Patent EA-001595-B1 (EA)
Title: Irreversible inhibitors of tyrosine kinases.
Inventor: BRIDGES ALEXANDER JAMES
IPC: C07D521/00
Filed: 1997-04-08
Abstract: 1. A nitrogen-containing heterocyclic compound having the Formula I   wherein X is -D-E-F and Y is -SR<4>, -OR<4>, -NHR<3>, or hydrogen, or X is -SR<4>, -OR<4>, -NHR<3>, or hydrogen, and Y is -D-E-F; D is  or absent; E is   F is   provided that when E is  D is not   R<1> is hydrogen, halogen, or alkyl with the number of carbon atoms from 1 to 6; R<2>, R<3>, and R<4> are independently hydrogen, alkyl with the number of carbon atoms from 1 to 6, -(CH2)n-N-piperidinyl, -(CH2)n-N-piperazinyl, -(CH2)n-N1-piperazinyl[N4-(C1-C6)alkyl], -(CH2)n-N-pyrrolidyl,-(CH2)n-pyridinyl, -(CH2)n-N-imidazolyl,-(CH2)n-imidazolyl, -(CH2)n-N-morpholino-,-(CH2)n-N-thiomorpholino-, -(CH2)n-N-hexahydroazepine or substituted alkyl with the number of carbon atoms from 1 to 6, wherein the substituents are selected from -OH, -NH2, or  A and B are independently hydrogen, alkyl with the number of hydrogen atoms from 1 to 6, -(CH2)nOH, -(CH2)n-N-piperidinyl, -(CH2)n-N-piperazinyl, -(CH2)n-N1-piperazinyl[N4-(C1-C6)alkyl], -(CH2)n-N-pyrrolidyl,-(CH2)n-N-pyridyl, -(CH2)n-imidazolyl or -(CH2)n-N-imidazolyl; Z<1>, Z<2>, or Z<3> are independently hydrogen, halogen, alkyl with the number of carbon atoms from 1 to 6, cycloalkyl with the number of carbon atoms from 3 to 8, alkoxy-group with the number of carbon atoms from 1 to 6, cycloalkoxy-group with the number of carbon atoms from 3 to 8, nitro, perfluoroalkyl with the number of carbon atoms from 1 to 6, hydroxyl, acyloxy-group with the number of carbon atoms from 1 to 6, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -NH(C3-C8cycloalkyl), -N(C3-C8 cycloalkyl)2, hydroxymethyl, acyl with the number of carbon atoms from 1 to 6, cyano-group, azido-group, thioalkyl with the number of carbon atoms from 3 to 8, sulfonylcycloalkyl with the number of carbon atoms from 3 to 8, mercapto-group, alkoxycarbonyl with the number of carbon atoms from 1 to 6, cycloalkoxycarbonyl with the number of carbon atoms from 3 to 8, alkenyl with the number of carbon atoms from 2 to 4, cycloalkenyl with the number of carbon atoms from 4 to 8, or alkynyl with the number of carbon atoms from 2 to 4; and R<5> is hydrogen, halogen, perfluoroalkyl with the number of carbon atoms from 1 to 6, 1,1-difluoroalkyl with the number of carbon atoms from 1 to 6, alkyl with the number of carbon atoms from 1 to 6, -(CH2)n-N-piperidinyl, -(CH2)n-piperazinyl, -(CH2)n-piperazinyl[N4-(C1-C6)alkyl], -(CH2)n-N-pyrrolidyl, -(CH2)n-pyridinyl, -(CH2)n-N-imidazolyl, -(CH2)n-N-morpholino-, -(CH2)n-N-thiomorpholino-,  , -CH=CH-(C1-C6)alkyl, -(CH2)n-N-hexahydroazepine, -(CH2)nNH2,-(CH2)nNH(C1-C6 alkyl), -(CH2)nN(C1-C6 alkyl)2, -1-oxo(C1-C6)alkyl, carboxy-, alkyloxycarbonyl with the number of carbon atoms from 1 to 6, N-alkylcarbamoyl with the number of carbon atoms from 1 to 6, phenyl or substituted phenyl, wherein the substituted phenyl can have from one to three substituents independently selected from Z<1>, Z<2>, Z<3> or a monocyclic heteroaryl group with 5 or 6 ring atoms, comprising at least one geteroatom selected from N, O, S and P, and each alkyl group with the number of carbon atoms from 1 to 6 can be substituted by -OH, -NH2, or NAB, where A and B are as defined above, R<6> is hydrogen or alkyl with the number of carbon atoms from 1 to 6; n is 1 to 4, p is 0 or 1, and the pharmaceutically acceptable salts, esters, amides, and prodrugs thereof. 2. A nitrogen-containing heterocyclic compound having the Formula II   wherein Q is   X is -D-E-F and Y is -SR<4>, -OR<4>, -NHR<3> or hydrogen, or X is -SR<4>, -OR<4>, -NHR<3> or hydrogen, and Y is -D-E-F; D is   or absent; E is   F is   provided that when E is   D is not   R<1> is hydrogen, halogen, or alkyl with the number of carbon atoms from 1 to 6; R<2>, R<3>, and R<4> are independently hydrogen, alkyl with the number of carbon atoms from 1 to 6, -(CH2)n-N-piperidinyl,-(CH2)n-N-piperazinyl, -(CH2)n-N1-piperazinyl[N4-(C1-C6)alkyl], -(CH2)n-N-pyrrolidyl, -(CH2)n-pyridinyl, -(CH2)n-N-imidazolyl, -(CH2)n-imidazolyl, -(CH2)n-N-morpholino-,-(CH2)n-N-thiomorpholino-, -(CH2)n-N-hexahydroazepine or substituted alkyl with the number of carbon atoms from 1 to 6, wherein the substituents are selected from -OH, -NH2, or   A and B are independently hydrogen, alkyl with the number of carbon atoms from 1 to 6, -(CH2)nOH, -(CH2)n-N-piperidinyl, -(CH2)n-N-piperazinyl, -(CH2)n-N1-piperazinyl[N4-(C1-C6)alkyl], -(CH2)n-N-pyrrolidyl, -(CH2)n-N-pyridyl, -(CH2)n-imidazolyl or -(CH2)n-N-imidazolyl; E<1>, E<2>, and E<3> are independently halogen, alkyl with the number of carbon atoms from 1 to 6, cycloalkyl with the number of carbon atoms from 3 to 8, alkoxy-group with the number of carbon atoms from 1 to 6, cycloalkoxy-group with the number of carbon atoms from 3 to 8, nitro-group, perfluoroalkyl with the number of carbon atoms from 1 to 6, hydroxyl, acyloxy-group with the number of carbon atoms from 1 to 6, -NH2, -NH(C1-C6alkyl), -N(C1-C6 alkyl)2, -NH(C3-C8cycloalkyl), -N(C3-C8 cycloalkyl)2, hydroxymethyl, acyl with the number of carbon atoms from 1 to 6, cyano-group, azido-group, thioalkyl with the number of carbon atoms from 1 to 6, sulfinylalkyl with the number of carbon atoms from 1 to 6, sulfonylalkyl with the number of carbon atoms from 1 to 6, thiocycloalkyl with the number of carbon atoms from 3 to 8, sulfinylcycloalkyl with the number of carbon atoms from 3 to 8, sulfonylcycloalkyl with the number of carbon atoms from 3 to 8, mercapto-group, alkoxycarbonyl with the number of carbon atoms from 1 to 6, cycloalkoxycarbonyl with the number of carbon atoms from 3 to 8, alkenyl with the number of carbon atoms from 2 to 4, cycloalkenyl with the number of carbon atoms from 4 to 8, or alkynyl with the number of carbon atoms from 2 to 4; and R<5> is hydrogen, halogen, perfluoroalkyl with the number of carbon atoms from 1 to 6, 1,1-difluoroalkyl with the number of carbon atoms from 1 to 6, alkyl with the number of carbon atoms from 1 to 6, -(CH2)n-N-piperidinyl, -(CH2)n-piperazinyl, -(CH2)n-piperazinyl[N4-(C1-C6)alkyl], -(CH2)n-N-pyrrolidyl, -(CH2)n-pyridinyl, -(CH2)n-N-imidazolyl, -(CH2)n-N-morpholino-, -(CH2)n-N-thiomorpholino-,   -CH=CH-(C1-C6)alkyl, -(CH2)n-N-hexahydroazepine, -(CH2)nNH2,-(CH2)nNH(C1-C6 alkyl), -(CH2)nN(C1-C6 alkyl)2, -1-oxo(C1-C6)alkyl, carboxy-, alkyloxycarbonyl with the number of carbon atoms from 1 to 6, N-alkylcarbamoyl with the number of carbon atoms from 1 to 6, phenyl or substituted phenyl, wherein the substituted phenyl can have from one to three substituents independently selected from Z<1>, Z<2>, Z<3> or a monocyclic heteroaryl group with 5 or 6 ring atoms, comprising at least one heteroatom selected from N, O, S and P, and each alkyl-group with the number of carbon atoms from 1 to 6 can be substituted with -OH, -NH2 or -NAB, where A and B are as defined above, R<6> is hydrogen or alkyl with the number of carbon atoms from 1 to 6; n is 1 to 4, p is 0 or 1 and the pharmaceutically acceptable salts, esters, amides, and prodrugs thereof. 3. A nitrogen-containing heterocyclic compound having the Formula III   wherein Q is   X is -D-E-F, and Y is -OR<4>, -NHR<3> or hydrogen, or X is -OR<4>, -NHR<3> or hydrogen, and Y is -D-E-F; D is  or absent; E is   F is   wherein when E is  D is not   R<1> is hydrogen, halogen, or alkyl with the number of carbon atoms from 1 to 6; R<2>, R<3>, and R<4> are independently hydrogen, alkyl with the number of carbon atoms from 1 to 6, -(CH2)n-N-piperidinyl, -(CH2)n-N-piperazinyl, -(CH2)n-N1-piperazinyl[N4-(C1-C6)alkyl], -(CH2)n-N-pyrrolidyl, -(CH2)n-pyridinyl, -(CH2)n-N-imidazolyl, -(CH2)n-imidazolyl, -(CH2)n-N-morpholino-, -(CH2)n-N-thiomorpholino-, -(CH2)n-N-hexahydroazepine or substituted alkyl with the number of carbon atoms from 1 to 6, wherein the substituents are selected from -OH, -NH2, or   A and B are independently hydrogen, alkyl with the number of hydrogen atoms from 1 to 6, -(CH2)nOH, -(CH2)n-N-piperidinyl, -(CH2)n-N-piperazinyl, -(CH2)n-N1-piperazinyl[N4-(C1-C6)alkyl], -(CH2)n-N-pyrrolidyl, -(CH2)n-N-pyridyl, -(CH2)n-imidazolyl, or -(CH2)n-N-imidazolyl; E<1>, E<2>, and E<3> are independently halogen, alkyl with the number of carbon atoms from 1 to 6, cycloalkyl with the number of carbon atoms from 3 to 8, alkoxy-group with the number of carbon atoms from 1 to 6, cycloalkoxy-group with the number of carbon atoms from 3 to 8, nitro-group, perfluoroalkyl with the number of carbon atoms from 1 to 6, hydroxyl, acyloxy-group with the number of carbon atoms from 1 to 6, -NH2, -NH(C1-C6alkyl), -N(C1-C6 alkyl)2, -NH(C3-C8cycloalkyl), -N(C3-C8 cycloalkyl)2, hydroxymethyl, acyl with the number of carbon atoms from 1 to 6, cyano-group, azido-group, thioalkyl with the number of carbon atoms from 1 to 6, sulfinylalkyl with the number of carbon atoms from 1 to 6, sulfonylalkyl with the number of carbon atoms from 1 to 6, thiocycloalkyl with the number of carbon atoms from 3 to 8, sulfinylcycloalkyl with the number of carbon atoms from 3 to 8, sulfonylcycloalkyl with the number of carbon atoms from 3 to 8, mercapto-group, alkoxycarbonyl with the number of carbon atoms from 1 to 6, cycloalkoxycarbonyl with the number of carbon atoms from 3 to 8, alkenyl with the number of carbon atoms from 2 to 4, cycloalkenyl with the number of carbon atoms from 4 to 8, or alkynyl with the number of carbon atoms from 2 to 4; R<5> is hydrogen, halogen, perfluoroalkyl with the number of carbon atoms from 1 to 6, 1,1-difluoroalkyl with the number of carbon atoms from 1 to 6, alkyl with the number of carbon atoms from 1 to 6, -(CH2)n-N-piperidinyl, -(CH2)n-piperazinyl, -(CH2)n-piperazinyl[N4-(C1-C6)alkyl], -(CH2)n-N-pyrrolidyl, -(CH2)n-pyridinyl, -(CH2)n-N-imidazolyl, -(CH2)n-N-morpholino-, -(CH2)n-N-thiomorpholino-,   -CH=CH-(C1-C6)alkyl, -(CH2)n-N-hexahydroazepine, -(CH2)nNH2,-(CH2)nNH(C1-C6 alkyl), -(CH2)nN(C1-C6 alkyl)2, -1-oxo(C1-C6)alkyl, carboxy-, alkyloxycarbonyl with the number of carbon atoms from 1 to 6, N-alkylcarbamoyl with the number of carbon atoms from 1 to 6, phenyl or substitute