3-(Arylamino)methylene-1, 3-dihydro-2H-indol-2-ones as kinase inhibitors

A method for treating diseases related to unregulated tyrosine kinase signal transduction, the method comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound represented by the general formula I:

• 127
• wherein R′ is selected from the group consisting of halogen, NO2, CN, C1 to C4 alkyl and aryl;
• R2 is selected from the group consisting of hydrogen, C, to C8 alkyl, COCH3, CH2CH2OH, CH2CH2CH2OH and phenyl;
• R is selected from the group consisting of D, halogen, C, to C8 alkyl, CF3, OCF3, OCF2H, CH2CN, CN, SR2, (CR7R8)cC(O)OR2, C(O)N(R2)2, (CR7R8)cOR2, HNC(O)R2, HN —C(O)OR2, (CR7R8)cN(R2)2, SO2 (CR7R8)cN(R2)2, OP(O)(OR2)2, OC(O)OR2, OCH2O, HN—CH═CH, —N(COR2)CH2CH2, HC═N—NH, N═CH—S, O(CR7R8)d—R6, (CR7R8)c—R6 and NR2(CR7R8)dR6 wherein R6 is selected from the group consisting of halogen, 3-fluoropyrrolidinyl, 3-fluoropiperidinyl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 3-pyrrolinyl, pyrrolidinyl, methyl isonipecotate, N-(2-methoxyethyl)-N-methylamyl, 1,2,3,6-tetrahydropyridinyl, morpholinyl, hexamethyleneiminyl, piperazinyl-2-one, piperazinyl, N-(2-methoxyethyl)ethylaminyl, thiomorpholinyl, heptamethyleneiminyl, 1-piperazinylcarboxaldehyde, 2,3,6,7-tetrahydro-(1H)-1,4-diazepinyl-5(4H)-one, N-methylhomopiperazinyl, (dimethylamino)pyrrolidinyl, N-(2-methoxyethyl)-N-propylaminyl, isoindolinyl, nipecotamidinyl, isonipecotamidinyl, 1-acetylpiperazinyl, 3-acetamidopyrrolidinyl, trans-decahydroisoquinolinyl, cis-decahydroisoquinolinyl, N-acetylhomopiperazinyl, 3-(diethylamino)pyrrolidinyl, 1,4-dioxa-8-azaspiro[4.5]decaninyl, 1-(2-methoxyethyl)-piperazinyl, 2-pyrrolidin-3-ylpyridinyl, 4-pyrrolidin-3-ylpyridinyl, 3-(methylsulfonyl)pyrrolidinyl, 3-picolylmethylaminyl, 2-(2-methylaminoethyl)pyridinyl, 1-(2-pyrimidyl)-piperazinyl, 1-(2-pyrazinyl)-piperazinyl, 2-methylaminomethyl-1,3-dioxolane, 2-(N-methyl-2-aminoethyl)-1,3-dioxolane, 3-(N-acetyl-N-methylamino)pyrrolidinyl, 2-methoxyethylaminyl, tetrahydrofurfurylaminyl, 4-aminotetrahydropyran, 2-amino-1-methoxybutane, 2-methoxyisopropylaminyl, 1-(3-aminopropyl)imidazole, histamyl, N,N-diisopropylethylenediaminyl, 1-benzyl-3-aminopyrrolidyl 2-(aminomethyl)-5-methylpyrazinyl, 2,2-dimethyl-1,3-dioxolane-4-methanaminyl, (R)-3-amino-1-N-BOC-pyrrolidinyl, 4-amino-1,2,2,6,6-pentamethylpiperidinyl, 4-aminomethyltetrahydropyranyl, ethanolamine and lower alkyl-substituted derivatives thereof and wherein when c is 1 said CH2 may be
• 128
• and CH2CH2CH2;
• provided said alkyl or phenyl radicals may be substituted with one or two halo, hydroxy or lower alkyl amino radicals and wherein R7 and R8 are selected from the group consisting of H, F and C1-C4 alkyl or CR7R8 may represent a carbocyclic ring of from 3 to 6 carbons;
• b is 0 or an integer of from 1 to 3;
• a is 0 or an integer of from 1 to 5;
• c is 0 or an integer of from 1 to 4;
• d is an integer of from 2 to 5;
• the wavy line represents a E or Z bond and pharmaceutically acceptable salts thereof provided however said compound is not
• 3-Phenylaminomethylene-1,3-dihydro-indol-2-one,
• 3-[(3-Bromo-phenylamino)-methylene]-1,3-dihydro-indol-2-one,
• 3-[(4-Bromo-phenylamino)-methyl]-1,3-dihydro-indol-2-one,
• 3-[(3-Bromo-phenylamino)-methyl]-1,3-dihydro-indol-2-one,
• 3-[(4-Ethyl-phenylamino)-methylene]-1,3-dihydro-indol-2-one,
• 3-Ethyl-phenylamino)-methylene]-1,3-dihydro-indol-2-one,
• 3-[(4-Methoxy-phenylamino)-methylene]-1,3-dihydro-indol-2-one,
• 4-[(2-Oxo-1,3-dihydro-indol-3-ylididenemethyl)-amino]-benzoic acid ethyl ester,
• 3-[(2-Ethyl-phenylamino)-methylene}-1,3-dihydro-indol-2-one,
• 3-[(3-Fluoro-4-methyl-phenylamino)-methylene]-1,3-dihydro-indol-2-one,
• 3-[(3-Fluoro-2-methyl-phenylamino)-methylene]-1,3-dihydro-indol-2-one,
• 3-[(4-Hydroxy-phenylamino)-methylene]-1,3-dihydro-indol-2-one,
• 3-[(3-Chloro-4-hydroxy-phenylamino)-methylene]-1,3-dihydro-indol-2-one or
• 3-[(4-Fluoro-2-methyl-phenylamino)-methylene]-1,3-dihydro-indol-2-one.

A compound represented by the general formula II:

• 129
• wherein R5 is selected from the group consisting of halogen, nitro, hydroxy, hydrocarbyl, substituted hydrocarbyl, amide, thioamide, amine, thioether and sulfonyl;
• R3 is selected from the group consisting of D, halogen, nitro, hydroxy, hydrocarbyl, substituted hydrocarbyl, amide, thioamide, amine, thioether and sulfonyl and phosphonic acid;
• R4 is selected from the group consisting of hydrogen, hydrocarbyl and substituted hydrocarbyl;
• b is 0 or an integer from 1 to 3;
• a is 0 or an integer of from 1 to 5;
• the wavy line represents a E or Z bond and pharmaceutically acceptable salts thereof provided however said compound is not
• 3-Phenylaminomethylene-1,3-dihydro-indol-2-one,
• 3-[(3-Bromo-phenylamino)-methylene]-1,3-dihydro-indol-2-one,
• 3-[(4-Bromo-phenylamino)-methyl]-1,3-dihydro-indol-2-one,
• 3-[(3-Bromo-phenylamino)-methyl]-1,3-dihydro-indol-2-one,
• 3-[(4-Ethyl-phenylamino)-methylene]-1,3-dihydro-indol-2-one,
• 3-Ethyl-phenylamino)-methylene]-1,3-dihydro-indol-2-one,
• 3-[(4-Methoxy-phenylamino)-methylene]-1,3-dihydro-indol-2-one,
• 4-[(2-Oxo-1,3-dihydro-indol-3-ylididenemethyl)-amino]-benzoic acid ethyl ester,
• 3-[(2-Ethyl-phenylamino)-methylene}-1,3-dihydro-indol-2-one,
• 3-[(3-Fluoro-4-methyl-phenylamino)-methylene]-1,3-dihydro-indol-2-one,
• 3-[(3-Fluoro-2-methyl-phenylamino)-methylene]-1,3-dihydro-indol-2-one,
• 3-[(4-Hydroxy-phenylamino)-methylene]-1,3-dihydro-indol-2-one,
• 3-[(3-Chloro-4-hydroxy-phenylamino)-methylene]-1,3-dihydro-indol-2-one or
• 3-[(4-Fluoro-2-methyl-phenylamino)-methylene]-1,3-dihydro-indol-2-one.

A method for treating diseases related to unregulated tyrosine kinase signal transduction, the method comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound represented by the general formula II:

• 130
• wherein R5 is selected from the group consisting of halogen, nitro, hydroxy, hydrocarbyl, substituted hydrocarbyl, amide, thioamide, amine, thioether and sulfonyl;
• R3 is selected from the group consisting of D, halogen, nitro, hydroxy, hydrocarbyl, substituted hydrocarbyl, amide, thioamide, amine, thioether and sulfonyl and phosphonic acid;
• R4 is selected from the group consisting of hydrogen, hydrocarbyl and substituted hydrocarbyl;
• b is 0 or an integer from 1 to 3;
• a is 0 or an integer of from 1 to 5;
• the wavy line represents a E or Z bond and pharmaceutically acceptable salts thereof provided however said compound is not
• 3-Phenylaminomethylene-1,3-dihydro-indol-2-one,
• 3-[(3-Bromo-phenylamino)-methylene]-1,3-dihydro-indol-2-one,
• 3-[(4-Bromo-phenylamino)-methyl]-1,3-dihydro-indol-2-one,
• 3-[(3-Bromo-phenylamino)-methyl]-1,3-dihydro-indol-2-one,
• 3-[(4-Ethyl-phenylamino)-methylene]-1,3-dihydro-indol-2-one,
• 3-Ethyl-phenylamino)-methylene]-1,3-dihydro-indol-2-one,
• 3-[(4-Methoxy-phenylamino)-methylene]-1,3-dihydro-indol-2-one,
• 4-[(2-Oxo-1,3-dihydro-indol-3-ylididenemethyl)-amino]-benzoic acid ethyl ester,
• 3-[(2-Ethyl-phenylamino)-methylene}-1,3-dihydro-indol-2-one,
• 3-[(3-Fluoro-4-methyl-phenylamino)-methylene]-1,3-dihydro-indol-2-one,
• 3-[(3-Fluoro-2-methyl-phenylamino)-methylene]-1,3-dihydro-indol-2-one,
• 3-[(4-Hydroxy-phenylamino)-methylene]-1,3-dihydro-indol-2-one,
• 3-[(3-Chloro-4-hydroxy-phenylamino)-methylene]-1,3-dihydro-indol-2-one or
• 3-[(4-Fluoro-2-methyl-phenylamino)-methylene]-1,3-dihydro-indol-2-one.

A method for treating diseases related to unregulated tyrosine kinase signal transduction, the method comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound represented by the general formula I:

• 131
• wherein R is a nitrogen-containing radical selected from the group consisting of amino, mono and dialkylamino, piperidinyl, pyrrolidinyl, piperazinyl and morpholinyl, wherein said piperidinyl, pyrrolidinyl, piperazinyl and morpholinyl may be substituted with one or more alkyl or fluoro radicals and said nitrogen radical may be bound directly to the phenyl ring of the compound of formula I or bound to said phenyl ring by an alkyl, alkyloxy or an alkylamino linking group, R′ is selected from the group consisting of halogen, NO2, CN, C1 to C4 alkyl and aryl;
• R2 is selected from the group consisting of hydrogen, C1 to C8 alkyl and phenyl;
• provided said alkyl or phenyl radicals may be substituted with one or two halo, hydroxy or lower alkyl amino radicals;
• b is 0 or an integer of from 1 to 3;
• a is 0 or an integer of from 1 to 5;
• the wavy line represents a E or Z bond and pharmaceutically acceptable salts thereof.