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Details for Patent: 7,956,053

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Details for Patent: 7,956,053

Title:Inhibitors of tyrosine kinases
Abstract: The invention relates to compounds of formula ##STR00001## wherein the substituents R1, R2 and R4 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, especially a neoplastic disease, in particular leukaemia, and a method for the treatment of such a disease.
Inventor(s): Breitenstein; Werner (Basel, CH), Furet; Pascal (Thann, FR), Jacob; Sandra (Rantzwiller, FR), Manley; Paul W (Arlesheim, CH)
Assignee: Novartis AG (Basel, CH)
Filing Date:Jun 22, 2009
Application Number:12/489,049
Claims:1. A compound of formula ##STR00004## wherein R.sub.1 represents hydrogen, lower alkyl, lower alkoxy-lower alkyl, acyloxy-lower alkyl, carboxy-lower alkyl, lower alkoxycarbonyl-lower alkyl, or phenyl-lower alkyl; R.sub.2 represents lower alkyl substituted by one or more identical or different radicals R.sub.3, cycloalkyl, benocycloalkyl, heterocyclyl, or a mono- or bicyclic heteroaryl group comprising zero, one, two or three ring nitrogen atoms and zero or one oxygen atom and zero or one sulfur atom, which groups in each case are unsubstituted or mono- or polysubstituted; and R.sub.3 represents hydroxy, lower alkoxy, acyloxy, carboxy, lower alkoxycarbonyl, carbamoyl, N-mono- or N,N-disubstituted carbamoyl, phenylamino, N-lower alkyl-N-phenylamino, cycloalkyl, heterocyclyl, an aryl group, or a mono- or bicyclic heteroaryl group comprising zero, one, two or three ring nitrogen atoms and zero or one oxygen atom and zero or one sulfur atom, which groups in each case are unsubstituted or mono- or polysubstituted; R.sub.4 represents hydrogen, lower alkyl, or halogen; or a N-oxide or a pharmaceutically acceptable salt thereof.

2. A compound of formula I according to claim 1 wherein R.sub.1 represents hydrogen, lower alkyl, lower alkoxy-lower alkyl, acyloxy-lower alkyl, carboxy-lower alkyl; lower alkokycarbonyl-lower alkyl, or phenyl-lower alkyl; R.sub.2 represents lower alkyl substituted by one or two identical or different radicals R.sub.3, cycloalkyl, benzcycloalkyl, heterocyclyl, or a mono- or bicyclic heteroaryl group comprising one, two or three nitrogen atoms or one sulfur atom, which aryl and heteroaryl groups in each case are unsubstituted or mono- or polysubstituted; and R.sub.3 represents hydroxy, lower alkoxy, acyloxy, carboxy, lower alkoxycarbonyl, carbamoyl; N-mono- or N,N-disubstituted carbamoyl, cycloalkyl, heterocyclyl, an aryl group; or a mono- or bicyclic heteroaryl group comprising one, two or three ring nitrogen atoms, zero or one ring oxygen atom and zero or one ring sulphur atom, which aryl and heteroaryl groups in each case are unsubstituted or mono- or polysubstituted; R.sub.4 represents hydrogen, lower alkyl, or halogen; or a N-oxide or a pharmaceutically acceptable salt thereof.

3. A compound, of formula I according to claim 1 wherein R.sub.1 represents hydrogen, lower alkyl, lower alkoxy-lower alkyl, lower alkoxycarbonyl-lower alkyl, or phenyl-lower alkyl; R.sub.2 represents lower alkyl substituted by one or two identical or different radicals R.sub.3, cyclopentyl, benzyclopentyl, cyclohexyl, pyrrolidinyl, piperidinyl, N-substituted piperidinyl, morpholinyl, azepinyl, oxo-azepinyl, oxazepinyl, or a mono- or bicyclic heteroaryl group comprising one or two nitrogen atoms, wherein the heteroaryl group is a unsubstituted or mono- or polysubstituted, thienyl, or lower alkoxycarbonyl-lower alkylthienyl; and R.sub.3 represents hydroxy; lower alkoxy, acyloxy, carboxy, lower alkoxycarbonyl, carbamoyl, N-mono- or N,N-disubstituted carbamoyl, phenylamino, N-lower alkyl-N-phenylamino, pyrrolidino, oxopyrrolidino, piperidino, morpholino, imidazolino, oxoimidazolino, cycloalkyl, heterocyclyl, furyl, phenyl, naphthalinyl, tetrahydronaphthalenyl, or a mono- or bicyclic heteroaryl group comprising one or two nitrogen atoms, which phenyl, naphthalinyl and heteroaryl group are unsubstituted or mono- or polysubstituted; or wherein R.sub.4 represents hydrogen, lower alkyl, or halogen; or a N-oxide or a pharmaceutically acceptable salt thereof.

4. A compound of formula I according to claim 1 wherein R.sub.1 represents hydrogen, lower alkyl, lower alkoxy-lower alkyl, lower alkoxycarbonyl-lower alkyl or phenyl-lower alkyl; R.sub.2 represents lower alkyl substituted by one radical R.sub.3, by two phenyl groups, by two lower alkoxycarbonyl groups, by lower alkoxycarbonyl, or by hydroxyphenyl and lower alkoxycarbonyl; cyclopentyl; benzcyclopentyl; cyclohexyl; pyrrolidinyl; oxazolinyl; piperidinyl; N-lower alkylpiperidinyl; N-benzoylpiperidinyl; N-pyrimidinylpiperidinyl; morpholinyl; azepinyl; oxo-azepinyl; oxazepinyl; or a mono- or bicyclic heteroaryl group comprising one or two nitrogen atoms, wherein the heteroaryl group is unsubstituted or substituted by one or two substituents selected from the group consisting of lower alkyl, trifluoro-lower alkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl, amino-lower alkyl, lower alkylamino-lower alkyl, di-lower alkylamino-lower alkyl, N-cyclohexyl-N-lower alkylamino-lower alkyl, lower alkoxycarbonylpiperidino-lower alkyl, N-lower alkylpiperazino-lower alkyl, lower alkoxycarbonyl-lower alkyl, hydroxy, lower alkoxy, trifluoro-lower alkoxy, 1H-imidazolyl-lower alkoxy, lower alkanoyloxy, benzoyloxy, carboxy, lower alkoxycarbonyl, carbamoyl, lower alkyl carbamoyl, amino, lower alkanoylamino, benzoylamino, amino mono- or disubstituted by lower alkyl, by hydroxy-lower alkyl or by lower alkoxy-lower alkyl, 1H-imidazolyl, mono or di-lower alkyl-1H-imidazolyl, pyrrolidino, piperidino, piperazino, N-lower alkylpiperazino, morpholino, sulfamoyl, lower alkylsulfonyl, phenylsulfonyl, lower alkylsulfinyl, phenylsulfinyl, lower alkylthio, phenylthio, phenyl, pyridyl, halogenyl, or benzoyl, thienyl, or lower alkoxycarbonyl lower alkylthienyl, and R.sub.3 represents hydroxy, lower alkoxy, acyloxy, carboxy, lower alkoxycarbonyl, carbamoyl, carbamoyl mono- or disubstituted by lower alkyl, phenyl or lower alkylene, phenylamino, N-lower alkyl-N-phenylamino, pyrrolidino, oxopyrrolidino, piperidino, morpholino, imidazolino, oxoimidazolino, cycloalkyl, heterocycyl, furyl, phenyl, naphthalinyl, tetrahydroaphthalinyl, or a mono- or bicyclic heteroaryl group comprising one or two nitrogens atoms, which phenyl, naphthalinyl and heteroaryl group is unsubstituted or substituted by one or two substitutents selected from the group consisting of lower alkyl, influro-lower alkyl, lower alkoxycarbonyl-lower alkyl, hydroxy, lower alkoxy, trifluoro-lower alkoxy, lower alkanoyloxy, benzoyloxy, carboxy, lower alkoxycarbonyl, carbamoyl, amino, lower alkanoylamino, benzoylamino, amino mono- or disubstituted by lower alkyl, by hydroxy-lower alkyl or by lower alkoxy-lower alkyl, pyrrolidino, piperidino, morpholino, piperazino, N-lower alkylpiperazino, N-lower alkoxycarbonylpiperazino, phenyl, pyridyl, 1H-imidazolyl, lower alkyl-1H-imidazolyl, sulfamoyl, lower alkylsulfonyl, phenylsulfonyl, lower alkylsulfinyl, phenylsulfinyl, lower alkylthio, phenylthio, halogenyl, or benzoyl; R.sub.4 represents hydrogen or lower alkyl; or a N-oxide or a pharmaceutically acceptable salt thereof.

5. A compound of formula I according to claim 1 wherein R.sub.1 represents hydrogen, lower alkyl, lower alkoxy-lower alkyl, or benzyl; R.sub.2 represents lower alkyl substituted by one radical R.sub.3, by two phenyl groups, by two lower alkoxycarbonyl groups, by lower alkoxycarbonyl, or by hydroxyphenyl and lower alkoxycarbonyl; cyclopentyl; benzcyclopentyl; cyclohexyl; pyrrolidinyl; piperidinyl; N-lower alkylpiperidinyl; N-benzoylpiperidinyl; N-pyrrnidinylpiperindinyl; morpholinyl; azepinyl; oxoazepinyl; pyridyl; lower alkyl-pyridinyl; quinolinyl; thienyl; lower alkoxycarbonylmethyltheinyl; and R.sub.3 represents hydroxy, lower alkoxy, lower alkanoyloxy, benzoyloxy, carboxy, lower alkoxycarbonyl, carbamoyl, phenylamino, N-lower alkyl-N-phenylamino, pyrrolidine, oxopyrrolidino, piperidino, morpholino, imidazolino, oxoimidazolino, cyclopropyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, phenyl, naphthalinyl, tetrahydronaphthalenyl, furyl, a mono- or bicyclic heteroaryl group comprising one or two nitrogen atoms, which heteroaryl group is unsubstituted or mono- or disubstituted by lower alkyl hydroxy and lower alkoxy, or phenyl substituted by one or two substitutents selected from the group consisting of lower alkyl, trifluoro-lower alkyl, lower alkoxycarbonyl-lower alkyl, hydroxy, lower alkoxy, trifluoro-lower alkoxy, lower alkanoyloxy, benzoyloxy, carboxy, lower alkoxycarbonyl, carbamoyl, amino, lower alkanoylamino, benzoylamino, amino mono- or disubstituted by lower alkyl, by hydroxy-lower alkyl or by lower alkoxy-lower alkyl, pyrrolidino, piperidino, morpholino, piperazino, N-lower alkylpiperazino, N-lower alkoxycarbonylpiperazino, phenyl, pyridyl, 1H-imidazolyl, lower alkyl-1H-imidazolyl, sulfamoyl, lower alkylsulfonyl, halogenyl, or benzoyl; R.sub.4 represents hydrogen or methyl; or a N-oxide or a pharmaceutically acceptable salt thereof.

6. A pharmaceutical composition comprising as an active ingredient a compound of formula I according to claim 1 or a N-oxide or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier.

7. A method for the treatment of leukaemia which comprises administering a compound of formula I according to claim 1 or a N-oxide or a pharmaceutically acceptable salt thereof.
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