SCHEDULE OF ADMINISTRATION OF BENZAZOLE DERIVATIVES

IN THE TREATMENT OF LEUKEMIAS

Field of the invention

The present invention relates to pharmaceutical compositions comprising a compound of the general formula (I) or a salt or a stereoisomer thereof, for the use as a medicament, wherein 0.1 to 20 mg/kg, preferably 0.5 to 10 mg/kg, more preferably 1 to 3 mg/kg of the compound are administered from once every week to once every three weeks, preferably once every two weeks The compounds of the invention are exceptionally useful for the treatment of acute myelogenous leukemia (AML), also called acute myeloid leukemia, acute myeloblasts leukemia, and acute nonlymphocytic leukemia (ANLL), and lymphomas.

Description of Related Art

In WO2006069740 benzazoles as protein kinase inhibitors are disclosed. In WO2006069740 various routes of administration are disclosed. Doses vary from rates of about 1 to 100 mg/kg animal body weight preferably 1 to 50 mg kg. Described suitable dosage rates for larger mammals, for example humans, are of the order of from about 10 mg to 3 g day, conveniently administered once, in divided doses 2 to 4 times a day, or in sustained release form. Except for daily dosing and sustained release from no other dosing schedules are disclosed. There is a need to provide protein kinase inhibitors with improved properties.

According to the present invention dosing schedules of compounds are provided, that are surprisingly less toxic and more efficient in the treatment of cancer, especially AML. As demonstrated in a number of mouse xenograft studies, compounds of the present invention surprisingly display greatest efficacy when administered only once every two weeks as an intravenous slow bolus injection. On top of exhibiting maximum efficacy, surprisingly the same dosing schedule was also best tolerated by the animals. Description of the Invention

A pharmaceutical composition comprising a compound of the general formula (I) or a salt or a stereoisomer thereof, for the use as a medicament, wherein the compound is administered not more often than once a week,

formula (I) wherein

X independently represents S, or O;

R ¹ independently represents a hetero aromatic five-membered ring containing 1 to 4 heteroatoms selected from N, S, or O, optionally substituted by one to three substituents independently from each other selected from the group comprising halogen, CF ₃ , CHF ₂ , C¾F, OCF ₃ , COR ⁶ , COOH, COOR ⁶ , S0 ₃ H, SOR ⁶ , S0 ₂ R ⁶ , cyano, hydroxy, amino, nitro, alkoxy, alkylamino, alkyl, ethynyl, alkoxy, and haloalkoxy;

R ² independently represents H, -COR ⁶ , -C0 ₂ R ⁶ , -SOR ⁶ , -S0 ₂ R ⁶ , -S0 ₃ R ⁶ , -N0 ₂ , -CN, -CF ₃ , -OCH ₃ , -OCF ₃ , alkyl, cycloalkyl, alkoxy, NH ₂ , alkylamino, -NR ⁷ C0R ⁶ , halogen, -OH, -SH, alkylthio, haloalkyl, or haloalkyloxy;

R ⁶ independently represents H, alkyl, cycloalkyl, -NR ⁷ R ⁸ , alkylamino, arylamino, aryl or heteroaryl;

R ⁷ independently represents H, alkyl, cycloalkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl or heteroaryl;

R independently represents H, alkyl, cycloalkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl or heteroaryl;

R independently represents H, halogen, nitro, trifluoromethyl, alkyl, alkoxy, or -NR ⁷ R ⁸ (R ⁷ and R ⁸ being as defined above); and R ⁵ are independently selected from hydrogen, halogen, alkyl, cyano, nitro, trifluoromethyl, -NR R (R and R being as defined above), or -ELR , wherein E represents a direct bond, -0-, -CO-, -S-, -SO-, -S0 ₂ -, -NR ⁷ CO-, -CONR ⁷ -,

-S0 ₂ NR ⁷ -, -NR ⁷ S0 ₂ - or -NR ⁷ - (R ⁷ being as defined above),

L is absent or represents a divalent linkage group selected from alkylene, cycloalkylene, heterocyclylene, wherein one or more of the (-CH ₂ -)-groups may be replaced by an oxygen, S, SO, S0 ₂ , or a NR ⁶ (R ⁶ being as defined above), and wherein one or more carbon atoms may independently carry one or two substituents selected from halogen, hydroxy, alkoxy, haloalkyloxy, hydroxyalkyl, amino, phoshonooxy, or phoshonooxyalkyl, and,

R ⁹ is hydrogen, halogen, hydroxy, alkoxy, haloalkoxy, alkylamino, alkyl, cycloalkyl, haloalkyl, cyano, nitro, or a group selected from formula (II),

formula (I I)

wherein

# indicates the point of attachment to L;

X ^J is CH, N, or O;

R ¹¹ is hydrogen, alkyl, cycloalkyl, heterocyclyl, or X ¹ together with R ^{1 1} and R ¹² form a 3- to 10-membered mono- or bi cyclic, saturated, or unsaturated ring, which may contain heteroatoms like N, O, S, SO, or S0 ₂ and wherein one or more carbon atoms may independently carry one or two substituents independently selected from R ¹³ and each of the nitrogen atoms may independently carry a substituent 1 ⁴ ;

R ⁵² is absent, or independently represents hydrogen, alkyl, cycloalkyl, or heterocyclyl,;

R independently represents halogen, alkoxy, alkyl, cycloalkyl, haloalkyl, or haloalkoxy;

R ¹⁴ independently represents hydrogen, alkyl, or -CO-C¾-OH. in the context of the present invention, an alkyl group, if not stated otherwise, denotes a linear or branched Ci-C ₆ -alkyl, preferably a linear or branched chain of one to five carbon atoms; an alkenyl group, if not stated otherwise, denotes a linear or branched C ₂ -C ₆ -alkenyl; and an alkynyl group, if not stated otherwise, denotes a linear or branched C ₂ -C6-alkynyl group, which may be substituted by one or more substituents

R\

The Ci-Ce-alkyl, C ₂ -C ₆ -alkenyl and C ₂ -C ₆ -alkynyl residue may be selected from the group consisting of -CH ₃ , -C ₂ H ₅ , -CH=CH ₂ , -C≡CH, -C ₃ H ₇ , -CH(CH ₃ ) ₂ , -CH ₂ - CH=CH ₂ , -C(CH ₃ )=CH ₂ , -CH=CH-C¾, -C≡C-CH ₃ , -CH ₂ -C≡CH, -C ₄ H ₉ , -CH ₂ - CH(CH ₃ ) _2j -CH(CH ₃ )-C ₂ H ₅ , -C(CH ₃ ) ₃ , -C ₅ H„, -C ₆ H ₁₃ , -C(R') ₃ , -C ₂ (R') ₅ , -CH ₂ -

C(R% -C ₃ (R') ₇ ,

-C ₂ H ₄ -C(R') ₃ , -C ₂ H ₄ -CH=CH ₂ , -CH=CH-C ₂ H ₅ , -CH=C(CH ₃ ) ₂ , -CH ₂ -CH=CH-CH ₃ , -CH=CH-CH=CH ₂ , -C ₂ H ₄ -C≡CH, -C≡C-C ₂ H ₅ , -CH ₂ -C≡C-CH ₃ , -C≡C-CH=CH ₂ , -CH=CH-C≡CH, -C≡C-C≡CH, -C ₂ H ₄ -CH(CH ₃ ) ₂ , -CH(CH ₃ )-C ₃ H ₇ , -CH ₂ -CH(CH ₃ )- C ₂ H ₅ , -CH(CH ₃ )-CH(CH ₃ ) ₂ , -C(CH ₃ ) ₂ -C ₃ H ₅ , -CH ₂ -C(CH ₃ ) ₃ , -C ₃ H ₆ -CH=CH ₂ ,

-CH=CH-C ₃ H ₇ , -C ₂ H ₄ -CH=CH-CH ₃ , -CH ₂ -CH=CH-C ₂ H ₅ , -CH ₂ -CH=CH-CH=CH ₂ , -CH=CH-CH=CH-CH ₃ , -CH=CH~CH ₂ -CH=CH ₂ , -C(CH ₃ )=CH-CH=CH ₂ ,

-CH=C(CH ₃ )-CH=CH ₂ , -CH=CH-C(CH ₃ )=CH ₂ , -CH ₂ -CH=C(CH ₃ ) ₂ ,

C(CH ₃ )-C(CH ₃ ) ₂ , -C ₃ ¾-C≡CH, -C≡C-C ₃ H ₇ , -C ₂ H ₄ -C≡C-CH ₃ , -CH ₂ -C≡C-C ₂ H ₅ , - CH ₂ -C≡C-CH=CH ₂ , -CH ₂ -CH-CH-C≡CH, -CH ₂ -C≡C-C≡CH, -C≡C-CH=CH-CH ₃ , -

CH=CH-C≡C-CH ₃ ,

-C≡C-C≡C-CH ₃ , -C≡C-CH ₂ -CH=CH ₂ , -CH=CH-CH ₂ -C≡CH, -C≡C-CH ₂ -C≡CH, -C(C¾)=CH-CH=CH ₂ , -CH=C(CH ₃ )-CH-CH ₂ , -CH=CH-C(CH ₃ )=CH ₂ , C(CH ₃ )=CH-C≡CH, -CH=C(CH ₃ )-C≡CH, -C≡C-C(CH ₃ )=CH ₂ , -C ₃ H ₆ -CH(CH ₃ ) _2; - C ₂ H ₄ -CH(CH ₃ )-C ₂ H ₅ , -CH(CH ₃ )-C ₄ H _¾ -CH ₂ -CH(CH ₃ )-C H ₇ , -CH(CH ₃ )-C¾-

CH(CH ₃ ) ₂ , -CH(CH ₃ )-CH(CH ₃ )-C ₂ H ₅ , -CH ₂ -CH(CH ₃ )-CH(C¾) ₂ , -CH ₂ -C(CH ₃ ) ₂ - C ₂ H ₅ , -C(CH ₃ ) ₂ -C ₃ H ₇ , -C(CH ₃ ) ₂ -CH(CH ₃ ) ₂ , -C ₂ H ₄ -C(CH ₃ ) ₃ , -CH(CH ₃ )-C(CH ₃ ) ₃ , - C ₄ ¾-CH-CH ₂ , -CH=CH-C ₄ H ₉ , -C ₃ H ₆ -CH=CH-CH ₃ , -CH ₂ -CH=CH-C ₃ H ₇ , -C ₂ H ₄ - CH=CH-C ₂ H ₅ , -CH ₂ -C(CH ₃ )=C(CH ₃ ) ₂ , -C ₂ H ₄ -CH=C(CH ₃ ) ₂ , -C ¾-C≡CH, -C≡C- C ₄ H ₉ , -C ₃ ¾-C≡C-CH ₃ ,

-CH ₂ -C≡C-C ₃ H ₇ , and -C ₂ H ₄ -C≡C-C ₂ H ₅ ; To keep the definitions as short as possible, in the following paragraphs "alkyl" is to be understood to encompass alkyl, alkenyl and alkynyl.

IT independently represents H, -C0 ₂ R ^" , -CONHR", -CR"0, -SO2NR ^" , -NR ^{¾ ,} -CO- haloalkyl, -N0 ₂ , -NR ^" -S0 ₂ -haloalkyl, -NR ^{, ,} -S0 ₂ -alkyl, -S0 ₂ -alkyl, -NR"-CO-alkyl,

-CN, alkyl, cycloalkyl, aminoalkyl, alkylamino, alkoxy, -OH, -SH, alkylthio, hydroxyalkyl, hydroxyalkylamino, halogen, haloalkyl, haloalkoxy, aryl, arylalkyl or heteroaryl; R ^" independently represents H, haloalkyl, hydroxyalkyl, alkyl, cycloalkyl, aryl, heteroaryl or aminoalkyl; an alkylene group denotes a divalent linear or branched Cj-C ₆ -alkylene, preferably a linear or branched chain of one to five carbon atoms, a linear or branched C ₂ -C6- alkenylene or a linear or branched C ₂ -C ₆ -alkynylene group, which may be substituted by one or more substituents R'; a cycloalkylene group denotes a divalent non-aromatic ring system containing three to eight carbon atoms, preferably four to eight carbon atoms, wherein one or more of the carbon atoms in the ring may be replaced by a group E, E being O, S, SO, S0 _2; N, or

NR", R" being as defined above; a heterocyclylene group denotes a 3 to 8-membered divalent heterocyclic non- aromatic group which contains at least one heteroatom selected from O, N, and S, wherein the heterocyclylene group may be fused to another non-aromatic ring and may carry one or more substituents R wherein R ^T is as defined above; an arylene group denotes an aromatic divalent group having five to fifteen carbon atoms, which may carry one or more substituents R", and may be fused to another aromatic ring, where R" is as defined above; a heteroarylene group denotes a divalent 5- or 6-membered heterocyclic group, which contains at least one heteroatom selected from O, N, and S, which may be fused to another aromatic ring, and which may carry one or more substituents R\ wherein R' is as defined above; a cycloalkyl group denotes a non-aromatic ring system containing three to eight carbon atoms, preferably four to eight carbon atoms, wherein one or more of the carbon atoms in the ring may be replaced by a group E, E being O, S, SO, S0 ₂ , N, or NR", R" being as defined above; the C ₃ -C ₈ -cycloalkyl residue may be selected from the group consisting of -cyclo-Cs j, -cyclo-C ₄ H ₇ , -cyclo-C ₅ ]¾, -cyclo-C ₆ Hn, -cyclo- C ₇ Hi3, -cyclo-C ₈ H i5, moφholine-4-yl, piperazinyl, and l -alkylpiperazine-4-yl; an alkoxy group denotes an O-alkyl group, the alkyl group being as defined above; the alkoxy group is preferably a methoxy, ethoxy, isopropoxy, i-butoxy or pentoxy group; an alkylthio group denotes a S-alkyl group, the alkyl group being as defined above; a haloalkyl group denotes an alkyl group which carries as substituents one to five halogen atoms, the alkyl group being as defined above; the haloalkyl group is preferably a -C(R ⁱ⁰ ) ₃ , -CR ⁱ⁰ (R ^10' ) ₂ , -CR ¹⁰ (R ^10' )R ^{l i} , -C ₂ (R ¹⁰ ) _5! -CH ₂ -C(R ¹⁰ ) ₃ , -CH ₂ - CR ^!0 (R ^{1 0} ')2, -CH ₂ -CR ¹⁰ (R ^{, 0'} )R ^10" , -C ₃ (R ¹⁰ ) ₇ , or -C ₂ H ₄ -C(R ^I0 ) _3> wherein R ¹⁰ , R ^10' , R ^10" represent F, CI, Br or 1, preferably F; a hydroxyalkyl group denotes a HO- alkyl group, the alkyl group being as defined above; a haloalkoxy group denotes an alkoxy group which carries one to five halogen atoms, the alkyl group being as defined above; the haloalkoxy group is preferably a -OC(R ¹⁰ ) ₃ , -OCR ¹⁰ (R ^l(r ) ₂ , -OCR ¹⁰ (R ^10, )R ^10" , -OC ₂ (R ^{, 0} ) ₅ , -OCH ₂ -C(R ¹⁰ ) ₃ , -OC¾- CR ¹⁰ (R ^1Q' ) ₂ , -OCH ₂ -CR ¹⁰ (R ^!0' )R ^!0" , -OC ₃ (R ^l0 ) ₇ or -OC ₂ H ₄ -C(R ¹⁰ ) _3, wherein R ¹⁰ , R ^10' , R ¹⁰ represent F, CI, Br or I, preferably F; a hydroxyalkylamino group denotes a (HO-alkyl) ₂ -N- group or HO-alkyl-NH- group, the alkyl group being as defined above; an alkylamino group denotes a HN-alkyl or N-dialkyl group, the alkyl group being as defined above; a halogen group is fluorine, chlorine, bromine, or iodine; an aryl group denotes an aromatic group having five to fifteen carbon atoms, which may carry one or more substituents R\ and may be fused to another aromatic ring, where R' is as defined above; the aryl group is preferably a phenyl group, -o-C ₆ H ₄ - R ^' , -m-C ₆ H4- R\ -p-C ₆ H ₄ - R\ 1-naphthyl, 2-naphfhyl, 1-anthracenyl or 2-anthracenyl; a heteroaryl group denotes a 5- or 6-membered heterocyclic group which contains at least one heteroatom like O, N, S. This heterocyclic group can be fused to another aromatic ring. For example, this group can be selected from a thiadiazole, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, isothiazo!-3-yi, isothiazol-4-yl, isothiazol-5-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isooxazol-3-yl, isooxazol-4-yl, isooxazol-5-yl, 1,2,4- oxadiazol-3-yl, l,2,4-oxadiazol-5-yl, l ,2,5-oxadiazol-3-yl, benzooxazol-2-yl, benzooxazol-4-yl, benzooxazol-5-yl, benzoisooxazol-3-yl, benzoisooxazol-4-yl, benzoisooxazol-5-yl, l,2,5-oxadiazol-4-yl, l,2,4-thiadiazol-3-yl, l ,2,4-thiadiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, benzoisothiazol-3-yl, benzoisothiazol- 4-yl, benzoisothiazol-5-yl, l,2,5-thiadiazol-3-yl, 1-imidazolyl, 2-imidazolyI, 1,2,5- thiadiazol-4~yl. 4-imidazolyl, benzoimidazol-4-yl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2- furanyl, 3-furanyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyranyl, 3- pyranyl, 4-pyranyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyrid-2-yl, pyrid-3- yl, pyrid-4-yl, pyrid-5-yl, pyrid-6-yl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrazinyl, 1- pyrazoiyl, 3-pyrazolyl, 4-pyrazolyl, l,2,3-triazol-4-yl, l,2,3-triazol-5-yl, 1,2,4-triazol-

3-yl, l,2,4-triazol-5-yl, lH-tetrazol-2-yl, lH-tetrazol-3-yl, tetrazolyl, acridyl, phenazinyl, carbazolyl, phenoxazinyl, indolizine, 2-indolyl, 3-indolyl, 4-indolyl, 5- indolyl, 6-indoiyl, 7-indolyl, 1 -isoindolyl, 3-isoindolyl, 4-isoindolyl, 5-isoindolyl, 6- isoindolyl, 7-isoindolyl, 2-indolinyl, 3-indolinyl, 4-indolinyl, 5-indolinyl, 6-indolinyl, 7-indolinyl, benzo[b]furanyl, benzofurazane, benzothiofurazane, benzotriazol-l-yl, benzotriazol-4-yl, benzotriazol-5-yl, benzotriazol-6-yl, benzotriazol-7-yl, benzotriazine, benzo[b]thiophenyl, benzimidazolyl, benzothiazolyl, quinazolinyl, quinoxazolinyl, cinnoline, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, or tetrahydroisoquinolinyl, purine, phthalazine, pteridine, thiatetraazaindene, thiatriazaindene, isothiazolopyrazine, 6-pyrimidinyl, 2,4-diniethoxy-6-pyrimidinyl, benzimidazol-2-yl, lH-benzimidazolyl, benzimidazol-4-yl, benz-imidazol-5-yl, benzimidazol-6-yl, benzimidazol-7-yl, tetrahydro-thieno[3,4-d]imidazol-2-one, pyrazolo[5,l-c][l ,2,4]triazine, isothiazolopyrimidine, pyrazolotriazine, pyrazolopyrimidine, imidazopyridazine, imidazopyrimidine, imidazopyridine, irnidazolotriazine, triazolotriazine, triazolopyridine, triazolopyrazine, triazolopyrimidine, or triazolopyridazine group. This heterocyclic group can carry one or more substituents R\ wherein R ^" is as defined above; a heterocyclyl group denotes a 3 to 8-membered heterocyclic non-aromatic group which contains at least one heteroatom selected from O, N, and S, wherein the heterocyclyl group may be fused to another non-aromatic ring and may carry one or more substituents R wherein R" is as defined above.

The term "stereoisomer" as used herein refers to compounds with at least one stereogenic center, which can be R- or S- configurated. It has to be understood that, in compounds with more than one stereogenic center, each center independently from each other can be R- or S-configurated. The term "stereoisomer" as used herein also refers to salts of the compounds described herein with optically active acids or bases.

A preferred embodiment of the invention is a pharmaceutical compositions comprising a compound of the general formula (I) or a salt or a stereoisomer thereof, for the use as a medicament, wherein the compound is administered not more often than once a week, and wherein R ¹ is phenyl, 2-thienyl or 3-thienyl which may be independently substituted by one to three halogen, CF ₃ , CHF ₂ , CH ₂ F, OCF ₃ , COR ⁶ , COOH, COOR ⁶ , S0 ₃ H, SOR ⁶ , S0 ₂ R ⁶ , cyano, hydroxy, amino, nitro, alkoxy, alkylamino, alkyl, ethynyl, alkoxy, and haloalkoxy, R ⁶ being as defined above. In another preferred embodiment, the invention provides a pharmaceutical compositions comprising a compound of the general formula (I) or a salt or a stereoisomer thereof, for the use as a medicament, wherein the compound is administered not more often than once a week, and where X is S. In another preferred embodiment, the invention provides a pharmaceutical compositions comprising a compound of the general formula (I) or a salt or a stereoisomer thereof, for the use as a medicament, wherein the compound is administered not more often than once a week, and where X is O.

In another preferred embodiment, the invention provides a pharmaceutical composition comprising a compound of the general formula (I) or a salt or a stereoisomer thereof, for the use as a medicament, wherein the compound is administered not more often than once a week, and where R ⁴ is methoxy.

In another preferred embodiment, the invention provides a pharmaceutical composition comprising a compound of the general formula (I) or a salt or a stereoisomer thereof, for the use as a medicament, wherein the compound is administered not more often than once a week, and where is hydrogen.

In another preferred embodiment, the invention provides a pharmaceutical composition comprising a compound of the general formula (I) or a salt or a stereoisomer thereof, for the use as a medicament, wherein the compound is administered not more often than once a week, and where R is hydrogen.

In another preferred embodiment, the invention a pharmaceutical composition comprising a compound of the general formula (I) or a salt or a stereoisomer thereof, for the use as a medicament, wherein the compound is administered not more often than once a week, and where R is selected from the group comprising 2-morpholin-4- yl-ethyl, 3-morpholin-4-yl-propyl, 2-(4-methyl-piperazin-l -yl)-ethyl, 3-(4-methyl- piperazin-l-yl)-propyl, 2-pyrrolidin-l -yl-ethyl, 3-pyrrolidin-l-yl-propyl, 2-(l-methyl- piperidin-4-yl)-ethyl, 3-(l -methyl-piperidin-4-yi)-propyl, 2-dimethylamino-ethyl, 3- dimethyl amino-propyl, (3-morpholin-4-yl)-2-hydroxy-propyl, [3-(4-methyl-piperazin- 1 -yl)]-2-hydroxy-propyl, (3-pyrrolidin- 1 -yl)-2-hydroxy-propyl, [3-(l -methyl- piperidin-4-yl)]-2-hydroxy-propyl, 2-(3-hydroxy-pyrrolidin)-l -yl-ethyl, 3-(3-hydroxy- pyrrolidin)-l -yl-propyl, 2-(2-hydroxymethyl-pyrrolidin)-l -yl-ethyl, 3-(2- hydroxymethyl-pyrrolidin)- 1 -yl-propyl, 2-methoxy-ethyl, 2-thiomorpholin-4-yl-efhyl, 2-(thiomorpholin-4-yl S-oxide)-ethyl, 2-(thiomorpholin-4-yl S-dioxide)-ethyl, 3- thiomorpholin-4-yl-propyl, 3-(morpholin-4-yI S-oxide)-propyl, and 3-(morpholin-4-yl S-dioxide)-propyl.

In another even more preferred embodiment, the invention provides a pharmaceutical composition comprising a compound of the general formula (I) or a salt or a stereoisomer thereof, for the use as a medicament, wherein the compound is administered not more often than once a week, and where R ⁴ is methoxy and R ⁵ is selected from the group comprising 2-morpholin-4-yl-ethyl, 3-morphohn-4-yl-propyl, 2~(4-methyl-piperazin- 1 -yl)-ethyl, 3 -(4-methyl-piperazin- 1 -yl)-propyl, 2-pyrrolidin- 1 - yl-ethyl, 3-pyrrolidin-l -yl-propyl, 2-(l-methyl-piperidin-4-yl)-ethyl, 3-(l-methyl- piperidin-4-yl)-propyl, 2-dimethylamino-ethyl, 3 -dimethylamino -propyl, (3- morpholin-4-yl)-2-hydroxy-propyl, [3-(4-methyl-piperazin- 1 -yl)]-2-hydroxy-propyl, (3-pyrrolidin-l-yl)-2-hydroxy-propyl, [3-(l-methyl-piperidin-4-yl)]-2-hydroxy~propyl, 2-(3-hydroxy-pyrrolidin)-l -yl-ethyl, 3-(3-hydroxy-pyrrolidin)-l-yl-propyl, 2-(2- hydroxymethyl-pyrrolidm)- 1 -yl-ethyl, 3-(2-hydroxymethyl-pyrrolidin)- 1 -yl-propyl, 2- methoxy-ethyl, 2-thiomorpholin-4~ yl-ethyl, 2-(thiomorpholin-4-yl S-oxide)-ethyl, 2- (thiomorpholin-4-yl S-dioxide)-ethyl, 3-thiomorpholin-4-yl-propyl, 3-(morpholin-4-yl S-oxide)-propyl, and 3-(morpholin-4-yl S-dioxide)~propyl.

A more preferred embodiment of the invention is a pharmaceutical composition comprising a compound of the general formula (I) or a salt or a stereoisomer thereof, for the use as a medicament, wherein the compound is administered not more often than once a week, and where, X is S and R ¹ is phenyl, 2-thienyl or 3-thienyl which may be independently from each other substituted by one to three halogen, CF ₃ , CHF ₂ , CH ₂ F, OCF ₃ , COR ⁶ , COOH, COOR ⁶ , S03H, SOR ⁶ , S0 ₂ R ⁶ , cyano, hydroxy, amino, nitro, alkoxy, alkylamino, alkyl, ethynyl, alkoxy, and haloalkoxy, R ⁶ being as defined above.

A more preferred embodiment of the invention is a pharmaceutical composition comprising a compound of the general formula (I) or a salt or a stereoisomer thereof, for the use as a medicament, wherein the compound is administered not more often than once a week, and where, X is O and R ¹ is 2-thienyl or 3-thienyl which may be independently from each other substituted by one to three halogen, CF ₃ , CHF ₂ , CH ₂ F, OCF ₃ , COR ⁶ , COOH, COOR ⁶ , S03H, SOR ⁶ , S0 ₂ R ⁶ , cyano, hydroxy, amino, nitro, alkoxy, alkylamino, alkyl, ethynyl, alkoxy, and haloalkoxy, R ⁶ being as defined above.

A more preferred embodiment of the invention is a pharmaceutical composition comprising a compound of the general formula (I) or a salt or a stereoisomer thereof, for the use as a medicament, wherein the compound is administered not more often

2 1

than once a week, and where, R is hydrogen and R is 2-thienyl or 3-thienyl which may be independently from each other substituted by one to three halogen, CF ₃ , CHF ₂ , CH ₂ F, OCF ₃ , COR ⁶ , COOH, COOR ⁶ , S0 ₃ H, SOR ⁶ , S0 ₂ R ⁶ , cyano, hydroxy, amino, nitro, alkoxy, alkylamino, alkyl, ethynyl, alkoxy, and haloalkoxy, R ⁶ being as defined above.

A more preferred embodiment of the invention is a pharmaceutical composition comprising a compound of the general formula (I) or a salt or a stereoisomer thereof, for the use as a medicament, wherein the compound is administered not more often than once a week, and where, R ³ is hydrogen and R ¹ is phenyl, 2-thienyl or 3-thienyl which may be independently from each other substituted by one to three halogen, CF ₃ , CHF ₂ , C¾F, OCF3, COR ⁶ , COOH, COOR ⁶ , S03H, SOR ⁶ , S0 ₂ R ⁶ , cyano, hydroxy, amino, nitro, alkoxy, alkylamino, alkyl, ethynyl, alkoxy, and haloalkoxy, R ⁶ being as defined above.

A more preferred embodiment of the invention is a pharmaceutical composition comprising a compound of the general formula (I) or a salt or a stereoisomer thereof, for the use as a medicament, wherein the compound is administered not more often than once a week, and where, X is S and R ⁴ is methoxy.

In another even more preferred embodiment, the invention provides a pharmaceutical composition comprising a compound of the general formula (I) or a salt or a stereoisomer thereof, for the use as a medicament, wherein the compound is administered not more often than once a week, and where X is S and R ⁵ is selected from the group comprising 2-morpholin-4-yl-ethyl, 3-morpholin-4-yl-propyl, 2-(4- methyl-piperazin- 1 -yl)-ethyl, 3-(4-methyl-piperazin- 1 -yl)-propyl, 2-pyrrolidin- 1 -yl- ethyl, 3-pyrrolidin-l-yl-propyl, 2-(l-methyl-piperidin-4-yl)-ethyl, 3-(l -methyl- piperidin-4-yl)-propyl, 2-dimethylamino-ethyl, 3-dimethylamino-propyl, (3- morpholin-4-yl)-2-hydroxy-propyl, [3-(4-methyl-piperazin- 1 -yl)]-2-hydroxy-propyl, (3-pynOlidin-l -yl)-2-hydroxy-propyl, [3-(l-methyl-piperidin-4-yl)]-2-hydroxy-propyl, 2-(3-hydroxy-pyrrolidin)-l-yl-ethyl, 3-(3-hydroxy-pyrrolidin)-l -yl-propyl, 2-(2- hydroxymethyl-pyrrolidin)- 1 -yl-ethyl, 3-(2-hydroxymethyl-pyrrolidin)- 1 -yl-propyl, 2- methoxy-ethyl, 2-thiomorpholin-4-yl-ethyl, 2-(thiomorpholin-4-yl S-oxide)-ethyl, 2- (thiomorpholin-4-yl S-dioxide)-ethyl, 3-thiomorpholin-4-yl-propyl, 3-(morpholin-4-yl S-oxide)-propyl, and 3-(morpholin-4-yl S-dioxide)-propyl.

A more preferred embodiment of the invention is a pharmaceutical composition comprising a compound of the general formula (I) or a salt or a stereoisomer thereof, for the use as a medicament, wherein the compound is administered not more often than once a week, and where X is S, R ⁴ is methoxy and R ⁵ is selected from 2- morpholin-4-yl-ethyl, 3-morpholin-4-yl-propyl, 2-(4-methyl-piperazin-l-yl)-ethyl, 3- (4-methyl-piperazin-l -yl)-propyl, 2-pyrrolidin-l -yl-ethyl, 3 -pyrrolidin-1 -yl-propyl, 2- (1 -methyl-piperidin-4-yl)-ethyl, 3 -( 1 -methyl -piperidin-4-yl)-propyl, 2-dimethylamino- ethyl, 3-dimethylamino-propyl, (3-morpholin-4-yl)-2-hydroxy-propyl, [3-(4-methyl- piperazin-1 -yl)]-2 -hydroxy-propyl, (3 -pyrrolidin-1 -yl)-2-hydroxy-propyl, [3-(l - methyl-piperidin-4-yl)]-2-hydroxy-propyl, 2-(3-hydroxy-pyrrolidin)-l-yl-ethyl, 3-(3- hydroxy-pyriOlidin)-l -yl-propyl, 2-(2-hydroxymethyl-pyrrolidin)-l -yl-ethyl, 3-(2- hydroxymethyl-pyrrolidin)-l -yl-propyl, 2-methoxy-ethyl, 2-thiomorpholin-4-yl-ethyl, 2-(thiomoφholin-4-yl S-oxide)-ethyl, 2-(thiomorpholin-4-yl S-dioxide)-ethyl, 3- thiomorpholin-4-yl-propyl, 3-(morpholin-4-yl S-oxide)-propyl, and 3-(morpholin-4-yl S-dioxide)-propyl.

A more preferred embodiment of the invention is a pharmaceutical composition comprising a compound of the general formula (I) or a salt or a stereoisomer thereof, for the use as a medicament, wherein the compound is administered not more often than once a week, and where X is O, R ⁴ is methoxy and R ⁵ is selected from 2- morpholin-4-yl-ethyl, 3-morpholin-4-yl-propyl, 2-(4-methyl-piperazin-l-yl)-ethyl, 3- (4-methyl-piperazin-l-yl)-propyl, 2-pyrrolidin-l -yl-ethyl, 3 -pyrrolidin-1 -yl-propyl, 2- (1 -methyl-piperidin-4-yl)-ethyl, 3-(l -methyl -piperidin-4-yl)-propyl, 2 -dimethyl amino- ethyl, 3-dimethylamino-propyl, (3-morpholin-4-yl)-2-hydroxy-propyl, [3-(4-methyl- piperazin- 1 -yl)]-2-hydroxy-propyl, (3 -pyrrolidin- 1 -yl)-2-hydroxy-propyl, [3-(l - methyl-piperidin-4-yl)]-2-hydroxy-propyl, 2-(3 -hydroxy-pyrrolidin)- 1 -yl-ethyl, 3 -(3- hydroxy-pyiTolidin)-l -yl-propyl, 2-(2-hydroxymethyl-pyrrolidin)-l-yl-etliyl, 3-(2- hydroxym ethyl -pyrrolidin)- 1 -yl-propyl, 2-methoxy-ethyl, 2-thiomorpholin-4-yl-ethyl, 2-(thiomorpholin-4-yl S-oxide)-ethyl, 2-(thiomorpholin-4-yl S-dioxide)-ethyl, 3- thiomorpholin-4-yl-propyl, 3-(morpholin-4-yl S-oxide)-propyl, and 3-(morpholin-4-yl S-dioxide)-propyl.

A more preferred embodiment of the invention is a pharmaceutical composition comprising a compound of the general formula (I) or a salt or a stereoisomer thereof, for the use as a medicament, wherein the compound is administered not more often than once a week, and wherein R ¹ is phenyl, 2-thienyl or 3-thienyl which may be independently substituted by one to three halogen, CF ₃ , CHF ₂ , CH ₂ F, OCF ₃ , COR ⁶ , COOH, COOR ⁶ , S0 ₃ H, SOR ⁶ , S0 ₂ R ⁶ , cyano, hydroxy, amino, nitro, alkoxy, alkylamino, alkyl, ethynyl, alkoxy, and haloalkoxy, R ⁶ being as defined above, and R ⁴ is methoxy and R is selected from 2-morpholin-4-yI-ethyl, 3-morpholin-4-yl-propyl, 2-(4-methyl-piperazin-l -yl)-ethyl, 3-(4-methyl-piperazin-l-yl)-propyl, 2-pyrrolidin-l- yl-ethyl, 3 -pyrrolidin- 1 -yl-propyl, 2-(l-methyl-piperidin-4-yl)-ethyl, 3-(l-methyl- piperidin-4-yl)-propyl, 2-dimethylamino-efhyl, 3-dimethylamino-propyl, (3- morpholin-4-yl)-2-hydroxy-propyl, [3-(4-methyl-piperazin-l -yl)]-2-hydroxy-propyl, (3 -pyrrolidin- l-yl)-2-hydroxy-propyl, [3-(l-methyl-piperidin-4-y])]-2-hydroxy-propyl, 2-(3-hydroxy-pyrrolidin)- 1 -yl-ethyl, 3 -(3 -hydroxy-pyrrolidin)- 1 -yl-propyl, 2-(2- hydroxymethyl-pyrrolidin)-l -yl-ethyl, 3 - (2-hydroxymethyl-pyrrolidin) - 1 -yl-propyl, 2- methoxy-ethyl, 2-thiomorpholin-4-yl-ethyl, 2-(thiomorpholin-4-yl S-oxide)-ethyl, 2- (thiomorpholin-4-yl S-dioxide)-ethyl, 3-thiomorpholin-4-yl-propyl, 3-(morpholin-4-yl S-oxide)-propyl, and 3-(morpholin-4-yl S-dioxide)-propyl.

A more preferred embodiment of the invention is a pharmaceutical composition comprising a compound of the general formula (I) or a salt or a stereoisomer thereof, for the use as a medicament, wherein the compound is administered not more often than once a week, and wherein R ¹ is phenyl, 2-thienyl or 3-thienyl which may be independently substituted by one to three halogen, CF ₃ , CHF ₂ , CH ₂ F, OCF ₃ , COR ⁶ , COOH, COOR ⁶ , S0 ₃ H, SOR ⁶ , S0 ₂ R ⁶ , cyano, hydroxy, amino, nitro, alkoxy, alkylamino, alkyl, ethynyl, alkoxy, and haloalkoxy, R ⁶ being as defined above, X is S and R is hydr gen.

A more preferred embodiment of the invention is a pharmaceutical composition comprising a compound of the general formula (I) or a salt or a stereoisomer thereof, for the use as a medicament, wherein the compound is administered not more often than once a week, and wherein R ^l is phenyl, 2-thienyl or 3-thienyl which may be independently substituted by one to three halogen, CF ₃ , CHF , CH ₂ F, OCF ₃ , COR ⁶ , COOH, COOR ⁶ , S0 ₃ H, SOR ⁶ , S0 ₂ R ⁶ , cyano, hydroxy, amino, nitro, alkoxy, alkylamino, alkyl, ethynyl, alkoxy, and haloalkoxy, R ⁶ being as defined above, X is S and R is hydrogen.

A more preferred embodiment of the invention is a pharmaceutical composition comprising a compound of the general formula (I) or a salt or a stereoisomer thereof, for the use as a medicament, wherein the compound is administered not more often than once a week, and wherein R ¹ is phenyl, 2-thienyl or 3-thienyl which may be independently substituted by one to three halogen, CF ₃ , CHF ₂ , C¾F, OCF ₃ , COR ⁶ , COOH, COOR ⁶ , S0 ₃ H, SOR ⁶ , S0 ₂ R ⁶ , cyano, hydroxy, amino, nitro, alkoxy, alkylamino, alkyl, ethynyl, alkoxy, and haloalkoxy, R ⁶ being as defined above, X is S and R ⁴ is methoxy.

A more preferred embodiment of the invention is a pharmaceutical composition comprising a compound of the general formula (I) or a salt or a stereoisomer thereof, for the use as a medicament, wherein the compound is administered not more often than once a week, and wherein R ¹ is phenyl, 2-thienyl or 3-thienyl which may be independently substituted by one to three halogen, CF ₃ , CHF ₂ , CH ₂ F, OCF ₃ , COR ⁶ , COOH, COOR ⁶ , S0 ₃ H, SOR ⁶ , S0 ₂ R ⁶ , cyano, hydroxy, amino, nitro, alkoxy, alkylamino, alkyl, ethynyl, alkoxy, and haloalkoxy, R ⁶ being as defined above, X is S and R ⁵ is selected from 2-morpholin-4-yl-ethyl, 3-morpholin-4-yl-propyl, 2-(4-methyl- piperazin-l-yl)-ethyl, 3~(4-methyl-piperazin-l-yl)-propyl, 2-pyrrolidin-l-yl-ethyl, 3- pyiTolidin- 1 -yl-propyl, 2-(l -methyl-piperidin-4-yl)-ethyl, 3-(l -methyl-piperidin-4-yl)- propyl, 2-dimethylamino-ethyl, 3 -dimethyl amino-propyl, (3-morphoHn-4-yl)-2- hydroxy-propyl, [3-(4-methyl-piperazin-l-yl)]-2-hydroxy-propyl, (3-pyrrolidin-l-yl)- 2-hydroxy-propyl, [3 -(1 -methyl -piperidin-4-yl)]-2-hydroxy-propyl, 2-(3-hydroxy- pyrrolidin)-! -yl-ethyl, 3-(3-hydroxy-pyrrolidin)-l -yl -propyl, 2-(2-hydroxymethyl- pyrrolidin)-! -yl-ethyl, 3-(2-hydroxymethyl-pyirolidin)-l -yl-propyl, 2-methoxy-ethyl, 2-thiomorpholin-4-yl-ethyl, 2-(thiomorpholin-4-yl S-oxide)-ethyl, 2-(thiomorpholin-4- yl S-dioxide)-ethyl, 3-thiomorpholin-4-yl-propyl, 3-(morpholin-4-yl S -oxide) -propyl, and 3-(morpholin-4-yl S-dioxide)-propyl.

An even more preferred embodiment of the invention is a pharmaceutical composition comprising a compound of the general formula (I) or a salt or a stereoisomer thereof, for the use as a medicament, wherein the compound is administered not more often than once a week, and wherein R ¹ is phenyl, 2-thienyl or 3-thienyl which may be independently substituted by one to three halogen, CF ₃ , CHF ₂ , CH ₂ F, OCF ₃ , COR ⁶ , COOH, COOR ⁶ , S0 ₃ H, SOR ⁶ , S0 ₂ R ⁶ , cyano, hydroxy, amino, nitro, alkoxy, alkylamino, alkyl, ethynyl, alkoxy, and haloalkoxy, R ⁶ being as defined above, and X is S, and R ⁴ is methoxy and R ⁵ is selected from 2-morpholin-4~yl-ethyl, 3~morpholin-

4- yl-propyl, 2-(4-methyl-piperazin-l-yl)-ethyl, 3-(4-methyl-piperazin-l-yl)-propyl, 2- pyrrolidin-1 -yl-ethyl, 3-pyrrolidin-l-yl-propyl, 2-(l-methyl-piperidin-4-yl)-ethyl, 3-(l- methyl-piperidin-4-yl)-propyl, 2-dimethylamino-ethyl, 3 -dim ethyl amino -propyl, (3- morpholin-4-yl)-2-hydroxy-propyl, [3-(4-methyl-piperazin-l-yl)]-2-hydroxy-propyl, (3-pyrrolidin-l-yl)-2-hydroxy-propyl, [3-(l-methyl-piperidin-4-yl)]-2-hydroxy-propyl, 2-(3-hydroxy-pyrrolidin)-l -yl-ethyl, 3-(3-hydroxy-pyrrolidin)-l-yl-propyl, 2-(2- hydroxymethyl-pyrrolidin)- 1 -yl-ethyl, 3-(2-hydroxymethyl-pyrrolidin)- 1 -yl-propyl, 2- methoxy-ethyl, 2-thiomorpholin-4-yl-ethyl, 2-(thiomorpholin-4-yl S-oxide)-ethyl, 2- (thiomorpholin-4-yl S-dioxide)-ethyl, 3-thiomorpholin-4-yl-propyl, 3-(morpholin-4-yl

5- oxide)-propyl, and 3-(morpholin-4-yl S-dioxide)-propyl.

An even more preferred embodiment of the invention is a pharmaceutical composition comprising a compound of the general formula (Ϊ) or a salt or a stereoisomer thereof, for the use as a medicament, wherein the compound is administered not more often than once a week, and wherein R ¹ is phenyl, 2-thienyl or 3-thienyl which may be independently substituted by one to three halogen, CF ₃ , CHF ₂ , CH ₂ F, OCF ₃ , COR ⁶ , COOH, COOR ⁶ , S0 ₃ H, SOR ⁶ , S0 ₂ R ⁶ , cyano, hydroxy, amino, nitro, alkoxy, alkylamino, alkyl, ethynyl, alkoxy, and haloalkoxy, R ⁶ being as defined above, and X is O, and R ⁴ is methoxy and R ⁵ is selected from 2-morpholin-4-yl-ethyl, 3-morpholin-

4- yl-propyl, 2-(4-methyl-piperazin-l-yl)-ethyl, 3-(4-methyl-piperazin-l-yl)-propyl, 2- pyrrolidin-l-yl-ethyl, 3 -pyrrolidin-l-yl -propyl, 2-(l-methyl-piperidin-4-yl)-ethyl, 3-(l- methyl-piperidin-4-yl)-propyl, 2-dimethyIamino-ethyl, 3-dimethylamino-propyl, (3- morpholin-4-yl)-2-hydroxy-propyl, [3-(4-methyl-piperazin- 1 -yl)]-2-hydroxy-propyl,

(3-pyrrolidin-l-yl)-2-hydroxy-propyl, [3-(l-methyl~piperidin-4-yl)]-2-riydroxy-propyl,

2- (3-hydroxy-pyrrolidin)-l -yl-ethyl, 3-(3-hydroxy-pyrrolidin)-l -yl-propyl, 2-(2- hydroxym ethyl-pyrroli din) - 1 -yl-ethyl, 3 - (2 -hydro xymethyl-pyrrolidin)- 1 -yl -propyl , 2 - methoxy-ethyl, 2-thiomorpholin-4-yl-ethyl, 2-(thiomorpholin-4-yl S-oxide)~ethyl, 2- (thiomorpholin-4-yl S-dioxide)-ethyl, 3-thiomorpholin-4-yl-propyl, 3-(morpholin-4-yl

5- oxide)-propyl, and 3-(morpholin-4-yl S-dioxide)-propyl.

A an even more preferred embodiment of the invention is a pharmaceutical composition comprising a compound of the general formula (I) or a salt or a stereoisomer thereof, for the use as a medicament, wherein the compound is administered not more often than once a week, and wherein R ¹ is phenyl, 2-thienyl or

3- thienyl which may be independently substituted by one to three halogen, CF ₃ , CHF ₂ , C¾F, OCF ₃ , COR ⁶ , COOH, COOR ⁶ , S0 ₃ H, SOR ⁶ , S0 ₂ R ⁶ , cyano, hydroxy, amino, nitro, alkoxy, alkylamino, alkyl, ethynyl, alkoxy, and haloalkoxy, R ⁶ being as defined above, and X is S, and R ⁴ is methoxy and R ² is hydrogen.

An even more preferred embodiment of the invention is a pharmaceutical composition comprising a compound of the general formula (I) or a salt or a stereoisomer thereof, for the use as a medicament, wherein the compound is administered not more often than once a week, and wherein R ¹ is phenyl, 2-thienyl or 3-thienyl which may be independently substituted by one to three halogen, CF ₃ , CHF ₂ , C¾F, OCF ₃ , COR ⁶ , COOH, COOR ⁶ , SO ₃ H, SOR ⁶ , S0 ₂ R ⁶ , cyano, hydroxy, amino, nitro, alkoxy, alkylamino, alkyl, ethynyl, alkoxy, and haloalkoxy, R ⁶ being as defined above, and X is S, and R ⁴ is methoxy and R ³ is hydrogen.

An even more preferred embodiment of the invention is a pharmaceutical composition comprising a compound of the general formula (I) or a salt or a stereoisomer thereof, for the use as a medicament, wherein the compound is administered not more often than once a week, and wherein R ¹ is phenyl, 2-thienyI or 3-thienyl which may be independently substituted by one to three halogen, CF ₃ , CHF ₂ , CH ₂ F, OCF ₃ , COR ⁶ , COOH, COOR ⁶ , SOjH, SOR ⁶ , S0 ₂ R ⁶ , cyano, hydroxy, amino, nitro, alkoxy, alkylamino, alkyl, ethynyl, alkoxy, and haloalkoxy, R ⁶ being as defined above, and X is S, and R" is hydrogen and R is hydrogen.

An even more preferred embodiment of the invention is a pharmaceutical composition comprising a compound of the general formula (I) or a salt or a stereoisomer thereof, for the use as a medicament, wherein the compound is administered not more often than once a week, and wherein R ¹ is phenyl, 2-thienyl or 3-thienyl which may be independently substituted by one to three halogen, CF ₃ , CHF ₂ , CH ₂ F, OCF ₃ , COR ⁶ , COOH, COOR ⁶ , S0 ₃ H ₅ SOR ⁶ , S0 ₂ R ⁶ , cyano, hydroxy, amino, nitro, alkoxy, alkylamino, alkyl, ethynyl, alkoxy, and haloalkoxy, R ⁶ being as defined above, and X is S, and R ² is hydrogen, and R ⁴ is methoxy and R ⁵ is selected from 2-morpholin-4-yl- ethyl, 3-morpholin-4-yl-propyl, 2-(4-methyl-piperazin-l-yl)~ethyl, 3-(4~methyl- piperazin-l-yl)-propyl, 2-pyrrolidin-l-yl-ethyl, 3-pyrrolidin-l-yl-propyl, 2-(l-methyl- piperidin-4-yl)-efhyl, 3-(l-metl yl-piperidin-4-yl)-propyl, 2-dimethylamino-ethyl, 3- dimethylamino-propyl, (3-morpholin-4-yl)-2-hydroxy-propyl, [3-(4-methyl-piperazin-

1- yl)]-2-hydroxy-propyl, (3-pyrrolidin-l -yl)-2-hydroxy-propyl, [3~(1 -methyl- piperidin-4-yl)]-2-hydroxy-propyl, 2-(3-hydroxy-pyrrolidin)-l-yl-ethyl, 3-(3-hydroxy- pyrrolidin)- -yl-propyl, 2-(2-hydroxymethyl-pyrrolidin)- 1 -yl-ethyl, 3 -(2- hydroxymethyl-pyrrolidin)-l -yl-propyl, 2-methoxy-ethyl, 2-thiomorpholin-4-yl-ethyl,

2- (thiomorpholin-4-yl S-oxide)-ethyl, 2-(thiomorpholin-4-yl S-dioxide)-ethyl, 3- thiomorpholin-4~yl-propyl, 3-(morpholin-4-yl S-oxide)-propyl, and 3-(morpholin-4~yl S-dioxide)-propyl.

An even more preferred embodiment of the invention is a pharmaceutical composition comprising a compound of the general formula (I) or a salt or a stereoisomer thereof, for the use as a medicament, wherein the compound is administered not more often than once a week, and wherein R ¹ is phenyl, 2-thienyl or 3-thienyl which may be independently substituted by one to three halogen, CF ₃ , CHF ₂ , CH ₂ F, OCF ₃ , COR ⁶ , COOH, COOR ⁶ , S0 ₃ H, SOR ⁶ , S0 ₂ R ⁶ , cyano, hydroxy, amino, nitro, alkoxy, alkylamino, alkyl, ethynyl, alkoxy, and haloalkoxy, R ⁶ being as defined above, and X is S, and R ³ is hydrogen, and R ⁴ is methoxy and R ⁵ is selected from 2-morpholin-4-yl- ethyl, 3-morpholin-4-yl-propyl, 2-(4-methyl-piperazin-l-yl)-ethyl, 3-(4-methyl- piperazin-l-yl)-propyl, 2-pyrrolidin-l-yl-ethyl, 3 -pyrrolidin-1 -yl-propyl, 2-(l-methyl- piperidin-4-yl)-ethyl, 3-(l-methyl-piperidin-4-yl)-propyl, 2-dimethylamino-ethyl, 3- dim ethyl amino-propyl, (3-morpholin-4-yl)-2-hydroxy-propyl, [3-(4-methyl-pi erazin-

1- yl)]-2-hydroxy-propyl, (3 -pyrrolidin-1 -yl)-2-hydroxy-propyl, [3-(l-methyl- piperidin-4-yl)]-2-hydroxy-propyl, 2-(3-hydroxy-pyrrolidin)-l -yl-ethyl, 3-(3-hydroxy- pyrrolidin)-l -yl-propyl, 2-(2-hydroxymethyl-pyrrolidin)-l -yl-ethyl, 3-(2- hydroxymethyl-pyrrolidin)-! -yl-propyl, 2-methoxy-ethyl, 2-thiomorpholin-4-yl-ethyl,

2- (thiomorpholin-4-yl S-oxide)-ethyl, 2-(thiomorpholin-4-yI S-dioxide)-ethyl, 3- thiomorpholin-4-yl -propyl, 3-(πιοψ]ιο1ίη-4^1 S-oxide)-propyl, and 3-(morpholin-4-yl S-dioxide)-propyl.

An even more preferred embodiment of the invention is a pharmaceutical composition comprising a compound of the general formula (I) or a salt or a stereoisomer thereof, for the use as a medicament, wherein the compound is administered not more often than once a week, and wherein R ¹ is phenyl, 2-thienyl or 3-thienyl which may be independently substituted by one to three halogen, CF ₃ , CHF ₂ , C¾F, OCF ₃ , COR ⁶ , COOH, COOR ⁶ , S0 ₃ H, SOR ⁶ , S0 ₂ R ⁶ , cyano, hydroxy, amino, nitro, alkoxy, alkylamino, alkyl, ethynyl, alkoxy, and haloalkoxy, R ⁶ being as defined above, and X is S, and R ² is hydrogen, R ³ is hydrogen, and R ⁴ is methoxy and R ⁵ is selected from 2- morpholin-4-yl-ethyl, 3-morpholin-4-yl-propyl, 2-(4-methyl-piperazin-l-yl)-ethyl, 3- (4-methyl-piperazin-l-yl)-propyl, 2-pyrrolidin-l-yl-ethyl, 3 -pyrrolidin-1 -yl-propyl, 2- ( 1 -methyl-piperidin-4-yl)-ethyl, 3-(l -methyl-piperidin-4-yl)-propyl, 2-dimethylamino- ethyl, 3-dimethylamino-propyl, (3 -morpholin-4-yl) -2 -hydroxy-propyl, [3-(4-methyl- piperazin- 1 -yl)]-2-hydroxy-propyl, (3-pyrrolidin-l-yl)-2-hydroxy-propyl, [3-(l - methyl-piperidin-4-yl)]-2-hydroxy~propyl, 2-(3-hydroxy-pyrrolidin)-l -yl-etliyl, 3-(3- h}'droxy-pyrrolidin)- 1 -yl-propyl, 2-(2-hydroxymethyl-pyrrolidin)-l -yl-ethyl, 3-(2- hydroxymethyl-pyrrolidin)-! -yl-propyl, 2-methoxy-ethyl, 2-thiomo holi -4-yl-ethyl, 2-(thiomorpholin-4-yl S-oxide)-ethyl, 2-(thiomorpholin-4-yl S-dioxide)-ethyl, 3- thiomorpholin-4-yl~propyl, 3-(mo holin-4-yl S-oxide)-propyl, and 3-(morpholin-4-yl S-dioxide)-propyl. Exemplary compounds of formula (I) of the present invention include, but are not limited to, the following:

Example Compound_IUP AC_nam e

l-(3-fluorophenyl)-3-(6-(6-methoxy-7-(3-(4-methylpiperazin-l -

1

yl)propoxy)quinazolin-4-ylamino)benzo[d]thiazol-2-yl)urea acetate l-(4-fluorophenyl)-3-(6-(6-methoxy-7-(3-(4-methylpiperazin-l -

2

yl)propoxy)quinazolin-4-ylamino)benzo[d]thiazol-2-yl)urea acetate l-(6-(6-methoxy-7-(3-(4-methylpiperazin-l -yl)propoxy)quinazolin-4-

3

ylamino)benzo[d]thiazol-2-yl)-3-(3-methoxyphenyl)urea

l-(6-6-Methoxy-7-[3-(4-methyl-piperazin-l-yl)-propoxy]-quina zolin-4-

4

ylamino-benzothiazol-2-yl)-3-(2-methoxy-phenyl)-urea acetate l-(2-Methoxy-5-methyl-phenyl)-3-(6-6-methoxy-7-[3-(4-methyl- piperazin-

5

1 -yl)-propoxy] -quinazolin-4-ylamino-benzothiazol-2-yl)-urea

l-(4-Chloro-3-trifluoromethyl-phenyi)-3-(6-6-methoxy-7-[3-(4 -methyl-

6

piperazin-l-yl)-propoxy]-quinazolin-4-ylamino-benzothiazol-2 -yl)-urea

1 -(3-cyanophenyl)-3-(6-(6-methoxy-7-(3-(4-methylpiperazin-l -

7

yl)propoxy)quinazolin~4-ylamino)benzo[d]thiazol-2-yl)urea

l-(2~fluoro-5-methylphenyl)-3-(6-(6-methoxy-7-(3-(4-methylpi perazin-l-

8

yl)propoxy)quinazolin-4-ylamino)benzo[d]oxazol-2-yl)urea

l-(5-chloro-2-metboxyphenyl)-3-(6-(6-methoxy-7-(3-(4-methylp iperazin-

9

l-yl)propoxy)quinazolin-4-ylamino)benzo[d]thiazol-2-yl)urea

3-(3-(6-(6-methoxy-7-(3-(4-methylpiperazin-l-yl)propoxy)q uinazolin-4~

10

ylamino)benzo[d]thiazol-2-yl)ureido)benzenesulfonamide

l-(2,4-difluorophenyl)-3-(6-(6-methoxy-7-(3-(4-methylpiperaz in-l-

11

yl)propoxy)quinazolin-4-ylamino)benzo[d]thiazol-2-yl)urea

3-(3-(6-(6-methoxy-7-(3-(4-methylpiperazin-l-yl)propoxy)quin azolin-4-

12

ylamino)benzo[d]thiazol-2-yl)ureido)propanoic acid

Ethyl 2-(3 -(6- (6-methoxy-7-(3 -(4-methylpiperazin- 1 -

13

yl)propoxy)quinazolin-4-ylamino)benzo[d]thiazol-2-yl)ureido) acetate l-(6-(6-methoxy-7-(3 -(4-methylpiperazin- l-yl)propoxy)quinazolin-4-

14

ylamino)benzo[d]thiazol-2-yl)-3-m-tolylurea

l-(2-chlorophenyl)-3-(6-(6-methoxy-7-(3-(4-methylpiperazin-l -

15

yl)propoxy)quinazolin-4-ylamino)benzo[d]thiazol-2-yl)urea

Methyl 3-(3-(6-(6-methoxy-7-(3-(4-methylpiperazin-l -

16

yl)propoxy)quinazolin-4-ylamino)benzo[d]thiazol-2-yl)ureido) benzoate

1 -benzyl-3-(6-(6-methoxy-7-(3-(4-methylpiperazin-l -

17

yl )propoxy)quinazolin-4-yl amino)benzo [d] thiazol-2 -yl)urea

1 -(6-(6-methoxy-7-(3-(4-methylpiperazin- 1 -yl)propoxy)quinazolin-4-

18

ylamino)benzo[d]thiazol-2-yl)-3-(4-methylbenzyl)urea

l-(2,5-dimethoxyphenyl)-3-(6-(6-methoxy-7-(3-(4-methylpipera zin-l-

19

yl)propoxy)quinazolin-4-ylamino)benzo[d]thiazol-2-yl)urea Methyl 2-(3-(6-(6-methoxy-7-(3-(4-methylpiperazin- 1 - yl)propoxy)quinazolin-4-ylamino)benzo[d]thiazol-2-yl)ureido) benzoate

1 -(6-(6-methoxy-7-(3-(4-methylpiperazin- 1 -yi)propoxy)quinazolin-4- ylamino)benzo[d]thiazol-2-yl)-3-o-tolylurea

3 - (3 - (6-(6-methoxy- 7-(3 - (4-m ethylpiperazin- 1 -yl)propoxy)quinazolin-4- ylamino)benzo [d] thi azol-2 -yl)ureido)b enzoic aci d

1 -(6-(7-(3-(l , 1 -dioxothiomoipholin-4-yl)propoxy)-6-methoxyquinazolin-4- ylamino)benzo[d]thiazol-2-yl)-3-(2-methoxy-5-methylphenyl)ur ea

1 -(3-fluorobenzyl)-3-(6-(6-methoxy-7-(3-(4-methylpiperazin-l - yl)propoxy)quinazolin-4-ylamino)benzo[d]thiazol-2-yl)urea

l-(2-fluorophenyl)-3-(6-(6-methoxy-7-(3-(4-methylpiperazi n-l- yl)propoxy)quinazolin-4-ylamino)benzo[d]thiazol-2-yl)urea

l-(3,4-dimethoxyphenyl)-3-(6-(6-methoxy-7-(3-(4-methylpip erazin-l- yl)propoxy)quinazolin-4-ylamino)benzo[d]thiazol-2-yl)urea

l-(6-(6-methoxy-7-(3-(pyrrolidin-l-yl)propoxy)quinazolin- 4- ylamino)benzo[d]thiazol~2-yl)-3-(thiophen-2-yl)urea

1 -(6-(6-methoxy-7-(3-(pyrrolidin- 1 -yl)propoxy)quinazolin-4- ylamino)benzo[d]thiazol-2-yl)-3-(thiophen-3-yl)urea

1 -(6-(6-methoxy-7-(3-(pyrrolidin- 1 -yl)propoxy)quinazolin-4- ylamino)benzo[d]thiazol-2-yl)-3-phenyhirea

l-(2-methoxy-5-methylphenyl)-3-(6-(6-methoxy-7-(3-(4-meth ylpiperazin- l-yl)propoxy)quinazolin-4-ylamino)benzo[d]oxazol-2-yl)urea

1 -(6-(6-methoxy-7-(3-(4-m ethylpiperazin- 1 -yl)propoxy)quinazolin-4- ylamino)benzo[d]thiazol-2-yl)-3-(3-methoxybenzyl)urea

l-(2-methoxy-5-methylphenyl)-3-(6-(quinazolin-4- ylamino)benzo[d]thiazol-2-yl)urea

l-(2-chlorobenzyl)-3-(6-(6-methoxy-7-(3-(4-methylpiperazi n-l- yl)propoxy)quinazolin-4-ylamino)benzo[d]thiazol-2-yl)urea

3 - (3 - (6 - (6 , 7- dimethoxyquinazolin-4-ylamino)benzo [d] thiazol-2- yl)ureido)benzenesulfonamide

l-(furan-2-ylmethyl)-3-(6-(6-methoxy-7-(3-(4-methylpipera zin-l- yl)propoxy)quinazolin-4-ylamino)benzo[d]thiazol-2-yl)urea

l-(2,3-dihydrobenzo[b][l,4]dioxin-6-yl)-3-(6-(6-methoxy-7 -(3-(4- methylpiperazin-l-yl)propoxy)quinazolin-4-ylamino)benzo[d]th iazol-2- yl)urea

l-(6-(6-methoxy-7-(3-(4-methylpiperazin-l-yl)propoxy)quin azolin-4- ylamino)benzo[d]thiazol-2-yl)-3-(3-(morpholinomethyl)phenyl) urea l -(3-chlorophenyl)-3-(6-(6-methoxy-7-(3-(4-m ethylpiperazin- 1- yl)propoxy)quinazolin-4-ylamino)benzo[d]thiazol-2-yl)urea

1 -(3,4-difluorophenyl)-3-(6-(6-methoxy-7-(3-(4-methylpiperazi n- 1 - yl)propoxy)quinazolin-4-ylamino)benzo[d]thiazol-2-yl)urea formiate 1 - (6 - (6 -m ethoxy-7 - (3 - (4-methylpiperazin~ 1 -yl)propoxy)quinazolin-4- ylamino)benzo[d]oxazol-2-yl)-3-phenyhirea

l-(6-(6-methoxy-7-(3-(4-methylpiperazin-l-yl)propoxy)q inazolin-4- yl amino)b enzo [d]thiazol-2 -yl) -3 -phenyhirea

l -(2,4-dimetl oxyphenyl)-3-(6-(6-metlioxy-7-(3-(4-metliylpiperazin-l- yl)propoxy)quinazolin-4-ylamino)benzo[d]thiazol-2-yl)urea

l -(3,5-dimethylisoxazol-4-yl)-3-(6-(6-methoxy-7-(3-(4-methylp iperazin-l- yl)propoxy)quinazolin-4-ylamino)benzo[d]thiazol-2-yl)urea

1 -(6 -(6 -methoxy- 7- (3 -(4-methylpiperazin- 1 -yl)propoxy) quinazolin-4 - ylamino)benzo[d]thiazol-2-yl)-3-(iliiophen-3-yl)urea

1 -( -(7 - (3 - ( 1 , 1 -dioxothiomorpholin-4-yl)propoxy)- 6 -methoxyquinazo lin-4- ylamino)benzo[d]thiazol-2-yl)-3-(thiophen-2-yl)urea

l-(4-chlorophenyl)-3-(6-(6-methoxy-7-(3-(4-methylpiperazi n-l- yl)propoxy)quinazolin-4-ylamino)benzo[d]thiazol-2-yl)urea

l-(6-(6-methoxy-7-(3-(4-methylpiperazin-l-yl)propoxy)quin azolin-4- ylamino)benzo[d]thiazol-2-yl)-3-(2,3,4-trifluorophenyl)urea

1 -(2,5-difluorophenyl)-3 -(6-(6-methoxy-7-(3-(4-methylpiperazin- 1 - yl)propoxy)quinazolin-4-ylamino)benzo[d]thiazol-2-yl)urea

l-(6-(6,7-dimethoxyquinazolin-4-ylamino)benzo[d]thiazol-2 -yl)-3-(2- methoxy- 5 -methylphenyl )urea

1 -(6-(6-methoxy-7-(3-(4-methylpiperazin- 1 -yl)propoxy)quinazolin-4- ylamino)benzo[d]thiazol-2-yl)-3-(4-(trifluoromethyl)phenyl)u rea

1 -(6-(6-methoxy-7-(3-(4-methylpiperazin- 1 -yl)propoxy)quinazolin-4- ylamino)benzo[d]oxazol-2-yl)-3-(thiopb.en-3-yl)urea

l-(6-(6-methoxy-7-(3-(4-methylpiperazin-l-yl)propoxy)quin azolin-4- ylamino)b enzo[d] ibiazol -2 -yl)-3 - (3 -methylb enzyl)urea

1 -(2,6-difluorophenyl)-3-(6-(6-methoxy-7-(3-(4-methylpiperazi n- 1 - yl)propoxy)quinazolin-4-ylammo)benzo[d]thiazol-2-yl)urea formiate

1 -(2-fluoro-5-methylphenyl)-3-(6-(6-methoxy-7-(3-(pyrrolidin- 1 - yl)propoxy)quinazolin-4-ylamino)benzo[d]thiazol-2-yl)urea

2-(3-(6-(6-methoxy-7-(3-(4-methylpiperazin-l-yl)propoxy)quin azoHn-4- yl amino)benzo [ d] thiazol-2 -yl)ureido) acet i c acid

1 -(6-(7-(3-(l , 1 -dioxothiomorpholin-4-yl)propoxy)-6-methoxyquinazolin-4- ylamino)benzo[d]thiazol-2-yl)-3-(2-fluoro-5-methylphenyl)ure a

1 -(6-(7-(3-(l , 1 -dioxothjomorpholm-4-yl)propoxy)-6~methoxyquinazolin-4- ylamino)benzo[d]thiazol-2-yl)-3-phenylurea

Methyl 2-(3-(6-(6-methoxy-7-(3-(4-methylpiperazin- 1 - yl)propoxy)quinazolin-4-ylamino)benzo[d]thiazol-2-yl)ureido) thiophene-3- carboxylate

l-(4-fluorobenzyl)-3-(6-(6-methoxy-7-(3-(4-methylpiperazi n-l- yl)propoxy)quinazolin-4-ylamino)benzo[d]thiazol-2-yl)urea 1 -(6-(6-methoxy-7-(3 -(4-methylpiperazin- 1 -yl)propoxy)quinazolin-4-

60

ylamino)benzo[d]thiazol-2-yl)-3-(4-methoxyphenyl)urea

l-(6-(6-methoxy-7-(3 -(4-methylpiperazin- 1 -yl )propoxy)quinazolin-4-

61

ylamino)benzo[d]oxazol-2-yl)-3-(thiophen-2-yl)urea

1 -(6-(6-methoxy-7-(3 -(4-methylpiperazin- 1 -yl)propoxy)quinazoIin-4-

62

ylamino)benzo[d]thiazol-2-yl)-3-(4-methoxybenzyl)urea

l-(2-methoxy-5-methylphenyl)-3-(6-(7-methoxyquinazolin-4-

63

ylamino)benzo[d]thiazol-2-yl)urea

1 -(6-(6-meihoxy-7-(3 -(4-methylpiperazin- 1 -yl)propoxy)quinazolin-4-

64

ylamino)benzo[d3thiazol-2-yl)-3-(3-methylruran-2-yl)urea

l-(2-Methoxy-5-methyl-phenyl)-3-6-[6-methoxy-7-(3-pyrrolidin -l-yl-

65

propoxy)-quinazolin-4-ylamino]-benzothiazol-2-yl-urea

1 -(6-(6-methoxy-7-(3-(4-methylpiperazin- 1 -yl)propoxy)quinazolin-4-

66

ylamino)benzo[d]thiazol-2-yl)-3-(2-(trifluoromethoxy)phenyl) nrea

1 -(2-fluoro-5-methylphenyl)-3-(6-(6-methoxy-7-(3-(4-methylpip erazin- 1 -

67

yl)propoxy)quinazolin-4-ylamino) benzo[d]thiazol-2-yl)urea

Methyl 3-(3-(6-(6-methoxy-7-(3-(4-methylpiperazin-l -

68 yl)propoxy)quinazolin-4-ylamino)benzo[d]thiazol-2-yl)ureido) thiophene-2- carboxylate

l-(6-(6-methoxy-7-(3 -(4-methylpiperazin- l-yl)propoxy)quinazolin-4-

69

ylamino)benzo[d]thiazol-2-yl)-3-(thiophen-2-yl)urea

l-(3~chloro-4-methoxyphenyl)-3-(6-(6-methoxy-7-(3-(4-methylp iperazin-

70

l-yl)propoxy)quinazolin-4-ylamino)benzo[d]thiazol-2-yl)urea

1 -(6-(6-methoxy-7-(3 -(4-methylpiperazin- 1 -yl)propoxy)quinazolin-4-

71

ylamino)benzo[d]thiazol-2-yl)-3-(3-(trifluoromethyl)phenyl)u rea

Ethyl 3-(3-(6-(6-methoxy-7-(3-(4-methylpiperazin-l -

72

yl)propoxy)quinazolin-4-ylamino)benzo[d]thiazol-2-yl)ureido) propanoate l-(6-(6-methoxy-7-(3-(4-methylpiperazin-l-yl)propoxy)qxiinaz olin-4-

73

ylamino)benzo[d]thiazol-2-yl)-3-(2-methoxybenzyl)urea

l-(6-(6-methoxy-7-(3-(4-methylpiperazin-l-yl)propoxy)quinazo lin-4-

74

ylamino)benzo[d]thiazol-2-yl)-3-(4-methylthiophen-2-yl)urea

1 -(6-(6-methoxy-7-(3-(pyrrolidin- 1 -yl)propoxy)quinazolin-4-

75

ylamino)benzo[d]thiazol-2-yl)-3-m-tolylurea

1 -(2-fluorobenzyl)-3-(6-(6-methoxy-7-(3-(4-methylpiperazin-l -

76

yl)propoxy)quinazolin-4-ylamino)benzo[d]thiazol-2-yl)urea

1 - (6 -(6-methoxy- 7- (3 -(4-m ethylpiperazin- 1 -yl)propoxy) quinazolin-4-

77 ylamino)benzo[d]thiazol-2-yl)-3-(5-methyl-3-(trifluoromethyl )ruran-2- yl)urea

Another embodiment are compounds of the formula (I) that, although administered not more often than once a week, are very effective in in vivo efficacy models as described in the result section below, leading to a T/C (tumor to control, day 1 to 24) ratio of >0.5.

Another more preferred embodiment are compounds of the formula (I) that, although administered not more often than once a week, are very effective in in vivo efficacy models as described in the result section below, leading to a T/C (tumor to control, day 1 to 24) ratio of >0.35.

Another even more preferred embodiment are compounds of the formula (I) that, although administered not more often than once a week, are very effective in in vivo efficacy models as described in the result section below, leading to a T/C (tumor to control, day 1 to 24) ratio of >0.15.

For the sake of clarity the above cited T/C ratios are calculated by in vivo efficacy models which can be summarized as follows: implantation of human derived cancer cells (MV4-11) into mice, establishment of tumor for a few days, treatment start, tumor volume and body weight assessment during treatment phase, sacrifice of mice and tumor weight assessment A more detailed description of the in vivo efficacy models is given in the result section below.

Another embodiment are compounds of the formula (I) that are more effective in the reduction of blast cell counts of AML patients when administered not more often than once a week compared to more than once weekly administration.

Another more preferred embodiment are compounds of the formula (I) that are more effective in the reduction of blast cell counts of AML patients when administered not more often than once every two weeks compared to more than biweekly administration. For en effect of an FLT3 inhibitor on peripheral blast count see: R.M.

Stone et al., Blood, 2005, 105 (1), 54-60.

Another embodiment are compounds of the formula (I) that are less toxic, e.g lead to less than 20% body weight loss in in vivo animal studies as described in the results section, when administered not more often than once a week compared to more than once weekly administration. Another more preferred embodiment are compounds of the formula (I) that are less toxic, e.g lead to less than 10% body weight loss in in vivo animal studies as described in the results section, when administered not more often than once a week compared to more than once weekly administration. Another more preferred embodiment are compounds of the formula (I) that are less toxic, e.g lead to less than 10% body weight loss in in vivo animal studies as described in the results section, when administered not more often than once every two week compared to more than biweekly administration. Another more preferred embodiment are compounds of the formula (I) that are less toxic, e.g lead to less than 5% body weight loss in in vivo animal studies as described in the results section, when administered not more often than once every two week compared to more than biweekly administration. For the sake of clarity the above cited anima body weight loss was calculated by in vivo efficacy models which can be summarized as follows: implantation of human derived cancer cells (MV4-11) into mice, establishment of tumor for a few days, treatment start, tumor volume and body weight assessment during treatment phase, sacrifice of mice and tumor weight assessment

A more detailed description of the in vivo efficacy models and the effect of compounds of the present invention on the animal body weight is given in the result section below. Another preferred embodiment are pharmaceutical compositions comprising a compound of the general formula (I) or a salt or a stereoisomer thereof, for the use as a medicament, wherein 0.1 to 20 mg/kg of the compound are administered not more often than once a week. Another even more preferred embodiment are pharmaceutical compositions comprising a compound of the general formula (I) or a salt or a stereoisomer thereof, for the use as a medicament, wherein 0.5 to 10 mg/kg of the compound are administered not more often than once a week.

Another even more preferred embodiment are pharmaceutical compositions comprising a compound of the general formula (I) or a salt or a stereoisomer thereof, for the use as a medicament, wherein 1 to 3 mg/kg of the compound are administered not more often than once a week.

Another preferred embodiment are pharmaceutical compositions comprising a compound of the general formula (I) or a salt or a stereoisomer thereof, for the use as a medicament, wherein the compound is administered not more often than once every two weeks.

Another preferred embodiment are pharmaceutical compositions comprising a compound of the general formula (I) or a salt or a stereoisomer thereof, for the use as a medicament, wherein the compound is administered not more often than once every three weeks.

Another preferred embodiment are pharmaceutical compositions comprising a compound of the general formula (I) or a salt or a stereoisomer thereof, for the use as a medicament, wherein the compound is administered once every two weeks.

Another preferred embodiment are pharmaceutical compositions comprising compound 5 or compound 4 or a salt or a stereoisomer thereof, for the use as a medicament, wherein 1 to 3 mg/kg of the compound are administered once every two weeks.

Another preferred embodiment are pharmaceutical compositions comprising a compound of the general formula (I) or a salt or a stereoisomer thereof, for the use as a medicament, wherein the compound is administered to animals, preferably to mammals, and in particular to humans. According to the invention pharmaceutical acceptable salts of the compounds of the present invention are also included. These salts are selected but not limited to the group comprising acetate, 2,2-dichloroacetate, adipate, alginate, ascorbate, aspartate, benzoate, benzenesulfonate, 2-acetamidobenzoate, caproate, caprate, camphorate, camphorsulfonate, cinnamate, citrate, cyclamate, laurylsulfate, edisilate, esylate, isetionate, formate, furnarate, galactarate, gentisate, gluceptate, gluconate, glucuronate, glutamate, oxoglutarate, glycol ate, hippurate, bromide or hydrobromide, chloride or hydrochloride, lactate, lactobionate, malate, maleate, malonate, mandelate, mesylate, napsilate, napadisilate, xinafoate, nicotinate, nitrate, oleate, orotate, oxalate, palmitate, embonate, phosphate, hydrogenphosphate or dihydrogenphosphate, pidolate, salicylate, p-aminosalicylate, sebacate, stearate, succinate, sulfate or hydro gensulfate, tannate, tartrate, rhodanide, tosylate, undecylenate, ammonia, arginine, benethamine, benzathine, calcium, choline, deanol, diethanol amine, diethylammonium, ethanolamine, ethylendiamine, meglumine, hydrabamine, imidazole, lysine, magnesium, hydroxyethylmorpholine, piperazine, potassium, epolamine, sodium, trolamine, tromethamine or zinc [for further references see: Handbook of Pharmaceutical Salts, Ed. P.H. Stahl, C.G. Wermuth, Zurich 2002].

Such salts of the compounds of the present invention may be anhydrous or solvated. Such salts can be produced by methods known to someone skilled in the art and described in the prior art.

Other salts like oxalate derived from oxalic acid, which is not considered as pharmaceutically acceptable can be appropriate as intermediates for the production of compounds of the present invention or a pharmaceutically acceptable salt thereof or a stereoisomer thereof.

Physiologically functional derivatives of the inventive compounds are also encompassed by the present invention.

The term "physiologically functional derivative" used herein relates to any physiologically acceptable derivative of an inventive compound of the present invention for example an ester which on administration to a mammal, for example humans, is capable of forming (directly or indirectly) a compound of the present invention or an active metabolite thereof.

The physiologically functional derivatives also include prodrugs of the compounds of the invention. Such prodrugs may be metabolized in vivo to a compound of the invention. These prodrugs may or may not be active themselves.

The physiologically functional derivatives furthermore include, for example, glucuronides, sulfuric acid esters, glycosides and ribosides.

The dose can vary within wide limits and is to be suited to the individual conditions in each individual case. However, in contrast to the compounds known in the art, the compounds of the present invention are surprisingly less toxic and more effective if administered less often, e.g. once or twice every week or every two weeks or every three weeks, e.g. in a slow bolus injection, compared to administration of the same total amount in multiple doses.

The compounds according to the invention and medicaments prepared therewith are useful for treating, relieving, and/or preventing cancer or other diseases where it is beneficial to inhibit one or more kinases selected from ALK, Aurora-A, Aurora-B, AXL, EPHB4, FA , FGF-R3, FLT3, IGF1-R, KIT, PDGFR, SAK, SRC, TIE2, TRK, TYR03, VEGF-R2, and VEGF-R3. Such cancers among others are: breast, lung, colon, ovarian, pancreatic, prostate, thyroid, gastric, esophageal, and non-small cell lung cancer, or leukemias, or lymphomas due to Aurora-A or Aurora-B inhibition, gastrointestinal stromal tumor (GIST), and chronic myelomonocytic leukaemia (CMML) due to PDGFR inhibition, GIST due to KIT inhibition, adenocarcinoma due to TRK-A inhibition, solid tumors in general due to TRK-B inhibition, solid tumors due to inhibition of angiogenesis mediated by inhibition of EPHB4 and/or VEGF-R2 and/or VEGF-R3 and/or TIE2, acute myeloid leukaemia (AML) due to inhibition of FLT3 and/or TYR03, and/or AXL, and/or Trk-A, and/or VEGF-R1 and/or VEGF-R2, metastatic colorectal, esophageal, tyroid, breast, brain, lung, und melanomas due to inhibition of AXL, myelomas due to inhibition of TYR03, anaplastic large cell lymphoma due to inhibition of ALK, colorectal due to SAK inhibition, and metastasizing tumors due to inhibition of FAK and/or SRC and/or TRK-B.

Cancer is a group of diseases with more than 200 different types displaying different pathophysiology. The enormous heterogeneity of the multiple genetic changes that occur in different cancer types limits the efficacy of treatment that target only a single deregulated protein. So far, for instance, several anti-angiogenic kinase inhibitors, mainly VEGF-R2 inhibitors, were described some of which entered clinical trials. However the clinical results are rather disappointing, indicating that sole inhibition of angiogenesis is not effective enough in cancer treatment. A compound that acts against angiogenesis but in addition inhibits proliferation should be far more effective in the treatment of e.g. solid tumors due to additive or synergistic effects. A compound that in addition to proliferation inhibits metastasis should be more effective in the treatment of disseminating tumors, e.g. late state tumors, than a sole proliferation inhibitor. In addition, simultaneous inhibition of not only one molecular mechanism in tumor progression should greatly reduce the risk of resistance formation.

The compounds according to the present invention may thus be formulated for parenteral administration (e.g. by injection, for example bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, pre-filled syringes, small volume infusion or in multi-dose containers with an added preservative. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulation agents such as suspending, stabilising and/or dispersing agents. Alternatively, the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilization from solution, for constitution with a suitable vehicle, e.g. sterile, pyrogen-free water, before use.

The following examples and figures are included to demonstrate preferred embodiments of the invention. It should be appreciated by those of skill in the art that the techniques disclosed in the examples that follow represent techniques discovered by the inventors to function well in the practice of the invention, and thus can be considered preferred modes for its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments that are disclosed without departing from the spirit and scope of the invention as set out in the appended claims. All references cited are incorporated herein by reference.

Examples

Analytical data of compounds of formula (I) of the present invention:

32

57 634

0

NH

58 663

59 631

H

Materials and methods

Results

Compared to other kinase inhibitors in development for the treatment of AML, the compounds of the present invention are unique in terms of its efficacy and dosing schedule. Effects of compound 5 on tumor srowth and animal weight:

The effect of compound 5 was investigated in xenograft animal efficacy models with MV4-1 1 cells (an AML cell line) subcutaneously implanted into female NMRI nu/nu mice. In initial studies, the compound was applied i.p. (different doses twice a day (BID)). Here, no clear separation between tumor regression and body weight loss was observed. Various doses and dosing schedules were then examined employing intravenous applications of the compound. These studies were used to derive the optimum dosing schedule according to maximum efficacy combined with minimum body weight loss.

In all studies, MV4-1 1 cells (5x10 ⁶ cells per mouse in PBS mixed with Matrigel) were implanted subcutaneously into the flanks of NMRI nu/nu mice. After randomization and allocation to treatment groups (8 mice per group) therapy was started when the cells reached a measurable tumor volume of approximately 70-100 mm ³ . As vehicle control 10 mM acetate/0.9%NaCI buffer, pH 5.0, was used in all studies.

Every other day (Monday, Wednesday, Friday) all appearing subcutaneous tumors were measured by callipering and multiplying the distances of two dimensions

(formula; [x *X/2]; x= short, X- long 2D-measure). In addition, animal weights were measured three times weekly during the treatment period. Animal behaviour was monitored daily. The study or an individual group was terminated when the mean body weight loss in one group exceeded 20% or when the mean tumor volume exceeded 1000 mm ^" .

In three studies, dosing schedules involving treatment every other day, five days continuously or once every 14 days were evaluated. Results of these individual studies are presented in the remainder. In the first study, groups were treated with either 8, 16, or 32 mg/kg compound 5 or with vehicle on days 1, 3, 5, and 7. The groups treated with 16 or 32 mg/kg compound 5 were sacrificed on day 12 due to excessive weight loss. The other two groups were treated again on day 11 and sacrified on day 15 for logistic reasons. Tumor volumes and body weights are shown in Figure I and Figure 2 respectively. Dosing days are marked with arrows (black = all groups, grey = only vehicle and 8 mg kg).

In the second study, groups were treated daily on days 1-5 and 15-19 with either 2, 4 or 8 mg/kg compound 5 or vehicle. The groups treated with vehicle or 2 mg/kg compound 5 were sacrificed on day 24 due to excessive tumor growth. The other two groups were treated again on days 30-32 and sacrificed on day 38. The third treatment cycle was not finalized in these animals due to damage of the veins. Tumor volumes and body weights of animals treated with this schedule are shown in Figure 3 and Figure 4 respectively. Dosing days are indicated by black arrows.

In the third study, groups were treated on day 1 with either 16; 32; 64 or 128 mg/kg of compound 5 or vehicle. The group treated with 128 mg/kg compound 5 was sacrificed on day 12 due to excessive weight loss. The other groups were treated again on day 18 and sacrificed on day 25 (day 29 in the 64 mg/kg group). Tumor volumes and body weights of animals treated with this schedule are shown in Figure 5 and Figure 6, respectively. Dosing days are indicated by black arrows.

Since all animals of the 128 mg/kg group showed excessive weight loss and appeared more and more apathetic, the whole group was sacrificed. In these animals, almost no tumor was detectable at necropsy. Animals of the 64 mg/kg lost weight but recovered from the first and second applications. Necropsy of the 64 mg/kg group was performed 4 days after that of the 32 mg/kg, 16 mg/kg and vehicle groups, to gain further information on body weight recovery after the second treatment.

Surprisingly, none of the animals of the 32 mg/kg or 16 mg/kg group showed any side effects. Their body weight development was comparable to that of the vehicle group. Calculation of the Optimum Treatment Schedule

By comparing efficacy and toxicity of the doses and dosing schedules, the optimum treatment schedule was derived from the results of the three studies described above.

To make the data comparable, standardization was applied. Efficacy was described as

T/C ratio using tumor volume AUCs after the start of the therapy.

T/C = (tumor volume AUC, treated)/(tumor volume AUC, control)

Tumor volume was measured by callipering and multiplying the distances of two dimensions (formula: x2*X/2; x=short, X=long 2D-distance).

No further normalization was applied, as the group mean tumor volumes were always comparable after randomization of groups. Individual T/C values were calculated for all animals and group means were then compared.

Toxicity was quantified as relative body weight development (% gain or loss) compared to pre-dose body weights. For all individual animals, their body weight on the last evaluable day used for tumor volume AUC calculation was compared to their body weight on the last day before first dosing. Individual % body weight values were calculated for all animals and group means were then compared.

Due to the different treatment durations between studies and also between individual groups in one study, the following standardizations were made:

Schedule 1 : All groups were evaluated from days 1-12.

Schedule 2 : All groups were evaluated from days 1 -24.

Schedule 3: All groups were evaluated from days 1-24. Body weights of the 128 mg/kg group sacrificed on day 12 were evaluated from days 1-12. T/C values were calculated from days 1-24 as tumors had practically vanished on day 12.

The results of the three studies are summarized in

Table 1. Table 1: Summary of Schedule-finding Studies with compound 5

Treatments on days 30-32 not used for evaluation (evaluated days: 1-24)

Animals prematurely sacrificed on day 12

Evaluation across studies showed that the optimum dose and schedule was 32 mg/kg compound 5 administered on days 1 and 18. With this treatment, a T/C ratio of 0.14 was achieved without reduction in body weight.

The second best dose and schedule was 1 mg kg compound 5 given on days 1 and 18.

Here, a T/C ratio of 0.34 was achieved without any visible signs of toxicity. Body weight gain in this group was almost identical to that in the vehicle group.

Treatment with 4 mg/kg compound 5 on days 1 -5 and 15-19 also led to a remarkable reduction of tumor growth (T/C = 0.30) without body weight loss. Compared to the 16 nig/kg group in schedule 3, which showed a comparable T/C ratio, the body weight development in this group was compromised in comparison to its respective vehicle group (+ 4.6% compared to + 7.8%). Furthermore, the therapeutic window in this treatment schedule seemed to be narrower, as treatment with 2 mg/kg compound 5 on days 1-5 and 15-19 had no effect on tumor growth at all.

Treatments with compound 5 every other day (schedule 1) showed the least efficacy combined with the most remarkable weight loss (already on day 12). It was deduced that the optimum treatment effects of compound 5 were obtained with infrequent, but comparably high doses of the compound.

As demonstrated in a number of mouse xenograft studies and in contrast to what is known in the art, compound 5 surprisingly displays its greatest efficacy when administered only once every two weeks as an intravenous slow bolus injection. On top of exhibiting maximum efficacy, surprisingly the same dosing schedule was also best tolerated by the animals.

Figure description

Figure 1 : Tumor Volumes in MV4-11 Xenograft Model Schedule 1

Figure 2: Animal Weights in MV4-11 Xenograft Model Schedule 1 Figure 3: Tumor Volumes in MV4-11 Xenograft Model Schedule 2 Figure 4: Animal Weights in MV4-11 Xenograft Model Schedule 2 Figure 5: Tumor Volumes in MV4-11 Xenograft Model Schedule 3 Figure 6: Animal Weights in MV4-11 Xenograft Model Schedule 3