Patent EA-004403-B1 (EA)
Title: Pirazolotriazine derivatives, pharmaceutical compositions containing them, methods of treating
Inventor: ARVANITIS ARGYRIOS GEORGIOS
IPC: A61P19/10
Filed: 1997-07-23
Abstract: 1. A compound of Formula (1) and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salts or prodrugs thereof, wherein: A is N; Z is CR<2>; Ar is selected from the group: phenyl, pyridyl, where each Ar is optionally substituted with 1 to 5 R<4> groups; R<1> is independently selected at each occurrence from H, C1-C4 alkyl; R<2> is selected from H, C1-C4 alkyl; R<3> is selected from: -H, OR<7>, NR<6A>R<7A> or phenyl, substituted with 1-3 halogen atoms or morpholino, or -C1-C10 alkyl, optionally substituted with 1 to 3 substituents independently selected at each occurrence from CO2R<15>, NR<16>R<15>, phenyl, optionally substituted with halogen; R<4> is independently selected at each occurrence from: C1-C10 alkyl, halo, CN, C1-C4 haloalkyl, NR<6>R<7>, OR<7>, R<6>, R<7>, R<6A> are independently selected at each occurrence from: H, C1-C10 alkyl, C2-C8 alkoxyalkyl, C4-C12 cycloalkylalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, cyano, OR<15>, COR<15>, CO2R<15>, NR<16>R<15>, phenyl, optionally substituted with halo; R<15> and R<16> are independently selected at each occurrence from H, C1-C6 alkyl, C3-C6 alkyl; with proviso that: when A is N, Z is CR<2>, R<2> is H, R<3> is -OR<7> and R<7> is H, R<1> is not H; when A is N, Z is CR<2>, R<1> is CH3, or C2H5, R<2> is H, and R<3> is OH, H, CH3, C2H5, C6H5, n-C3H7, iso- C3H7, NHC4H9, or N(C2H5)2, then Ar is not phenyl or m-CH3-phenyl; when A is N, Z is CR<2>, R2 is H, and Ar is pyridyl, and R<3> is NR<6A>R<7A>, then R<6A> and R<7A> are not H or alkyl; when A is N, Z is CR<2>, R<1> is methyl or ethyl, R<2> is H, and R<3> is H, OH, CH3, C2H5, C6H5, n-C3 H7, iso-C3H7, NH(n-C4H9), or N(C2H5)2, then Ar is not unsubstituted phenyl or m-methylphenyl; 2. A compound of claim 1 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salts and prodrugs thereof, wherein Ar is phenyl, pyridyl, each being optionally substituted with 1-4 substituents R<4>. 3. A compound of claim 2 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salts and prodrugs thereof, wherein A is N, Z is CR<2>, Ar is 2,4-dihydrophenyl, 2,4-dimethylphenyl or 2,4,6,-trimethylphenyl, R<1> or R<2> are CH3 and R<3> is NR<6A>R<7A>. 4. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 2. 5. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 3. 6. A compound of claim 1 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salts and prodrugs thereof, wherein R<3> is NR<6A>R<7A> or OR<7>. 7. A compound of claim 1 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, wherein Ar is phenyl, pyridyl, each being optionally substituted with 1-4 substituents R<4>, R<3> is NR<6A>R<7A> or OR<7>. 8. A compound of claim 1 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, wherein Ar is phenyl, pyridyl, each being optionally substituted with 1-4 substituents R<4>, - R<3> is NR<6A>R<7A> or OR<7> - R<1> and R<2> are independently selected from H, C1-C4-alkyl. 9. A compound of claim 6 or 8 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, wherein R<6A> is independently selected from the group: -H, -C1-C10 alkyl, C2-C8 alkoxyalkyl, C4-C12 cycloalkylalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, cyano, OR<15>, COR<15>, CO2R<15>, NR<16>R<15>, phenyl, optionally substituted with halo; R<7A> is selected independently in each occurrence from the group: - H, -C5-C10 alkyl, C2-C8 alkoxyalkyl, C4-C12 cycloalkylalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, cyano, OR<15>, COR<15>, CO2R<15>, NR<16>R<15>, phenyl, optionally substituted with halo; 10. A compound of claim 6 or 8 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, wherein R<6A> and R<7A> is independently selected from the group: -C1-C4 alkyl optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, cyano, OR<15>, COR<15>, CO2R<15>, NR<16>R<15>, phenyl, optionally substituted with halo. 11. A compound of claim 6 or 8 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, wherein R<6A> is independently selected from the group: -H, -C1-C10 alkyl, C2-C8 alkoxyalkyl, C4-C12 cycloalkylalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, cyano, OR<15>, COR<15>, CO2R<15>, NR<16>R<15>, phenyl, optionally substituted with halo; R<7A> is selected independently in each occurrence from the group: -C1-C4 alkyl and each of -C1-C4 alkyl is optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, cyano, OR<15>, COR<15>, CO2R<15>, NR<16>R<15>, phenyl, optionally substituted with halo. 12. A compound of claim 6 or 8 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salts and prodrugs thereof, wherein R<6A> and R<7A> are independently H or C1-C10 alkyl, each of that C1-C10 alkyl is optionally substituted with 1-3 substituents, independently selected in each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, cyano, OR<15>, COR<15>, CO2R<15>, NR<16>R<15>, phenyl, optionally substituted with halo. 13. A compound of claim 1 of Formula (50) and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salts and prodrugs thereof, selected from the group, comprising: compound of formula (50), wherein where R<3> is -NHCH(n-Pr)2, R<4A> is Cl, R<4B> is H, R<4C> is Cl, R<4D> is H and R<4E> is H; compound of formula (50), where R<3> is -N(Et)(n-Bu), R<4A> is Cl, R<4B> is H, R<4C> is Cl, R<4D> is H and R<4E> is H; compound of formula (50), where R<3> is -(n-Pr)(CH2 and-Pr), R<4A> is Cl, R<4B> is H, R<4C> is Cl, R<4D> is H and R<4E> is H; compound of formula (50), where R<3> is -N(CH2CH2OMe)2, R<4A> is Cl, R<4B> is H, R<4C> is Cl, R<4D> is H and R<4E> is H; compound of formula (50), where R<3> is -NHCH(Et)(n-Bu), R<4A> is Cl, R<4B> is H, R<4C> is Cl, R<4D> is H and R<4E> is H; compound of formula (50), where R<3> is -NHCH(Et)(CH2OMe) R<4A> is Cl, R<4B> is H, R<4C> is Cl, R<4D> is H and R<4E> is H; compound of formula (50), where R<3> is -NHCH(CH2OMe)2, R<4A> is Cl, R<4B> is H, R<4C> is Cl, R<4D> is H and R<4E> is H; compound of formula (50), where R<3> is -N(Et)2, R<4A> is Cl, R<4B> is H, R<4C> is Cl, R<4D> is H and R<4E> is H; compound of formula (50), where R<3> is -NHCH(CH2OEt)2, R<4A> is Cl, R<4B> is H, R<4C> is Cl, R<4D> is H and R<4E> is H; compound of formula (50), where R<3> is -NHCH(Et)2, R<4A> is Cl, R<4B> is H, R<4C> is Cl, R<4D> is H and R<4E> is H; compound of formula (50), where R<3> is -N(Me)(Ph), R<4A> is Cl, R<4B> is H, R<4C> is Cl, R<4D> is H and R<4E> is H; compound of formula (50), where R<3> is -N(n-Pr)2, R<4A> is Cl, R<4B> is H, R<4C> is Cl, R<4D> is H and R<4E> is H; compound of formula (50), where R<3> is -NHCH(Et)(n-Pr), R<4A> is Cl, R<4B> is H, R<4C> is Cl, R<4D> is H and R<4E> is H; compound of formula (50), where R<3> is -NHCH(CH2OMe)2, R<4A> is Me, R<4B> is H, R<4C> is Me, R<4D> is H and R<4E> is Me; compound of formula (50), where R<3> is -NHCH(CH2OMe)2, R<4A> is Me, R<4B> is H, R<4C> is Me, R<4D> is H and R<4E> is H; compound of formula (50), where R<3> is -N(CH2CH2OMe)2, R<4A> is Me, R<4B> is H, R<4C> is Me, R<4D> is H and R<4E> is H; compound of formula (50), where R<3> is -NHCH(Et)(CH2OMe), R<4A> is Me, R<4B> is H, R<4C> is Me, R<4D> is H and R<4E> is H; compound of formula (50), where R<3> is -NHCH(Et)2, R<4A> is Me, R<4B> is H, R<4C> is Me, R<4D> is H and R<4E> is H; compound of formula (50), where R<3> is -OEt, R<4A> is Cl, R<4B> is H, R<4C> is Cl, R<4D> is H and R<4E> is H; compound of formula (50), where R<3> is -N(Et)2, R<4A> is Me, R<4B> is H, R<4C> is Me, R<4D> is H and R<4E> is H; compound of formula (50), where R<3> is -N(CH2CN)2, R<4A> is Me, R<4B> is H, R<4C> is Me, R<4D> is H and R<4E> is H; compound of formula (50), where R<3> is -NHCH(Me)(CH2OMe), R<4A> is Me, R<4B> is H, R<4C> is Me, R<4D> is H and R<4E> is H; compound of formula (50), where R<3> is -OCH(Et)(CH2OMe), R<4A> is Me, R<4B> is H, R<4C> is Me, R<4D> is H and R<4E> is H; compound of formula (50), where R<3> is -N(n-Pr)(CH2 and-Pr), R<4A> is Me, R<4B> is H, R<4C> is Me, R<4D> is H and R<4E> is H; compound of formula (50), where R<3> is -NHCH(Me)(CH2N(Me)2), R<4A> is Me, R<4B> is H, R<4C> is Me, R<4D> is H and R<4E> is H; compound of formula (50), where R<3> is -N(and-Pr)(CH2CH2CN), R<4A> is Me, R<4B> is H, R<4C> is Me, R<4D> is H and R<4E> is H; compound of formula (50), where R<3> is -N(n-Pr)(CH2CH2CN), R<4A> is Me, R<4B> is H, R<4C> is Me, R<4D> is H and R<4E> is H; compound of formula (50), where R<3> is -N(n-Bu)(CH2CN), R<4A> is Me, R<4B> is H, R<4C> is Me, R<4D> is H and R<4E> is H; compound of formula (50), where R<3> is -NHCH(Et)(CH2OMe), R<4A> is Me, R<4B> is H, R<4C> is Me, R<4D> is H and R<4E> is Me; compound of formula (50), where R<3> is -NHCH(Et)2, R<4A> is Me, R<4B> is H, R<4C> is Me, R<4D> is H and R<4E> is Me; compound of formula (50), where R<3> is -N(CH2CH2OMe)2, R<4A> is Me, R<4B> is H, R<4C