SUBSTITUTED AROMATIC N-HETEROCYCLIC COMPOUNDS AS INHIBITORS OF MITOGEN-ACTIVATED PROTEIN KINASE INTERACTING KINASE 1 (MNK1) AND 2 (MNK2)

摘要

Disclosed are substituted aromatic N-heterocyclic compounds. The disclosed compounds typically exhibit kinase inhibition activity, for example, and inhibit Mnk1 kinase and/or Mnk2 kinase. The disclosed compounds may be used in pharmaceutical compositions and methods for treating diseases or disorders associated with Mnk1 kinase activity and/or Mnk2 kinase activity, such as cancers, diabetes, autism, and fragile X syndrome.

主权项

1. A compound having a Formula I:wherein:
X1, X2, and X3 are the same or different and are C or N, and preferably no more than one of X1, X2, and X3 is N; Z is N or O; n=0, 1, 2, or 3; R1 is hydrogen, alkyl, alkyoxyl, hydroxyl, hydroxyalkyl, carboxyl, carboxyalkylester, cycloalkyl optionally substituted at one or more positions with hydroxyl or alkoxyl, amino optionally substituted with alkyl, amido optionally substituted with phenyl or substituted phenyl, thioamido, phenyl optionally substituted at one or more positions with halo or amido, pyridinyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrofuranyl, oxetanyl, pyrrolidonyl, piperidinyl, piperazinyl optionally substituted with alkyl, morpholinyl, imidazolyl optionally substituted at one or more positions with alkyl, pyrazolyl, benzyamidyl, N-methylbenzamid-4-yl, benzoyl, benzoylpiperazine, N-phenylformamidyl, indolyl, or R1 has a structure selected from R2 is hydrogen or R2 and R1 together form one 5-membered ring, one 6-membered ring, or one 7-membered ring which ring is optionally aromatic and saturated or unsaturated and optionally substituted with one or more heteroatoms or R2 and R1 together form two fused rings which may be 5-membered rings or 6-membered rings which rings are optionally aromatic and saturated or unsaturated and optionally substituted with one or more heteroatoms; R3 has a structure selected fromor R3 is aminoalkylindolyl, aminoalkylpyridinyl, aminoalkylpyrrolidonyl, or aminohydroxyalkyl;
R4 is hydrogen, alkyl, haloalkyl, halo, alkoxy, cyano, amino, hydroxyl, carboxyl, or carboxy alkyl ester; R5 is hydrogen, amino, carboxyl, carboxy alkyl ester, carboxy amido, carboxy alkyl amido, or N-benzimidazole; R6 is hydrogen, alkyl, phenyl optionally substituted at one or more positions with alkyoxy or halo, tetrahydropuranyl, alkylmorpholinyl, and benzyl; Y1, Y2, Y3, and Y4 are the same or different and are C or N; R7 is hydrogen, or alkyl; R8 is hydrogen or phenyl optionally substituted at one or more positions with alkyoxy; and R9, R10, and R11 are the same or different and are hydrogen, alkyl, or phenyl.