Pyridyl alkane acid amides as cytostatics and immunosuppressives

Compounds of formula (I) and pharmaceutically acceptable salts of formula (I)

• wherein
• R1 is selected from the group consisting of hydrogen, halogen, cyano, C1-C6-alkyl, trifluoromethyl, C3-C8-cycloalkyl, C1-C4-hydroxyalkyl, hydroxy, C1-C4-alkoxy, benzyloxy, C1-C4-alkanoyloxy, C1-C4-alkylthio, C2-C5-alkoxycarbonyl, aminocarbonyl, C3-C9-dialkylaminocarbonyl, carboxy, phenyl, phenoxy, NR5R6, and bridged R1R2, wherein
• R5 is selected from the group consisting of hydrogen and and C1-C6-alkyl and
• R6 is selected from the group consisting of hydrogen and C1-C6-alkyl,
• R2 is selected from the group consisting of hydrogen, halogen, C1-C6-alkyl, trifluoromethyl, hydroxy, and bridged R1R2,
• wherein bridged R1R2 is where R1R2 are adjacent and form a bridge which is selected from the bridge members —(CH2)4— and —(CH═CH)2— and —CH2O—CR7R8—O—, wherein
• R7 is selected from the group consisting of hydrogen and C1-C6-alkyl and
• R8 is selected from the group consisting of hydrogen or C1-C6-alkyl,
• R3 is selected from the group consisting of hydrogen, halogen, and C1-C6-alkyl,
• R4 is selected from the group consisting of hydrogen, C1-C6-alkyl, C3-C6-alkenyl, hydroxy, C1-C6-alkoxy and benzyloxy,
• k is 0 or 1,
• A is selected from the group consisting of C1-C6-alkylene, a substituted C1-C6-alkylene which is substituted once to three-fold by C1-C3-alkyl, hydroxy, fluorine or phenyl,
• 1,2-cyclopropylene and
• an isosterically substituted C2-C6-alkylene, wherein the isosterically substituted C2-C6 alkylene has a methylene unit which is isosterically replaced by O, S, NR9, CO, SO or SO2, and wherein the isosteric replacement, with the exception of ═CO, is not adjacent to the amide group, and wherein
• R9 is selected from the group consisting of hydrogen, C1-C3-alkyl, C1-C6-acyl and methanesulfonyl,
• D is selected from the group consisting of C1-C10-alkylene, a substituted C1-C10-alkylene which is substituted once or twice by C1-C3-alkyl or hydroxy,
• a C2-C10-alkenylene, a C2-C10-alkenylene which is substituted once or twice by C1-C3-alkyl or hydroxy,
• an E double bonded C2-C10 alkenylene which has a double bond to ring E,
• an E double bonded substituted C2-C10-alkenylene which has a double bond to ring E,
• a C3-C10-alkinylene,
• a substituted C3-C10-alkinylene which is substituted once or twice by C1-C3-alkyl, hydroxy, and an isosterically replaced C1-C10-alkylene, C2-C10-alkenylene or C3-C10-alkinylene, having an isosterically replaced group having one to three methylene units which are each isosterically replaced by O, S, NR10, CO, SO or SO2, wherein
• R10 has the same meaning as R9, but is selected independently therefrom,
• E is
• R11 is selected from the group consisting of hydrogen, C1-C3-alkyl, hydroxy, hydroxymethyl, carboxy and C2-C7-alkoxycarbonyl,
• R12 is selected from the group consisting of hydrogen an oxo group adjacent to the nitrogen atom,
• G is selected from the group consisting of hydrogen, G1, G2, G3, G4 and G5, wherein
• G1 is
• —(CH2)r—(CR14R15)s—R13 (G1)
• wherein
• r is 0, 1 or 2 and
• s is 0 or 1,
• R13 is selected from the group consisting of hydrogen, C1-C6-alkyl, C3-C6-alkenyl, C3-C6-alkinyl, C3-C8-cycloalkyl, benzyl, phenyl, anellated bi- and tricyclic aromatic or partially hydrogenated carbocyclic ring systems with 8 to 16 ring atoms and at least one aromatic ring, whereby the bond occurs either over an aromatic or a hydrogenated ring and either directly or over a methylene group,
• R14 has the same meaning as R13, but is selected independently thereof,
• R15 is selected from hydrogen, hydroxy, methyl, benzyl, phenyl, anellated bi- and tricyclic aromatic or partially hydrogenated carbocyclic ring systems with 8 to 16 ring atoms and at least one aromatic ring, wherein the bond occurs either over an aromatic or a hydrogenated ring and either directly or over a methylene group,
• G2 is
• wherein the substituents R3 and R15 have the above meaning,
• G3 is —SO2—(CH2)rR13
• G4 is
• wherein
• Ar1 is selected from the group consisting of phenyl, and naphthyl,
• Ar2 is selected from the group consisting of phenyl, and naphthyl, and
• G5 is —COR16 (G5) wherein
• R16 is selected from the group consisting of trifluoromethyl, C1-C6-alkoxy, C3-C6-alkenyloxy, and benzyloxy,
• and wherein aromatic rings in the substituents R1, R2, R4, R13, R14, R15, R16, AR1 and Ar2 are substituted or unsubstituted the substituted rings in R1, R2, R4, R13, R14, R15, R16 Ar1 and Ar2 having one to three substituents which are independently selected from the group consisting of halogen, cyano, C1-C6-alkyl, trifluoromethyl, C3-C8-cycloalkyl, phenyl, benzyl, hydroxy, C1-C6-alkoxy, benzyloxy, phenoxy, mercapto, C1-C6-alkylthio, carboxy, C1-C6-alkoxycarbonyl, benzyloxycarbonyl, nitro, amino, mono-C1-C6-alkylamino, di-(C1-C6-alkyl)-amino, and substituted C1-C6-alkoxy, wherein two adjacent groups on the aromatic ring may form an additional ring over a methylenedioxy bridge.

Compounds having a general formula (I) and pharmaceutically acceptable salts of formula (I)

• wherein
• R1 is selected from the group consisting of hydrogen, fluorine, methyl, trifluoromethyl and hydroxy,
• R2 and R3 are hydrogen,
• R4 is hydrogen or hydroxy,
• A is selected from the group consisting of ethylene, propylene, butylene, substituted ethylene substituted by hydroxy or one or two fluorine, substituted propylene substituted by hydroxy or one or two fluorine, and substituted butylene substituted by hydroxy or one or two fluorine,
• D is selected from the group consisting of C2-C6-alkylene, C2-C6-alkenylene, an E double bonded C2-C6-alkylene which has a double bond to ring E,
• E is piperidine,
• G is selected from the group consisting of benzyl, phenethyl, fluorenylmethyl, anthrylmethyl, diphenylmethyl, fluorenyl, dihydrodibenzocycloheptenyl, acetyl, pivaloyl, phenylacetyl, diphenylacetyl, diphenylpropionyl, naphthylacetyl, benzoyl, naphthoyl, anthrylcarbonyl, oxofluorenylcarbonyl, oxodihydroanthrylcarbonyl, dioxodihydroanthrylcarbonyl, naphthylsulfonyl, and diphenylphosphinoyl,
• wherein aromatic rings in G may be substituted independently of each other by one to three substituents which are independently selected from the group consisting of halogen, cyano, C1-C6-alkyl, trifluoromethyl, C3-C6-cycloalkyl, phenyl, benzyl, hydroxy, C1-C6-alkoxy, benzyloxy, phenoxy, mercapto, C1-C6-alkylthio, carboxy, C1-C6-alkoxycarbonyl, benzyloxycarbonyl, nitro, amino, mono-C1-C6-alkylamino, di-(C1-C6-alkyl)-amino, substituted C1-C6-alkoxy which is entirely or partially substituted by fluorine, wherein two adjacent groups in the ring may form an additional ring over a methylenedioxy bridge.

A method for the production of compounds having general formula (I)

• the method comprising:
• reacting a carboxylic acids of formula (II)
• with compounds of formula (III)
• wherein
• R1 is selected from the group consisting of hydrogen, halogen, cyano, C1-C6-alkyl, C3-C6-alkenyl, C3-C6-alkinyl, trifluoromethyl, C3-C8cycloalkyl, C1-C6-hydroxyalkyl, hydroxy, C1-C6-alkoxy, C3-C6-alkenyloxy, C3-C6-alkinyloxy, benzyloxy, C1-C7-alkanoyloxy, C2-C7-alkoxycarbonyloxy, C1-C6-alkylthio, C3-C6-alkenylthio, C3-C6-alkinylthio, C3-C8-cycloalkyloxy, C3-C8-cycloalkylthio, C2-C7-alkoxycarbonyl, aminocarbonyl, C2-C7-alkylaminocarbonyl, C3-C13-dialkylaminocarbonyl, carboxy, phenyl, phenoxy, phenylthio, NR5R6, and bridged R1R2 wherein
• R5 is selected from the group consisting of hydrogen, C1-C6-alkyl, C3-C6-alkenyl and C3-C6-alkinyl,
• R6 is selected from the group consisting of hydrogen, C1-C6-alkyl, C3-C6-alkenyl and C3-C6-alkinyl,
• R2 is selected from the group consisting of hydrogen, halogen, cyano, C1-C6-alkyl, trifluoromethyl, hydroxy, C1-C6-alkoxy, benzyloxy, C1-C7-alkanoyloxy, and bridged R1R2;
• wherein bridged R1R2 is where R1R2 are adjacent and form a bridge which is selected from the group consisting of —(CH2)4— and —(CH═CH)2— and —CH2O—CR7R8—O—, wherein
• R7 is selected from the group consisting of hydrogen and C1-C6-alkyl and
• R8 is selected from the group consisting of hydrogen and C1-C6-alkyl,
• R3 is selected from the group consisting of hydrogen, halogen, C1-C6-alkyl, trifluoromethyl and C1-C6-hydroxyalkyl;
• R4 is selected from the group consisting of hydrogen, C1-C6-alkyl, C3-C6-alkenyl, C3-C6-alkinyl, C3-C6-cycloalkyl, hydroxy, C1-C6-alkoxy and benzyloxy;
• k is 0 or 1,
• A is selected from the group consisting of C1-C6-alkylene, a substituted C1-C6-alkylene which is substituted once to three-fold by C1-C3-alkyl, hydroxy, C1-C3-alkoxy, fluorine or phenyl,
• a 1,2-cyclopropylene and an isosterically substituted C2-C6-alkylene, which has a methylene unit which is isosterically replaced by O, S, NR9, CO, SO or SO2, wherein the isosteric replacement, with the exception of CO, is not adjacent to the amide group, and wherein
• R9 is selected from the group consisting of hydrogen, C1-C6-alkyl, C3-C6-alkenyl, C3-C6-alkinyl, C1-C6-acyl and C1-C6-alkylsulfonyl,
• D is selected from the group consisting of C1-C10-alkylene, a substituted C1-C10-alkylene which is substituted once or twice by C1-C6-alkyl, hydroxy, or C1-C6-alkoxy,
• a C2-C10-alkenylene, a substituted C2-C10-alkenylene which is substituted once or twice by C1-C6-alkyl, hydroxy, C1-C6-alkoxy,
• an E double bonded C2-C10-alkenylene which has a double bond to ring E,
• an E double bonded substituted C2-C10-alkenylene which has a double bond to ring E,
• a C3-C10-alkinylene, a substituted C3-C10-alkinylene which is substituted once or twice by C1-C6-alkyl, hydroxy, or C1-C6-alkoxy, and
• an isosterically replaced C1-C10-alkylene, C2-C10-alkenylene or C3-C10-alkinylene having an isosterically replaced group having one to three methylene units are each isosterically replaced by O, S, NR10, CO, SO or SO2, wherein
• R10 has the same meaning as R9, but is selected independently therefrom,
• E is
• R11 is selected from the group consisting of hydrogen, C1-C6-alkyl, hydroxy, hydroxymethyl, carboxy and C2-C7-alkoxycarbonyl, and
• R12 is selected from the group consisting of hydrogen, C1-C6-alkyl and an oxo group adjacent to the nitrogen atom, or
• R11 and R12 together form a C1-C3-alkylene bridge under formation of a bi-cyclic ring system,
• G is selected from the group consisting of hydrogen, G1, G2, G3, G4 and G5, wherein
• G1 is
• —(CH2)r—(CR14R15)s—R13
• wherein
• r is an integer from 1 to 3 or 0,
• s is 0 or 1,
• R13 is selected from the group consisting of hydrogen, C1-C6-alkyl, C3-C6-alkenyl, C3-C6-alkinyl, C3-C8-cycloalkyl, benzyl, phenyl, anellated bi- and tricyclic aromatic or partially hydrogenated carbocyclic ring systems with 8 to 16 ring atoms and at least one aromatic ring, wherein the linkage occurs either over an aromatic or a hydrogenated ring and either directly or over a methylene group,
• R14 has the same meaning as R13, but is selected independently thereof,
• R15 is selected from the group consisting of hydrogen, hydroxy, methyl, benzyl, phenyl, anellated bi- and tricyclic aromatic or partially hydrogenated carbocyclic ring systems with 8 to 16 ring atoms and at least one aromatic ring, wherein the linkage occurs either over an aromatic or a hydrogenated ring and either directly or over a methylene group,
• G2 is selected from the group consisting of
• wherein the substituents R3 and R15 have the above meaning,
• G3 is SO2—(CH2)rR13 and
• G4 is wherein
• Ar1 is selected from the group consisting of phenyl, and naphthyl, Ar2 is selected from the group consisting of phenyl, and naphthyl, and
• G5 is —COR16 wherein
• R16 is selected from the group consisting of trifluoromethyl, C1-C6-alkoxy, C3-C6-alkenyloxy, and benzyloxy,
• and wherein aromatic rings in the substituents R1, R2, R4, R13, R14, R15, R16, AR1 and Ar2 are substituted and unsubstituted the substituted rings in R1, R2, R4, R13, R14, R15, R16, AR1 and Ar2 having substitutents which are independently selected from halogen, cyano, C1-C6-alkyl, trifluoromethyl, C3-C8-cycloalkyl, phenyl, benzyl, hydroxy, C1-C6-alkoxy, benzyloxy, phenoxy, mercapto, C1-C6-alkylthio, carboxy, C1-C6-alkoxycarbonyl, benzyloxycarbonyl, nitro, amino, mono-C1-C6-alkylamino, di-(C1-C6-alkyl)-amino, and substituted C1-C6 alkoxy which is entirely or partially substituted by fluorine, wherein two adjacent groups on the aromatic ring may form an additional ring over a methylenedioxy bridge.

Compounds of formula (I) and pharmaceutically acceptable salts of formula (I)

• wherein
• R1 is selected from the group consisting of hydrogen, halogen, cyano, C1-C6-alkyl, C3-C6-alkenyl, C3-C6-alkinyl, trifluoromethyl, C3-C8-cycloalkyl, C1-C6-hydroxyalkyl, hydroxy, C1-C6-alkoxy, C3-C6-alkenyloxy, C3-C6-alkinyloxy, benzyloxy, C2-C7-alkanoyloxy, C2-C7-alkoxycarbonyloxy, C1-C6-alkylthio, C3-C6-alkenylthio, C3-C6-alkinylthio, C3-C8-cycloalkyloxy, C3-C8-cycloalkylthio, C2-C7-alkoxycarbonyl, aminocarbonyl, C2-C7-alkylaminocarbonyl, C3-C13-dialkylaminocarbonyl, carboxy, phenyl, phenoxy, phenylthio, NR5R61 and bridged R1R2 wherein
• R5 is selected from the group consisting of hydrogen, C1-C6-alkyl, C3-C6-alkenyl and C3-C6-alkinyl,
• R6 is selected from the group consisting of hydrogen, C1-C6-alkyl, C3-C6-alkenyl and C3-C6-alkinyl,
• R2 is selected from the group consisting of hydrogen, halogen, cyano, C1-C6-alkyl, trifluoromethyl, hydroxy, C1-C6-alkoxy, benzyloxy, C1-C7-alkanoyloxy, and bridged R1R2;
• wherein bridged R1R2 is where R1R2 are adjacent and form a bridge which is selected from the group consisting of —(CH2)4— and —(CH═CH)2— and —CH2O—CR7R8—O—, wherein
• R7 is selected from the group consisting of hydrogen and C1-C6-alkyl and
• R8 is selected from the group consisting of hydrogen and C1-C6-alkyl,
• R3 is selected from the group consisting of hydrogen, halogen, C1-C6-alkyl, trifluoromethyl and C1-C6-hydroxyalkyl;
• R4 is selected from the group consisting of hydrogen, C1-C6-alkyl, C3-C6-alkenyl, C3-C6-alkinyl, C3-C6-cycloalkyl, hydroxy, C1-C10-alkoxy and benzyloxy;
• k is 0 or 1,
• A is selected from the group consisting of C1-C6-alkylene, a substituted C1-C6-alkylene which is substituted once to three-fold by C1-C3-alkyl, hydroxy, C1-C3-alkoxy, fluorine or phenyl,
• a 1,2-cyclopropylene and an isosterically substituted C2-C6-alkylene, which has a methylene unit which is isosterically replaced by O, S, NR9, CO, SO or SO2, wherein the isosteric replacement, with the exception of ═CO, is not adjacent to the amide group, and wherein
• R9 is selected from the group consisting of hydrogen, C1-C6-alkyl, C3-C6-alkenyl, C3-C6-alkinyl, C1-C6-acyl and C1-C6-alkylsulfonyl,
• wherein DEG is selected from the group consisting of