Patent EA-005287-B1 (EA)
Title: Pteridinones as kinase inhibitors
Inventor: DENNY WILLIAMS ALEXANDER
IPC: C07D475/00
Filed: 2000-06-21
Abstract: 1. A compound of the formula and pharmaceutically acceptable salts, esters, amides, and prodrugs thereof, wherein: R<2> is: (CH2)n-aryl and (CH2)n-heteroaryl, wherein each of the foregoing aryl and heteroaryl groups can be unsubstituted or substituted with from 1 to 5 substituent groups selected from: (a) halogen; (b) amino, alkylamino, and dialkylamino; (c) C1-C10 alkoxy, aminoalkoxy, alkylaminoalkoxy, and dialkylaminoalkoxy; (d) hydroxy; (e) alkanoyl, aminoalkanoyl, alkylaminoalkanoyl, and dialkylaminoalkanoyl; (f) aminocarbonyl, alkylaminocarbonyl, and dialkylaminocarbonyl; (g) amino-C3-C7 cycloalkylcarbonyl, alkylamino-C3-C7 cycloalkylcarbonyl, and dialkylamino-C3-C7 cycloalkylcarbonyl; (h) COZ, CO2Z, SOZ, SO2Z, and PO3Z, where Z is hydrogen, hydroxy, C1-C10 alkoxy, C1-C10 alkyl, amino, alkylamino, dialkylamino, piperidinyl, substituted piperidinyl, morpholinyl, piperazinyl; (i) a carbocyclic group containing from 3 to 7 ring members, one or two of which may be a heteroatom selected from O or N, and wherein the carbocyclic group may be substituted with one, two, or three substituent groups selected from: (1) halogen, (2) hydroxy, (3) C1-C10alkyl, aminoalkyl, alkyl and dialkylaminoalkyl, (4) C1-C10alkoxy, (5) amino, alkylamino, dialkylamino, alkanoylamino, (6) COZ, CO2Z, SOZ, SO2Z, or PO3Z, (7) (CH2)n morpholino, (8) (CH2)n piperazinyl, (9) (CH2)n piperadinyl, R<4> and R<6> are: (a) the same or different and are independently hydrogen, C1-C10alkyl, or C1-C10alkoxy, amino, aminoalkoxy, hydroxy, mono- or dialkylamino, mono- or dialkylaminoalkoxy; (b) the same or different and are independently (CH2)n-aryl, (CH2)n-heteroaryl, arylalkyl, or heteroarylalkyl, wherein each aryl and heteroaryl is unsubstituted or substituted with up to five groups selected from halogen, hydroxy, C1-C10alkyl, C1-C10alkoxy, amino, mono- or dialkylamino; R<8> is: C1-C10alkyl or (CH2)n-carbocyclic group containing from 3-7 members, n is 0; and wherein alkyl part in said radicals having 1-10 carbon atoms; containing from 1 to 10 carbon atoms; aryl is meant an aromatic carbocyclic group having a single ring, multiple rings or multiple condensed rings in which at least one is aromatic, heteroaryl is meant one or more aromatic ring systems of 5-, 6-, or 7-members containing at least one and up to four heteroatoms selected from nitrogen, oxygen, or sulfur; carbocyclic group means a nonaromatic cyclic ring or fused rings having from 3 to 7 ring carbon members. 2. A compound of the formula and pharmaceutically acceptable salts, esters, amides, and prodrugs thereof, wherein: R<2> is: (CH2)n-aryl and (CH2)n-heteroaryl, wherein each of the foregoing aryl and heteroaryl groups can be unsubstituted or substituted with from 1 to 5 substituent groups selected from: (a) halogen; (b) amino, alkylamino, and dialkylamino; (c) C1-C10 alkoxy, aminoalkoxy, alkylaminoalkoxy, and dialkylaminoalkoxy; (d) hydroxy; (e) alkanoyl, aminoalkanoyl, alkylaminoalkanoyl, and dialkylaminoalkanoyl; (f) aminocarbonyl, alkylaminocarbonyl, and dialkylaminocarbonyl; (g) amino-C3-C7 cycloalkylcarbonyl, alkylamino-C3-C7 cycloalkylcarbonyl, and dialkylamino-C3-C7 cycloalkylcarbonyl; (h) COZ, CO2Z, SOZ, SO2Z, and PO3Z, where Z is hydrogen, hydroxy, C1-C10 alkoxy, C1-C10 alkyl, amino, alkylamino, dialkylamino, piperidinyl, substituted piperidinyl, morpholinyl, piperazinyl; (i) a carbocyclic group containing from 3 to 7 ring members, one or two of which may be a heteroatom selected from O or N, and wherein the carbocyclic group may be substituted with one, two, or three substituent groups selected from: (1) halogen, (2) hydroxy, (3) C1-C10alkyl, aminoalkyl, alkyl and dialkylaminoalkyl, (4) C1-C10alkoxy, (5) amino, alkylamino, dialkylamino, alkanoylamino, (6) COZ, CO2Z, SOZ, SO2Z, or PO3Z, (7) (CH2)n morpholino, (8) (CH2)n piperazinyl, (9) (CH2)n piperadinyl, R<4> is: (a) hydrogen, C1-C10alkyl, C1-C10alkoxy, amino, aminoalkoxy, hydroxy, mono- or dialkylamino, mono- or dialkylaminoalkoxy; (b) (CH2)n-aryl, (CH2)n-heteroaryl, arylalkyl, or heteroarylalkyl, wherein each aryl and heteroaryl is unsubstituted or substituted with up to five groups selected from halogen, hydroxy, C1-C10alkyl, C1-C10alkoxy, amino, mono- or dialkylamino; R<8> is: C1-C10alkyl or (CH2)n-carbocyclic group containing from 3-7 members, n is 0; and wherein alkyl part in said radicals having 1-10 carbon atoms; containing from 1 to 10 carbon atoms; aryl is meant an aromatic carbocyclic group having a single ring, multiple rings or multiple condensed rings in which at least one is aromatic, heteroaryl is meant one or more aromatic ring systems of 5-, 6-, or 7-members containing at least one and up to four heteroatoms selected from nitrogen, oxygen, or sulfur; carbocyclic group means a nonaromatic cyclic ring or fused rings having from 3 to 7 ring carbon members. 3. A compound of the formula and pharmaceutically acceptable salts, esters, amides, and prodrugs thereof, wherein: R<5> and R<7> are the same or different and selected from: (a) hydrogen, halogen, amino, aminoalkoxy, C1-C10alkoxy, hydroxy, mono- or dialkylamino, mono- or dialkylaminoalkoxy, aminocarbonyl, amino-C3-C7-cycloalkylcarbonyl, and N-mono- or N, N-dialkylaminocarbonyl; (b) COZ, CO2Z, SOZ, SO2Z, and PO3Z, where Z is hydrogen, hydroxy, C1-C10 alkoxy, C1-C10 alkyl, amino, alkylamino, dialkylamino, piperidinyl, substituted piperidinyl, morpholinyl, piperazinyl; (c) a carbocyclic group containing from 3 to 7 ring members, one or two of which may be a heteroatom selected from O or N, and wherein the carbocyclic group may be substituted with one, two, or three substituent groups independently selected from the group consisting of halogen, hydroxy, C1-C10alkyl, C1-C10alkoxy, amino, or mono- or dialkylamino, carboxylic acid, carboxamide, carboxylic acid ester, aryl, heteroaryl, morpholinoalkyl, piperazinylalkyl, piperadinylalkyl, tetrazolylalkyl, aminoalkyl and alkanoylamino; R<4> and R<6> are: (a) the same or different and are independently hydrogen, C1-C10alkyl, or C1-C10alkoxy, amino, aminoalkoxy, hydroxy, mono- or dialkylamino, mono- or dialkylaminoalkoxy; (b) the same or different and are independently (CH2)n-aryl, (CH2)n-heteroaryl, arylalkyl, or heteroarylalkyl, wherein each aryl and heteroaryl is unsubstituted or substituted with up to five groups selected from halogen, hydroxy, C1-C10alkyl, C1-C10alkoxy, amino, mono- or dialkylamino; R<8> is: C1-C10alkyl or (CH2)n-carbocyclic group containing from 3-7 members, n is 0; and wherein alkyl part in said radicals having 1-10 carbon atoms; containing from 1 to 10 carbon atoms; aryl is meant an aromatic carbocyclic group having a single ring, multiple rings or multiple condensed rings in which at least one is aromatic, heteroaryl is meant one or more aromatic ring systems of 5-, 6-, or 7-members containing at least one and up to four heteroatoms selected from nitrogen, oxygen, or sulfur; carbocyclic group means a nonaromatic cyclic ring or fused rings having from 3 to 7 ring carbon members. 4. A compound of the formula and pharmaceutically acceptable salts, esters, amides, and prodrugs thereof, wherein: A, B, and C are the same or different and represent N or CH, provided that at least one of A, B, or C is CH; R<5> and R<7> are the same or different and selected from: (a) hydrogen, halogen, amino, aminoalkoxy, C1-C10alkoxy, hydroxy, mono- or dialkylamino, mono- or dialkylaminoalkoxy, carbamoyl, amino-C3-C7cycloalkylcarbonyl, N-mono- or N,N-dialkylcarbamoyl, (b) a carbocyclic group containing from 3-7 members, up to two of which members are hetero atoms selected from oxygen and nitrogen, wherein the carbocyclic group is unsubstituted or substituted with one, two or three groups independently selected from the group consisting of halogen, hydroxy, C1-C10alkyl, C1-C10alkoxy, amino, mono- or dialkylamino, morpholino, piperazinyl, piperadinyl and aminoalkyl; R<4> and R<6> are (a) the same or different and are independently hydrogen, C1-C10alkyl, C1-C10 alkoxy, amino, aminoalkoxy, hydroxy, mono- or dialkylamino, mono- or dialkylaminoalkoxy; (b) the same or different and are independently (CH2)n-aryl, (CH2)n-heteroaryl, wherein each aryl and heteroaryl is unsubstituted or substituted with up to five groups selected from halogen, hydroxy, C1-C10alkyl, C1-C10alkoxy, amino, mono- or dialkylamino; R<8> is: C1-C10alkyl or (CH2)n-carbocyclic group containing from 3-7 members, n is 0; and wherein alkyl part in said radicals having 1-10 carbon atoms; containing from 1 to 10 carbon atoms; aryl is meant an aromatic carbocyclic group having a single ring, multiple rings or multiple condensed rings in which at least one is aromatic, heteroaryl is meant one or more aromatic ring systems of 5-, 6-, or 7-members containing at least one and up to four heteroatoms selected from nitrogen, oxygen, or sulfur; carbocyclic group means a nonaromatic cyclic ring or fused rings having from 3 to 7 ring carbon members. 5. A compound of the formula and pharmaceutically acceptable salts, esters, amides, and prodrugs thereof, wherein: R<5> and R<7> are the same or different and are selected from (a) hydrogen halogen, amino, aminoalkoxy, C1-C10alkoxy, hydroxy, mono- or dialkylamino, mono- or dialkylaminoalkoxy, carbamoyl, amino-C3-C7-cycloalkylcarbonyl, N-mono- or N,N-dialkylcarbamoyl, (b) COZ, CO2Z, SOZ, SO2Z, and PO3Z, where Z is hydrogen, C1-C10alkyl, hydroxy, C1-C10alkoxy, amino, mono- or dialkylamino, piperidinyl, morpholinyl or piperazinyl, (c) a carbocyclic group containing from 3-7 members, up to two of which members are hetero atoms selected from oxygen and nitrogen, wherein the carbocyclic group is unsubstituted or substituted with one, two or three groups independently selected from the group consisting of halogen, hydroxy, C1-C10alkyl, C1-C10alkoxy, amino, mono- or dialkylamino, morpholino, piperazinyl, piperadinyl, aminoalkyl and alkanoylamino; R<4>, R<6>, R<6>, and R<9> are: (a) the same or different and are independently hydrogen,