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Review
. 2014 Nov 28;19(12):19935-79.
doi: 10.3390/molecules191219935.

The azaindole framework in the design of kinase inhibitors

Jean-Yves Mérour  1 , Frédéric Buron  2 , Karen Plé  3 , Pascal Bonnet  4 , Sylvain Routier  5
Affiliations
Review

The azaindole framework in the design of kinase inhibitors

Jean-Yves Mérour et al. Molecules. .

Abstract

This review article illustrates the growing use of azaindole derivatives as kinase inhibitors and their contribution to drug discovery and innovation. The different protein kinases which have served as targets and the known molecules which have emerged from medicinal chemistry and Fragment-Based Drug Discovery (FBDD) programs are presented. The various synthetic routes used to access these compounds and the chemical pathways leading to their synthesis are also discussed. An analysis of their mode of binding based on X-ray crystallography data gives structural insights for the design of more potent and selective inhibitors.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Scheme 1
Scheme 1
Preparation of several 3,5-disubstituted-7-azaindole derivatives.
Scheme 2
Scheme 2
Synthesis of an Aurora inhibitor (8).
Scheme 3
Scheme 3
Synthesis of GSK 1070916.
Scheme 4
Scheme 4
Synthesis of compounds 22 and 27.
Scheme 5
Scheme 5
Synthesis of compound 30.
Scheme 6
Scheme 6
Synthesis of Cdc7 inhibitors 34.
Scheme 7
Scheme 7
Synthesis of Cdc7 inhibitors 37.
Scheme 8
Scheme 8
Synthesis of Cdc7 inhibitors 45.
Scheme 9
Scheme 9
Synthesis of Cdc7 inhibitors 48 and 50.
Scheme 10
Scheme 10
Synthesis of CHK1 inhibitors 55.
Scheme 11
Scheme 11
Synthesis of c-Met kinase inhibitors 59 and 61.
Scheme 12
Scheme 12
C-Met kinase inhibitors 62–65 following lead optimization.
Scheme 13
Scheme 13
Synthesis of c-Met kinase inhibitor 68 and analogues.
Scheme 14
Scheme 14
Synthesis of DYRK1A inhibitors 77.
Scheme 15
Scheme 15
Synthesis of DYRK1A inhibitors 79 and 80.
Scheme 16
Scheme 16
Synthesis of Focal adhesion kinase inhibitors.
Scheme 17
Scheme 17
Synthesis of IKK2 inhibitors.
Scheme 18
Scheme 18
Synthesis of JAK kinase inhibitors.
Scheme 19
Scheme 19
Synthesis of decernotinib (104).
Scheme 20
Scheme 20
Development and synthesis of a dual KIT/FMS kinase inhibitor.
Scheme 21
Scheme 21
Synthesis of PAK1 inhibitors.
Scheme 22
Scheme 22
Synthesis of MAP kinase inhibitors.
Scheme 23
Scheme 23
Synthesis of MAP kinase inhibitors.
Scheme 24
Scheme 24
Synthesis of PIM kinase inhibitors.
Scheme 25
Scheme 25
Synthesis of PI3Kα inhibitors.
Scheme 26
Scheme 26
Synthesis of B-Raf inhibitors 139.
Scheme 27
Scheme 27
Synthesis of Rho kinase inhibitors.
Figure 1
Figure 1
Structure of ROCK inhibitor 150.
Scheme 28
Scheme 28
Various m-Tor inhibitors.
Scheme 29
Scheme 29
Synthesis of TrkA kinase inhibitors.
Figure 2
Figure 2
Binding mode representation of ATP in the schematic active site (Left) and in the CDK2 X-ray crystal structure (PDB code: 1FYN).
Figure 3
Figure 3
X-ray crystal structures of (a) 4-azaindole binding to c-Met kinase (PDB code: 2WD1); (b) 5-azaindole binding to TTK kinase (PDB code: 4C4J); (c) 7-azaindole binding to PKA-PKB chimera kinase (PDB code: 2UVX).
Figure 4
Figure 4
Structure of vemurafenib.
Figure 5
Figure 5
Representation of the two binding mode orientations of 7-azaindoles interacting with the backbone amides in the hinge region of the kinase.
Scheme 30
Scheme 30
Synthesis of meriolin (164).
Scheme 31
Scheme 31
Monoazaanalogues of rebeccamycin.
Scheme 32
Scheme 32
N7-glycosylated monoazaanalogues of rebeccamycin.
Scheme 33
Scheme 33
The 5-azaindole rebeccamycin series.
Scheme 34
Scheme 34
3-(7-azaindolyl)-4-(het)arylmaleimides.
Figure 6
Figure 6
GSK-3 inhibitor 184.
Scheme 35
Scheme 35
Synthesis of 4-azaindolyl–indolyl-maleimide GSK-3β inhibitors.
Figure 7
Figure 7
Macrocyclic polyoxygenated bis-7-azaindolylmaleimides as GSK-3β inhibitors.
Scheme 36
Scheme 36
Synthesis of azaindirubins.
Figure 8
Figure 8
Potent C-C linked azaindole compounds.
Scheme 37
Scheme 37
Synthesis of hybrid indolylthiazole CDK1 inhibitors.
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