US 8,008,317 B2 · Inhibitors of akt activtiy

Abstract

The instant invention provides for substituted naphthyridine compounds that inhibit Akt activity. In particular, the compounds disclosed selectively inhibit one or two of the Akt isoforms. The invention also provides for compositions comprising such inhibitory compounds and methods of inhibiting Akt activity by administering the compound to a patient in need of treatment of cancer.

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Drawings

Claims4

Dependent claims

A compound according to Formula E:

wherein:
a is 0 or 1;
b is 0 or 1;
m is 0, 1 or 2;
the dashed line represents an optional double bond;
R1 is selected from:
H, oxo, (C═O)aOb(C1-C10)alkyl, (C═O)aOb-aryl, (C═O)aOb(C2-C10)alkenyl, (C═O)aOb(C2-C10)alkynyl, CO2H, halo, OH, Ob(C1-C6)perfluoroalkyl, (C═O)aNR7R8, CN, (C═O)aOb(C3-C8)cycloalkyl, S(O)mNR7R8, SH, S(O)m—(C1-C10)alkyl and (C═O)aOb-heterocyclyl, said alkyl, aryl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more substituents selected from R6;
R3 is selected from:
H, oxo, (C═O)aOb(C1-C10)alkyl, (C═O)aOb-aryl, (C═O)aOb(C2-C10)alkenyl, (C═O)aOb(C2-C10)alkynyl, CO2H, halo, OH, Ob(C1-C6)perfluoroalkyl, (C═O)aNR7R8, CN, (C═O)aOb(C3-C8)cycloalkyl, S(O)mNR7R8, SH, S(O)m—(C1-C10)alkyl, (C1-C6)alkyl-heterocyclyl and (C═O)aOb-heterocyclyl, said alkyl, aryl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more substituents selected from R6;
R6 is:
(C═O)aObC1-C10 alkyl, (C═O)aObaryl, C2-C10 alkenyl, C2-C10 alkynyl, (C═O)aOb heterocyclyl, CO2H, halo, CN, OH, ObC1-C6 perfluoroalkyl, Oa(C═O)bNR7R8, oxo, CHO, (N═O)R7R8, S(O)mNR7R8, SH, S(O)m—(C1-C10)alkyl or (C═O)aObC3-C8 cycloalkyl, said alkyl, aryl, alkenyl, alkynyl, heterocyclyl, and cycloalkyl optionally substituted with one or more substituents selected from R6a;
R6a is selected from:
(C═O)aOb(C1-C10)alkyl, Oa(C1-C3)perfluoroalkyl, (C0-C6)alkylene-S(O)mRa;
SH, oxo, OH, halo, CN, (C2-C10)alkenyl, (C2-C10)alkynyl, (C3-C6)cycloalkyl, (C0-C6)alkylene-aryl, (C0-C6)alkylene-heterocyclyl, (C0-C6)alkylene-N(Rb)2, C(O)Ra, (C0-C6)alkylene-CO2Ra, C(O)H, and (C0-C6)alkylene-CO2H, said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl is optionally substituted with up to three substituents selected from Rb, OH, (C1-C6)alkoxy, halogen, CO2H, CN, Oa(C═O)b(C1-C6)alkyl, oxo, and N(Rb)2;
R7 and R8 are independently selected from:
H, (C═O)aOb(C1-C10)alkyl, (C═O)aOb(C3-C8)cycloalkyl, (C═O)aOb-aryl, (C═O)aOb-heterocyclyl, (C2-C10)alkenyl, (C2-C10)alkynyl, SH, SO2Ra, and (C═O)aNRb2, said alkyl, cycloalkyl, aryl, heterocylyl, alkenyl, and alkynyl is optionally substituted with one or more substituents selected from R6a, or R7 and R8 can be taken together with the nitrogen to which they are attached to form a monocyclic or bicyclic heterocycle with 3-7 members in each ring and optionally containing, in addition to the nitrogen, one or two additional heteroatoms selected from N, O and S, said monocyclic or bicyclic heterocycle optionally substituted with one or more substituents selected from R6a;
Ra is (C1-C6)alkyl, (C3-C6)cycloalkyl, aryl, or heterocyclyl;
and
Rb is independently:
H, (C1-C6)alkyl, aryl, heterocyclyl, (C3-C6)cycloalkyl, (C═O)aOb(C1-C6)alkyl, or S(O)mRa;
or a pharmaceutically acceptable salt, tautomer, or a stereoisomer thereof.

18 more elements

A compound according to Formula J:

wherein:
a is 0 or 1;
b is 0 or 1;
m is 0, 1 or 2;
the dashed line represents an optional double bond;
R1 is selected from:
CF3, H, oxo, (C═O)aOb(C1-C10)alkyl, (C═O)aOb-aryl, (C═O)aOb(C2-C10)alkenyl, (C═O)aOb(C2-C10)alkynyl, CO2H, halo, OH, Ob(C1-C6)perfluoroalkyl, (C═O)aNR7R8, CN, (C═O)aOb(C3-C8)cycloalkyl, S(O)mNR7R8, SH, S(O)m—(C1-C10)alkyl and (C═O)aOb-heterocyclyl, said alkyl, aryl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl is optionally substituted with one to six substituents selected from R6;
R3′ and R3″ are independently selected from:
CF3, H, oxo, (C═O)aOb(C1-C10)alkyl, (C═O)aOb-aryl, (C═O)aOb(C2-C10)alkenyl, (C═O)aOb(C2-C10)alkynyl, CO2H, halo, OH, Ob(C1-C6)perfluoroalkyl, (C═O)aNR7R8, CN, (C═O)aOb(C3-C8)cycloalkyl, S(O)mNR7R8, SH, S(O)m—(C1-C10)alkyl, (C1-C6)alkyl-heterocyclyl and (C═O)aOb-heterocyclyl, said alkyl, aryl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl is optionally substituted with one to five substituents selected from R6;
or R3′ and R3″ can be taken together with the nitrogen to which they are attached to form a piperidine or pyrrolidine which may be optionally substituted with one to five substituents selected from R6;
R4 and R5 are independently:
H, (C1-C6)alkyl, (C1-C6)alkenyl, (C1-C6)alkynyl, wherein said alkyl is optionally substituted with up to three substituents selected from:
OH and halo;
and wherein R4 and R5 can be taken together to form a (C3-C7)cycloalkyl, wherein said cycloalkyl is optionally substituted with up to three substituents selected from R6;
R6 is:
CF3, (C═O)aObC1-C10 alkyl, (C═O)aObaryl, C2-C10 alkenyl, C2-C10 alkynyl, (C═O)aOb heterocyclyl, CO2H, halo, CN, OH, ObC1-C6 perfluoroalkyl, Oa(C═O)bNR7R8, oxo, CHO, (N═O)R7R8, S(O)mNR7R8, SH, S(O)m—(C1-C10)alkyl or (C═O)aObC3-C8 cycloalkyl, said alkyl, aryl, alkenyl, alkynyl, heterocyclyl, and cycloalkyl optionally substituted with one to five substituents selected from R6a;
R6a is selected from:
CF3, (C═O)aOb(C1-C10)alkyl, Oa(C1-C3)perfluoroalkyl, (C0-C6)alkylene-S(O)mRa, SH, oxo, OH, halo, CN, (C2-C10)alkenyl, (C2-C10)alkynyl, (C3-C6)cycloalkyl, (C0-C6)alkylene-aryl, (C0-C6)alkylene-heterocyclyl, (C0-C6)alkylene-N(Rb)2, (C═O)aNRb2, C(O)Ra, (C0-C6)alkylene-CO2Ra, C(O)H, and (C0-C6)alkylene-CO2H, said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl is optionally substituted with up to three substituents selected from Rb, OH, (C1-C6)alkoxy, halogen, CO2H, CN, Oa(C═O)b(C1-C6)alkyl, oxo, and N(Rb)2;
R7 and R8 are independently selected from:
CF3, H, (C═O)aOb(C1-C10)alkyl, (C═O)aOb(C3-C8)cycloalkyl, (C═O)aOb-aryl, (C═O)aOb-heterocyclyl, (C2-C10)alkenyl, (C2-C10)alkynyl, SH, SO2Ra, and (C═O)aNRb2, said alkyl, cycloalkyl, aryl, heterocylyl, alkenyl, and alkynyl is optionally substituted with one to five substituents selected from R6a, or R7 and R8 can be taken together with the nitrogen to which they are attached to form a monocyclic or bicyclic heterocycle with 3-7 members in each ring and optionally containing, in addition to the nitrogen, one or two additional heteroatoms selected from N, O and S, said monocyclic or bicyclic heterocycle optionally substituted with one to six substituents selected from R6a;
Ra is (C1-C6)alkyl, NRb2, (C3-C6)cycloalkyl, aryl, or heterocyclyl;
and
Rb is independently:
H, (C1-C6)alkyl, NH2, aryl, heterocyclyl, (C3-C6)cycloalkyl, (C═O)aOb(C1-C6)alkyl, or S(O)mRa;
or a pharmaceutically acceptable salt, tautomer, or a stereoisomer thereof.

22 more elements

A compound which is selected from:

9-phenyl-8-(4-{[4-(5-pyridin-2-yl-1H-1,2,4-triazol-3-yl)piperidin-1-yl]methyl}phenyl) [1,2,4]triazolo[3,4-f]-1,6-naphthyridin-3-amine;
9-phenyl-8-(4-{[4-(5-pyridin-2-yl-1H-1,2,4-triazol-3-yl)piperidin-1-yl]methyl}phenyl)[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-3-ol;
9-phenyl-8-(4-{[4-(4-pyridin-2-yl-1H-imidazol-1-yl)piperidin-1-yl]methyl}phenyl) [1,2,4]triazolo[3,4-f]-1,6-naphthyridin-3-amine;
9-phenyl-8-(4-{[4-(5-pyridin-2-yl-1H-1,2,4-triazol-3-yl)piperidin-1-yl]methyl}phenyl)[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-3-thiol;
3-methyl-9-phenyl-8-(4-{[4-(5-pyridin-2-yl-1H-1,2,4-triazol-3-yl)piperidin-1-yl]methyl}phenyl)[1,2,4]triazolo[3,4-f]-1,6-naphthyridine;
9-phenyl-8-(4-{[4-(5-pyridin-2-yl-1H-1,2,4-triazol-3-yl)piperidin-1-yl]methyl}phenyl)[1,2,4]triazolo[3,4-f]-1,6-naphthyridine;
3-(chloromethyl)-9-phenyl-8-(4-{[4-(4-pyridin-2-yl-1H-imidazol-1-yl)piperidin-1-yl]methyl}phenyl) [1,2,4]triazolo[3,4-f]-1,6-naphthyridine;
3-[(4-methylpiperazin-1-yl)methyl]-9-phenyl-8-(4-{[4-(5-pyridin-2-yl-1H-1,2,4-triazol-3-yl)piperidin-1-yl]methyl}phenyl) [1,2,4]triazolo[3,4-f]-1,6-naphthyridine;
2-({[9-phenyl-8-(4-{[4-(5-pyridin-2-yl-1H-1,2,4-triazol-3-yl)piperidin-1-yl]methyl}phenyl) [1,2,4]triazolo[3,4-f]-1,6-naphthyridin-3-yl]methyl}amino)ethanol;
8-(4-Aminomethyl-phenyl)-9-phenyl-[1,2,4]triazolo[3,4-f][1,6]naphthyridin-3-ol;
1-[4-(9-Phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)phenyl]methanamine;
4-(3-Methyl-9-phenyl-[1,2,4]triazolo[3,4-f][1,6]naphthyridin-8-yl)-benzylamine;
8-[4-(Aminomethyl)phenyl]-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-3-amine;
1-[4-(9-Phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)phenyl]ethanamine;
9-Phenyl-8-{4-[4-(5-pyridin-2-yl-4H-[1,2,4]triazol-3-yl)-piperidin-1-ylmethyl]-phenyl}-[1,2,4]triazolo[3,4-f][1,6]naphthyridine;
9-phenyl-8-(4-{[4-(5-pyridin-2-yl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]methyl}phenyl)-3-(1H-1,2,3-triazol-4-yl)[1,2,4]triazolo[3,4-f]-1,6-naphthyridine;
3-(1H-imidazol-4-yl)-9-phenyl-8-(4-{[4-(5-pyridin-2-yl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]methyl}phenyl) [1,2,4]triazolo[3,4-f]-1,6-naphthyridine;
tert-butyl[9-phenyl-8-(4-{[4-(5-pyridin-2-yl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]methyl}phenyl)
[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-3-yl]methylcarbamate;
[9-phenyl-8-(4-{[4-(5-pyridin-2-yl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]methyl}phenyl)[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-3-yl]methanol;
5-[9-phenyl-8-(4-{[4-(5-pyridin-2-yl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]methyl}phenyl) [1,2,4]triazolo[3,4-f]-1,6-naphthyridin-3-yl]-2,4-dihydro-3H-1,2,4-triazol-3-one;
3-(3-methyl-1H-1,2,4-triazol-5-yl)-9-phenyl-8-(4-{[4-(5-pyridin-2-yl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]methyl}phenyl)[1,2,4]triazolo[3,4-f]-1,6-naphthyridine;
3-imidazo[2,1-b][1,3]thiazol-6-yl-9-phenyl-8-(4-{[4-(5-pyridin-2-yl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]methyl}phenyl)[1,2,4]triazolo[3,4-f]-1,6-naphthyridine;
9-phenyl-8-(4-{[4-(5-pyridin-2-yl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]methyl}phenyl)-3-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl[1,2,4]triazolo[3,4-f]-1,6-naphthyridine;
3-imidazo[1,2-a]pyridin-2-yl-9-phenyl-8-(4-{[4-(5-pyridin-2-yl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]methyl}phenyl) [1,2,4]triazolo[3,4-f]-1,6-naphthyridine;
9-phenyl-8-(4-{[4-(5-pyridin-2-yl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]methyl}phenyl)-3-(1H-1,2,4-triazol-5-yl)[1,2,4]triazolo[3,4-f]-1,6-naphthyridine;
3-(1H-benzimidazol-6-yl)-9-phenyl-8-(4-{[4-(5-pyridin-2-yl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]methyl}phenyl) [1,2,4]triazolo[3,4-f]-1,6-naphthyridine;
3-(1,5-dimethyl-1H-pyrazol-3-yl)-9-phenyl-8-(4-{[4-(5-pyridin-2-yl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]methyl}phenyl)[1,2,4]triazolo[3,4-f]-1,6-naphthyridine;
3-imidazo[1,2-a]pyrimidin-2-yl-9-phenyl-8-(4-{[4-(5-pyridin-2-yl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]methyl}phenyl) [1,2,4]triazolo[3,4-f]-1,6-naphthyridine;
5-[9-phenyl-8-(4-{[4-(5-pyridin-2-yl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]methyl}phenyl) [1,2,4]triazolo[3,4-f]-1,6-naphthyridin-3-yl]pyridin-2-amine;
9-phenyl-3-pyrazolo[1,5-a]pyrimidin-3-yl-8-(4-{[4-(5-pyridin-2-yl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]methyl}phenyl) [1,2,4]triazolo[3,4-f]-1,6-naphthyridine;
3-(5-methyl-1H-pyrazol-3-yl)-9-phenyl-8-(4-{[4-(5-pyridin-2-yl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]methyl}phenyl) [1,2,4]triazolo[3,4-f]-1,6-naphthyridine;
3-[9-phenyl-8-(4-{[4-(5-pyridin-2-yl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]methyl}phenyl) [1,2,4]triazolo[3,4-f]-1,6-naphthyridin-3-yl]pyridin-2-amine;
4-[9-phenyl-8-(4-{[4-(5-pyridin-2-yl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]methyl}phenyl) [1,2,4]triazolo[3,4-f]-1,6-naphthyridin-3-yl]phenol;
3-[9-phenyl-8-(4-{[4-(5-pyridin-2-yl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]methyl}phenyl) [1,2,4]triazolo[3,4-f]-1,6-naphthyridin-3-yl]phenol;
2-[9-phenyl-8-(4-{[4-(5-pyridin-2-yl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]methyl}phenyl) [1,2,4]triazolo[3,4-f]-1,6-naphthyridin-3-yl]phenol;
1-{4-[3-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]benzyl}piperidine-4-carboxamide;
1-[4-(3-imidazo[1,2-a]pyridin-2-yl-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)benzyl]piperidine-4-carboxamide;
9-phenyl-8-(4-{[4-(5-pyrazin-2-yl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]methyl}phenyl) [1,2,4]triazolo[3,4-f]-1,6-naphthyridine;
9-phenyl-8-(4-{[4-(5-pyrimidin-2-yl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]methyl}phenyl)-3-(1H-1,2,3-triazol-4-yl)[1,2,4]triazolo[3,4-f]-1,6-naphthyridine;
3-(1-methyl-1H-imidazol-4-yl)-9-phenyl-8-(4-{[4-(5-pyrimidin-2-yl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]methyl}phenyl) [1,2,4]triazolo[3,4-f]-1,6-naphthyridine;
3-(1-methyl-1H-imidazol-4-yl)-9-phenyl-8-(4-{[4-(5-pyridin-2-yl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]methyl}phenyl) [1,2,4]triazolo[3,4-f]-1,6-naphthyridine;
3-(1-methyl-1H-imidazol-4-yl)-9-phenyl-8-(4-{[4-(5-pyrazin-2-yl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]methyl}phenyl) [1,2,4]triazolo[3,4-f]-1,6-naphthyridine;
N-[2-(4-methyl-1H-imidazol-2-yl)ethyl]-N-{4-[3-(1-methyl-1H-imidazol-4-yl)-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]benzyl}amine;
N1-(2-hydroxyphenyl)-N3-{4-[3-(1-methyl-1H-imidazol-4-yl)-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]benzyl}-beta-alaninamide;
1-{4-[3-(1-methyl-1H-imidazol-4-yl)-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]benzyl}piperidine-4-carboxamide;
5-[({4-[3-(1-methyl-1H-imidazol-4-yl)-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]benzyl}amino)methyl]pyridin-2-ol;
N1,N1,2,2-tetramethyl-N3-{4-[3-(1-methyl-1H-imidazol-4-yl)-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]benzyl}propane-1,3-diamine;
3-hydroxy-2,2-dimethyl-N-[4-(3-methyl-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)benzyl]propan-1-amine;
2-fluoro-3-hydroxy-N-[4-(3-methyl-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)benzyl]propan-1-amine;
2,2-difluoro-3-hydroxy-N-[4-(3-methyl-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)benzyl]propan-1-amine;
2,3-dihydroxy-N-[4-(3-methyl-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)benzyl]propan-1-amine;
4-hydroxy-N-[4-(3-methyl-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)benzyl]cyclohexanamine;
4-hydroxy-N-[4-(3-methyl-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)benzyl]cyclohexanamine;
3-hydroxy-2,2-dimethyl-N-{4-[3-(1-methyl-1H-imidazol-4-yl)-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]benzyl}propan-1-amine;
3-hydroxy-2,2-dimethyl-N-[4-(9-phenyl-3-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)benzyl]propan-1-amine;
3-hydroxy-2,2-dimethyl-N-[4-(9-phenyl-3-pyrazolo[1,5-a]pyrimidin-2-yl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)benzyl]propan-1-amine;
3-hydroxy-2,2-dimethyl-N-{4-[9-phenyl-3-(1H-1,2,3-triazol-4-yl) [1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]benzyl}propan-1-amine;
tert-butyl {[8-(4-{[(3-hydroxy-2,2-dimethylpropyl)amino]methyl}phenyl)-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-3-yl]methyl}carbamate;
N-{4-[3-(ammoniomethyl)-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]benzyl}-3-hydroxy-2,2-dimethylpropan-1-amine;
[9-phenyl-8-(4-{[4-(5-pyrazin-2-yl-4H-1,2,4-triazol-3-yl)piperidin-1yl]methyl}phenyl)[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-3-yl]methanol;
N3-{4-[3-(hydroxymethyl)-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]benzyl}-N1-(2-hydroxyphenyl)-beta-alaninamide;
(8-{4-[(cyclohexylamino)methyl]phenyl}-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-3-yl)methanol;
N3-{4-[3-(hydroxymethyl)-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]benzyl}-N1-(4-hydroxyphenyl)-beta-alaninamide;
[9-phenyl-8-(4-{[4-(5-pyridin-3-yl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]methyl}phenyl)[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-3-yl]methanol;
1-{4-[3-(hydroxymethyl)-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]benzyl}piperidine-4-carboxamide;
{8-[4-(1-aminocyclopropyl)phenyl]-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-3-yl}methanol;
1-[4-(9-phenyl-3-pyridin-4-yl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)phenyl]methanamine;
1-{4-[3-(1-oxidopyridin-3-yl)-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]phenyl}methanamine;
1-[4-(3,9-diphenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)phenyl]methanamine;
1-{4-[3-(4-fluorophenyl)-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]phenyl}methanamine;
4-{8-[4-(aminomethyl)phenyl]-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-3-yl}benzonitrile;
4-(9-phenyl-3-pyrimidin-4-yl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)benzylamine;
1-{4-[3-(1-oxidopyridin-2-yl)-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]phenyl}methanamine;
5-{8-[4-(aminomethyl)phenyl]-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-3-yl}yridine-2-ol;
1-[4-(9-phenyl-3-pyridin-3-yl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)phenyl]methanamine;
4-(9-phenyl-3-pyrimidin-2-yl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)benzylamine;
1-[4-(9-phenyl-3-pyridin-2-yl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)phenyl]methanamine;
1-[4-(9-phenyl-3-pyrazin-2-yl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)phenyl]methanamine;
1-{4-[9-phenyl-3-(1H-1,2,4-triazol-3-yl)[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]phenyl}methanamine;
1-{4-[9-phenyl-3-(1,3-thiazol-4-yl)[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]phenyl}methanamine;
1-{4-[9-phenyl-3-(1H-pyrazol-4-yl) [1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]phenyl}methanamine;
1-{4-[3-(3-methyl-1H-pyrazol-4-yl)-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]phenyl}methanamine;
1-{4-[3-(3-methyl-1H-1,2,4-triazol-5-yl)-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]phenyl}methanamine;
1-{4-[3-(1-methyl-1H-pyrazol-4-yl)-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]phenyl}methanamine;
1-{4-[9-phenyl-3-(1,2,5-thiadiazol-3-yl) [1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]phenyl}methanamine;
1-{4-[9-phenyl-3-(1,2,3-thiadiazol-4-yl) [1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]phenyl}methanamine;
1-[4-(9-phenyl-3-pyrazolo[1,5-a]pyrimidin-3-yl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)phenyl]methanamine;
{8-[4-(aminomethyl)phenyl]-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-3-yl}methanamine;
{8-[4-(aminomethyl)phenyl]-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-3-yl}methanol;
1-{4-[9-phenyl-3-(2,2,2-trifluoroethyl)[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]phenyl}methanamine;
1-{4-[9-phenyl-3-(1H-tetraazol-1-ylmethyl) [1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]phenyl}methanamine;
8-[4-(aminomethyl)phenyl]-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridine-3-carboxamide;
1-{4-[3-(1H-imidazol-1-ylmethyl)-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]phenyl}methanamine;
1-(4-{3-[(methylsulfonyl)methyl]-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl}phenyl)methanamine;
{8-[4-(aminomethyl)phenyl]-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-3-yl}acetonitrile;
2-{8-[4-(aminomethyl)phenyl]-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-3-yl}ethanol;
N-({8-[4-(aminomethyl)phenyl]-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-3-yl}methyl)acetamide;
4-[3-(2-methylimidazo[1,2-a]pyridin-3-yl)-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]benzylamine;
1-[4-(9-phenyl-3-pyrazolo[1,5-a]pyridin-3-yl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)phenyl]methanamine;
1-[4-(3-imidazo[1,2-a]pyridin-2-yl-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)phenyl]methanamine;
1-{4-[9-phenyl-3-(4,5,6,7-tetrahydro-1,2-benzisoxazol-3-yl)[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]phenyl}methanamine;
1-[4-(3-imidazo[2, 1-b][1,3]thiazol-6-yl-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)phenyl]methanamine;
1-{4-[3-(1-methyl-1H-imidazol-5-yl)-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]phenyl}methanamine;
1-{4-[3-(1-methyl-1H-imidazol-4-yl)-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]phenyl}methanamine;
4-[3-(1-methyl-5-phenyl-1H-pyrazol-4-yl)-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]benzylamine;
1-{4-[9-phenyl-3-(4,5,6,7-tetrahydro-1-benzothien-3-yl) [1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]phenyl}methanamine;
1-{4-[3-(1-isopropyl-1H-pyrazol-4-yl)-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]phenyl}methanamine;
1-{4-[9-phenyl-3-(1,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl) [1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]phenyl}methanamine;
1-(4-{9-phenyl-3-[(2S)-pyrrolidin-2-yl][1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl}phenyl)methanamine;
4-[3-(1-aminoethyl)-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]benzylamine;
1-{4-[3-(1H-imidazol-2-yl)-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]phenyl}methanamine;
1-[4-(3-cyclopropyl-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)phenyl]methanamine;
1-{4-[9-phenyl-3-(trifluoromethyl) [1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]phenyl}methanamine;
1-{4-[3-(5-methyl-1H-pyrazol-3-yl)-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]phenyl}methanamine;
1-{4-[3-(1,5-dimethyl-1H-pyrazol-3-yl)-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]phenyl}methanamine;
4-[3-(1H-indol-2-yl)-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]benzylaminen;
1-{4-[3-(1-methyl-1H-imidazol-2-yl)-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]phenyl}methanamine;
1-{4-[3-(3-methyl-2H-3lambda5-imidazol-4-yl)-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]phenyl}methanamine;
4-[3-(6-chloroimidazo[1,2-a]pyridin-2-yl)-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]benzylamine;
1-{4-[3-(1H-benzimidazol-2-yl)-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]phenyl}methanamine;
4-[3-(5-cyclopropyl-4H-pyrazol-3-yl)-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]benzylamine;
1-{4-[9-phenyl-3-(4,5,6,7-tetrahydro-1H-indazol-3-yl) [1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]phenyl}methanamine;
4-[9-phenyl-3-(3-phenyl-1H-pyrazol-5-yl)[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]benzylamine;
1-(4-{9-phenyl-3-[3-(trifluoromethyl)-1H-pyrazol-5-yl][1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl}phenyl)methanamine;
1-[4-(9-phenyl-3-pyrazolo[1,5-a]pyrimidin-2-yl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)phenyl]methanamine;
1-{4-[3-(1-benzyl-1H-pyrazol-4-yl)-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]phenyl}methanamine;
1-[4-(9-phenyl-3-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)phenyl]methanamine;
4-[9-phenyl-3-(1-phenyl-1H-pyrazol-4-yl)[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]benzylamine;
1-{4-[9-phenyl-3-(4,5,6,7-tetrahydro-2-benzothien-1-yl)[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]phenyl}methanamine;
1-{4-[9-phenyl-3-(5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl)[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]phenyl}methanamine;
2-{8-[4-(aminomethyl)phenyl]-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-3-yl}propan-2-amine;
1-{8-[4-(aminomethyl)phenyl]-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-3-yl}ethane-1,2-diol;
4-{8-[4-(aminomethyl)phenyl]-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-3-yl}imidazolidin-2-one;
(2R)-2-amino-2-{8-[4-(aminomethyl)phenyl]-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-3-yl}ethanol;
(2R)-2-{8-[4-(aminomethyl)phenyl]-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-3-yl}-2-(methylamino)ethanol;
1-{4-[3-(5-ethylisoxazol-3-yl)-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]phenyl}methanamine;
5-{8-[4-(aminomethyl)phenyl]-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-3-yl}-2,4-dihydro-3H-1,2,4-triazol-3-one;
6-{8-[4-(aminomethyl)phenyl]-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-3-yl}-4,5-dihydropyridazin-3(2H)-one;
6-{8-[4-(aminomethyl)phenyl]-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-3-yl}pyridazin-3(2H)-one;
N-(4-{8-[4-(aminomethyl)phenyl]-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-3-yl}phenyl)acetamide;
1-{4-[3-(4-phenoxyphenyl)-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]phenyl}methanamine;
1-{4-[3-(1H-benzimidazol-5-yl)-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]phenyl}methanamine;
(4-{8-[4-(aminomethyl)phenyl]-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-3-yl}phenyl)methanol;
4-[3-(4-cyclohexylphenyl)-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]benzylamine;
4-{8-[4-(aminomethyl)phenyl]-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-3-yl}-1,3-dihydro-2H-imidazol-2-one;
1-{4-[3-(4-methyl-1H-imidazol-5-yl)-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]phenyl}methanamine;
4-[9-phenyl-3-(1-propyl-1H-imidazol-4-yl)[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]benzylamine;
1-{4-[3-(1-isopropyl-1H-imidazol-4-yl)-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]phenyl}methanamine;
1-{4-[3-(1-butyl-1H-imidazol-4-yl)-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]phenyl}methanamine;
1-[4-(3-imidazo[1,2-a]pyrimidin-2-yl-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)phenyl]methanamine;
5-({[4-(3-methyl-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)benzyl]amino}methyl)pyridin-2-ol;
1-(6-methoxypyridin-3-yl)-N-[4-(3-methyl-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)benzyl]methanamine;
N-[(2-methoxypyrimidin-5-yl)methyl]-N-[4-(3-methyl-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)benzyl]amine;
1-[4-(3-ethyl-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)phenyl]methanamine;
1-[4-(9-phenyl-3-propyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)phenyl]methanamine;
N-[4-(9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)benzyl]acetamide;
4-({[4-(9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)benzyl]amino}methyl)phenol;
1-[9-phenyl-8-(4-{[4-(5-pyridin-2-yl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]methyl}phenyl) [1,2,4]triazolo[3,4-f]-1,6-naphthyridin-3-yl]methanamine;
9-phenyl-3-(1H-1,2,3-triazol-4-yl)-8-(4-{[4-(4H-1,2,4-triazol-3-yl)piperidin-1-yl]methyl}phenyl)
[1,2,4]triazolo[3,4-f]-1,6-naphthyridine;
1-{4-[3-(1H-Imidazol-4-yl)-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]phenyl}methanamine;
1-{4-[9-phenyl-3-(3H-1 lambda4,3-thiazol-5-yl) [1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]phenyl}methanamine;
1-{4-[9-phenyl-3-(1H-pyrazol-3-yl)-2H-4lambda5-[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]phenyl}methanamine;
1-{4-[9-phenyl-3-(1,3-thiazol-4-yl)[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]phenyl}methanamine;
4-[9-Phenyl-3-(pyrrolidin-1-ylmethyl)[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]benzylamine;
1-{4-[3-(azetidin-1-ylmethyl)-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]phenyl}methanamine;
1-({8-[4-(aminomethyl)phenyl]-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-3-yl}methyl)piperidine-4-carboxamide;
1-{4-[3-(morpholin-4-ylmethyl)-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]phenyl}methanamine;
2-[({8-[4-(aminomethyl)phenyl]-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-3-yl}methyl)amino]ethanol;
1-(4-{3-[(4-methyl piperazin-1-yl)methyl]-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl}phenyl)methanamine;
4-[9-phenyl-3-(piperazin-1-ylmethyl)[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]benzylamine;
N-({8-[4-(aminomethyl)phenyl]-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-3-yl}methyl)-N-methylamine;
N-({8-[4-(aminomethyl)phenyl]-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-3-yl}methyl)-N,N-dimethylamine;
[4-(3-Methyl-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)phenyl]methanol;
{4-[3-(1-Methyl-1H-imidazol-4-yl)-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]phenyl}methanol;
1-[4-(9-Phenyl-3-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)phenyl]ethanol;
9-phenyl-8-(4-{[4-(4H-1,2,4-triazol-3-yl)piperidin-1-yl]methyl}phenyl)[1,2,4]triazolo[3,4-f]-1,6-naphthyridine;
3-methyl-9-phenyl-8-(4-{[4-(4H-1,2,4-triazol-3-yl)piperidin-1-yl]methyl}phenyl) [1,2,4]triazolo[3,4-f]-1,6-naphthyridine;
9-phenyl-8-(4-{[4-(4H-1,2,4-triazol-3-yl)piperidin-1-yl]methyl}phenyl)[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-3-ol;
1-[4-(3-Methyl-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)phenyl]cyclopropanamine;
1-{4-[3-(1-methyl-1H-imidazol-4-yl)-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]phenyl}cyclo propanamine;
1-[4-(9-phenyl-3-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)phenyl]cyclopropanamine;
1-{4-[9-phenyl-3-(5,6,7,8-tetrahydro imidazo[1,2-a]pyridin-2-yl) [1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]phenyl}cyclopropanamine;
1-[4-(9-phenyl-3-pyrimidin-2-yl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)phenyl]cyclopropanamine;
1-{4-[3-(1,5-dimethyl-1H-pyrazol-3-yl)-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]phenyl}cyclopropanamine;
(1R)-1-[4-(3-Methyl-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)phenyl]ethanamine;
(1R)-1-[4-(9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)phenyl]ethanamine;
(1R)-1-{4-[9-Phenyl-3-(5-pyridin-2-yl-1H-pyrazol-3-yl)[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]phenyl}ethanamine;
(1R)-1-{4-[3-(hydroxymethyl)-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]phenyl}ethanamine;
(1R)-1-{4-[3-(1-methyl-1H-imidazol-4-yl)-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]phenyl}ethanamine;
(1R)-1-[4-(9-phenyl-3-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)phenyl]ethanamine;
(1R)-1-[4-(3-imidazo[2,1-b][1,3]thiazol-6-yl-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)phenyl]ethanamine;
(1R)-1-[4-(9-phenyl-3-pyrimidin-2-yl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)phenyl]ethanamine;
(1R)-1-[4-(9-Phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)phenyl]propan-1-amine;
2-[4-(3-methyl-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)phenyl]propan-2-amine;
2-[4-(9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)phenyl]propan-2-amine;
3-(2-{[4-(3-methyl-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)benzyl]amino}-2-oxoethyl)pyridine;
N-[4-(3-methyl-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)benzyl]-5-pyridin-4-yl-2-furamide;
N-[4-(3-methyl-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)benzyl]-5-pyridin-3-yl-2-furamide;
N-[4-(3-methyl-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)benzyl]-5-pyridin-3-yl-1H-pyrrole-3-carboxamide;
2-hydroxy-N-[4-(3-methyl-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)benzyl]acetamide;
tert-butyl (2-{[4-(3-methyl-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)benzyl]amino}-2-oxoethyl)carbamate;
4-(2-{[4-(3-methyl-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)benzyl]amino}-2-oxoethyl)morpholine;
2-{[4-(3-methyl-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)benzyl]amino}-2-oxoethanamine;
4-(2-{[4-(3-methyl-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)benzyl]amino}-2-oxoethyl)pyridine;
2,4-dihydroxy-6-(2-{[4-(3-methyl-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)benzyl]amino}-2-oxoethyl)pyrimidine;
2-(2-{[4-(3-methyl-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)benzyl]amino}-2-oxoethyl)pyridine;
3-(2-{[4-(3-methyl-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)benzyl]amino}-2-oxoethyl)pyridine;
N-[4-(3-methyl-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)benzyl]-2-pyrazin-2-ylacetamide;
3-methyl-9-phenyl-8-[4-({[(pyridin-3-ylamino)carbonyl]amino}methyl)phenyl][1,2,4]triazolo[3,4-f]-1,6-naphthyridine;
2-(2-hydroxyphenyl)-N-[4-(3-methyl-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)benzyl]acetamide;
2-(3-hydroxyphenyl)-N-[4-(3-methyl-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)benzyl]acetamide;
2-(4-hydroxyphenyl)-N-[4-(3-methyl-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)benzyl]acetamide;
2-(3,4-dihydroxyphenyl)-N-[4-(3-methyl-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)benzyl]acetamide;
N-[4-(3-methyl-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)benzyl]-2-phenylacetamide;
3-methyl-9-phenyl-8-(4-{[(pyridin-3-ylcarbonyl)amino]methyl}phenyl)[1,2,4]triazolo[3,4-f]-1,6-naphthyridine;
2-hydroxy-N-[4-(3-methyl-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)benzyl]benzamide;
2-(4-hydroxyphenyl)-2-methyl-N-[4-(3-methyl-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)benzyl]propanamide;
methyl 4-{[4-(3-methyl-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)benzyl]amino}-4-oxobutanoate;
2-hydroxy-N-(2-{[4-(3-methyl-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)benzyl]amino}-2-oxoethyl)benzamide;
N-[4-(3-methyl-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)benzyl]-2-(5-phenyl-4H-1,2,4-triazol-3-yl)acetamide;
3-methyl-9-phenyl-8-(4-{[(quinolin-3-ylcarbonyl)amino]methyl}phenyl)[1,2,4]triazolo[3,4-f]-1,6-naphthyridine;
N-[4-(3-methyl-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)benzyl]-2-(4-oxoquinazolin-3(4H)-yl)acetamide;
N-[4-(3-methyl-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)benzyl]-2-(2-oxo-1,3-benzoxazol-3(2H)-yl)acetamide;
8-(4-{[(1H-benzimidazol-1-ylacetyl)amino]methyl}phenyl)-3-methyl-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridine;
8-(4-{[(1H-benzimidazol-2-ylacetyl)amino]methyl}phenyl)-3-methyl-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridine;
2-(4-methyl-1,2,5-oxadiazol-3-yl)-N-[4-(3-methyl-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)benzyl]acetamide;
2-(1H-indazol-1-yl)-N-[4-(3-methyl-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)benzyl]acetamide;
2-(5,6-dimethyl-4-oxothieno[2,3-d]pyrimidin-3(4H)-yl)-N-[4-(3-methyl-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)benzyl]acetamide;
3-methyl-8-[4-({[(6-morpholin-4-ylpyridin-3-yl)carbonyl]amino}methyl)phenyl]-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridine;
2-(6-chloropyridin-3-yl)-N-[4-(3-methyl-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)benzyl]acetamide;
3-cyano-N-[4-(3-methyl-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)benzyl]propanamide;
3-methyl-9-phenyl-8-(4-{[(3-pyridin-3-ylpropanoyl)amino]methyl}phenyl)[1,2,4]triazolo[3,4-f]-1,6-naphthyridine;
3-(1-methyl-1H-imidazol-4-yl)-9-phenyl-8-(4-{[(pyridin-3-ylacetyl)amino]methyl}phenyl)[1,2,4]triazolo[3,4-f]-1,6-naphthyridine;
9-phenyl-3-pyrazolo[1,5-a]pyrimidin-3-yl-8-(4-{[(pyridin-3-ylacetyl)amino]methyl}phenyl)[1,2,4]triazolo[3,4-f]-1,6-naphthyridine;
N-(3-hydroxy-2,2-dimethylpropyl)-N-[4-(3-methyl-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl) benzyl]acetamide;
N-(3-hydroxy-2,2-dimethylpropyl)-N-{4-[3-(1-methyl-1H-imidazol-4-yl)-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]benzyl}-2-(4-oxoquinazolin-3(4H)-yl)acetamide;
tert-butyl {2-[[4-(3-{[(tert-butoxycarbonyl)amino]methyl}-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)benzyl](3-hydroxy-2,2-dimethylpropyl)amino]-2-oxoethyl}carbamate;
3-methyl-9-phenyl-8-(4-{1-[(pyridin-3-ylacetyl)amino]cyclopropyl}phenyl)[1,2,4]triazolo[3,4-f]-1,6-naphthyridine;
3-methyl-9-phenyl-8-(4-{1-[(quinolin-3-yl carbonyl)amino]cyclopropyl}phenyl)[1,2,4]triazolo[3,4-f]-1,6-naphthyridine;
N-{1-[4-(3-methyl-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)phenyl]cyclopropyl}-2-(4-oxoquinazolin-3(4H)-yl)acetamide;
3-(1-methyl-1H-imidazol-4-yl)-9-phenyl-8-(4-{1-[(pyridin-3-ylacetyl)amino]cyclopropyl}phenyl) [1,2,4]triazolo[3,4-f]-1,6-naphthyridine;
N-{(1R)-1-[4-(3-methyl-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)phenyl]ethyl}-2-pyridin-3-ylacetamide;
N-{(1R)-1-[4-(3-methyl-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)phenyl]ethyl}acetamide;
N-((1R)-1-{4-[3-(hydroxymethyl)-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]phenyl}ethyl)-2-pyridin-3-ylacetamide;
N-{1-methyl-1-[4-(9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)phenyl]ethyl}acetamide;
and
N-{1-methyl-1-[4-(3-methyl-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)phenyl]ethyl}acetamide;
or a pharmaceutically acceptable salt or stereoisomer thereof.

247 more elements

Dependencies are inferred from the claim text.

Description35,584 words

Summary1,071 words

#The present invention relates to substituted naphthyridine compounds which are inhibitors of the activity of one or more of the isoforms of the serine/threonine kinase, Akt (also known as PKB; hereinafter referred to as “Akt”). The present invention also relates to pharmaceutical compositions comprising such compounds and methods of using the instant compounds in the treatment of cancer.

#Apoptosis (programmed cell death) plays essential roles in embryonic development and pathogenesis of various diseases, such as degenerative neuronal diseases, cardiovascular diseases and cancer. Recent work has led to the identification of various pro- and anti-apoptotic gene products that are involved in the regulation or execution of programmed cell death. Expression of anti-apoptotic genes, such as Bcl2 or Bcl-xL, inhibits apoptotic cell death induced by various stimuli. On the other hand, expression of pro-apoptotic genes, such as Bax or Bad, leads to programmed cell death (Adams et al. Science, 281:1322-1326 (1998)). The execution of programmed cell death is mediated by caspase-1 related proteinases, including caspase-3, caspase-7, caspase-8 and caspase-9 etc (Thornberry et al. Science, 281:1312-1316 (1998)).

#The phosphatidylinositol 3′-OH kinase (PI3K)/Akt pathway appears important for regulating cell survival/cell death (Kulik et al. Mol. Cell. Biol. 17:1595-1606 (1997); Franke et al, Cell, 88:435-437 (1997); Kauffmann-Zeh et al. Nature 385:544-548 (1997) Hemmings Science, 275:628-630 (1997); Dudek et al., Science, 275:661-665 (1997)). Survival factors, such as platelet derived growth factor (PDGF), nerve growth factor (NGF) and insulin-like growth factor-1 (IGF-1), promote cell survival under various conditions by inducing the activity of PI3K (Kulik et al. 1997, Hemmings 1997). Activated PI3K leads to the production of phosphatidylinositol (3,4,5)-triphosphate (PtdIns(3,4,5)-P3), which in turn binds to, and promotes the activation of, the serine/threonine kinase Akt, which contains a pleckstrin homology (PH)-domain (Franke et al Cell, 81:727-736 (1995); Hemmings Science, 277:534 (1997); Downward, Curr. Opin. Cell Biol. 10:262-267 (1998), Alessi et al., EMBO J. 15: 6541-6551 (1996)). Specific inhibitors of PI3K or dominant negative Akt mutants abolish survival-promoting activities of these growth factors or cytokines. It has been previously disclosed that inhibitors of PI3K (LY294002 or wortmannin) blocked the activation of Akt by upstream kinases. In addition, introduction of constitutively active PI3K or Akt mutants promotes cell survival under conditions in which cells normally undergo apoptotic cell death (Kulik et al. 1997, Dudek et al. 1997).

Detailed description34,513 words

#The compounds of the instant invention are useful in the inhibition of the activity of the serine/threonine kinase Akt. In a first embodiment of this invention, the inhibitors of Akt activity are illustrated by the Formula A:

#wherein:

#E, F, G, H, I, J, K, L and M are independently selected from: C or N, wherein each E, F, G, H, I, J, K, L and M is optionally substituted with R1;

Facts

Application

11/921,352Filed 7 Jun 2006 · us provisional application

Priority

10 Jun 2005

Published

US 2010/0222321 A12 Sep 2010

Granted

30 Aug 2011

Term ends

23 Dec 2028

Estimated · how

20 years from earliest known nonprovisional domestic filing plus recorded patent term adjustment, including 930 days of adjustment. Maintenance-fee lapses, terminal disclaimers and statutory extensions have not been checked. The continuity chain may be incomplete; this is not an enforceability determination.

Classification6 codes

C07D 471/14
In which the condensed system contains three hetero rings: ortho-condensed systems
A61P 35/00
Antineoplastic agents
A61P 43/00
Drugs for specific purposes, not provided for in groups a61p1/00-a61p41/00
C07D 487/14
In which the condensed system contains three hetero rings: ortho-condensed systems

Timeline

10 Jun 2005Priority claimedParent application 60/689,726
7 Jun 2006Application filedUS 11/921,352
27 Jul 2009Assigned to Merck & Co., Inc.assignment of assignor's interest
26 Jan 2010Assigned to Merck Sharp & Dohme Corp.change of name
2 Sep 2010PublishedUS 2010/0222321 A1
30 Aug 2011GrantedUS 8,008,317 B2
27 Aug 2012Assigned to Schering Corporationmerger
29 Aug 2012Assigned to Merck Sharp & Dohme Corp.change of name
8 Aug 2022Assigned to Merck Sharp & Dohme LLCmerger
12 Oct 2026TodayWithin its term
23 Dec 2028Term endsEstimated, includes 930 days of adjustment

Inhibitors of akt activtiy

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Inhibitors of akt activtiy

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Abstract

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Claims4

Description35,584 words

Drawings

Classification6 codes

Life of this patent

Description35,584 words