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US 2010/0075970 A1Published application
Inhibitors of akt activity
AssigneeMerck Sharp & Dohme Corp.
InventorsMark T. Bilodeau, Peter C. Chua, Nicholas D.P. Cosford, Jacob M. Hoffman, Johnny Yasou Nagasawa
Life of this patent
Estimating the term…
Abstract
The present invention is directed to compounds which contain substituted pyridazines and pyrimidines moieties which inhibit the activity of Akt, a serine/threonine protein kinase. The invention is further directed to chemotherapeutic compositions containing the compounds of this invention and methods for treating cancer comprising administration of the compounds of the invention.
Claims9
A compound of the Formula A-3:
- wherein:
- X is CH and Y is N;
- Q is:
- R1;
- a is 0 or 1;
- b is 0 or 1;
- m is 0, 1, or 2;
- n is 0, 1, 2, 3 or 4;
- p is 0, 1, 2, 3,4 or 5;
- R1 is independently selected from:
- H, (C═O)aObC1-C10 alkyl, (C═O)aOb aryl, (C═O)aObC2-C10 alkenyl, (C═O)aObC2-C10 alkynyl, CO2H, halo, OH, ObC1-C6 perfluoroalkyl, (C═O)aNR7R8, CN, (C═O)aObC3-C8 cycloalkyl, S(O)mNR7R8, S(O)m-(C1-C10)alkyl and (C═O)aObheterocyclyl, said alkyl, aryl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more substituents selected from R6;
- R2′ is independently selected from:
- H, (C═O)aObC1-C10 alkyl, (C═O)aOb aryl, (C═O)aObC2-C10 alkenyl, (C═O)aObC2-C10 alkynyl, CO2H, halo, OH, ObC1-C6 perfluoroalkyl, (C═O)aNR7R8, CN, (C═O)aObC3-C8 cycloalkyl, S(O)mNR7R8, S(O)m—(C1-C10)alkyl and (C═O)aObheterocyclyl, said alkyl, aryl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more substituents selected from R6;
- R6 is independently:
- (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, 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 independently selected from:
- (C═O)aOb(C1-C10)alkyl, Oa(C1-C3)perfluoroalkyl, (C0-C6)alkylene-S(O)mRa, 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, O(C═O)C1-C6 alkyl, oxo, and N(Rb)2;
- R7 and R8 are independently selected from:
- H, (C═O)ObC1-C10 alkyl, (C═O)ObC3-C8 cycloalkyl, (C═O)Obaryl, (C═O)Obheterocyclyl, C1-C6alkyl, aryl, C2-C10 alkenyl, C2-C10 alkynyl, heterocyclyl, C3-C9 cycloalkyl, SO2Ra, and (C═O)NRb2, 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 5-7 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 independently:
- (C1-C6)alkyl, (C3-C6)cycloalkyl, aryl, or heterocyclyl;
- and
- Rb is independently:
- H, (C1-C6)alkyl, aryl, heterocyclyl, (C3-C6)cycloalkyl, (C═O)OC1-C6 alkyl, (C═O)C1-C6 alkyl or S(O)2Ra;
- or a pharmaceutically acceptable salt or a stereoisomer thereof.
22 more elements
A compound which is selected from:
- 5-phenyl-2-pyridin-2-yl-4-(4-{[4-(5-pyridin-2-yl-1H-1,2,4-triazol-3-yl)piperidin-1-yl]methyl}phenyl)pyrimidine;
- 5-phenyl-4-(4-{[4-(5-pyridin-2-yl-1H-1,2,4-triazol-3-yl)piperidin-1-yl]methyl}phenyl)pyrimidin-2-amine;
- 1-{4-[5-phenyl-2-(pyridine-3-ylamino)pyrimidin-4-yl]benzyl}-4-(5-pyridin-2-yl-4H-1,2,4-triazol-3-yl)piperidine;
- 1-{4-[2-(5-amino-1,3,4-thiadiazol-2-yl)-5-phenylpyrimidin-4-yl]benzyl}-4-(5-pyridin-2-yl-4H-1,2,4-triazol-3-yl)piperidine;
- 1-methyl-4-(2-{[5-phenyl-4-(4-{[4-(5-pyridin-2-yl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]methyl}phenyl)pyrimidin-2-yl]amino}ethyl)piperzine;
- 1-[4-(2-amino-5-phenylpyrimidin-4-yl)benzyl]-4-(5-pyridin-2-yl-4h-1,2,4-triazol-3-yl)piperidine;
- 1-{4-[2-(methylthio)-5-phenylpyrimidin-4-yl]benzyl}-4-(5-pyridin-2-yl-4h-1,2,4-triazol-3-yl)piperidine;
- 1-{4-[2-(4-acetylppiperazin-1-yl)-5-phenylpyrimidin-4-yl]benzyl}-4-(5-pyridin-2-yl-4h-1,2,4-triazol-3-yl)piperidine;
- 1-[4-(2-{[1-(ethoxycarbonyl)piperidin-4-yl]amino}-5-phenylpyrimidin-4-yl)benzyl]-4-(5-pyridin-2-yl-4h-1,2,4-triazol-3-yl)piperidine;
- 1-methyl-4-[5-phenyl-4-(4-{[4-(5-pyridin-2-yl-4h-1,2,4-triazol-3-yl)piperidin-1-yl]methyl}phenyl)pyrimidin-2-yl]piperazine;
- 1-(2-hydroxyethyl)-4-[5-phenyl-4-(4-{[4-(5-pyridin-2-yl-4h-1,2,4-triazol-3-yl)piperidin-1-yl]methyl}phenyl)pyrimidin-2-yl]piperazine;
- 1-[2-(dimethylamino)ethyl]-4-[5-phenyl-4-(4-{[4-(5-pyridin-2-yl-4h-1,2,4-triazol-3-yl)piperidin-1-yl]methyl}phenyl)pyrimidin-2-yl]piperazine;
- 1-(4-{5-phenyl-2-[(pyridin-3-ylmethyl)amino]pyrimidin-4-yl}benzyl)-4-(5-pyridin-2-yl-4h-1,2,4-triazol-3-yl)piperidine;
- 2-{[5-phenyl-4-(4-{[4-(5-pyridin-2-yl-4h-1,2,4-triazol-3-yl)piperidin-1-yl]methyl}phenyl)pyrimidin-2-yl]amino}pyridine;
- 2-{5-[1-(4-{2-[methyl(pyridin-2-yl)amino]-5-phenylpyrimidin-4-yl}benzyl)piperidin-4-yl]-4h-1,2,4-triazol-3-yl}pyridine;
- 1-{4-[2-(dimethylamino)-5-phenylpyrimidin-4-yl]benzyl}-4-(5-pyridin-2-yl-4h-1,2,4-triazol-3-yl)piperidine;
- 1-(4-{2-[[2-(dimethylamino)ethyl](methyl)amino]-5-phenylpyrimidin-4-yl}benzyl)-4-(5-pyridin-2-yl-4h-1,2,4-triazol-3-yl)piperidine;
- 1-[4-(2-{[3-(dimethylammonio)propyl]amino}-5-phenylpyrimidin-4-yl)benzyl]-4-(5-pyridin-2-yl-4h-1,2,4-triazol-3-yl)piperidine;
- 1-[4-(2-{[2-(dimethylammonio)ethyl]amino}-5-phenylpyrimidin-4-yl)benzyl]-4-(5-pyridin-2-yl-4h-1,2,4-triazol-3-yl)piperidine;
- and
- 1-(4-{2-[[3-(dimethylammonio)propyl](methyl)amino]-5-phenylpyrimidin-4-yl}benzyl)-4-(5-pyridin-2-yl-4h-1,2,4-triazol-3-yl)piperidine;
- or a pharmaceutically acceptable salt or a stereoisomer thereof.
19 more elements
(canceled)
Dependencies are inferred from the claim text.