Patent EA-003640-B1 (EA)
Title: Bicyclic pyrimidines and bicyclic 3,4-dihydropyrimidines as inhibitors of cellular proliferation
Inventor: DOBRUSIN ELLEN MYRA
IPC: A61K31/5377
Filed: 1999-05-10
Abstract: 1. A compound of Formula I and the pharmaceutically acceptable salts thereof, wherein: the dotted line represents an optional double bond; Z is N or CH; G is N or CH; W is NH, S, SO, or SO2; X is either O, S, or NR<10>; R<1>. R<2>, and R<10> are independently selected from the group consisting of: H, (CH2)nAr, wherein Ar is phenyl, 3-chlorophenyl, 2,6-dibromophenyl, 2,4,6-tribromophenyl, 1-naphthyl, 4,7-dichloro-2-naphthyl , and n is 0, 1, 2 or 3, a COR<4> group, (CH2)nheteroaryl, wherein heteroaryl having 4-9 ring atoms, of which 1-4 atoms are independently selected from the group comprising O, S and N or are 2-pyridyl, 3-methyl-2-pyridyl, 3-benzothienyl, 4-ethyl-2-benzothienyl, 2-furanyl, 3,4-diethyl-2-furanyl, pyrrolyl, pyrazolyl, imidazolyl or thiazolyl, and n is as defined above, heterocyclyl, which is cycloalkyl, having at least one heteroatom from O and S, or pyrrolidinyl, piperidyl and morpholinyl, branched or not C1-C10 alkyl, C3-C10 cycloalkyl, C2-C10 alkenyl, and C2-C10 alkynyl, wherein (CH2)nAr, (CH2)nheteroaryl, alkyl, cycloalkyl, alkenyl and alkynyl may be substituted by 1-5 moieties from the group, comprising NR<4>R<5>, N(O)R<4>R<5>, NR<4>R<5>R<6>Y, wherein Y is halogen counter-ion from the group, comprising fluoro, chloro, bromo and iodo, branched or not C1-C10 alkyl, phenyl substituted or unsubstituted by chloro in position 3, bromo in position 2, 6 or 2, 4 and 6, (CH2)nheteroaryl, wherein heteroaryl is selected from the group, comprising 2-pyridyl, 3-methyl-2-pyridyl, 3-benzothienyl, 4-ethyl-2-benzothienyl, 2-furanyl, 3,4-diethyl-2-furanyl, pyrrolyl, pyrazolyl, imidazolyl or thiazolyl, and n is as defined above, hydroxyl, branched or not C1-C10 alkoxy group, a -O-(CH2)2-O-CH3 group, phenoxy, thiol, thioalkyl, wherein alkyl is as defined above, fluoro, chloro, bromo iodo, COR<4>, CO2R<4>, CONR<4>R<5>, SO2NR<4>R<5>, SO3R<4>, PO3R<4>, aldehyde, nitrile, nitro, heteroaryloxy, wherein heteroaryl is 2-pyridyl, 3-methyl-2-pyridyl, 3-benzothienyl, 4-ethyl-2-benzothienyl, 2-furanyl, 3,4-diethyl-2-furanyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, C(O)T(CH2)mQR<4>, NHC(O)T(CH2)mQR<4>, T (CH2)mC(O)NR<4>NR<5>, T(CH2)mCO2R<4> wherein each m is independently 1-6, T is O, S, NR<4>, N(O)R<4>, NR<4>R<6>Y, or CR<4>R<5>, and Q is O, S, NR<5>, N(O)R<5>, or NR<5>R<6>Y, wherein Y is as defined above, or CR<4>R<5>, and Q is O, S, NR<5>, N(O)R<5>, or NR<5>R<6>Y, wherein Y is as defined above, when the dotted line is present, R<3> is absent, otherwise R<3> has the meanings of R<2>, wherein R<2> is as defined above, as well as OH, NR<4>R<5>, COOR<4>, OR<4>, CONR<4>R<5>, SO2NR<4>R<5>, SO3R<4>, PO3R<4>, wherein T and Q are as defined above; R<4> and R<5> are each independently selected from the group consisting of hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, N(C1-C6 alkyl)1 or 2, (CH2)nAr, wherein Ar is as defined above, C3-C10cycloalkyl, heterocyclyl, having the above meaning, heteroaryl, having the above meaning, or R<4> and R<5> together with the nitrogen to which they are attached optionally form a ring having 3 to 7 carbon atoms and said ring optionally contains 1,2, or 3 heteroatoms selected from the group consisting of nitrogen, unsubstituted or substituted by C1-C10 alkyl, or by a (CH2)nPh, wherein Ph is phenyl and n is as defined above, oxygen and sulfur, said ring is optionally substituted by 1 to 3 groups selected from OH, OR<4>, NR<4>R<5>, (CH2)mOR<4>, (CH2)mNR<4>R<5>, T-(CH2)mQR<4>, CO-T-(CH2)mQR<4>, NH(CO)T(CH2)mQR<4>, T-(CH2)mCO2R<4>, or T (CH2)mCONR<4>R<5>, wherein R<4>, R<5>, T, Q and m are as defined above, R<6> is alkyl having the above meaning; R<8> and R<9> independently are H, C1-C3 alkyl, NR<4>R<5>, N(O)R<4>R<5>, NR<4>R<5>R<6>Y, wherein R<4>, R<5> have the above meaning, hydroxy, alkoxy, having the above meaning, thiol, thioalkyl, having the above meaning, halo, having the above meaning, COR<4>, CO2R<4>, CONR<4>R<5>, SO2NR<4>R<5>, SO3R<4>, PO3R<4>, wherein R<4>, R<5> have the above meaning, CHO, CN, or NO2; wherein when the dotted line is absent, R<9> is additionally (O, (S, (NH or (NOH. 2. A compound of Claim 1 wherein Z and G both are N, W is NH, and R<8> and R<9> both are hydrogen. 3. A compound of Claim 2 wherein the dotted line is a double bond, R<3> is absent and X is O. 4. A compound of Claim 3 wherein R<1> is phenyl or substituted phenyl, pyridyl or substituted pyridyl. 5. A compound of Claim 4 wherein R<2> is an alkyl, substituted alkyl, or cycloalkyl unsubstituted or substituted. 6. A compound selected from any one of Claims 1-5 selected from: 1-Methyl-7-[4-(pyrazol-1-yl)phenylamino]pyrimido[4,5-d]pyrimidin-2(1H)-one; 1-Methyl-7-[4-(4-methylpiperazin-1-yl)phenylamino]pyrimido[4,5-d]pyrimidin-2(1H)-one; 1-Methyl-7-[4-(4-hydroxypiperidin-1-yl)phenylamino]pyrimido[4,5-d]pyrimidin-2(1H)-one; 1-Methyl-7-{4-[4-(dimethylamino)piperidin-1-yl]phenylamino}-pyrimido[4,5-d]pyrimidin-2(1H)-one; 1-Isopropyl-7-[4-(pyrazol-1-yl)phenylamino]pyrimido[4,5-d]pyrimidin-2(1H)-one; 1-Isopropyl-7-[4-(4-methylpiperazin-1-yl)phenylamino]pyrimido[4,5-d]pyrimidin-2(1H)-one; 1-Isopropyl-7-[4-(4-hydroxypiperidin-1-yl)phenylamino]pyrimido[4,5-d]pyrimidin-2(1H)-one; 1-Isopropyl-7-{4-[4-(dimethylamino)piperidin-1-yl]phenylamino}-pyrimido[4,5-d]pyrimidin-2(1H)-one; 1-Bicyclo[2.2.1]hept-2-yl-7-[4-(pyrazol-1-yl)phenylamino]pyrimido[4,5-d]pyrimidin-2(1H)-one(exo); 1-Bicyclo[2.2.1]hept-2-yl-7-[4-(4-methylpiperazin-1-yl)phenylamino]pyrimido[4,5-d]pyrimidin-2(1H)-one(exo); 1-Bicyclo[2.2.1]hept-2-yl-7-[4-(4-hydroxypiperidin-1-yl)phenylamino]pyrimido[4,5-d]pyrimidin-2(1H)-one(exo); 1-Bicyclo[2.2.1]hept-2-yl-7-{4-[4-(dimethylamino)piperidin-1-yl]phenylamino}pyrimido[4,5-d]pyrimidin-2(1H)-one(exo); 7-[4-(4-Aminoacetyl-piperazin-1-yl)-phenylamino]-1-cyclopentyl-pyrimido[4,5-d]pyrimidin-2(1H)-one; 7-{4-[4-(2-Amino-4-methyl-pentanoyl)-piperazin-1-yl]-phenylamino}-1-cyclopentyl-pyrimido[4,5-d]pyrimidin-2(1H)-one; 1-Methyl-7-{4-[4-(3-morpholin-4-ylpropyl)piperidin-1-yl]phenylamino}pyrimido[4,5-d]pyrimidin-2(1H)-one; 1-Isopropyl-7-{4-[4-(3-morpholin-4-ylpropyl)piperidin-1-yl]phenylamino}pyrimido[4,5-d]pyrimidin-2(1H)-one; 1-Cyclopentyl-7-{4-[4-(3-morpholin-4-ylpropyl)piperidin-1-yl]phenylamino}pyrimido[4,5-d]pyrimidin-2(1H)-one; 1-Bicyclo[2.2.1]hept-2-yl-7-{4-[4-(3-morpholin-4-ylpropyl)piperidin-1-yl]phenylamino}pyrimido[4,5-d]pyrimidin-2(1H)-one(exo); 1-Cyclopentyl-7-(4-methanesulfonyl-phenylamino)-pyrimido[4,5-d]pyrimidin-2(1H)-one; 1-Cyclopentyl-7-(4-fluoro-3-methyl-phenylamino)-pyrimido[4,5-d]pyrimidin-2(1H)-one; 7-[4-(3-Amino-pyrrolidin-1-yl)-phenylamino]-1-cyclopentyl-pyrimido[4,5-d]pyrimidin-2(1H)-one; 1-Cyclopentyl-7-(4-piperazin-1-yl-phenylamino)-pyrimido[4,5-d]pyrimidin-2(1H)-one; 1-Cyclopentyl-7-[4-(5-methyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-phenylamino]-pyrimido[4,5-d]pyrimidin-2(1H)-one; 7-[4-(4-Acetyl-piperazin-1-yl)-phenylamino]-1-cycloheptyl-pyrimido[4,5-d]pyrimidin-2(1H)-one; and 1-Cyclopentyl-7-(pyridin-4-ylamino)pyrimido[4,5-d]pyrimidin-2(1H)-one. 7. A compound of Claim 2 wherein the dotted line is absent, R<3> is as claimed in Claim 1 and X is O. 8. A compound of Claim 7 wherein R<1> is alkyl, pyridyl, or phenyl, each optionally substituted with hydroxy, alkoxy, NR<4>R<5>, or T(CH2)mQR<4>. 9. A compound of Claims 7 and 8 selected from: 1-Methyl-7-[4-(pyrazol-1-yl)phenylamino]-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2(1H)-one; 1-Methyl-7-[4-(4-methylpiperazin-1-yl)phenylamino]-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2(1H)-one; 1-Methyl-7-[4-(4-hydroxypiperidin-1-yl)phenylamino]-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2(1H)-one; 1-Methyl-7-{4-[4-(dimethylamino)piperidin-1-yl]phenylamino}3,4-dihydro-pyrimido[4,5-d]pyrimidin-2(1H)-one; 1-Isopropyl-7-[4-(pyrazol-1-yl)phenylamino]-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one; 1-Isopropyl-7-[4-(4-methylpiperazin-1-yl)phenylamino]-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2(1H)-one; 1-Isopropyl-7-[4-(4-hydroxypiperidin-1-yl)phenylamino]-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2(1H)-one; 1-Isopropyl-7-{4-[4-(dimethylamino)piperidin-1-yl]phenylamino}3,4-dihydro-pyrimido[4,5-d]pyrimidin-2(1H)-one; 1-Bicyclo[2.2.1]hept-2-yl-7-[4-(pyrazol-1-yl)phenylamino]-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2(1H)-one(exo); 1-Bicyclo[2.2.1]hept-2-yl-7-[4-(4-methylpiperazin-1-yl)phenylamino]-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2(1H)-one(exo); 1-Bicyclo[2.2.1]hept-2-yl-7-[4-(4-hydroxypiperidin-1-yl)phenylamino]-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2(1H)-one(exo); 1-Bicyclo[2.2.1]hept-2-yl-7-{4-[4-(dimethylamino)piperidin-1-yl]phenylamino}-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2(1H)-one(exo); 7-[4-(4-Aminoacetyl-piperazin-1-yl)-phenylamino]-1-cyclopentyl-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2(1H)-one; 7-{4-[4-(2-Amino-4-methyl-pentanoyl)-piperazin-1-yl]phenylamino}-1-cyclopentyl-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2(1H)-one; 1-Methyl-7-{4-[4-(3-morpholin-4-ylpropyl)piperidin-1-yl]phenylamino}-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2(1H)-one; 1-Isopropyl-7-{4-[4-(3-morpholin-4-ylpropyl)piperidin-1-yl]phenylamino}-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2(1H)-one; 1-Cyclopentyl-7-{4-[4-(3-morpholin-4-ylpropyl)piperidin-1-yl]phenylamino}-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2(1H)-one; 1-Bicyclo[2.2.1]hept-2-yl-7-{4-[4-(3-morpholin-4-ylpropyl)piperidin-1-yl]phenylamino}-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2(1H)-one(exo); 1-Cyclopentyl-7-(pyridin-4-ylamino)-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2(1H)-one; 1-Cyclopentyl-7-(4-methanesulfonyl-phenylamino)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one; 1-Cyclopentyl-7-(4-fluoro-3-methyl-phenylamino)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one; 7-[4-(3-Amino-pyrrolidin-1-yl)-phenylamino]-1-cyclopentyl-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2(1H)-one; 7-[4-(4-Acetyl-piperazin-1-yl)-phenylamino]-1-cyclopentyl-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2(1H)-one; 1-Cyclopentyl-7-(4-piperazin-1-yl-phenylamino)-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2(1H)-one; 1-Cyclopentyl-7-[4-(5-methyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-phenylamino]-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2(