US 9,284,300 B2Granted

Pyridazinone derivatives

AssigneeMerck Patent GmbH

InventorsDieter Dorsch, Frank Stieber, Oliver Schadt, Andree Blaukat

Life of this patent

Estimating the term…

Abstract

Compounds of formula (I) and their uses as inhibitors of tyrosine kinases, in particular Met kinase, and their employment in methods for the treatment of tumors.

Claims20

Dependent claims

A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of formula I or a pharmaceutically acceptable solvate, salt, tautomer or stereoisomer thereof in an amount of 0.5 mg to 1 g per unit dosage, wherein the pharmaceutical composition is in the form of one or more dosage units,

in which
R1 denotes Ar or Het,
R2 denotes pyrimidinyl, which is unsubstituted or mono-, di- or trisubstituted by Hal, A, [C(R3)2]nOR3, N═CR3N(R3)2, SR3, NO2, CN, COOR3, CON(R3)2, NR3COA, NR3SO2A, SO2N(R3)2, S(O)mA, [C(R3)2]nN(R3)2, [C(R3)2]nHet, O[C(R3)2]pOR3, O[C(R3)2]nN(R3)2,O[C(R3)2]nC≡C[C(R3)2]nN(R3)2, O[C(R3)2]nN+O−(R3)2, O[C(R3)2]nHet, S[C(R3)2]nN(R3)2, S[C(R3)2]nHet, NR3[C(R3)2]nN(R3)2, NR3[C(R3)2]nHet, NHCON(R3)2, NHCONH[C(R3)2]nN(R3)2, NHCONH[C(R3)2]nHet, [C(R3)2]nNHCO[C(R3)2]nN(R3)2, [C(R3)2]nNHCO[C(R3)2]nHet, CON(R3)2, CONR3[C(R3)2]nN(R3)2, CONR3[C(R3)2]nNR3COOA, CONR3[C(R3)2]nOR3, CONR3[C(R3)2]nHet, COHet, COA, CH═CH—COOR3, CH═CH—N(R3)2 and/or ═O,
R3 denotes H or A,
R4, R4′ each, independently of one another, denote H, Hal, A, OR3, CN, COOR3, CON(R3)2, NR3COA, NR3SO2A, SO2N(R3)2 or S(O)m,A,
Ar denotes phenyl, naphthyl or biphenyl, each of which is unsubstituted or mono-, di- or trisubstituted by Hal, A, [C(R3)2]nOR3, [C(R3)2]nN(R3)2, SR3, NO2, CN, COOR3, CON(R3)2, NR3COA, NR3SO2A, SO2N(R3)2, S(O)m,A, CO—Het, Het,O[C(R3)2]n−N(R3)2, O[C(R3)2]nHet, NHCOOA, NHCON(R3)2, NHCOO[C(R3)2]nN(R3)2, NHCOO[C(R3)2]nHet, NHCONH[C(R3)2]nN(R3)2, NHCONH[C(R3)2]nHet, OCONH[C(R3)2]nN(R3)2, OCONH[C(R3)2]nHet, CONR3[C(R3)2]nN(R3)2, CONR3[C(R3)2]nHet and/or COA,
Het denotes a mono-, bi- or tricyclic saturated, unsaturated or aromatic heterocycle having 1 to 4 N, O and/or S atoms, which is unsubstituted or mono-, di-, tri-, tetra- or penta-substituted by Hal, A, [C(R3)2]nOR3, [C(R3)2]nN(R3)2, SR3, NO2, CN, COOR3, CON(R3)2, NR3COA, NR3SO2A, SO2N(R3)2, S(O)m,A, CO—Het1, [C(R3)2]nHet1, O[C(R3)2]nN(R3)2, O[C(R3)2]nHet1, NHCOOA, NHCON(R3)2, NHCOO[C(R3)2]nN(R3)2, NHCOO[C(R3)2]nHet1, NHCONH[C(R3)2]nN(R3)2, NHCONH[C(R3)2]nHet1, OCONH[C(R3)2]nN(R3)2, OCONH[C(R3)2]nHet1, CO—Het1, CHO, COA, ═S, ═NH, ═NA and/or ═O and where a ring nitrogen is optionally oxidized,
Het1 denotes a monocyclic saturated heterocycle having 1 to 2 N and/or O atoms, which is unsubstituted or mono- or disubstituted by A, OA, OH, Hal and/or ═O,
A denotes unbranched or branched alkyl having 1-10 C atoms, in which 1-7 H atoms are optionally replaced by F and/or in which one or two non-adjacent CH2 groups are optionally replaced by O, NH, S, SO, SO2 and/or by CH═CH groups, or cyclic alkyl having 3-7 C atoms,
Hal denotes F, Cl, Br or I,
m denotes 0, 1 or 2,
n denotes 0, 1, 2, 3 or 4, and
p denotes 1, 2, 3 or 4.

10 more elements

A pharmaceutical composition comprising a pharmaceutically acceptable carrier and one of the compounds below or a pharmaceutically acceptable solvate, salt, tautomer or stereoisomer thereof in an amount of 0.5 mg to 1 g per unit dosage, wherein the pharmaceutical composition is in the form of one or more dosage units

No.
Name and/or structure
“A1”
2-[3-(5-methylpyrimidin-2-yl)benzyl]-6-(3,4,5-trifluorophenyl)-2H-pyridazin-3-one
“A2”
6-(3,5-difluorophenyl)-2-[3-(5-methylpyrimidin-2-yl)benzyl]-2H-pyridazin-3-one
“A3”
2-[3-(4-methylpyrimidin-2-yl)benzyl]-6-(3,4,5-trifluorophenyl)-2H-pyridazin-3-one
“A4”
2-(3-pyrimidin-2-ylbenzyl)-6-(3,4,5-trifluorophenyl)-2H-pyridazin-3-one
“A13”
6-(3,5-difluorophenyl)-2-[3-(4-piperazin-1-ylpyrimidin-2-yl)-benzyl]-2H-pyridazin-3-one
“A14”
6-(3,5-difluorophenyl)-2-{3-[5-(4-methylpiperazin-1-ylmethyl)-pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one
“A15”
3-{1-[3-(5-methylpyrimidin-2-yl)benzyl]-6-oxo-1,6-dihydro-pyridazin-3-yl}benzonitrile
“A16”
N′-(2-{3-[3-(3,5-difluorophenyl)-6-oxo-6H-pyridazin-1-ylmethyl]-phenyl}pyrimidin-5-yl)-N,N-dimethylformamidine
“A17”
2-[3-(5-aminopyrimidin-2-yl)benzyl]-6-(3,5-difluorophenyl)-2H-pyridazin-3-one
“A18”
6-(3,5-difluorophenyl)-2-{3-[5-(4-methylpiperazin-1-yl)pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one
“A19”
6-(3,5-difluorophenyl)-2-[3-(5-piperazin-1-ylpyrimidin-2-yl)-benzyl]-2H-pyridazin-3-one
“A20”
2-{3-[5-(4-methylpiperazin-1-yl)pyrimidin-2-yl]benzyl}-6-(3,4,5-trifluorophenyl)-2H-pyridazin-3-one
“A21”
6-(3,5-difluorophenyl)-2-[3-(5-hydroxypyrimidin-2-yl)benzyl]-2H-pyridazin-3-one
“A22”
6-(3,5-difluorophenyl)-2-{3-[5-(3-dimethylaminopropoxy)-pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one
“A23”
“A25”
2-[3-(5-bromopyrimidin-2-yl)benzyl]-6-(3,5-difluorophenyl)-2H-pyridazin-3-one
“A26”
6-(3,5-difluorophenyl)-2-{3-[5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one
“A29”
ethyl 2-{3-[6-oxo-3-(3,4,5-trifluorophenyl)-6H-pyridazin-1-ylmethyl]phenyl}pyrimidine-5-carboxylate
“A30”
“A31”
2-{3-[6-oxo-3-(3,4,5-trifluorophenyl)-6H-pyridazin-1-ylmethyl]-phenyl}pyrimidine-5-carboxylic acid
“A32”
2-{3-[3-(3,5-difluorophenyl)-6-oxo-6H-pyridazin-1-ylmethyl]-phenyl}pyrimidine-5-carboxylic acid
“A33”
N-(2-dimethylaminoethyl)-2-{3-[6-oxo-3-(3,4,5-trifluorophenyl)-6H-pyridazin-1-ylmethyl]phenyl}pyrimidine-5-
carboxamide
“A34”
“A35”
“A36”
“A37”
“A38”
“A39”
“A40”
“A41”
“A42”
“A43”
“A44”
“A44a”
“A45”
“A46”
“A47”
“A48”
“A49”
“A50”
“A51”
N-[2-(1H-imidazol-4-yl)ethyl]-2-{3-[6-oxo-3-(3,4,5-trifluoro-phenyl)-6H-pyridazin-1-ylmethyl]phenyl}pyrimidine-5-
carboxamide
“A52”
“A53”
“A54”
2-[3-(5-chloropyrimidin-2-yl)benzyl]-6-(3,4,5-trifluorophenyl)-2H-pyridazin-3-one
“A55”
4-{1-[3-(5-methylpyrimidin-2-yl)benzyl]-6-oxo-1,6-dihydro-pyridazin-3-yl}-N-(3-piperidin-1-ylpropyl)benzamide
“A56”
6-(3,5-difluorophenyl)-2-{3-[5-(3-pyrrolidin-1-ylpropoxy)-pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one
“A57”
6-(3,5-difluorophenyl)-2-(3-{5-[2-(4-methylpiperazin-1-yl)-ethoxy]pyrimidin-2-yl}benzyl)-2H-pyridazin-3-one
“A58”
6-(3,5-difluorophenyl)-2-[3-(5-dimethylaminomethylpyrimidin-2-yl)benzyl]-2H-pyridazin-3-one
“A59”
“A60”
2-{3-[5-(3-dimethylaminopropoxy)pyrimidin-2-yl]benzyl}-6-(3,4,5-trifluorophenyl)-2H-pyridazin-3-one
“A63”
“A64”
2-{3-[5-(2-dimethylaminoethoxy)pyrimidin-2-yl]benzyl}-6-(3,5-difluorophenyl)-2H-pyridazin-3-one
“A65”
2-{3-[5-(piperazin-1-yl)pyrimidin-2-yl]benzyl}-6-(3,4,5-trifluoro-phenyl)-2H-pyridazin-3-one
“A66”
6-(3,5-difluorophenyl)-2-{3-[5-(1-methylpiperidin-4-ylmethoxy)-pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one
“A71”
“A72”
“A73”
“A74”
“A75”
“A76”
N′-(2-{3-[3-(3,4,5-trifluorophenyl)-6-oxo-6H-pyridazin-1-yl-methyl]phenyl}pyrimidin-5-yl)-N,N-dimethylformannidine
“A77”
“A78”
“A79”
“A80”
6-(3,5-difluorophenyl)-2-[3-(6-oxo-1,6-dihydropyrimidin-2-yl)-benzyl]-2H-pyridazin-3-one
“A81”
6-(3,5-difluorophenyl)-2-{3-[4-(3-dimethylaminopropoxy)-pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one
“A82”
2-[3-(5-aminopyrimidin-2-yl)benzyl]-6-(3,4,5-trifluorophenyl)-2H-pyridazin-3-one
“A83”
2-(3-pyrimidin-5-ylbenzyl)-6-(3,4,5-trifluorophenyl)-2H-pyridazin-3-one
“A84”
“A85”
N-(2-{3-[3-(3,5-difluorophenyl)-6-oxo-6H-pyridazin-1-ylmethyl]-phenyl}pyrimidin-5-yl)-2-dimethylaminoacetamide
“A87”
“A88”
“A89”
“A90”
“A92”
“A93”
2-[3-(5-aminomethylpyrimidin-2-yl)benzyl]-6-(3,4,5-trifluoro-phenyl)-2H-pyridazin-3-one
“A95”
“A96”
“A97”
“A98”
“A99”
“A100”
2-[3-(5-methylpyrimidin-2-yl)benzyl]-6-(2H-pyrazol-3-yl)-2H-pyridazin-3-one
“A101”
6-(3,5-difluorophenyl)-2-[3-(5-hydroxymethylpyrimidin-2-yl)-benzyl]-2H-pyridazin-3-one
“A102”
6-(3,5-difluorophenyl)-2-{3-[5-(piperidin-4-yloxy)pyrimidin-2-yl]-benzyl}-2H-pyridazin-3-one
“A103”
“A104”
“A105”
“A106”
“A107”
“A108”
“A109”
“A110”
“A111”
“A112”
“A113”
“A114”
“A115”
“A116”
“A117”
“A118”
“A119”
“A120”
“A121”
“A122”
6-(3,5-difluorophenyl)-2-{3-[5-((R)-1-methylpyrrolidin-3-yloxy)-pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one,
“A123”
“A124”
“A125”
“A126”
“A127”
6-(3,5-difluorophenyl)-2-{3-[5-(2-pyrrolidin-1-ylethoxy)-pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one
“A128”
6-(3,5-difluorophenyl)-2-{3-[5-(3-morpholin-4-ylpropoxy)-pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one
“A129”
“A130”
6-(3,5-difluorophenyl)-2-{3-[5-(2-morpholin-4-ylethoxy)-pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one, hydrochloride
“A131”
“A132”
6-(3,5-difluorophenyl)-2-{3-[5-(4-methylaminobutoxy)pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one
“A133”
6-(3,5-difluorophenyl)-2-{3-[5-(3-methylaminopropoxy)-pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one
“A134”
6-(3,5-difluorophenyl)-2-{3-[5-(pyrrolidin-3-ylmethoxy)-pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one
“A135”
6-(3,5-difluorophenyl)-2-{3-[5-(3-ethylaminopropoxy)pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one
“A136”
2-{3-[5-(2-aminoethoxy)pyrimidin-2-yl]benzyl1-6-(3,5-difluoro-phenyl)-2H-pyridazin-3-one
“A137”
6-(3,5-difluorophenyl)-2-{3-[5-(piperidin-3-yloxy)pyrimidin-2-yl]-benzyl}-2H-pyridazin-3-one
“A138”
6-(3,5-difluorophenyl)-2-{3-[5-(piperidin-4-ylmethoxy)pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one
“A139”
6-(3,5-difluorophenyl)-2-{3-[5-(pyrrolidin-3-yloxy)pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one
“A140”
6-(3,5-difluorophenyl)-2-{3-[5-((S)-pyrrolidin-3-yloxy)pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one
“A141”
6-(3,5-difluorophenyl)-2-{3-[5-((R)-pyrrolidin-3-yloxy)pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one
“A142”
“A143”
“A144”
3-(6-oxo-1-{3-[5-(piperidin-4-yloxy)pyrimidin-2-yl]benzyl}-1,6-dihydropyridazin-3-yl)benzonitrile
“A145”
6-(3,5-difluorophenyl)-2-{3-[5-(2-piperazin-1-ylethoxy)pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one
“A146”
6-(3,5-difluorophenyl)-2-{3-[5-(piperidin-4-yloxy)pyrimidin-2-yl]-benzyl}-2H-pyridazin-3-one
“A147”
3-(6-oxo-1-{3-[5-(2-piperazin-1-ylethoxy)pyrimidin-2-yl]benzyl}-1,6-dihydropyridazin-3-yl)benzonitrile
“A148”
6-(3-fluorophenyl)-2-{3-[5-(piperidin-4-ylmethoxy)pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one
“A149”
“A150”
“A151”
“A152”
6-(3-methoxyphenyl)-2-{3-[5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one
“A153”
6-(3-fluorophenyl)-2-{3-[5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one
“A154”
“A155”
“A156”
“A157”
“A158”
“A159”
“A160”
“A161”
“A162”
“A163”
“A164”
“A165”
“A166”
“A167”
“A168”
“A169”
“A170”
“A171”
“A172”
6-(3,5-difluorophenyl)-2-(3-{5-[1-(3-dimethylaminopropyl)-1H-pyrazol-4-yl]pyrimidin-2-yl]benzyl)-2H-pyridazin-3-one
“A173”
6-(3,5-difluorophenyl)-2-(3-{5-[1-(2-pyrrolidin-1-ylethyl)-1H-pyrazol-4-yl]pyrimidin-2-yl]benzyl)-2H-pyridazin-3-one
“A174”
“A175”
“A176”
“A177”
2-(3-{5-[1-(2-morpholin-4-ylethyl)-1H-pyrazol-4-yl]pyrimidin-2-yl}benzyl)-6-pyridin-4-yl-2H-pyridazin-3-one
“A178”
6-(4-methanesulfonylphenyl)-2-(3-{5-[1-(2-morpholin-4-ylethyl)-1H-pyrazol-4-yl]pyrimidin-2-yl]benzyl)-2H-pyridazin-3-
one
“A179”
6-pyridin-4-yl-2-(3-{5-[1-(2-pyrrolidin-1-ylethyl)-1H-pyrazol-4-yl]pyrimidin-2-yl]benzyl)-2H-pyridazin-3-one
“A180”
“A181”
2-(3-{5-[1-(2-morpholin-4-ylethyl)-1H-pyrazol-4-yl]pyrimidin-2-yl}benzyl)-6-pyridin-4-yl-2H-pyridazin-3-one
“A182”
“A183”
6-(4-methanesulfonylphenyl)-2-(3-{5-[1-(2-morpholin-4-ylethyl)-1H-pyrazol-4-yl]pyrimidin-2-yl}benzyl)-2H-pyridazin-3-
one
“A184”
“A185”
6-(3-fluorophenyl)-2-(3-{5-[1-(2-pyrrolidin-1-ylethyl)-1H-pyrazol-4-yl]pyrimidin-2-yl}benzyl)-2H-pyridazin-3-one
“A186”
“A187”
“A188”
“A188a”
“A189”
3-(1-{3-[5-(3-dimethylaminopropoxy)pyrimidin-2-yl]benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile
“A190”
“A191”
2-{3-[5-(3-dimethylaminopropoxy)pyrimidin-2-yl]benzyl}-6-(3-fluorophenyl)-2H-pyridazin-3-one
“A192”
2-{3-[5-(3-dimethylaminopropoxy)pyrimidin-2-yl]benzyl}-6-thiazol-2-yl-2H-pyridazin-3-one
“A193”
2-{3-[5-(3-dimethylaminopropoxy)pyrimidin-2-yl]benzyl}-6-phenyl-2H-pyridazin-3-one
“A194”
4-(1-{3-[5-(3-dimethylaminopropoxy)pyrimidin-2-yl]benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile
“A195”
2-{3-[5-(3-dimethylaminopropoxy)pyrimidin-2-yl]benzyl}-6-p-tolyl-2H-pyridazin-3-one
“A196”
2-{3-[5-(3-dimethylaminopropoxy)pyrimidin-2-yl]benzyl}-6-(2H-pyrazol-3-yl)-2H-pyridazin-3-one
“A197”
6-(3,4-difluorophenyl)-2-{3-[5-(3-dimethylaminopropoxy)-pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one
“A198”
2-{3-[5-(3-dimethylaminopropoxy)pyrimidin-2-yl]benzyl}-6-(4-methanesulfonylphenyl)-2H-pyridazin-3-one
“A199”
2-{3-[5-(3-dimethylaminopropoxy)pyrimidin-2-yl]benzyl}-6-[4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]-2H-pyridazin-3-one
“A200”
2-{3-[5-(3-dimethylaminopropoxy)pyrimidin-2-yl]benzyl}-6-pyridin-4-yl-2H-pyridazin-3-one
“A201”
6-(3-bromophenyl)-2-{3-[5-(3-dimethylaminopropoxy)pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one
“A202”
2-{3-[5-(3-dimethylaminopropoxy)pyrimidin-2-yl]benzyl}-6-(3,4,5-trifluorophenyl)-2H-pyridazin-3-one
“A203”
6-(3,5-dimethoxyphenyl)-2-{3-[5-(3-dimethylaminopropoxy)-pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one
“A204”
2-{3-[5-(3-dimethylaminopropoxy)pyrimidin-2-yl]benzyl}-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one
“A205”
2-{3-[5-(3-dimethylaminopropoxy)pyrimidin-2-yl]benzyl}-6-(4-methoxyphenyl)-2H-pyridazin-3-one
“A206”
2-{3-[5-(3-dimethylaminopropoxy)pyrimidin-2-yl]benzyl}-6-(3-trifluoromethylphenyl)-2H-pyridazin-3-one,
“A207”
6-(3-chlorophenyl)-2-{3-[5-(3-dimethylaminopropoxy)pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one
“A208”
2-{3-[5-(3-dimethylaminopropoxy)pyrimidin-2-yl]benzyl}-6-pyridin-3-yl-2H-pyridazin-3-one
“A209”
2-{3-[5-(3-dimethylaminopropoxy)pyrimidin-2-yl]benzyl}-6-(1-methyl-1H-pyrazol-4-yl)-2H-pyridazin-3-one
“A210”
6-(3-chloro-5-fluorophenyl)-2-{3-[5-(3-dimethylaminopropoxy)-pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one
“A211”
2-{3-[5-(3-dimethylaminopropoxy)pyrimidin-2-yl]benzyl}-6-(4-fluoro-3-methoxyphenyl)-2H-pyridazin-3-one
“A212”
6-(4-chlorophenyl)-2-{3-[5-(3-dimethylaminopropoxy)pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one
“A213”
2-{3-[5-(3-dimethylaminopropoxy)pyrimidin-2-yl]benzyl}-6-(4-fluorophenyl)-2H-pyridazin-3-one
“A214”
2-{3-[5-(3-dimethylaminopropoxy)pyrimidin-2-yl]benzyl}-6-thiophen-2-yl-2H-pyridazin-3-one
“A215”
“A216”
6-(3,4-dimethoxyphenyl)-2-{3-[5-(3-dimethylaminopropoxy)-pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one
“A217”
“A218”
2-{3-[5-(3-dimethylaminopropoxy)pyrimidin-2-yl]benzyl}-6-furan-3-yl-2H-pyridazin-3-one
“A219”
2-{3-[5-(3-dimethylaminopropoxy)pyrimidin-2-yl]benzyl}-6-(5-methyl-1,2,4-oxadiazol-3-yl)-2H-pyridazin-3-one
“A220”
4-(1-{3-[5-(1-methylpiperidin-4-yloxy)pyrimidin-2-yl]benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile
“A221”
3-(1-{3-[5-(1-methylpiperidin-4-yloxy)pyrimidin-2-yl]benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile
“A222”
3-(1-{3-[5-(2-morpholin-4-ylethoxy)pyrimidin-2-yl]benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile
“A223”
2-{3-[5-(1-methylpiperidin-4-yloxy)pyrimidin-2-yl]benzyl}-6-pyridin-4-yl-2H-pyridazin-3-one
“A224”
6-(4-methanesulfonylphenyl)-2-{3-[5-(1-methylpiperidin-4-yloxy)-pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one
“A225”
“A226”
2-{3-[5-(1-methylpiperidin-4-yloxy)pyrimidin-2-yl]benzyl}-6-(1-methyl-1H-pyrazol-4-yl)-2H-pyridazin-3-one
“A227”
“A228”
“A229”
6-(1-methyl-1H-pyrazol-4-yl)-2-{3-[5-(2-morpholin-4-ylethoxy)-pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one
“A230”
2-[3-(5-bromopyrimidin-2-yl)benzyl]-6-(1-methyl-1H-pyrazol-4-yl)-2H-pyridazin-3-one
“A231”
2-[3-(5-hydroxypyrimidin-2-yl)benzyl]-6-(1-methyl-1H-pyrazol-4-yl)-2H-pyridazin-3-one
“A235”
6-(3-fluorophenyl)-2-{3-[5-(2-morpholin-4-ylethoxy)pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one
“A237”
2-{3-[5-(1-methylpiperidin-4-ylmethoxy)pyrimidin-2-yl]benzyl}-6-(1-methyl-1H-pyrazol-4-yl)-2H-pyridazin-3-one
“A238”
2-{3-[5-(1-methylpiperidin-4-yloxy)pyrimidin-2-yl]benzyl}-6-(1-methyl-1H-pyrazol-4-yl)-2H-pyridazin-3-one
“A239”
2-[3-(5-methoxypyrimidin-2-yl)benzyl]-6-(1-methyl-1H-pyrazol-4-yl)-2H-pyridazin-3-one
“A240”
2-{3-[5-(3-methoxypropoxy)pyrimidin-2-yl]benzyl}-6-(1-methyl-1H-pyrazol-4-yl)-2H-pyridazin-3-one
“A241”
2-{3-[5-(2-methoxyethoxy)pyrimidin-2-yl]benzyl}-6-(1-methyl-1H-pyrazol-4-yl)-2H-pyridazin-3-one
“A242”
2-{3-[5-(2-morpholin-4-ylethoxy)pyrimidin-2-yl]benzyl}-6-(1-propyl-1H-pyrazol-4-yl)-2H-pyridazin-3-one
“A243”
2-(3-{5-[2-(4-methylpiperazin-1-yl)ethoxy]pyrimidin-2-yl)-benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-2H-pyridazin-3-one
“A244”
“A245”
6-(1-methyl-1H-pyrazol-4-yl)-2-{3-[5-(3-morpholin-4-ylpropoxy)-pyrimidin-2-yl]benzyl1-2H-pyridazin-3-one
“A246”
“A247”
“A248”
2-{3-[5-(2-dimethylaminoethoxy)pyrimidin-2-yl]benzyl1-6-(1-methyl-1H-pyrazol-4-yl)-2H-pyridazin-3-one
“A249”
“A250”
6-(1-methyl-1H-pyrazol-4-yl)-2-{3-[5-(2-pyrrolidin-1-ylethoxy)-pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one
“A251”
2-[3-(5-ethoxypyrimidin-2-yl)benzyl]-6-(1-methyl-1H-pyrazol-4-yl)-2H-pyridazin-3-one
“A252”
“A253”
6-(3-chlorophenyl)-2-{3-[5-(2-morpholin-4-ylethoxy)pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one
“A254”
“A255”
“A256”
“A257”
3-(1-{3-[5-(1-methylpiperidin-4-ylmethoxy)pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile
“A260”
3-(1-{3-[5-(3-dimethylaminopropoxy)pyrimidin-2-yl]benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzamide
“A261”
“A262”
3-{1-[3-(5-bromopyrimidin-2-yl)benzyl]-6-oxo-1,6-dihydro-pyridazin-3-yl}benzonitrile
“A263”
3-{1-[3-(5-hydroxypyrimidin-2-yl)benzyl]-6-oxo-1,6-dihydro-pyridazin-3-yl}benzonitrile
“A264”
3-(6-oxo-1-{3-[5-(piperidin-4-ylmethoxy)pyrimidin-2-yl]benzyl}-1,6-dihydropyridazin-3-yl)benzonitrile
“A265”
tert-butyl 4-(2-{3-[3-(3-cyanophenyl)-6-oxo-6H-pyridazin-1-ylmethyl]phenyl}pyrimidin-5-yloxymethyl)piperidine-l-
carboxylate
“A266”
6-(1-methyl-1H-pyrazol-4-yl)-2-{3-[5-(piperidin-4-yloxy)-pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one
“A267”
6-(1-methyl-1H-pyrazol-4-yl)-2-{3-[5-(piperidin-4-ylmethoxy)-pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one
“A268”
“A269”
“A270”
3-[1-(3-{5-[2-(4-methylpiperazin-1-yl)ethoxy]pyrimidin-2-yl}-benzyl)-6-oxo-1,6-dihydropyridazin-3-yl]benzonitrile
“A271”
3-(1-{3-[5-(2-methoxyethoxy)pyrimidin-2-yl]benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile
“A272”
3-(1-{3-[5-(3-methoxypropoxy)pyrimidin-2-yl]benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile
“A273”
6-(3-fluorophenyl)-2-{3-[5-(1-methylpiperidin-4-ylmethoxy)-pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one
“A274”
2-{3-[5-(1-methylpiperidin-4-yloxy)pyrimidin-2-yl]benzyl}-6-(1-propyl-1H-pyrazol-4-yl)-2H-pyridazin-3-one
“A275”
6-(3-chlorophenyl)-2-{3-[5-(1-methylpiperidin-4-ylmethoxy)-pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one
“A276”
“A276a”
“A277”
5-(1-{3-[5-(1-methylpiperidin-4-yloxy)pyrimidin-2-yl]benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)thiophene-2-carboxylic acid
“A278”
5-(1-{3-[5-(1-methylpiperidin-4-yloxy)pyrimidin-2-yl]benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)thiophene-2-carboxamide
“A279”
N-methyl-5-(1-{3-[5-(1-methylpiperidin-4-yloxy)pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)thiophene-2-
carboxamide
“A283”
methyl (E)-3-(2-{3-[6-oxo-3-(3,4,5-trifluorophenyl)-6H-pyridazin-1-ylmethyl]phenyl}pyrimidin-5-yl)acrylate
“A284”
2-{3-[54(E)-3-aminopropenyl)pyrimidin-2-yl]benzyl}-6-(3,4,5-trifluorophenyl)-2H-pyridazin-3-one
“A285”
2-{3-[5-(3-aminopropyl)pyrimidin-2-yl]benzyl}-6-(3,4,5-trifluoro-phenyl)-2H-pyridazin-3-one
“A286”
2-{3-[5-(4-methylpiperazin-1-yl)pyrimidin-2-yl]benzyl}-6-(1-methyl-1H-pyrazol-4-yl)-2H-pyridazin-3-one
“A287”
3-(1-{3-[5-(4-methylpiperazin-1-yl)pyrimidin-2-yl]benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile
“A288”
3-{6-oxo-1-[3-(5-piperazin-1-ylpyrimidin-2-yl)benzyl]-1,6-dihydropyridazin-3-yl}benzonitrile
“A289”
6-(4-methanesulfonylphenyl)-2-[3-(5-piperazin-1-ylpyrimidin-2-yl)benzyl]-2H-pyridazin-3-one
“A290”
4-{1-[3-(5-aminopyrimidin-2-yl)benzyl]-6-oxo-1,6-dihydro-pyridazin-3-yl}benzonitrile
“A291”
3-{1-[3-(5-aminopyrimidin-2-yl)benzyl]-6-oxo-1,6-dihydro-pyridazin-3-yl}benzonitrile
“A292”
6-(1-methyl-1H-pyrazol-4-yl)-2-[3-(5-piperazin-1-ylpyrimidin-2-yl)benzyl]-2H-pyridazin-3-one
“A293”
2-[3-(5-aminopyrimidin-2-yl)benzyl]-6-(1-methyl-1H-pyrazol-4-yl)-2H-pyridazin-3-one
“A294”
2-{3-[5-(2-hydroxyethoxy)pyrimidin-2-yl]benzyl}-6-(1-methyl-1H-pyrazol-4-yl)-2H-pyridazin-3-one
“A295”
3-(1-{3-[5-(3-hydroxypropoxy)pyrimidin-2-yl]benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile
“A296”
3-(1-{3-[5-(2-hydroxyethoxy)pyrimidin-2-yl]benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile
“A297”
2-{3-[5-(3-hydroxypropoxy)pyrimidin-2-yl]benzyl}-6-(1-methyl-1H-pyrazol-4-yl)-2H-pyridazin-3-one
“A298”
3-[1-(1-{3-[5-(3-dimethylaminopropoxy)pyrimidin-2-yl]phenyl}-ethyl)-6-oxo-1,6-dihydropyridazin-3-yl]benzonitrile
“A299”
6-(3,5-difluorophenyl)-2-(1-{3-[5-(3-dimethylaminopropoxy)-pyrimidin-2-yl]phenyl}ethyl)-2H-pyridazin-3-one
“A300”
6-(3,5-difluorophenyl)-2-((R)-1-{3-[5-(3-dimethylaminopropoxy)-pyrimidin-2-yl]phenyl}ethyl)-2H-pyridazin-3-one
“A301”
6-(3,5-difluorophenyl)-2-((S)-1-{3-[5-(3-dimethylaminopropoxy)-pyrimidin-2-yl]phenyl}ethyl)-2H-pyridazin-3-one
“A302”
3-(1-{3-[5-(1-methyl-1-oxypiperidin-4-ylmethoxy)pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile
“A303”
3-(1-{3-[5-(1-formylpiperidin-4-ylmethoxy)pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile
“A304”
“A305”
“A306”
“A307”
“A308”
“A309”
“A310”
“A311”
“A312”
“A313”
“A314”
or a pharmaceutically acceptable solvate, salt, tautomer or stereoisomer thereof.

451 more elements

No.
Name and/or structure
“A23”
“A30”
“A34”
“A35”
“A36”
“A37”
“A38”
“A39”
“A40”
“A41”
“A42”
“A43”
“A44”
“A44a”
“A45”
“A46”
“A47”
“A48”
“A49”
“A50”
“A52”
“A53”
“A59”
“A63”
“A71”
“A72”
“A73”
“A74”
“A75”
“A77”
“A78”
“A79”
“A84”
“A87”
“A88”
“A89”
“A90”
“A92”
“A95”
“A96”
“A97”
“A98”
“A99”
“A103”
“A104”
“A105”
“A106”
“A107”
“A108”
“A109”
“A110”
“A111”
“A112”
“A113”
“A114”
“A115”
“A116”
“A117”
“A118”
“A119”
“A120”
“A121”
“A123”
“A124”
“A125”
“A126”
“A129”
“A131”
“A142”
“A143”
“A149”
“A150”
“A151”
“A154”
“A155”
“A156”
“A157”
“A158”
“A159”
“A160”
“A161”
“A162”
“A163”
“A164”
“A165”
“A166”
“A167”
“A168”
“A169”
“A170”
“A171”
“A174”
“A175”
“A176”
“A180”
“A182”
“A184”
“A186”
“A187”
“A188”
“A188a”
“A190”
“A215”
“A217”
“A225”
“A227”
“A228”
“A244”
“A246”
“A247”
“A249”
“A252”
“A254”
“A255”
“A256”
“A261”
“A268”
“A269”
“A276”
“A276a”
“A304”
“A305”
“A306”
“A307”
“A308”
“A309”
“A310”
“A311”
“A312”
“A313”
“A314”
or a pharmaceutically acceptable solvate, salt, tautomer or stereoisomer thereof.

131 more elements

Dependencies are inferred from the claim text.

Facts

Application: 14/496,746Filed 25 Sep 2014 · division
Priority: DE 10 2007 032 50712 Jul 2007
Published: US 2015/0011534 A18 Jan 2015
Granted: 15 Mar 2016
Term ends: Not estimatedThe source records don’t support an estimate.

Classification50 codes

C07D 403/10
Containing two hetero rings: linked by a carbon chain containing aromatic rings
A61K 9/0014
Galenical forms characterised by the site of application: skin, i.e. galenical aspects of topical compositions
A61K 9/0019
Galenical forms characterised by the site of application: injectable compositions; Intramuscular, intravenous, arterial, subcutaneous…
A61K 9/0031
Galenical forms characterised by the site of application: rectum, anus

Family

PCT/EP2008/003473Parent of this division · filed 29 Apr 2008
Application13/785,580Parent of this division · filed 5 Mar 2013
Application13/785,471Parent of this division · filed 5 Mar 2013
US 8,580,781 B2Parent of this division · filed 12 Nov 2013
US 2015/0011534 A1Pre-grant publication · published 8 Jan 2015
US 8,927,540 B2Parent of this division
US 8,921,357 B2Parent of this division
Application12/668,535Parent of this division
US 2010/0234354 A1Published application
US 2013/0184260 A1Published application
US 2013/0184261 A1Published application
US 9,284,300 B2This patent

From the US filing history. Foreign family members aren’t listed.

Timeline

Citations

Open elsewhere

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Abstract

Compounds of formula (I) and their uses as inhibitors of tyrosine kinases, in particular Met kinase, and their employment in methods for the treatment of tumors.

in which
R1 denotes Ar or Het,
R2 denotes pyrimidinyl, which is unsubstituted or mono-, di- or trisubstituted by Hal, A, [C(R3)2]nOR3, N═CR3N(R3)2, SR3, NO2, CN, COOR3, CON(R3)2, NR3COA, NR3SO2A, SO2N(R3)2, S(O)mA, [C(R3)2]nN(R3)2, [C(R3)2]nHet, O[C(R3)2]pOR3, O[C(R3)2]nN(R3)2,O[C(R3)2]nC≡C[C(R3)2]nN(R3)2, O[C(R3)2]nN+O−(R3)2, O[C(R3)2]nHet, S[C(R3)2]nN(R3)2, S[C(R3)2]nHet, NR3[C(R3)2]nN(R3)2, NR3[C(R3)2]nHet, NHCON(R3)2, NHCONH[C(R3)2]nN(R3)2, NHCONH[C(R3)2]nHet, [C(R3)2]nNHCO[C(R3)2]nN(R3)2, [C(R3)2]nNHCO[C(R3)2]nHet, CON(R3)2, CONR3[C(R3)2]nN(R3)2, CONR3[C(R3)2]nNR3COOA, CONR3[C(R3)2]nOR3, CONR3[C(R3)2]nHet, COHet, COA, CH═CH—COOR3, CH═CH—N(R3)2 and/or ═O,
R3 denotes H or A,
R4, R4′ each, independently of one another, denote H, Hal, A, OR3, CN, COOR3, CON(R3)2, NR3COA, NR3SO2A, SO2N(R3)2 or S(O)m,A,
Ar denotes phenyl, naphthyl or biphenyl, each of which is unsubstituted or mono-, di- or trisubstituted by Hal, A, [C(R3)2]nOR3, [C(R3)2]nN(R3)2, SR3, NO2, CN, COOR3, CON(R3)2, NR3COA, NR3SO2A, SO2N(R3)2, S(O)m,A, CO—Het, Het,O[C(R3)2]n−N(R3)2, O[C(R3)2]nHet, NHCOOA, NHCON(R3)2, NHCOO[C(R3)2]nN(R3)2, NHCOO[C(R3)2]nHet, NHCONH[C(R3)2]nN(R3)2, NHCONH[C(R3)2]nHet, OCONH[C(R3)2]nN(R3)2, OCONH[C(R3)2]nHet, CONR3[C(R3)2]nN(R3)2, CONR3[C(R3)2]nHet and/or COA,
Het denotes a mono-, bi- or tricyclic saturated, unsaturated or aromatic heterocycle having 1 to 4 N, O and/or S atoms, which is unsubstituted or mono-, di-, tri-, tetra- or penta-substituted by Hal, A, [C(R3)2]nOR3, [C(R3)2]nN(R3)2, SR3, NO2, CN, COOR3, CON(R3)2, NR3COA, NR3SO2A, SO2N(R3)2, S(O)m,A, CO—Het1, [C(R3)2]nHet1, O[C(R3)2]nN(R3)2, O[C(R3)2]nHet1, NHCOOA, NHCON(R3)2, NHCOO[C(R3)2]nN(R3)2, NHCOO[C(R3)2]nHet1, NHCONH[C(R3)2]nN(R3)2, NHCONH[C(R3)2]nHet1, OCONH[C(R3)2]nN(R3)2, OCONH[C(R3)2]nHet1, CO—Het1, CHO, COA, ═S, ═NH, ═NA and/or ═O and where a ring nitrogen is optionally oxidized,
Het1 denotes a monocyclic saturated heterocycle having 1 to 2 N and/or O atoms, which is unsubstituted or mono- or disubstituted by A, OA, OH, Hal and/or ═O,
A denotes unbranched or branched alkyl having 1-10 C atoms, in which 1-7 H atoms are optionally replaced by F and/or in which one or two non-adjacent CH2 groups are optionally replaced by O, NH, S, SO, SO2 and/or by CH═CH groups, or cyclic alkyl having 3-7 C atoms,
Hal denotes F, Cl, Br or I,
m denotes 0, 1 or 2,
n denotes 0, 1, 2, 3 or 4, and
p denotes 1, 2, 3 or 4.

10 more elements

Facts

Application

14/496,746Filed 25 Sep 2014 · division

Priority

DE 10 2007 032 50712 Jul 2007

Published

US 2015/0011534 A18 Jan 2015

Granted

15 Mar 2016

Term ends

Not estimatedThe source records don’t support an estimate.

Classification50 codes

C07D 403/10
Containing two hetero rings: linked by a carbon chain containing aromatic rings
A61K 9/0014
Galenical forms characterised by the site of application: skin, i.e. galenical aspects of topical compositions
A61K 9/0019
Galenical forms characterised by the site of application: injectable compositions; Intramuscular, intravenous, arterial, subcutaneous…
A61K 9/0031
Galenical forms characterised by the site of application: rectum, anus

Family

PCT/EP2008/003473Parent of this division · filed 29 Apr 2008

Application13/785,580Parent of this division · filed 5 Mar 2013

Application13/785,471Parent of this division · filed 5 Mar 2013

US 8,580,781 B2Parent of this division · filed 12 Nov 2013

US 2015/0011534 A1Pre-grant publication · published 8 Jan 2015

US 8,927,540 B2Parent of this division

US 8,921,357 B2Parent of this division

Application12/668,535Parent of this division

US 2010/0234354 A1Published application

US 2013/0184260 A1Published application

US 2013/0184261 A1Published application

US 9,284,300 B2This patent

From the US filing history. Foreign family members aren’t listed.