Potency switch between CHK1 and MK2: Discovery of imidazo[1,2-a]pyrazine- and imidazo[1,2-c]pyrimidine-based kinase inhibitors

Chemistry has been developed to access both imidazo[1,2-a]pyrazines and imidazo[1,2-c]pyrimidines. Small structural modifications in both series led to a switch of potency between two kinases involved in mediating cell cycle checkpoint control, CHK1 and MK2.     

Design and evaluation of 3,6-di(hetero)aryl imidazo[1,2-a]pyrazines as inhibitors of checkpoint and other kinases

A range of 3,6-di(hetero)arylimidazo[1,2-a]pyrazine ATP-competitive inhibitors of CHK1 were developed by scaffold hopping from a weakly active screening hit. Efficient synthetic routes for parallel synthesis were developed to prepare analogues with improved potency and ligand efficiency against CHK1. Kinase profiling showed that the imidazo[1,2-a]pyrazines could inhibit other kinases, including CHK2 and ABL, with equivalent or better potency depending on the pendant substitution. These 3,6-di(hetero)aryl imidazo[1,2-a]pyrazines appear to represent a general kinase inhibitor scaffold.     

Discovery of imidazo[1,2-a]pyrazine-based Aurora kinase inhibitors

The synthesis and structure–activity relationships (SAR) of novel, potent imidazo[1,2-a]pyrazine-based Aurora kinase inhibitors are described. The X-ray crystal structure of imidazo[1,2-a]pyrazine Aurora inhibitor 1j is disclosed. Compound 10i was identified as lead compound with a promising overall profile.     

2- and 3-substituted imidazo[1,2-a]pyrazines as inhibitors of bacterial type IV secretion

A novel series of 8-amino imidazo[1,2-a]pyrazine derivatives has been developed as inhibitors of the VirB11 ATPase HP0525, a key component of the bacterial type IV secretion system. A flexible synthetic route to both 2- and 3-aryl substituted regioisomers has been developed. The resulting series of imidazo[1,2-a]pyrazines has been used to probe the structure–activity relationships of these inhibitors, which show potential as antibacterial agents.     

Structure-based design of imidazo[1,2-a]pyrazine derivatives as selective inhibitors of Aurora-A kinase in cells

Co-crystallisation of the imidazo[1,2-a]pyrazine derivative 15 (3-chloro-N-(4-morpholinophenyl)-6-(pyridin-3-yl)imidazo[1,2-a]pyrazin-8-amine) with Aurora-A provided an insight into the interactions of this class of compound with Aurora kinases. This led to the design and synthesis of potent Aurora-A inhibitors demonstrating up to 70-fold selectivity in cell-based Aurora kinase pharmacodynamic biomarker assays.     

Design,synthesis and biological evaluation of imidazo[2,1-b]thiazole and benzo[d]imidazo[2,1-b]thiazole derivatives as Mycobacterium tuberculosis pantothenate synthetase inhibitors

In the present study, we have designed imidazo[2,1-b]thiazole and benzo[d]imidazo[2,1-b]thiazole derivatives from earlier reported imidazo[1,2-a]pyridine based Mycobacterium tuberculosis (MTB) pantothenate synthetase (PS) inhibitors. We synthesized thirty compounds and they were evaluated for MTB PS inhibition study, in vitro anti-TB activities against replicative and non-replicative MTB, in vivo activity using Mycobacterium marinum infected Zebra fish and cytotoxicity against RAW 264.7 cell line. Among them compound 2-methyl-N′-(4-phenoxybenzoyl)benzo[d]imidazo[2,1-b]thiazole-3-carbohydrazide (5bc) emerged as potent compound active against MTB PS with IC₅₀ of 0.53 ± 0.13 μM, MIC of 3.53 μM, 2.1 log reduction against nutrient starved MTB, with 33% cytotoxicity at 50 μM. It also showed 1.5 log reduction of M. marinum load in Zebra fish at 10 mg/kg.     

Spiro(imidazo[1,2-a]pyrano[2,3-c]pyridine-9-indenes) as inhibitors of gastric acid secretion

Asymmetric and symmetric spiro(imidazo[1,2-a]pyrano[2,3-c]pyridine-9-indenes) were prepared using a synthetic approach that comprised a cross-metathesis reaction and an acid-catalyzed cycloisomerisation as key steps. The target compounds constitute potent inhibitors of the gastric proton pump enzyme with inhibitory activity comparable to potassium-competitive acid blockers (P-CABs) belonging to the known 9-aryl-7H-8,9-dihydropyrano[2,3-c]imidazo[1,2-a]pyridine series. Spiro(imidazo[1,2-a]pyrano[2,3-c]pyridine-9,2′-indenes) represent the first example for P-CABs, in which the distance between the heterocyclic scaffold and the aryl residue has been modified, and are promising candidates for further development as anti-ulcer drugs.     

Scaffold-switching: An exploration of 5,6-fused bicyclic heteroaromatics systems to afford antituberculosis activity akin to the imidazo[1,2-a]pyridine-3-carboxylates

A set of 5,6-fused bicyclic heteroaromatic scaffolds were investigated for their in vitro anti-tubercular activity versus replicating and non-replicating strains of Mycobacterium tuberculosis (Mtb) in an attempt to find an alternative scaffold to the imidazo[1,2-a]pyridine and imidazo[1,2-a]pyrimidines that were previously shown to have potent activity against replicating and drug resistant Mtb. The five new bicyclic heteroaromatic scaffolds explored in this study include a 2,6-dimethylimidazo[1,2-b]pyridazine-3-carboxamide (7), a 2,6-dimethyl-1H-indole-3-carboxamide (8), a 6-methyl-1H-indazole-3-carboxamide (9), a 7-methyl-[1,2,4]triazolo[4,3-a]pyridine-3-carboxamide (10), and a 5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carboxamide (11). Additionally, imidazo[1,2-a]pyridines isomers (2 and 12) and a homologous imidazo[1,2-a]pyrimidine isomer (6) were prepared and compared. Compounds 2 and 6 were found to be the most potent against H₃₇Rv Mtb (MIC’s of 0.1 μM and 1.3 μM) and were inactive (MIC >128 μM) against Staphylococcus aureus, Escherichia coli and Candida albicans. Against other non-tubercular mycobacteria strains, compounds 2 and 6 had activity against Mycobacterium avium (16 and 122 μM, respectively), Mycobacterium kansasii (4 and 19 μM, respectively), Mycobacterium bovis BCG (1 and 8 μM, respectively) while all the other scaffolds were inactive (>128 μM).     

3-(3-Aryloxyaryl)imidazo[1,2-a]pyridine sulfones as liver X receptor agonists

Replacement of a quinoline with an imidazo[1,2-a]pyridine in a series of liver X receptor (LXR) agonists incorporating a [3-(sulfonyl)aryloxyphenyl] side chain provided high affinity LXR ligands 7. In functional assays of LXR activity, good agonist potency and efficacy were found for several analogs.     

Orally active C-6 heteroaryl- and heterocyclyl-substituted imidazo[1,2-a]pyridine acid pump antagonists (APAs)

Acid pump antagonists (APAs) such as the imidazo[1,2-a]pyridine AZD-0865 2 have proven efficacious at low oral doses in acid related gastric disorders. Herein we describe some of the broader SAR in this class of molecule and detail the discovery of an imidazo[1,2-a]pyridine 15 which has excellent efficacy in animal models of gastric acid secretion following oral administration, as well as a good overall developability profile. The discovery strategy focuses on use of heteroaryl and heterocyclic substituents at the C-6 position and optimization of developability characteristics through modulation of global physico-chemical properties.     

New imidazo[1,2-a]pyridines carrying active pharmacophores: Synthesis and anticonvulsant studies

Five new series of imidazo[1,2-a]pyridines carrying biologically active pyrazoline (4a–e), cyanopyridone (5a, b), cyanopyridine (6a–f), 2-aminopyrimidine (7a–f) and pyrimidine-2-thione (8a–d) systems were designed and synthesized as prominent anticonvulsant agents. The target compounds were screened for their in vivo anticonvulsant activity following maximal electroshock (MES) and subcutaneous pentylene tetrazole (scPTZ) methods at a small test dose of 10 mg/kg. Further, Rotarod toxicity method was used to study the toxicity profile of selected compounds. Compounds 4b, 5a, 5b, 6a, 7e and 8d possessing 4-fluorophenyl substituent at 2nd position of imidazo[1,2-a]pyridine ring displayed potent anticonvulsant activity without displaying any toxicity. Enhanced activity profile was observed for new compounds in PTZ method over MES method.     

Discovery of orally bioavailable imidazo[1,2-a]pyrazine-based Aurora kinase inhibitors

We report a series of potent imidazo[1,2-a]pyrazine-based Aurora kinase inhibitors. Optimization of the solvent accessible 8-position led to improvements in both oral bioavailability and off-target kinase inhibition. Compound 25 demonstrates anti-tumor activity in an A2780 ovarian tumor xenograft model.     

Discovery of imidazo[1,2-a]pyridines as potent MCH1R antagonists

A series of imidazo[1,2-a]pyridine derivatives was identified and evaluated for MCH1R binding and antagonistic activity. Introduction of a methyl substituent at the 3-position of imidazo[1,2-a]pyridine provided compounds with a significant improvement in MCH1R affinity. Representative compounds in this series exhibited good potency and brain exposure in rats.     

Design,synthesis, and evaluation of imidazo[1,2-b]pyridazine derivatives having a benzamide unit as novel VEGFR2 kinase inhibitors

The vascular endothelial growth factor (VEGF) signaling pathway has been implicated in tumor angiogenesis, and inhibition of the VEGF pathway is considered an efficacious method for treating cancer. Herein, we describe synthetic studies of imidazo[1,2-b]pyridazine derivatives as VEGF receptor 2 (VEGFR2) kinase inhibitors. The imidazo[1,2-b]pyridazine scaffold was designed and synthesized as a hinge binder according to the previously reported crystal structure of pyrrolo[3,2-d]pyrimidine 1 with VEGFR2. Structure–activity relationship studies revealed that meta-substituted 6-phenoxy-imidazo[1,2-b]pyridazine derivatives had potent affinity for VEGFR2. In particular, N-[3-(imidazo[1,2-b]pyridazin-6-yloxy)phenyl]-3-(trifluoromethyl)benzamide (6b) exhibited strong inhibitory activity against VEGFR2 with an IC₅₀ value of 7.1 nM, and it inhibited platelet-derived growth factor receptor β kinase with an IC₅₀ value of 15 nM.     

Efficient one-pot synthetic protocols for iminosugar-bearing imidazo[1,2-a]pyridines from carbohydrates

This letter describes two unprecedented one-pot high yielding synthetic approaches to imidazo[1,2-a]pyridine scaffolds from carbohydrates. The first approach involves microwave-assisted acid-catalyzed domino reactions of unprotected d-glucose/d-xylose with ammonium acetate and benzoin to afford polyhydroxy iminosugar-bearing tetrahydroimidazo[1,2-a]pyridines. In the second approach, polyhydroxy iminosugar-bearing tetrahydrobenzimidazo[1,2-a]pyridines were synthesized by using unprotected d-glucose/d-xylose and 1,2-diamines in the presence of 10 mol % of oxalic acid under solvent-free microwave irradiation conditions.     

Design,synthesis, and evaluation of novel VEGFR2 kinase inhibitors: Discovery of [1,2,4]triazolo[1,5-a]pyridine derivatives with slow dissociation kinetics

For the purpose of discovering novel type-II inhibitors of vascular endothelial growth factor receptor 2 (VEGFR2) kinase, we designed and synthesized 5,6-fused heterocyclic compounds bearing a anilide group. A co-crystal structure analysis of imidazo[1,2-b]pyridazine derivative 2 with VEGFR2 revealed that the N1-nitrogen of imidazo[1,2-b]pyridazine core interacts with the backbone NH group of Cys919. To retain this essential interaction, we designed a series of imidazo[1,2-a]pyridine, [1,2,4]triazolo[1,5-a]pyridine, thiazolo[5,4-b]pyridine, and 1,3-benzothiazole derivatives maintaining a ring nitrogen as hydrogen bond acceptor (HBA) at the corresponding position. All compounds thus designed displayed strong inhibitory activity against VEGFR2 kinase, and the [1,2,4]triazolo[1,5-a]pyridine 13d displayed favorable physicochemical properties. Furthermore, 13d inhibited VEGFR2 kinase with slow dissociation kinetics and also inhibited platelet-derived growth factor receptor (PDGFR) kinases. Oral administration of 13d showed potent anti-tumor efficacy in DU145 and A549 xenograft models in nude mice.     

Discovery of benzo[d]imidazo[5,1-b]thiazole as a new class of phosphodiesterase 10A inhibitors

The design, synthesis and structure activity relationship studies of a series of compounds from benzo[d]imidazo[5,1-b]thiazole scaffold as phosphodiesterase 10A (PDE10A) inhibitors are discussed. Several potent analogs with heteroaromatic substitutions (9a–d) were identified. The anticipated binding mode of these analogs was confirmed by performing the in silico docking experiments. Later, the heteroaromatics were substituted with saturated heteroalkyl groups which provided a tool compound 9e with excellent PDE10A activity, PDE selectivity, CNS penetrability and with favorable pharmacokinetic profile in rats. Furthermore, the compound 9e was shown to be efficacious in the MK-801 induced psychosis model and in the CAR model of psychosis.     

Discovery of N-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-methylphenyl]-1,3-dimethyl-1H-pyrazole-5-carboxamide (TAK-593), a highly potent VEGFR2 kinase inhibitor

Vascular endothelial growth factor (VEGF) plays important roles in tumor angiogenesis, and the inhibition of its signaling pathway is considered an effective therapeutic option for the treatment of cancer. In this study, we describe the design, synthesis, and biological evaluation of 2-acylamino-6-phenoxy-imidazo[1,2-b]pyridazine derivatives. Hybridization of two distinct imidazo[1,2-b]pyridazines 1 and 2, followed by optimization led to the discovery of N-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-methylphenyl]-1,3-dimethyl-1H-pyrazole-5-carboxamide (23a, TAK-593) as a highly potent VEGF receptor 2 kinase inhibitor with an IC₅₀ value of 0.95 nM. The compound 23a strongly suppressed proliferation of VEGF-stimulated human umbilical vein endothelial cells with an IC₅₀ of 0.30 nM. Kinase selectivity profiling revealed that 23a inhibited platelet-derived growth factor receptor kinases as well as VEGF receptor kinases. Oral administration of 23a at 1 mg/kg bid potently inhibited tumor growth in a mouse xenograft model using human lung adenocarcinoma A549 cells (T/C = 8%).     

Synthesis of novel macrolide derivatives with imidazo[4,5-b]pyridinyl sulfur contained alkyl side chains and their antibacterial activity

In an effort to find new antibiotics, a novel series of 14-membered macrolides with imidazo[4,5-b]pyridinyl sulfur contained alkyl side chains has been synthesized based on commercially available clarithromycin. Chemical transformation of hydroxy group at position C-3 afforded range of ketolides and acylides. Compared to telithromycin, compound 15a demonstrated improved in vitro activity against erythromycin-susceptible and -resistant strains.     

The discovery of furo[2,3-c]pyridine-based indanone oximes as potent and selective B-Raf inhibitors

Virtual and high-throughput screening identified imidazo[1,2-a]pyrazines as inhibitors of B-Raf. We describe the rationale, SAR, and evolution of the initial hits to a series of furo[2,3-c]pyridine indanone oximes as highly potent and selective inhibitors of B-Raf.