Patent ID: 6521620
Filing Date: 2003-02-18
Classification: A61K,A61P,C07D

Abstract:
A method of inhibiting epidermal growth factor receptor tyrosine kinase by treating, with an effective inhibiting amount, a mammal, in need thereof, a compound of Formula I: where:two of A-E are nitrogen, with the remaining atom(s) carbon, X is NH or NR7, wherein R7 is lower alkyl (1-4 carbon atoms), OH, NH2, lower alkoxy (1-4 carbon atoms) or lower monoalkylamino (1-4 carbon atoms); n is 0, 1, 2; R1 is H or lower alkyl (1-4 carbon atoms); if n is 2, R1 is independently H or lower alkyl (1-4 carbon atoms) on either linking carbon atom; R2 is lower alkyl (1-4 carbon atoms), cycloalkyl (3-8 carbon atoms), lower alkoxy (1-4 carbon atoms), cycloalkoxy (3-8 carbon atoms), nitro, halo (fluoro, chloro, bromo, iodo), lower perfluoroalkyl (1-4 carbon atoms), hydroxy, lower acyloxy (1-4 carbon atoms; â€”Oâ€”C(O)R), amino, lower mono or dialkylamino (1-4 carbon atoms), lower mono or dicycloalkylamino (3-8 carbon atoms), hydroxymethyl, lower acyl (1-4 carbon atoms; â€”C(O)R), cyano, lower thioalkyl (1-4 carbon atoms), lower sulfinylalkyl (1-4 carbon atoms), lower sulfonylalkyl (1-4 carbon atoms), thiocycloalkyl (3-8 carbon atoms), sulfinylcycloalkyl (3-8 carbon atoms), sulfonylcycloalkyl (3-8 carbon atoms), sulfonamido, lower mono or dialkylsulfonamido (1-4 carbon atoms), mono or dicycloalkylsulfonamido (3-8 carbon atoms), mercapto, carboxy, carboxamido (â€”C(O)â€”NH2), lower mono or dialkylcarboxamido (1-4 carbon atoms), mono or dicycloalkylcarboxamido (3-8 carbon atoms), lower alkoxycarbonyl (1-4 carbon atoms), cycloalkoxycarbonyl (3-8 carbon atoms), lower alkenyl (2-4 carbon atoms), cycloalkenyl (4-8 carbon atoms), lower alkynyl (2-4 carbon atoms), or two R2 taken together on contiguous carbon atoms can form a carbocyclic ring of 5-7 members or a monounsaturated 1,3-dioxolanyl, 1,4-dioxanyl, 1,4-dioxepinyl, pyranyl, furanyl, pyrrolidyl, piperidinyl, thiolanyl, oxazolanyl, thiazolanyl, diazolanyl, piperazinyl, morpholino or thiomorpholino ring; and m is 0-3; Ar is phenyl, thienyl, furanyl, pyrrolyl, pyridyl, pyrimidyl, imidazoyl, pyrazinyl, oxazolyl, thiazolyl, naphthyl, benzothienyl, benzofuranyl, indolyl, quinolinyl, isoquinolinyl or quinazolinyl; R3, R4, R5 and R6 are independently, H, lower alkyl (1-4 carbon atoms), cycloalkyl (3-8 carbon atoms), lower alkoxy (1-4 carbon atoms), cycloalkoxy (3-8 carbon atoms), hydroxy, lower acyloxy (1-4 carbon atoms), amino, lower mono or dialkylamino (1-4 carbon atoms), lower mono or dicycloalkylamino (3-8 carbon atoms), lower alkyl (1-4 carbon atoms) or cycloalkyl (3-8 carbon atoms), carbonato (â€”OC(O)OR) where the R is lower alkyl of 1 to 4 carbon atoms or cycloalkyl of 3-8 carbon atoms; or ureido or thioureido or N- or O-linked urethane any one of which is optionally substituted by mono or di-lower alkyl (1-4 carbon atoms) or cycloalkyl (3-8 carbon atoms); or lower thioalkyl (1-4 carbon atoms), thiocycloalkyl (3-8 carbon atoms), mercapto, lower alkenyl (2-4 carbon atoms), hydrazino, Nâ€²-lower alkylhydrazino (1-4 carbon atoms), lower acylamino (1-4 carbon atoms), hydroxylamino, or lower O-alkylhydroxylamino (1-4 carbon atoms); or any two of R3, R4, R5 or R6 taken together on contiguous carbon atoms form a carbocyclic ring of 5-7 members or a monounsaturated ring selected from the group consisting of 1,3-dioxolanyl, 1,4-dioxanyl, 1,4-dioxepinyl, pyranyl, furanyl, pyrrolidyl, piperidinyl, thiolanyl, oxazolanyl, thiazolanyl, diazolanyl, piperazinyl, morpholino and thiomorpholino ring; any lower alkyl group substituent on any of the substituents in R3-R6 is optionally substituted with one or more groups selected from the group consisting of hydroxy, amino, lower monoalkylamino, lower dialkylamino, N-pyrrolidyl, N-piperidinyl, N-pyridinium, N-morpholino, N-thiomorpholino and N-piperazino groups; if any of the substitutents R1, R2, R3, R4, R5 or R6 contain chiral centers, or in the case of R1 create chiral centers on the linking atoms, then all stereoisomers thereof both separately and as racemic and/or diastereoisomeric mixtures are included; or a pharmaceutical salt or hydrate thereof.