrimidin-5-ylnietbyl]-4-
[4-(2-ethoxy-ethyl)- piperazin-1-yl]-benzamide ##STR34## 479 (400
MHz, CDCl.sub.3): 7.91(s, 1H), 7.59(d, 2H), 7.45(t, 1H), 6.79(d,
2H), 6.37(t, 1H), 4.45(d, 2H), 3.52(t, 2H), 3.47(q, 2H), 3.28(m,
6H), 2.58(m, 4H), 1.16(q, 3H), 0.98(s, 9H). I-10 N-(2-Cyano-4-(2,2-
dimethyl-propylamino)- pyrimidin-5-ylmethyl]-4-
[4-(2-methoxy-ethyl)- piperazin-1-yl]-benzainide ##STR35## 466 (300
MHz, CDCl.sub.3): 7.93(s, 1H), 7.68(d, 2H), 7.59(t, 1H), 6.87(d,
2H), 6.52(t, 1H), 4.50(d, 2H), 3.55(t, 2H), 3.38(s, 3H), 3.33(m,
6H), 2.63(m, 6H), 0.98(s, 9H). I-11 N-[2-Cyano-4-(2,2-
dimethyl-propylamino)- pyrimidin-5-ylmethyl]-4-
piperazin-1-yl-benzamide ##STR36## 408 (400 MHz, CDCl.sub.3):
7.87(s, 1H), 7.61(d, 2H), 7.50(t, 1H), 6.80(d, 2N), 6.48(t, 1H),
4.44(d, 2H), 3.27(d, 2H), 3.20(m, 4N), 2.95(m, 4H), 0.90(s, 9H).
I-12 4-(4-{(2-Cyan-4-(2,2- dimethyl-propylamino)-
pyrimidin-5-ylmethyl]- carbamoyl}-phenyl)- piperazine-1-carboxylic
acid tert-butyl ester ##STR37## 508 (300 MHz, CDCl.sub.3): 7.95(s,
1H)7.68(d, 2H), 7.54(t, 1H), 6.88(d, 2H), 6.44(t, 1H), 4.52(d, 2H),
3.56(m, 4H), 3.36(d, 2H), 3.0(m, 4H), 1.48(s, 9H), 0.98(s, 9H).
I-13 4-(3-{[2-Cyano-4-(2,2- dimethyl-propylamino)-
pyrimidin-5-ylmethyl]- carbamoyl)-phenyl)- piperazine-1-carboxylic
acid tert-butyl ester ##STR38## 508 (300 MHz, CDCl.sub.3): 7.91(s,
1H), 7.48(t, 1H), 7.35-7.18(m, 3H), 7.10-7.02(m, 2H), 4.50(d, 2H),
3.55(m, 4H), 3.33(d, 2H), 3.16(m, 4H), 1.48(s, 9H), 0.99(s, 9H).
I-14 N-[2-Cyano-4-(2,2- dimethyl-propylamino)-
pyrimidin-5-ylmethyl]-3- (4-methyl-piperazin-1-yl)- benzamide
##STR39## 422 (400 MHz, CDCl.sub.3): 7.78(s, 1H), 7.49(s, 1H),
7.31-7.07(m, 3H), 6.72( 2t(broad), 2H), 4.45(d, 2H), 3.30(m, 6H),
2.65 (m, 4H), 2.42(s, 3H), 0.98 (s, 9H). I-15 N-[2-Cyano-4-(2,2-
dimethyl-propylamino)- pyrimidin-5-ylmethyl]-3-
(4-ethyl-piperazin-1-yl)- benzamide ##STR40## 436 (400 MHz,
CDCl.sub.3): 7.74(s, 1H), 7.49(s, 1H), 7.32-7.07(m, 3H), 6.72(
2t(broad), 2H), 4.42(d, 2H), 3.30(m, 6H), 2.65 (m, 4H), 2.52(q,
2H), 1.18(t, 3H), 0.97(s, 9H). I-16 N-[2-Cyano-4-(2,2-
dimethyl-propylamino)- pyrimidin-5-ylmethyl]-3-
(4-isopropyl-piperazin-1- yl)-benzainide ##STR41## 450 (300 MHz,
CDCl.sub.3): 7.91(s, 1H), 7.44(t, 1H, J=5 Hz), 7.34-7.24(m, 3H),
7.11(d, 1H, J=7 Hz), 7.05(d, 1H, J=7 Hz), 6.83(t, 1H, J=6 Hz),
4.50( d, 2H, 16 Hz), 3.32(d, 2H, J=5 Hz), 3.25(m, 4H), 2.72(m, 1H),
2.68(m, 4H), 7.09( d, 6H, J=8 Hz), 0.98(s, 9H). I-17
N-[2-Cyano-4-(2,2- dimethyl-propylamino)- pyrimidin-5-ylmethyl]-3-
[4-(2-methoxy-ethyl)- piperazin-1-yl]-benzamide ##STR42## 466 (300
MHz, CDCl.sub.3): 7.94(s, 1H), 7.42(t, 1H), 7.32-7.26(m, 2H),
7.12-7.04(m, 2H), 6.67(t, 1H), 4.52(d, 2H), 3.55(t, 2H), 3.37(s,
3H), 3.35(d 2H), 3.26(m, 4H), 2.68-2.61 (m, 6H), 0.98(s, 9H). I-18
N-[2-Cyano-4-(2,2- dimethyl-propylamino)- pyrimidin-5-ylmethyl]-3-
[4-(2-ethoxy-ethyl)- piperazin-1-yl]-benzamide ##STR43## 479
(300MHZ, CDCl.sub.3): 7 .92(s, 1H), 7.45(t, 1H), 7.36-7.26(m, 2H),
7.14-7.02(m, 2H), 6.75(t, 1H), 4.52(d, 2H), 3.62(t, 2H), 3.55(q,
2H), 3.34(d, 2H), 3.23(m, 4H), 2.68-2.60 (m, 6H), 1.22(t, 3H), 0.99
(s, 9H). I-19 N-[2-Cyano-4-(2,2- dimethyl-propylamino)-
pyrimidin-5-ylmethyl]-4- methoxy-3-(2-pyrrolidin-
1-yl-ethoxy)-benzamide ##STR44## 467 (300 MHz, CDCl.sub.3): 7.89(s,
1H), 7.55(t, 1H), 7.44-7.35(m, 2H), 7.0( t, 1H), 6.87(d, 1H), 4.50
(d, 2H), 4.20(t, 2H), 3.89 (s, 3H), 3.34(d, 2H), 2.94 (t, 2H),
2.62(m, 4H), 0.99 (s, 9H). I-20 N-[2-Cyano-4-(2,2-
dimethyl-propylamino)- pyrimidin-5-ylmethyl]-3-
(2-dimethylamino-ethoxy)- 4-methoxy-benzamide ##STR45## 441 (300
MHz, CDCl.sub.3): 7.92(s, 1H), 7.56(t, 1H), 7.42-7.35(m, 2H), 6.82
(d, 1H), 6.81(t, 1H), 4.52 (d, 2H), 4.18(t, 2H), 3.90 (s, 3H),
3.35(d, 2H), 2.80 (t, 2H), 2.37(s, 6H), 0.98 (s, 9H). I-21
N-{2-Cyano-4-(2,2- dimethyl-propylamino)- pyrimidin-5-ylmethyl]-4-
dimethylaminomethyl- benzamide ##STR46## 381 (300 MHz, CDCl.sub.3):
7.91(s, 1H), 7.72(d, 2H, J=8 Hz), 7.46(t, 1H, J=5 Hz), 7.39(d, 2H,
J=8 Hz), 6.79(t, 1H, J=7 Hz), 4.52(d, 2H, J=7 Hz), 3.46(s, 2H),
3.35(d, 2H, J=5), 2.23(s, 6H), 0.99 (s, 9H). I-22
N-[2-Cyano-4-(2,2- dimethyl-propylamino)- pyrimidin-5-ylmethyl]-4-
(4-methyl-piperazin-1-ylmethyl)-benzamide ##STR47## 436 (300 MHz,
CDCl.sub.3): 7.91(s, 1H), 7.72(d, 2H,J=8 Hz), 7.44(t, 1H, J=5 Hz),
7.21(d, 2H, J=8 Hz), 6.87(t, 1H, J=7 Hz), 4.52(d, 2H, J=7 Hz),
3.54(s, 2H); 3.35(d, 2H, J=5 Hz), 2.49(m, broad, 8H), 1.0(s, 9H).
I-23 N-[2-Cyano-4-(2,2- dimethyl-propylamino)-
pyrimidin-5-ylmethyl]-4- [1-(2-methoxy-ethyl)-
piperidin-4-ylmethyl]- benzamide ##STR48## 479 (300 MHz,
CDCl.sub.3): 7.89(s, 1H), 7.70(d, 2H), 7.53(t, 1H), 7.20(d, 2H),
6.88(t, 1H), 4.50(d, 2H), 3.48(t, 2H), 3.35(d, 2H), 3.33(s, 3H),
2.90(m, 2H), 2.60-2.50(,m, 4H), 1.90 (m, 2H), 1.60-1.28(M, 5H),
0.99(s, 9H). I-24 N-[2-Cyano-4-(2,2- dimethyl-propylamino)-
pyrimidin-5-ylmethyl]-4- methoxy-3-(2-piperidin-1-
yl-ethoxy)-benzamide ##STR49## 481 (300 MHz, CDCl.sub.3): 7.92(s,
1H), 7.56(t, 1H, J=6 Hz), 7.42-7.33(m, 2H), 6.88(d, 1H), 6.87(t,
1H),4.50(d, 2H, J=7 Hz), 4.20(t, 2H, J=7 Hz), 3.90(s, 3H), 3.36(d,
2H, J=6 Hz), 2.81((t, 2H, J=7 Hz), 2.51(m,4H), 1.60 (m, 4H),
1.45(m, 2H), 0.98(s, 9H). I-25 N-[2-Cyano-4-(2,2-
dimethyl-propylamino)-pyrimidin-5-ylmethyl]-3-[4-(4-ethyl-piperazin-1-yl)-
-phenyl]-2,2-dimethyl- propionamide ##STR50## 492 (300 MHz,
CDCl.sub.3): 7.66(t, 1H), 7.62(s, 1H), 6.88(d, 2H), 6.67(d, 2H),
5.94(t, 1H), 4.18(d, 2H), 3.36(d, 2H), 3.14(m, 4H), 2.71(s, 2H),
2.60(m, 4H), 2.47(q, 2H), 1.19(s, 6H), 1.14(t, 3H), 1.02(s, 9H).
I-26 N-[2-Cyano-4-(2,2- dimethyl-propylamino)-
pyrimidin-5-ylmethyl]-2,2- dimethyl-3-[4-(4-propyl-
piperazin-1-yl)-phenyl]- propionamide ##STR51## 506 (300 MHz,
CDCl.sub.3): 7.68(s, 1H), 7.64(t, 1H), 6.89(d, 2H), 6.67(d, 2H),
5.89(t, 1H), 4.18(d, 2H), 3.36(d, 2H), 3.15(m, 4H), 2.72(s, 2H),
2.62(m, 4H), 2.37(m, 2H), 1.57(q, 2H), 1.20(s, 6H), 1.02(s, 9H).
I-27 N-[2-Cyano-4-(2,2- dimethyl-propylamino)-
pyrimidin-5-ylmethyl]-2,2- dimethyl-3-(4-pyrrolidin-
1-yl-phenyl)-propionamide ##STR52## 449 (300 MHz, CDCl.sub.3):
7.69(s, 1H), 7.63(t, 1H), 6.84(d, 2H), 6.37(d, 2H), 5.84(t, 1H),
4.18 Cd, 2H), 3.37(d, 2H), 3.24(m, 4H), 2.69(s, 2H), 2.03(m, 4H),
1.18(s, 6H), 1.02(s, 9H). I-28 N-[2-Cyano-4-(2,2-
dimethyl-propylamino)- pyrimidin-5-ylmethyl]-3-
[3-(4-ethyl-piperazin-1-yl)- phenyl]-2,2-dmmethyl- propionamide
##STR53## 492 (300 MHz, CDCl.sub.3): 7.78(s, 1H), 7.49(1, 1H),
7.04(1, 1H), 6.78(m, 1H), 6.62(m, 1H), 6.50(m, 1H), 5.82(1, 1H),
4.18(d, 2H), 3.34(d, 2H), 3.16(m, 4H), 2.79(s, 2H), 2.61(m, 4H),
2.48(q, 4H), 1.20(s, 6H), 1.13(1,3H), 1.02(s, 9H). I-29
N-[2-Cyano-4-(2,2- dimethyl-propylamino)- pyrimidin-5-ylmethyl]-3-
{3-[4-(2-methoxy-ethyl)- piperazin-1-yl]-phenyl}- 2,2-dimethyl-
propionamide ##STR54## 522 (300 MHz, CDCl.sub.3): 7.80(s, 1H),
7.50(t, 1H), 7.05(t, 1H), 6.78(m, 1H), 6.62(m, 1H), 6.50(m, 1H),
5.80(t, 1H), 4.18(d, 2H), 3.55(t,2H), 3.37(s, 3H), 3.35(d, 2H),
3.18(m, 4H), 2.79(s, 2H), 2.66(m, 4H), 1.20(s, 6H), 1.02(s, 9H).
I-30 N-[2-Gyano-4-(2,2- dimethyl-propylamino)-
pyrimidin-5-ylmethyl]-3- {3-[4-(2-ethoxy-ethyl)-
piperazin-1-yl]-phenyl}- 2,2-dimethyl- propionamide ##STR55## 536
(300 MHz, CDCl.sub.3): 7.79(s, 1H), 7.50(t, 1H), 7.05(t, 1H),
6.78(m, 1H), 6.60(m, 1H), 6.49(m, 1H), 5.82(t, 1H), 4.17(d, 2H),
3.60(t,2H), 3.53(q, 2H), 3.36(d, 2H), 3.18(m, 4H), 2.79(s, 2H),
2.68(m, 4H), 1.25(q, 3H), 1.20(s, 6H), 1.02(s, 9H). I-31
N-[2-Cyano-4-(2,2- dimethyl-propylamino)-
pyrimidin-5-ylmethyl]-2,2- dimethyl-3-(3-pyrrolidin-
1-yl-phenyl)-propionamide ##STR56## 449 (300 MHz, CDCl.sub.3):
7.79(s, 1H), 7.54(t, 1H), 7.0(t, 1H), 6.42(m, 1H), 6.34(m, 1H),
6.28(m, 1H), 5.84(t, 1H), 4.18(d, 2H), 3.34(d, 2H), 322(m, 4H),
2.79(s, 2H), 2.0(m, 4H), 1.22(s, 6H), 1.02(s, 9H). I-32
N-[2-Cyano-4-(2,2- pyrimidin-5-ylmethyl]-2- dimethyl-propylamino)-
[4-(4-methyl-piperazin-1- yl)-phenyl]-isobutyramide ##STR57## 464
(300 MHz, CDCl.sub.3): 7.76(s, 1H) 7.22(t, 1H), 7.15(d, 2H),
6.87(d, 2H), 5.61(t, 1H),4.18(d, 2H), 3.24(d, 2H) 3.22(m, 4H),
2.58(m, 4H), 2.34(s, 3H), 1.53(s, 6H), 1.01(s, 9H). I-33
N-[2-Cyano-4-(2,2- dimethyl-propylamino)- pyrimidin-5-ylmethyl]-2-
(4-methoxy-phenyl)-acetamide ##STR58## 368 (300 MHz, CDCl.sub.3):
7.81(s, 1H), 7.25(t, 1H), 7.13(d, 2H), 6.88(d, 2H), 5.85(t, 1H),
4.25(d, 2H), 3.81(s, 3H), 3.33(d, 2H), 0.99(s, 9H). I-34
N-[2-Cyano-4-(2,2- dimethyl-propylamino)- pyrimidin-5-ylmethyl]-2-
(3-methoxy-phenyl)-acetamide ##STR59## 368 (300 MHz, CDCl.sub.3):
7.82(s, 1H), 7.25(m, 2H), 6.87-6.74(m, 3H), 5.88 (t, 1H), 4.25(d,
2H), 3.81 (s, 3H), 3.33(d, 2H), 0.99 (s, 9H). I-35
N-[2-Cyano-4-(2,2- dimethyl-propylamino)- pyrimidin-5-ylmethyl]-2-
[4-(4-methyl-piperazin-1- yl)-phenyl]-acetamide ##STR60## 436 (300
MHz, CDCl.sub.3): 7.80(s, 1H), 7.27(t, 1H), 7.06(d, 2H), 6.89(d,
2H), 5.82(t, 1H), 4.24(d, 2H), 3.54(s, 2H), 3.33(d, 2H), 3.22(m,
4H), 2.60(m, 4H), 2.46(q, 2H),1.04(t, 3H), 1.0(a, 9H). I-36
N-[2-Cyano-4-(2,2- dimethyl-propylamino)- pyrhnidin-5-ylmethyl]-2-
[4-(4-ethyl-piperazin-1-yl)- phenyl]-acetamide ##STR61## 450 (300
MHz, CDCl.sub.3): 7.80(s, 1H), 7.27(t, 1H), 7.06(d, 2H), 6.89(d,
2H), 5.84(t, 1H), 4.22(d, 2H), 3.54(s, 2H), 3.34(d, 2H), 3.20(m,
4H), 2.58(m, 4H), 2.36(s, 3H), 1.0(s, 9H). I-37 N-[2-Cyano-4-(2,2-
dimethyl-propylamino)- pyrimidin-5-ylmethyl]-2-
[4-(4-isopropyl-piperazin- 1-yl)-phenyl]-acetamide ##STR62## 464
(300 MHz, CDCl.sub.3): 7.80(s, 1H), 7.27(t, 1H), 7.06(d, 2H),
6.89(d, 2H), 5.83(t, 1H), 4.22(d, 2H), 3.54(s, 2H), 3.34(d, 2H),
3.21(m, 4H), 2.72(m,1H), 2.67(m, 4H), 1.11(d,6H), 0.98(s, 9H). I-38
N-[2-Cyano-4-(2,2- dimethyl-propylamino)- pyrimidin-5-ylmethyl]-2-
(4-pyrrolidin-1-yl-phenyl)- acetamide ##STR63## 407 (300 MHz,
CDCl.sub.3): 7.79(s 1H), 7.33(t, 1H), 7.02(d, 2H), 6.51(d, 2H),
5.85(t, 1H), 4.22(d, 2H), 3.50(s, 2H), 3.34(d, 2H), 3.26(m, 4H),
2.03(m, 4H), 1.0(s, 9H). I-39 N-[2-Cyano-4-(2,2-
dimethyl-propylamino)- pyrimidin-5-ylmethyl]-2- [4-(2-diethylamino-
ethylamino)-phenyl]- isobutyramide ##STR64## 480 (300 MHz,
CDCl.sub.3): 7.76(s, 1H), 7.34(t, 1H), 7.07(d, 2H), 6.58(d, 2H),
5.68(t, 1H), 4.48(t, broad, 1H), 4.18(d, 2H), 3.35(d, 2H), 3.10(t,
2H), 2.68(t, 2H), 2.54(q, 4H), 1.52(s, 6H), 1.03(m, 15H). I-40
N-[2-Cyano-4-(2,2- dimethyl-propylamino)-
pyrimidin-5-ylmethyl]-2-
(4-pyrrolidin-1-yl-phenyl)- isobutyramide ##STR65## 435 (300 MHz,
CDCl.sub.3): 7.75(s, 1H), 7.36(t, 1H), 7.12(d, 2H), 6.52(d, 2H),
5.66(t, 1H), 4.18(d, 2H), 3.34(s, 2H), 3.26(m, 4H), 2.00(m, 4H),
1.52(s, 6H), 1.0(s, 9H). ##STR66## I-41 N-(2-Cyano-4-
isobutylamino- pyrimidin-5- ylmethyl)-4-(4- methyl-piperazin-1-
yl)-benzamide ##STR67## 408 (300 MHz, CDCl.sub.3): 7.96(s, 1H),
7.70(t, 1H), 7.67(d, 2H), 6.89(d, 2H), 6.41(t, 1H), 4.50(d, 2H),
3.39-3.28(m, 6H), 2.56(m, 4H), 2.36 (s, 3H), 1.94(m, 1H), 0.94(d,
6H). I-42 N-(2-Cyano-4- isobutylamino- pyrimidin-5- ylmethyl)-4-(4-
ethyl-piperazin-1- yl)-benzamide ##STR68## 422 (300 MHz,
CDCl.sub.3): 7.90(s, 1H), 7.71(t, 1H), 7.67(d, 2H), 6.88(d, H),
6.52(t, 1H), 4.48(d, 2H), 3.38 .3.28(m, 6H), 2.59(m, 4H), 2.48 (q,
2H), 1.94(m, 1H), 1.13(t, 3H), 0.94(d, 6H). I-43 N-(2-Cyano-4-
isobutylamino- pyrimidin-5- ylmethyl)-4-(4- isopropyl-piperazin-
1-yl)-benzamide ##STR69## 436 (300 MHz, CDCl.sub.3): 7.89(s, 1H),
7.80(t, 1H), 7.68(d, 2H), 6.88(d, 2H), 6.73(t, 1H), 4.48(d, 2H),
3.36-3.25(m, 6H), 2.74(m, 1H), 2.66 (m,4H), 1.94(m, 0.94(d, 6H).
I-44 N-(2-Cyano-4- isobutylamino- pyrimidin-5- ylmethyl)-4-(4-
propyl-piperazin-1- yl)-benzamide ##STR70## 436 (300 MHz,
CDCl.sub.3): 7.90(s, 1H), 7.74(t, 1H), 7.68(d, 2H), 6.88(d, 2H),
6.57(t, 1H), 4.48(d, 2H), 3.36-3.26(m, 6H), 2.59(m, 4H), 2.35 (m,
2H), 1.95(m, 0.94(d & t, 9H). I-45 N-(2-Cyano-4- isobutylamino-
pyrimidin-5- ylmethyl)-4-[4-(2- methoxy-ethyl)- piperazin-1-yl]-
beuzamide ##STR71## 452 (300MHz, CDCl.sub.3): 7.90(s, 1H), 7.74(t,
1H), 7.68(d, 2H), 6.88(d, 2H), 6.56(t, 1H), 4.49(d, 2H), 3.55(t,
2H), 3.38(s, 3H), 3.36-3.28(m, 6H), 2.64(m, 6H), 1.95(m, 1H), 0.93
(d, 6H) I-46 N-(2-Cyano-4- isobutylamino- pyrimidin-5-
ylmethyl)-4-(1- propyl-piperidin-4- yl)-benzamide ##STR72## 435
(300 MHz, CDCl.sub.3): 7.91(s, 1H), 7.72 (d, 2H), 7.61(t, 1H),
7.30(d, 2H), 6.69(t, 1H), 4.51(d, 2H), 3.30(t, 2H), 3.08(d, broad,
2H), 2.56 (m, 1H), 2.35(m, 2H), 2.05(m, 2H), 1.94(m,1H),
1.87-1.70(m, 4H), 1.56 (m, 2H), 0.95(d, 6H), 0.94(t, 3H). I-47
N-(2-Cyano-4- isobutylamino- pyrimidin-5- ylmethyl)-4-[1-(2-
methoxy-ethyl)- piperidin-4-yl]- benzamide ##STR73## 451 (300 MHz,
CDCl.sub.3): 7.92(s, 1H), 7.70 (d, 2H), 7.63(t, 1H), 7.32(d, 2H),
6.73(t, 1H), 4.5(d, 2H), 3.54(t, 2H), 3.37(s, 3H), 3.30(t, 3H),
3.10(d, 2H), 2.62(t, 2H), 2.53(m, 1H), 2.13(m, 2H), 1.94 (m, 1H),
1.88-1.62 (m, 5H), 0.95(d, 6H). I-48 4-(4-{[N-2-Cyano-
4-isobutylamino- pyrimidin-5- ylmethyl]- carbainoyl)- phenyl)-4-
piperazine-1- carboxylic acid text- butyl ester ##STR74## 494 (300
MHz, CDCl.sub.3): 7.90(s, 1H), 7.72(t, 1H), 7.70(d, 2H), 6.88(d,
2H), 6.78(t, 1H), 4.48(d, 2H), 3.57(m, 4H), 3.28 (m, 6H), 1.94 (m,
1H), 1.49(s, 9H), 0.95(d, 6H). I-49 N-(2-Cyano-4- isobutylamino-
pyrimidin-5- ylmethyl)-4- piperazin-1-yl- benzamide ##STR75## 394
(300 MHz, CDCl.sub.3): 7.90(s, 1H), 7.72(t, 1H), 7.68(d, 2H),
6.88(d, 2H), 6.64(t, 1H), 4.48(d, 2H), 3.32-3.27(m, 6H),
3.02(m,4H), 1.95 (m, 1H), 0.95(d, 6H). ##STR76## The following
amine derivatives are obtained by
dissolving(2-Chloro-5-chloromethyl-
pyrimidin-4-yl)-(2,2-dimethyl-propyl)-amine(1B) and 1 equivalent of
DIEA in DMF, cooling to .degree. C. and adding 1 equivalent of the
corresponding amine dropwise at .degree. C. The reaction mixture is
stirred at .degree. C. for 12 h, then diluted with ethyl acetate
and extracted once with brine. The organic layer is separated and
dried over Na.sub.2SO.sub.4. The product is purified by flash
chromatography. I-50 4-(2,2-Dimethyl- propylamino)-5- [(4-methoxy-
beuzylamino)- methyl]- pyrimidme-2- carbonitrile ##STR77## 340 (300
MHz, CDCl.sub.3): 8.00(t, 1H), 7.84(s, 1H), 7.14(d, 2H), 6.86 (d,
2H), 3.80(s, 3H), 3.70(d, 2H), 3.30(d, 2H), 0.97(s, 9H). I-51
4-(2,2-Dimethyl- propylamino)-5- [(3-methoxy- beuzylamino)-
methyl]- pyrimidme-2- carbonitrile ##STR78## 340 (300 MHz,
CDCI.sub.3): 7.94(t, 1H), 7.85(s, 1H), 7.24(m, 1H), 6.84 7.77(m,
3H), 3.80(s, 3H), 3.74(d, 2H), 3.32 (d, 2H), 0.98(s, 9H). I-52
4-(2,2-Dimethyl- propylamino)-5- {[4-(4-methyl- piperazin-1-yl)-
benzylamino]- methyl}- pyrimidme-2- carbonitrile ##STR79## 408 (300
MHz, CDCl.sub.3): 8.04(t, 1H), 7.82(s, 1H), 7.12(d, 2H), 6.89 (d,
2H), 3.74(s, 2H), 3.65(s, 2H), 3.31(d, 2H), 3.22(m, 4H), 2.60 (m,
4H), 2.37(s, 3H), 0.97(s, 9H). I-53 4-(2,2-Dimethyl-
propylamino)-5- ({4-[4-(2-ethoxy- ethyl)-piperazin-1-
yl]-benzylamino)- methyl)- pyrimidine-2- carbonitrile ##STR80## 466
(300 MHz, CDCl.sub.3): 8.03(t, 1H), 7.82(s, 1H), 7.13(d, 2K), 6.89
(d, 2K), 3.73(s, 2H), 3.65(s, 2H), 3.61(t, 2H), 3.54(q, 2H), 3.31
(d, 2H), 3.22(m, 4H), 2.70-2.64(m, 6H), 1.33(t, 3H), 0.97(s, 9H).
I-54 4-(2,2-Dimethyl- propylamino)-5- [(1-methyl-1- phenyl-
ethylamino)- methyl]- pyrimidine-2- carbonitrile ##STR81## 338 (300
MHz,CDCl.sub.3): 7.88(s.1H), 7.80(t, 1H), 7.37(m, 5H),(s, 1H),
7.29(t, 1H), 3.41 (s, 2H), 3.34(d, 2H), 1.55(s, 6H), 1.01(s, 9H).
I-55 4-(2,2-Dimethyl- propylamino)-5- {[2-(4-methoxy- phenyl)-1,1-
dimethyl- ethylamino]- methyl)- pyrimidine-2- carbonitrile
##STR82## 382 (300 MHz, CDCl.sub.3): 7.95(t, 1H), 7.88 (s.1H),
7.03(d, 2H), 6.83(d, 2H), 3.80(s, 3H), 3.74(s, 2H), 3.27 (d, 2H),
2.70(s, 2H), 1.15(s, 6H), 0.95(s, 9H). I-56 4-(2,2-Dimethyl-
propylamino)-5- ([2-(4-fluoro- phenyl)-1,1- dimethyl- ethylamino)-
methyl)- pyrinuidine-2- carbonitrile ##STR83## 370 (300 MHz,
CDCl.sub.3): 7.90(s, 1H), 7.85(t, 1H), 7.10-6.94(m, 4H), 3.75(s,
2H), 3.28 (d, 2H), 2.74(s, 2H), 1.17(s, 6H), 0.95(s, 9H). I-57
5-({1,1-Dimethyl- 2-[4-(4-methyl- piperazin-1-yl)- phenyl]-
ethylaminol- methyl)-4-(2,2- dimethyl- propylammo)- pyrimidine-2-
carbonitrile ##STR84## 450 (300 MHz, CDCl.sub.3): 8.00(t, 1H),
7.87(s, 1H), 7.00(d, 2H), 6.85 (d, 2H), 3.74(s, 2H), 3.26(d, 2H),
3.18(m, 4H), 2.62(s, 3H), 2.58 (m, 4H), 2.35(s, 2H), 1.14(s,
6H),0.95(s, 9H). I-58 4-(2,2-Dimethyl- propylamino)-5- ({2-[4-(4-
isopropyl- piperazin-1-yl)- phenyl]-1,1- dimethyl- ethylamino)-
methyl)- pyrimidine-2- carbonitrile ##STR85## 478 (300 MHz,
CDCl.sub.3): 8.00(t, 1H), 7.87(s, 1H), 6.99(d, 2H), 6.84 (d, 2H),
3.74(d, 2H), 3.27(d, 2H), 3.18(m, 4H), 2.70(m, 1H), 2.68 (m, 6H),
1.15(s, 6H), 1.10(d, 6H), 0.95(s, 9H). I-59 4-(2,2-Dimethyl-
propylamino)-5- [(2-{4-[4-(2- methoxy-ethyl)- piperazin-1-yl]-
phenyl}-1,1- dimethyl- ethylamino)- methyl]- pyrimidine-2-
carbonitrile ##STR86## 494 (300 MHz, CDCl.sub.3): 8.00(t, 1H),
7.88(s, 1H), 7.00(d, 2H), 6.83 (d, 2H), 3.72(s, 2H), 3.55(t, 2H),
3.37(s, 3H), 3.27(d, 2H), 3.20 (m, 4H), 2.68-2.60 (m, 8H), 1.15(a,
6H), 0.95(a, 9H). I-60 4-(2,2-Dimethyl- propylamino)-5-
[(2-{3-(4-(2- ethoxy-ethyl)- piperazin-1-yl]- phenyl)-1,1-
dimethyl- ethylamino)- methyl]- pyrimidine-2- carbonitrile
##STR87## 508 (300 MHz, CDCl.sub.3): 8.00(t, 1H), 7.88(s, 1H),
7.00(d, 2H), 6.83 (d, 2H), 3.72(a, 2H), 3.55(t, 2H), 3.36(q, 2H),
3.27(d, 2H), 3.20 (m, 4H), 2.68-2.60 (m, 8H), 1.18(t, 3H), 1.15(s,
6H), 0.95(s, 9H). I-61 4-(2,2-Dimethyl- propylamino)-5-
({2-[3-(4-ethyl- piperazin-1-yl)- phenyl]-1,1- dimethyl-
ethylamino}- methyl)- pyrimidine-2- carbonitrile ##STR88## 464 (300
MHz, CDCl.sub.3): 8.00(t, 1H), 7.88(s, 1H), 7.16(m, 1H), 6.81(m,
1H), 6.63-6.60(m, 2H), 3.74(d, 2H), 3.27(d, 2H), 3.17 (m, 4H),
2.71(s, 3H), 2.59(m, 4H), 2.48(q, 2H), 1.17(s, 6H), 1.14 (t, 3H),
0.95(s, 9H). I-62 4-(2,2-Dimethyl- propylamino)-5- ({2-[3-(4-
isopropyl- piperazin-1-yl)- phenyl]-1,1- dimethyl- ethylamino}-
methyl)- pyrimidine-2- carbonitrile ##STR89## 478 (300 MHz,
CDCl.sub.3): 8.00(t, 1H), 7.88(s, 1H), 7.16(m, 1H), 6.83(m, 1H),
6.63-6.58(m, 2H), 3.75(s, 2H), 3.27(d, 2H), 3.17 (m, 4H), 2.73-2.64
(m, 7H), 1.17(s, 6H), 1.10(d, 6H), 0.95(s, 9H). I-63
4-(2,2-Dimethyl- propylamino)-5- {[1,1-dimethyl-2-
(3-pyrrolidin-1-yl- phenyl)- ethylamino]- methyl)- pyrimidine-2-
carbonitrile ##STR90## 421 (300 MHz, CDCl.sub.3): 8.08(t, 1H),
7.88(s, 1H), 7.12(m, 1H), 6.43-6.38(m, 2H), 6.26(s, 1H), 3.76(s,
2H), 3.27-3.20(m, 6H), 2.72(s, 2H), 2.00 (m, 4H), 1.18(s, 6H),
0.95(s, 9H). I-64 4-(2,2-Dimethyl- propylamino)-5- [(2-{3-[4-(2-
methoxy-ethyl)- piperazin-1-yl]- phenyl)-1,1- dimethyl-
ethylamino)- methyl)- pyrimidine-2- carbonitrile ##STR91## 494 (300
MHz, CDCl.sub.3): 8.00(t, 1H), 7.88(s, 1H), 7.16(m, 1H), 6.80(m,
1H), 6.63-6.58(m, 2H), 3.75(s, 2H), 3.55(t, 2H), 3.37 (s, 3H),
3.27(d, 2H), 3.18(m, 4H), 2.72(s, 2H), 2.68-2.60(m, 6H), 1.17(s,
6H), 0.95 (s, 9H). I-65 4-(2,2-Dimethyl- propylamino)-5-
{2-(4-methoxy- phenyl)- ethylamino]- methyl)- pyrimidine-2-
carbonitrile ##STR92## 354 (300 MHz, CDCl.sub.3): 8.05(t, 1H),
7.84(s, 1H), 7.06(d, 2H), 6.84 (d, 2H), 3.80(s, 3H), 3.75(s, 2H),
3.25(d, 2H), 2.77(m 4H), 0.97 (s, 9H). I-66 4-(2,2-Dimethyl-
propylamino)-5- ({2-[4-(4-methyl- piperazin-1-yl)- phenyl]-
ethylamino)- methyl)- pyrimidine-2- carbonitrile ##STR93## 422 (300
MHz, CDCl.sub.3): 8.10(t, 1H), 7.84(s, 1H), 7.05(d, 2H), 6.89 (d,
2H), 3.73(s, 2H), 3.26(d, 2H), 3.18(m, 4H), 2.83-2.70(m, 4H),
2.50(m, 4H), 2.36 (s, 3H), 0.99(s, 9H). I-67 4-(2,2-Dimethyl-
propylamino)-5- ({2-[4-(4- isopropyl- piperazin-1-yl)- phenyl]-
ethylamino}- methyl)- pyiimidine-2- carbonitrile ##STR94## 450 (300
MHz CDCl.sub.3): 8.10(t, 1H), 7.82(s, 1H), 7.04(d, 2H), 6.89 (d,
2H), 3.73(s, 2H), (d, 2H), 3.18(m, 4H), 2.84-2.68(m, 7H), 1.12(d,
6H), 0.99 (s, 9H). I-68 4-(2,2-Dimethyl- propylamino)-5-
[(2-{4-[4-(2- methoxy-ethyl)- piperazin-1-yl]- phenyl)-
ethylamino)- methyl]pyrimidine-2- carbonitrile ##STR95## 466 (300
MHz, CDCl.sub.3): 8.10(t, 1H), 7.82(s, 1H), 7.04(d, 2H), 6.86 (d,
2H), 3.75(s, 2H), 3.38(s, 3H), 3.30-3.19(m, 6H), 2.82-2.60(m, 11H),
0.96(s, 9H). I-69 4-(2,2-Dimethyl- propylamino)-5- {[2-(3-methoxy-
phenyl)- ethylamino]- methyl)- pyrimidine-2- carbonitrile ##STR96##
354 (300 MHz, CDCl.sub.3): 8.03(t, 1H), 7.82(s, 1H), 7.20(m, 1H),
6.80-6.70(m, 3H), 3.80(s, 3H), 3.75(s, 2H), 3.26 (d, 2H), 2.80(m,
4H), 0.96(s, 9H). I-70 4-(2,2-Dimethyl- propylamino)-5-
({2-[3-(4-methyl- piperazin-1-yl)- phenyl]- ethylamino)}- methyl)-
pyimidine-2- carbonitrile ##STR97## 422 (300 MHz, CDCl.sub.3):
8.07(t, 1H), 7.82(s, 1H), 7.18(m, 1H), 6.80-6.20(m, 3H), 3.75(s,
2H), 3.28(d, 2H), 3.22 (m, 4H), 2.80(m, 4H), 2.60(m, 4H), 2.37(s,
3H), 0.97(s, 9H). I-71 4-(2,2-Dimethyl- propylamino)-5- ({2-[4-(4-
isopropyl- piperazin-1-yl)- phenyl]- ethylamino}- methyl)-
pyrimidine-2- carbonitrile ##STR98## 450 (300 MHz, CDCl.sub.3):
8.07(t, 1H), 7.85(s, 1H), 7.19(m, 1H), 6.82-6.65(m, 3H), 3.75(s,
2H), 3.29(d, 2H), 3.22 (m, 4H), 2.86-2.70 (m, 6H), 1.13(d, 6H),
0.99(s, 9H). I-72 4-(2,2-Dimethyl- propylamino)-5- [(2-pyrrol-1-yl-
ethylamino)- methyl]- pyrimidine-2- carbonitrile ##STR99## 313 (300
MHz, CDCl.sub.3): 7.82(s, 1H), 7.72(t, 1H), 6.3(m, 2H), 6.17 (m,
2H), 4.02(t, 2H), 3.72(s, 2H), 3.30(d, 2H), 2.91(m, 2H), 0.99 (s,
9H). I-73 4-(2,2-Dimethyl- propylamino)-5- [(3-piperidin-1-yl-
propylamino)- methyl]- pyrimidine-2- carbonitrile ##STR100## 345
(300 MHz, CDCl.sub.3): 7.92(s, 1H), 7.80(t, 1H), 3.75(s, 2H), 3.30
(s, 2H), 2.94-2.59(m, 8H), 2.06-1.82(m, 6H), 1.60(m, 2H), 0.994(s,
(H). I-74 4-(2,2-Dimethyl- propylamino)-5- {[2-(4-methoxy-
phenyl)-2-methyl- propylamino]- methyl}- carbonitrile ##STR101##
382 (300 MHz, CDCl.sub.3): 7.81(s, 1H), 7.77(t, 1H), 7.21(d, 2H),
6.85 (d, 2H), 3.80(s, 3H),3.63(s, 2H), 3.23 (d, 2H), 2.65(s, 2H),
1.30(s, 6H), 0.92(s, 9H). I-75 4-(2,2-Dimethyl- propylamino)-5-
({2-methyl-2-[4- (4-methyl- piperazin-1-yl)- phenyl]- propylamino}-
methyl)- pyrimidine-2- carbonitrile ##STR102## 450 (300 MHz,
CDCl.sub.3): 7.84(t, 1H), 7.81(s, 1H), 7.18(d, 2H), 6.88 (d, 2H),
3.63(s, 2H), 3.28-3.21(m,6H), 2.63(s, 2H), 2.60(m, 4H), 2.37(s,
3H). 1.30 (s, 6H), 0.94(s, 9H). I-76 4-(2,2-Dimethyl-
propylamino)-5- ({2-[4-(4- isopropyl- piperazin-1-yl)-
phenyl-2-methyl- propylamino}- methyl)- pyrimidine-2- carbonitrile
##STR103## 478 (300 MHz, CDCl.sub.3): 7.85(t, 1H), 7.80(s, 1H),
7.19(d, 2H), 6.88 (d, 2H), 3.63(s, 2H), 3.26-3.18(m, 6H),
2.75-2.60(m, 7H), 1.30(s, 6H), 1.11(d, 6H), 0.94(s, 9H). I-77
4-(2,2-Dimethyl- propylamino)-5- [(2-{4-[4-(2- ethoxy-ethyl)-
piperazin-l-yl]- phenyl}-2-methyl- propylamino)- methyl]-
pyrimidine-2- carbonitrile ##STR104## 508 (300 MHz, CDCl.sub.3):
7.84(t, 1H), 7.80(s, 1H), 7.19(d, 2H), 6.87 (d, 2H), 3.63-3.59(m,
4H), 3.53(q, 2H), 3.26 3.18(m, 6H), 2.70-2.60(m, 8H), 1.30(s, 6H),
1.23(t, 6H), 0.94 (s, 9H). I-78 N-(2-Cyano-4- isobutylamino-
pyrimidin-5- ylmethyl)-4-(4- isopropyl- piperazin-1-yl)- benzamide
##STR105## 435 (300 MHz, CDCl.sub.3): 7.87(t, 1H), 7.80(s, 1H),
7.19(d, 2H), 6.88 (d, 2H), 3.61(s, 2H),2.35(d, 2H), 3.14 (m, 4H),
2.63(s, 2H), 1.72(m, 4H), 1.58(m, 2H), 1.30(s, 6H), 0.94 (s, 9H).
I-79 4-(2,2-Dimethyl- propylamino)-5-[4- (3-methoxy-
pbenyl)-piperazin- 1-ylmethyl]- pyiimidine-2- carbonitrile
##STR106## 395 (300 MHz, CDCl.sub.3): 7.93(s, 1H), 7.81(t, 1H),
7.19(m, 1H), 6.56 6.43 m, 3H),
3.79(s, 3H), 3.51(s, 2H), 3.32 (d, 2H), 3.19(m, 4H), 2.62(m, 4H),
0.98(s, 9H). I-80 4-(2,2-Dimethyl- propylamino)-5-[4-
(4-methoxy-phenyl)-piperazin- 1-ylmethyl]- pyimidine-2-
carbonitrile ##STR107## 395 (300 MHz, CDCl.sub.3): 7.93(s, 1H),
7.85(t, 1H), 6.88(2d, 4H), 3.79(s, 3H), 3.51(s, 2H), 3.32(d, 2H),
3.10 (m, 4H), 2.62(m, 4H), 0.98(s, 9H). I-81 4-(2,2-Dimethyl-
propylamino)-5- {[1-methyl-1-(1- phenyl- cyclopropyl)- ethylamino]-
methyl}- pyrimidine-2- carbonitrile ##STR108## 378 (300 MHz,
CDCl.sub.3): 7.91(s, 1H), 7.80(s, 1H), 7.34-7.21(m, 5H), 3.83(s,
2H)3.19 (d,2H), 1.11(s, 6H) 0.96(q, 2H), 0.86(s, 9H), 0.77(d,
2H).
[0108] The piperazinyl-benzoic acid precursors used in the
preparation of the above compounds may be prepared substantially as
described below for the reference
4-[(2-methoxy-ethyl)-piperazin-1-yl]benzoic acid precusor.
Preparation of Piperazinyl-Benzoic Acids: ##STR109##
A) 4-[4-(2-Methoxy-ethyl)-piperazin-1-yl]benzoic acid methyl
ester
[0109] To 10 ml of 1,4-dioxan is added 0.645 g (3.0 mmol) of
methyl-4-bromobenzoate 0.519 g (3.6 mmol) of
1-(2-methoxy-ethyl-piperazine, 0.892 g (8.47 mmol) of potassium
phosphate, 0.177 g (0.45 mmol) of
2-dicycohexylphosphino-2'-(N,N-dimethyl-amino)biphenyl and 0.137 g
(0.15 mmol) tris-(benzylideneacetone)palladium (0). The resulting
reaction mixture is stirred under argon for 5 hours at 100.degree.
C., then cooled to room temperature, diluted with ethyl acetate and
filtered. The filtrate is washed once with H.sub.2O and once with
brine, the organic layer separated and dried over Na.sub.2SO.sub.4.
Purification of the crude product by flash chromatography
(dichloromethane/methanol) yields 0.52 g of
4-[4-(2-methoxy-ethyl)-piperazin-1-yl)]benzoic acid methyl ester as
a solid.
[0110] MS (ES+): 279 (M+H).sup.+
[0111] .sup.1H-NMR (300 MHz, CDCl.sub.3): 7.94 (d, 2H), 6.87 (d,
2H), 3.88 (s, 3H), 3.55 (t, 2H), 3.38 (s, 3H), 3.36 (m, 4H), 2.68
(m, 6H). ##STR110##
B) 4-[4-(2-Methoxy-ethyl)-piperazin-1-yl)-benzoic acid sodium
salt
[0112] To 4 ml of MeOH/H.sub.2O (1:1) is added 0.52 g (1.87 mmol)
of 4-[4-(2-methoxy-ethyl)-piperazin-1-yl]benzoic acid methyl ester
and 0.078 g (1.96 mmol) of NaOH (30%). The resulting reaction
mixture is stirred 1 hour at 80.degree. C., then cooled to room
temperature and diluted with H.sub.2O. The H.sub.2O-layer is
extracted 3 times with diethyl ether and then lyophilised to yield
0.47 g of 4-[4-(2-methoxy-ethyl)-piperazin-1-yl)-benzoic acid
sodium salt as a white solid.
[0113] MS (ES+): 265 (M+H).sup.+
[0114] .sup.1H-NMR (300 MHz, CD.sub.3OD): 7.97 (d, 2H), 7.04 (d,
2H), 3.72 (t, 2H), 3.50 (s, 3H), 3.42 (m, 4H), 2.82 (m, 6H).
TABLE-US-00002 ##STR111## MS (ES+) Ex. R (M + H).sup.+ .sup.1H-NMR
I-82 4-(2,2-Dimethyl- propylamino)-5-[4- (2-pyridin-4-yl-
ethyl)-piperazin-1- ylmethyl]- pyrimidine-2- carbonitrile
##STR112## 394 (300 MHz, CDCl.sub.3): 8.50(d, 2H), 7.89(s, 1H),
7.83(t, 1H), 7.13 (d, 2H), 3.45(s, 2H), 3.31(d, 2H), 2.78(m, 2H),
2.65-2.40(m, 10H), 0.99(s, 9H). I-83 4-(2,2-Dimethyl-
propylamino)-5-[4- (2-pyridin-2-yl- ethyl)-piperazin-1- ylmethyl]-
pyrimidine-2- carbonitrile ##STR113## 394 (300 MHz, CDCl.sub.3):
8.50(d, 1H), 7.88(s t, 2H), 7.59(t, 1H), 7.19-7.10(m, 2H), 3.45(s,
2H), 3.31(d, 2H), 2.95(m, 2H), 2.78 (m, 2H), 2.60-2.41 (m, broad,
8H), 0.99(s, 9H). I-84 4-(2,2-Dimethyl- propylamino)-5-(4-
pyridin-4-ylmethyl- piperazin-1- ylmethyl)- pyrimidine-2-
carbonitrile ##STR114## 380 (300 MHz, CDCl.sub.3): 8.53(d, 2H),
7.89 s, 1H), 7.84(t, 1H), 7.27 (d, 2H), 3.52(s, 2H), 3.46(s, 2H),
3.30(d, 2H), 2.60-2.40(m, broad, 8H), 0.99(s, 9H). I-85
4-(2,2-Dimethyl- propylamino)-5-[4- (2-piperidin-1-yl-
ethyl)-piperazin-1- ylmethyl]- pyrimidine-2- carbonitrile
##STR115## 400 (300 MHz, CDCl.sub.3): 7.85(s & t, 2H), 3.44 (s,
2H), 3.30(d, 2H), 2.60-2.38(m, 16H), 1.60(m, 4H), 1.45(m, 2H),
0.99(s, 9H). I-86 4-(2,2-Dimethyl- propylamino)-5-[4-
(2-pyrrolidin-1-yl- ethyl)-piperazin-1- ylmethyl]- pyrimidine-2-
carbonitrile ##STR116## 386 (300 MHz, CDCl.sub.3): 7.86(s & t,
2H), 3.44 (s, 2H), 3.31(d, 2H), 2.70-2.40(m, 16H), 1.82(m, 4H),
1.00(s, 9H). I-87 Diethylamino- ethyl)-piperazin-1-
ylmethyl]-4-(2,2- dimethyl- propylamino)- pyrimidine-2-
carbonitrile ##STR117## 388 (300 MHz, CDCl.sub.3): 7.89(s & t,
2H), 3.44 (s, 2H), 3.31(d,2H), 2.64-2.42(m, 16H), 1.06(t,6H),
1.00(s, 9H). I-88 Diethylamino- propyl)-piperazin-1-
ylmethyl]-4-(2,2- dimethyl- propylamnino)- pyrimidine-2-
carbonitrile ##STR118## 402 (300 MHz, CDCl.sub.3): 7.89(s & t,
2H), 3.44 (s, 2H), 3.30(d, 2H), 2.60-2.32(m, 16H), 1.67(m, 2H),
1.06(t, 6H), 1.00(s, 9H). I-89 4-(2,2-Dimethyl- propylamino)-5-[4-
(1-methyl-piperidin- 4-yl)-piperazin-1- ylmethyl]- pyrimidine-2-
carbonitrile ##STR119## 386 (300 MHz, CDCl.sub.3): 7.92(t, 1H),
7.89(s, 1H), 3.44(s, 2H), 3.29 (d, 2H), 2.95(d, broad, 2H),
2.64-2.41(m, broad, 8H), 2.29(s, 3H), 2.25(m, 2H), 2.20 1.59(m,
5H), 0.99(s, 9H). I-90 4-(2,2-Dimethyl- propylamino)-5-(4-
pyrrolidin-1-yl- piperidin-1- ylmethyl)- pyrimidine-2- carbonitrile
##STR120## 357 (300 MHz, CDCl.sub.3): 7.96(t, 1H), 7.85(s, 1H),
3.44(s, 2H), 3.29 (d, 2H), 2.85(d, broad, 2H), 2.60(m, broad, 4H),
2.05(m, 3H), 1.99-1.50(m, 8H), 0.98(s, 9H). I-91 4-(2,2-Dimethyl-
propylamino)-5-[4- (2-methoxy-ethyl)- piperazin-1- ylmethyl]-
pyrimidine-2- carbonitrile ##STR121## 347 (300 MHz, CDCl.sub.3):
7.87(s & t, 2H), 3.50 (t, 2H), 3.45(s, 2H), 3.34(s, 3H),
3.30(d, 2H), 2.62-2.48(m, broad, 10H), 1.00(s, 9H).
[0115] Example II describes the preparation of 5-amido
substituted-pyrimidine-2-carbonitriles
Example II-1
2-Cyano-4-(2,2-dimethyl-propylamino)-pyrimidine-5-carboxylic acid
4-methoxy-benzylamide
[0116] ##STR122##
A.
2-Chloro-4-(2,2-dimethyl-propylamino)-pyrimidine-5-carbaldehyde
[0117] ##STR123##
[0118] To a solution of
(5-bromo-2-chloro-pyrimidin-4-yl)-(2,2-dimethyl-propyl)-amine (30
g, 108 mmol) in THF (500 ml) is added n-butyllithium (1.6 mol/l in
n-hexane, 148 ml, 237 mmol) dropwise at -78.degree. C. and the
mixture is stirred for 10 min. Ethylformate (19 ml, 230 mol) is
added dropwise to the mixture at -78.degree. C., and the reaction
mixture is allowed to warm to ambient temperature. After being
stirred for 1 hour, the reaction mixture is quenched with saturated
NH.sub.4Cl at -78.degree. C. and then extracted with AcOEt. The
combined extracts are washed with water, brine, dried over
MgSO.sub.4 and concentrated under reduced pressure. The residue is
purified by silica gel column chromatography
(eluent:n-hexane:AcOEt=4:1) give
2-chloro-4-(2,2-dimethyl-propylamino)-pyrimidine-5-carbaldehyde.
Rf=0.56 (n-hexane:AcOEt=1:1). .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 1.00 (s, 9H), 3.41 (d, 2H), 8.40 (s, 1H), 8.88 (brs, 1H),
9.84 (s, 1H).
B. 2-Chloro-4-(2,2-dimethyl-propylamino)-pyrimidine-5-carboxylic
acid 4-methoxy-benzylamide
[0119] ##STR124##
[0120] To a solution of
2-chloro-4-(2,2-dimethyl-propylamino)-pyrimidine-5-carbaldehyde
(1.2 g, 5.27 mmol) in THF (20 ml) is added sulfamic acid (0.819 g,
8.4 mmol) at ambient temperature. To the mixture, sodium chlorite
(1.43 g, 15.8 mmol) in water (10 ml) is added dropwise at 0.degree.
C. and the reaction mixture is allowed to warm to ambient
temperature. After being stirred for 30 min. at ambient
temperature, the reaction mixture is diluted with water and
extracted with CH.sub.2Cl.sub.2. The combined extracts are washed
with water, brine, dried over MgSO.sub.4 and concentrated under
reduced pressure to afford crude acid (1.17 g). To a solution of
the crude acid (0.5 g, 2.05 mmol) in CH.sub.2Cl.sub.2 (10 ml) are
added oxalyl chloride (0.36 ml, 4.1 mmol) and catalytic amount of
DMF successively at 0.degree. C., and the mixture is allowed to
warm to ambient temperature. After being stirred for 1 hour at
ambient temperature, the mixture is transferred to a solution of
p-methoxybenzylamine (2.25 g, 16.7 mmol) in THF (30 ml) at
-10.degree. C.--20.degree. C. and the reaction mixture is stirred
for 1 hour. The reaction mixture is quenched with cold water and
extracted with CH.sub.2Cl.sub.2. The combined extracts are washed
with water, brine, dried over MgSO.sub.4 and concentrated under
reduced pressure. The residue is purified by silica gel column
chromatography (eluent:n-hexane:AcOEt=2:1) give
2-chloro-4-(2,2-dimethyl-propylamino)-pyrimidine-5-carboxylic acid
4-methoxy-benzylamide. Rf=0.38 (n-hexane:AcOEt=2:1). .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 1.01 (s, 9H), 3.35 (d, 2H), 3.81
(s, 3H), 4.52 (d, 2H), 6.23 (brs, 1H), 6.90 (d, 2H), 7.25 (d, 2H),
8.15 (s, 1H), 9.09 (brs, 1H).
C. 2-Cyano-4-(2,2-dimethyl-propylamino)-pyrimidine-5-carboxylic
acid 4-methoxy-benzylamide
[0121] ##STR125##
[0122] To a solution of NaCN (95 mg, 1.9 mmol) in water (1 ml) and
DMSO (10 ml) are added 1,4-diazabicyclo[2,2,2]octane (48 mg, 0.43
mmol) and
2-chloro-4-(2,2-dimethyl-propylamino)-pyrimidine-5-carboxylic acid
4-methoxy-benzylamide (470 mg, 1.3 mmol) in DMSO (2 ml)
successively at ambient temperature. After being stirred for 2
hours at 50.degree. C., the reaction mixture is poured into cold
water and extracted with AcOEt. The combined extracts are washed
with water, brine and dried over MgSO.sub.4. The concentrated
residue is purified by silica gel column chromatography
(eluent:n-hexane:AcOEt=2:1) give
2-cyano-4-(2,2-dimethyl-propylamino)pyrimidine-5-carboxylic acid
4-methoxy-benzylamide. Rf=0.45 (n-hexane:AcOEt=2:1). .sup.1H NMR
(400 MHz, DMSO-d.sub.4) .delta. 1.00 (s, 9H), 3.37 (d, 2H), 3.81
(s, 3H), 4.53 (d, 2H), 6.36 (brs, 1H), 6.89 (d, 2H), 7.25 (d, 2H),
8.28 (s, 1H), 9.08 (brs, 1H).
II-2
2-Cyano-4-(2,2-dimethyl-propylamino)-pyrimidine-5-carboxylic acid
(5-methyl-2-phenyl-2.H.-pyrazol-3-yl)-amide
[0123] ##STR126##
A. 2-Chloro-4-(2,2-dimethyl-propylamino)-pyrimidine-5-carboxylic
acid
[0124] ##STR127##
[0125] To a solution of 2,4-Dichloro-pyrimidine-5-carboxylic acid
(1.04 g, 5.39 mmol) and triethylamine (1.65 ml, 11.9 mmol) in DMSO
(10 ml) is added neopentylamine (0.517 g, 5.93 mmol) at ambient
temperature under N.sub.2 atmosphere. After being stirred at
80.degree. C. for 3 hours, the reaction mixture is diluted with
cold water (50 ml) and 1 N aqueous hydrochloric acid (7.0 ml), and
extracted with CH.sub.2Cl.sub.2. The extract is washed with brine,
dried over MgSO.sub.4 and concentrated under reduced pressure to
give the crude product. Rf=0.27 (AcOEt:MeOH=10:1). .sup.1H NMR(400
MHz, DMSO-d.sub.6) .delta. 0.93(s, 9H), 3.31(d, 2H), 8.58(s, 1H),
8.77(br, 1H).
B. 2-Cyano-4-(2,2-dimethyl-propylamino)-pyrimidine-5-carboxylic
acid
[0126] ##STR128##
[0127] To a solution of NaCN (332 mg, 6.78 mmol) in water (2 ml)
and DMSO (8 ml) are added 1,4-diazabicyclo[2,2,2]octane (658 mg,
5.87 mmol) and
2-chloro-4-(2,2-dimethyl-propylamino)-pyrimidine-5-carboxylic acid
(1.10 g, 4.52 mmol) successively at ambient temperature. After
being stirred for 1 hours at 70.degree. C., the reaction mixture is
diluted with cold water (50 ml) and 1 N aqueous hydrochloric acid
(11.7 ml), and extracted with CH.sub.2Cl.sub.2. The extract is
washed with brine, dried over MgSO.sub.4 and concentrated under
reduced pressure to give the crude product. Rf=0.22
(AcOEt:MeOH=10:1). .sup.1H NMR(400 MHz, DMSO-4) .delta. 0.94(s,
9H), 3.34(d, 2H), 8.73(s, 1H), 8.94(br, 1H).
C. 2-Cyano-4-(2,2-dimethyl-propylamino)-pyrimidine-5-carboxylic
acid (5-methyl-2-phenyl-2H-pyrazol-3-yl)-amide
[0128] ##STR129##
[0129] To a solution of
2-Cyano-4-(2,2-dimethyl-propylamino)-pyrimidine-5-carboxylic acid
(150 mg, 0.640 mmol), 5-Methyl-2-phenyl-2H-pyrazol-3-ylamine (211
mg, 1.28 mmol) and 1-hydroxybenzotriazole(147 mg, 1.28 mmol) in DMF
(5 ml) is added 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (199
mg, 1.28 mmol) at ambient temperature. After being stirred for 15
hours at ambient temperature, the reaction mixture is diluted with
ethyl acetate, washed with saturated NaHCO.sub.3, dried over
MgSO.sub.4 and concentrated. The crude product is purified by
reverse-phase HPLC to give the product. Rf=0.44 (n-hexane:
AcOEt=1:1). .sup.1H NMR(400 MHz, CDCl.sub.3) .delta. 0.98(s, 9H),
2.33(s, 3H), 3.37(d, 2H), 6.55(s, 1H), 7.41-7.53(m, 5H), 8.24(s,
1H), 9.01(br, 1H).
[0130] By repeating the procedures described above using
appropriate starting materials and conditions the following
compounds of formula XI are obtained as identified below in Table
2. TABLE-US-00003 TABLE 2 XI ##STR130## Example No. ##STR131##
Yield (%) Rf(solvent) .sup.1H NMR(400 MHz, .delta.) II-3 ##STR132##
56 0.63 (n-hexane:AcOEt = 1:1) (CDCl.sub.3) 1.00(s, 9H), 3.37(d,
2H), 4.57(d, 2H), 6.61(br, 1H), 7.27(d, 2H), 7.33(d, 2H), 8.32(s,
1H), 9.05(br, 1H) II-4 ##STR133## 47 0.54 (n-hexane:AcOEt = 1:1)
(CDCl.sub.3) 1.00(s, 9H), 2.95(s, 6H), 3.36(d, 2H), 4.47(d, 2H),
6.37(br, 1H), 6.70(d, 2H), 7.19(d, 2H), 8.25(s, 1H), 9.11(br, 1H)
II-5 ##STR134## 27 0.64 (n-hexane:AcOEt = 1:1) (CDCl.sub.3) 1.00(s,
9H), 3.38(d, 2H), 4.61(d, 2H), 6.38(br, 1H), 7.32-7.38(m, 5H),
8.30(s, 1H), 9.07(br, 1H) II-2 ##STR135## 34 0.44 (n-hexane:AcOEt =
1:1) (CDCl.sub.3) 0.98(s, 9H), 2.33(s, 3H), 3.37(d, 2H), 6.55(s,
1H), 7.41-7.53(m,5H), 8.24(s, 1H), 9.01(br, 1H) II-6 ##STR136## 27
0.40 (n-hexane:AcOEt = 1:1) (CDCl.sub.3) 0.99(s, 9H), 3.39(d, 2H),
6.77(d, 1H), 7.47-7.58(m, 5H), 7.68(d, 1H), 8.24(s, 1H), 8.97(br,
1H) II-7 ##STR137## 26 0.73 (n-hexane:AcOEt = 1:1) (CDCl.sub.3)
1.00(s, 9H), 3.38(d, 2H), 7.28-7.54(m, 8H), 7.86(brs, 1H), 7.91(s,
1H), 8.31(d, 1H), 9.05(br, 1H) II-8 ##STR138## 22 0.67
(n-hexane:AcOEt = 1:1) (CDCl.sub.3) 1.00(s, 9H), 3.38(d, 2H),
6.47-6.49(m, 2H), 6.81-6.82(m, 2H), 7.26-7.29(m, 1H), 7.40-7.43(m,
1H), 7.45-7.49(m, 1H), 7.59(brs, 8.42(d, 1H), 9.05(br, 1H) II-9
##STR139## 22 0.46 (n-bexane:AcOEt = 1:1) (CDCl.sub.3) 0.97(s, 9H),
2.32(s, 3H), 3.37(d, 2H), 6.46(s, 1H), 7.38(d, 2H), 7.44(d, 2H),
8.32(s, 1H), 8.93(br, 1H) II-10 ##STR140## 23 0.37 (n-hexane:AcOEt
= 1:1) (CDCl.sub.3) 0.98(s, 9H), 2.31(s, 3H), 3.37(d, 2H), 6.48(s,
1H), 7.30-7.42(m, 3H), 7.49(m, 1H), 8.31(s, 1H), 8.91(br, 1H) II-11
##STR141## 10 0.50 (n-hexane:AcOEt = 1:1) (CDCl.sub.3) 0.97(s, 9H),
2.34(s, 3H), 3.35(d, 2H), 6.48(s, 1H), 7.38-7.45(m, 2H), 7.56(m,
1H), 7.83(br, 1H), 8.27(s, 1H), 8.81(br, 1H). MS (ES+) Ex. R (M +
H).sup.+ .sup.1H-NMR II-12 2-Cyano-4-(2,2-dimethyl-
propylamino)-pyrimidine-5- carboxylic acid[2-(4-methoxy-
phenyl)-1,1-dimethyl-ethyl]-amide ##STR142## 396 (300 MHz,
CDCl.sub.3): 8.92(t, 1H), 8.21(s, 1H), 7.03(d, 2H), 6.82(d, 2H),
5.67(s, 1H), 3.79(s, 3H), 3.38(d, 2H), 3.22 (s, 2H), 1.45(s, 6H),
1.00 (s, 9H). II-13 2-Cyano-4-(2,2-dimethyl-
propylamino)-pyrimidine-5- carboxylic acid {1,1-dimethyl-2-
[3-(4-methyl-piperazin-1-yl)- phenyl]-ethyl}-amide ##STR143## 464
(300 MHz, CDCl.sub.3): 8.97(t, 1H), 8.20(s, 1H), 7.40(s, 1H),
7.18(t, 1H), 6.80(m, 1H), 6.68-6.60 (m, 2H), 3.37(d, 2H), 3.16(m,
4H), 3.02(s, 2H), 2.58(m, 4H), 2.39 (s, 3H), 1.48(s, 6H), 1.00 (s,
9H). II-14 2-Cyano-4-(2,2-dimethyl- propylamino)-pyrimidine-5-
carboxylic acid {1,1-dimethyl-2- [4-(4-methyl-piperazin-1-yl)-
phenyl]-ethyl}-amide ##STR144## 464 (300 MHz, CDCl.sub.3): 8.92(t,
1H), 8.04(s, 1H), 7.02(d, 2H), 6.84(d, 2H), 5.71(s, 1H), 3.38 (d,
2H), 3.20(m, 4H), 2.98(s, 2H), 2.60(m, 4H), 2.36(s, 3H), 1.45(s,
6H), 1.00(s, 9H). II-15 2-Cyano-4-(2,2-dimethyl-
propylamino)-pyrimidine-5- carboxylic acid {1,1-dimethyl-2-
[3(2-pyrrolidin-1-yl-ethylamino)- phenyl]-ethyl)-amide ##STR145##
478 (300 MHz, CDCl.sub.3): 8.95(t, 1H), 8.05(s, 1H), 7.10(t, 1H),
6.54-6.40 (m, 3H), 5.93(s, 1H), 3.37(d, 2H), 3.18(t, 2H), 2.94(s,
2H), 2.80(t, 2H), 2.65(m, 4H), 1.84(m, 4H), 1.49(s, 6H), 1.00(s,
9H). II-16 2-Cyano-4-(2,2-dimethyl- propylamino)-pyrimidine-5-
carboxylic acid(2-{3-[4-(2- ethoxy-ethyl)-piperazin-1-yl]-
phenyl}-1,1-dimethyl-ethyl)-amide ##STR146## 522 (300 MHz,
CDCl.sub.3): 8.96(t, 1H), 8.20(s, 1H), 7.16(t, 1H), 6.80(m, 1H),
6.65-6.58(m, 2H), 5.80(s, 1H), 3.60(t, 2H), 3.52(q, 2H), 3.35(d,
2H), 3.13(m, 4H), 3.01 (s, 2H), 2.65(m, 6H), 1.47(s, 3H), 120(t,
3H), 1.00(s, 9H). II-17 2-Cyano-4-(2,2-dimethyl-
propylamino)-pyrimidine-5- carboxylic acid [2-(4-
difluoromethoxy-phenyl)-ethyl]- amide ##STR147## 404 (300 MHz,
CDCl.sub.3): 9.00(t, 1H), 8.18(s, 1H), 7.21(d, 2H), 7.08(d, 2H),
6.14(t, 1H), 3.68 (m, 2H), 3.36(d, 2H), 2.93(t, 2H), 1.00(s, 9H).
II-18 2-Cyano-4-(2,2-dimethyl- propylamino)-pyrimidine-5-
carboxylic acid {2-[3-(4-methyl- piperazin-1-yl)-phenyl]-ethyl}-
amide ##STR148## 436 (400 MHz, DMSO-d.sub.6): 9.28(t, 1H), 8.92(t,
1H), 7.21(t, 1H), 6.78(s, 1H), 6.76(d, 1H),6.64(d, 1H), 3.49(q,
2H), 3.30(d, 2H), 3.11(m, 4H), 2.78 (t, 2H), 2.48(m, 4H), 2.22(s,
3H), 0.98(s, 9H).
* * * * *