Pyridine and Imidazo[4,5-C]Pyridine Derivatives

molecules

Review Pharmacological Potential and Synthetic Approaches of Imidazo[4,5-b]pyridine and Imidazo[4,5-c]pyridine Derivatives

Malwina Krause, Henryk Foks and Katarzyna Gobis *

Department of Organic Chemistry, Medical University of Gda´nsk,107 Gen. Hallera Ave., 80-416 Gda´nsk,Poland; [email protected] (M.K.); [email protected] (H.F.) * Correspondence: [email protected]; Tel.: +48-58-349-1647; Fax: +48-58-349-12-77

Academic Editor: Diego Muñoz-Torrero Received: 16 February 2017; Accepted: 2 March 2017; Published: 4 March 2017

Abstract: The structural resemblance between the fused imidazopyridine heterocyclic ring system and purines has prompted biological investigations to assess their potential therapeutic significance. They are known to play a crucial role in numerous disease conditions. The discovery of their first bioactivity as GABAA receptor positive allosteric modulators divulged their medicinal potential. Proton pump inhibitors, aromatase inhibitors, and NSAIDs were also found in this chemical group. Imidazopyridines have the ability to influence many cellular pathways necessary for the proper functioning of cancerous cells, pathogens, components of the immune system, enzymes involved in carbohydrate metabolism, etc. The collective results of biochemical and biophysical properties foregrounded their medicinal significance in central nervous system, digestive system, cancer, inflammation, etc. In recent years, new preparative methods for the synthesis of imidazopyridines using various catalysts have been described. The present manuscript to the best of our knowledge is the complete compilation on the synthesis and medicinal aspects of imidazo[4,5-b]pyridines and imidazo[4,5-c]pyridines reported from the year 2000 to date, including structure–activity relationships.

Keywords: imidazo[4,5-b]pyridine; imidazo[4,5-c]pyridine; biological activity; synthesis; SAR analysis

1. Introduction The imidazopyridines comprised an imidazole ring fused with a pyridine moiety. The group contains compounds with different biological activity. In general, they are GABAA receptor agonists [1], however, recently proton pump inhibitors [2], aromatase inhibitors [3], NSAIDs [4] and other classes of drugs in this class have been developed as well. Imidazopyridines consist of various isomeric forms like imidazo[4,5-b]pyridines, imidazo[4,5-c]pyridines, imidazo[1,5-a]pyridines and imidazo[1,2-a]pyridines. Among the latter group, one can ﬁnd the most examples of drugs, such as ambien, miroprofen, and zolimidine (Figure1).

Molecules 2017, 22, 399; doi:10.3390/molecules22030399 www.mdpi.com/journal/molecules

Review Pharmacological Potential and Synthetic Approaches of Imidazo[4,5-b]pyridine and Imidazo[4,5-c]pyridine Derivatives

Malwina Krause, Henryk Foks and Katarzyna Gobis *

Department of Organic Chemistry, Medical University of Gdańsk, 107 Gen. Hallera Ave., 80-416 Gdańsk, Poland; [email protected] (M.K.); [email protected] (H.F.) * Correspondence: [email protected]; Tel.: +48-58-349-16-47; Fax: +48-58-349-12-77

Academic Editor: Diego Muñoz-Torrero Received: 16 February 2017; Accepted: 2 March 2017; Published: 4 March 2017

Abstract: The structural resemblance between the fused imidazopyridine heterocyclic ring system and purines has prompted biological investigations to assess their potential therapeutic significance. They are known to play a crucial role in numerous disease conditions. The discovery of their first bioactivity as GABAA receptor positive allosteric modulators divulged their medicinal potential. Proton pump inhibitors, aromatase inhibitors, and NSAIDs were also found in this chemical group. Imidazopyridines have the ability to influence many cellular pathways necessary for the proper functioning of cancerous cells, pathogens, components of the immune system, enzymes involved in carbohydrate metabolism, etc. The collective results of biochemical and biophysical properties foregrounded their medicinal significance in central nervous system, digestive system, cancer, inflammation, etc. In recent years, new preparative methods for the synthesis of imidazopyridines using various catalysts have been described. The present manuscript to the best of our knowledge is the complete compilation on the synthesis and medicinal aspects of imidazo[4,5-b]pyridines and imidazo[4,5-c]pyridines reported from the year 2000 to date, including structure–activity relationships.

Keywords: imidazo[4,5-b]pyridine; imidazo[4,5-c]pyridine; biological activity; synthesis; SAR analysis

1. Introduction The imidazopyridines comprised an imidazole ring fused with a pyridine moiety. The group contains compounds with different biological activity. In general, they are GABAA receptor agonists [1], however, recently proton pump inhibitors [2], aromatase inhibitors [3], NSAIDs [4] and other classes of drugs in this class have been developed as well. Imidazopyridines consist of various isomeric forms like imidazo[4,5-b]pyridines, imidazo[4,5-c]pyridines, imidazo[1,5-a]pyridines and Moleculesimidazo[1,2-2017, 22a]pyridines., 399 Among the latter group, one can find the most examples of drugs, such2 of as 25 ambien, miroprofen, and zolimidine (Figure 1).

N CH3 N N OH CH3 N O Miroprofen O N N O CH3 H3C S CH N 3 O Ambien Zolimidine Figure 1. Examples of bioactive agen agentsts possessing imidazo[1,2- a]pyridine core. Molecules 2017, 22, 399 2 of 24 Molecules 2017, 22, 399; doi:10.3390/molecules22030399 www.mdpi.com/journal/molecules However, the other two groups seem to also be veryvery potent.potent. In particular, somesome compounds of the imidazo[4,5-b]pyridine and imidazo[4,5- cc]pyridine]pyridine core core are are substances substances with with confirmed conﬁrmed activity, activity, and some areare atat variousvarious stagesstages of of clinical clinical trials. trials. Bamaluzole Bamaluzole with with the the imidazo[4,5- imidazo[4,5-c]pyridinec]pyridine system system is ais GABAa GABAA receptorA receptor agonist agonist patented patented as as an an anticonvulsant anticonvulsant byby Merck,Merck, butbut nevernever marketedmarketed (Figure 22))[ [5].5]. They also discovereddiscovered telcagepanttelcagepant (MK-0974), a calcitonincalcitonin gene related peptidepeptide receptorreceptor antagonistantagonist with an imidazo[4,5- bb]pyridine]pyridine moiety, moiety, which which was was in in clinical clinical trials trials as as a remedy a remedy for for migraines migraines but but its itsdevelopment development was was terminated terminated in in2009 2009 [6]. [6]. Mitsubishi Mitsubishi Tanabe Tanabe Pharma Pharma invented tenatoprazoletenatoprazole (TU-199)(TU-199) that that blocked blocked the the gastric gastric proton proton pump pump leading leading to a to decline a decline of gastric of gastric acid acidproduction. production. This Thisimidazo[4,5- imidazo[4,5-b]pyridineb]pyridine is actually is actually under under active activedevelopment development by SIDEM by SIDEM (France) (France) [7]. There [7]. is Therealso the is alsoimidazo[4,5- the imidazo[4,5-c]pyridinec]pyridine core in corethe instructure the structure of 3- ofdeazaneplanocin 3-deazaneplanocin A A(DZNep) (DZNep) acting acting as as a S-adenosyl-L-homocysteine synthesis inhibitor and a histon histonee methyltransferase EZH2 inhibitor, so it can be potentially applied in various typestypes ofof cancercancer andand EbolaEbola virusvirus diseasedisease [[8].8].

FigureFigure 2. Examples 2. Examples of ofbioactive bioactive agen agentsts possessing possessing imidazo[4,5- imidazo[4,5-bb]pyridine]pyridine or or imidazo[4,5- imidazo[4,5-c]pyridinec]pyridine cores. cores.

The above facts prompted us to take a look at imidazo[4,5-b]pyridines and The above facts prompted us to take a look at imidazo[4,5-b]pyridines and imidazo[4,5-c]pyridines imidazo[4,5-c]pyridines as well as their oxygen and sulfur analogues and compare their potency as as well as their oxygen and sulfur analogues and compare their potency as bioactive agents. The present bioactive agents. The present manuscript to the best of our knowledge is a complete review, manuscript to the best of our knowledge is a complete review, including the medicinal aspects, including the medicinal aspects, synthetic strategies and structure activity relationship of these synthetic strategies and structure activity relationship of these heterocyclic groups that is covered from heterocyclic groups that is covered from the year 2000 to present. the year 2000 to present. 2. Biological Properties of Imidazo[4,5-b]pyridines and Imidazo[4,5-c]pyridines

2.1. Antitumor Activity In connection with the population growth and an increase in the duration of life we can also observe an escalation of the incidence of non-communicable diseases. Among them cancer is one of the most common causes of death. Imidazopyridines have the ability to influence many cellular pathways necessary for the proper functioning of cancerous cells. The inhibited proteins include, inter alia, matrix metalloproteinase-2, RNA-dependent RNA polymerase, hepatocyte growth factor receptor (c-MET), serine/threonine-protein kinase or cell division cycle 25 phosphatases [9–18]. Aurora A, B and C kinases belong to the serine/threonine kinases family. Aurora A kinase (AURKA) is responsible for the proper conduct of mitosis, formation of the mitotic spindle, chromosome segregation and cytokinesis. Scientific research has revealed the overexpression of AURAK in the different types of cancer. There is a probability of connection of AURAK with the carcinogenesis process, therefore, the Aurora A kinase has become a promising molecular target for cancer therapy. Application of imidazo[4,5-b]pyridine derivatives 1–3 (Figure 3) as inhibitors of AURAKA have been extensively described in the literature [19–21].

Molecules 2017, 22, 399 3 of 25

2. Biological Properties of Imidazo[4,5-b]pyridines and Imidazo[4,5-c]pyridines

2.1. Antitumor Activity In connection with the population growth and an increase in the duration of life we can also observe an escalation of the incidence of non-communicable diseases. Among them cancer is one of the most common causes of death. Imidazopyridines have the ability to inﬂuence many cellular pathways necessary for the proper functioning of cancerous cells. The inhibited proteins include, inter alia, matrix metalloproteinase-2, RNA-dependent RNA polymerase, hepatocyte growth factor receptor (c-MET), serine/threonine-protein kinase or cell division cycle 25 phosphatases [9–18]. Aurora A, B and C kinases belong to the serine/threonine kinases family. Aurora A kinase (AURKA) is responsible for the proper conduct of mitosis, formation of the mitotic spindle, chromosome segregation and cytokinesis. Scientiﬁc research has revealed the overexpression of AURAK in the different types of cancer. There is a probability of connection of AURAK with the carcinogenesis process, therefore, the Aurora A kinase has become a promising molecular target for cancer therapy. Application of imidazo[4,5-b]pyridine derivatives 1–3 (Figure3) as inhibitors of AURAKAMolecules 2017 have, 22, 399 been extensively described in the literature [19–21]. 3 of 24

Figure 3. Inhibitors of serine/threonine kinases. Figure 3. Inhibitors of serine/threonine kinases.

There are also other serine/threonine kinases such as Tank binding kinase 1 (TBK1) and inhibitorThere of are nuclear also other factor serine/threonine kappa-B kinase kinases subunit such epsilon as Tank (IKK- bindingɛ) which kinase are 1used (TBK1) in the and search inhibitor for ε ofantitumor nuclear factordrugs. kappa-B IKK-ɛ and kinase TBK1 subunit activate epsilon nuclear (IKK- factor) which kappa-light-chain-enhancer are used in the search forof activated antitumor B ε drugs.cells (NF-kappaB) IKK- and through TBK1 activate the proc nuclearess of phosphorylation. factor kappa-light-chain-enhancer NF-kappaB is the oftranscription activated B factor cells (NF-kappaB)exhibiting antiapoptoic through the effects. process This of phosphorylation. results in defective NF-kappaB cell survival is the and transcription tumor development factor exhibiting [22,23]. antiapoptoicScientists are effects. trying Thisto develop results a in ne defectivew class of cell drugs survival that andwill tumorbe exhi developmentbit an inhibitory [22, 23effect]. Scientists on both areof the trying mentioned to develop enzymes. a new classImidazopyridine of drugs that deri willvatives be exhibit were an tested inhibitory by Wang. effect onSeveral both of thethe mentionedobtained compounds enzymes. ( Imidazopyridine4, 5, Figure 3) demonstrated derivatives inhibitory were tested potency by Wang. in the Severalrange ofof 0.004–0.046 the obtained µM µ compoundsand good selectivity (4, 5, Figure towards3) demonstrated cyclin-dependent inhibitory potencykinase 2 in (CDK2) the range and of 0.004–0.046Aurora B enzymesM and good[24]. selectivityJohanne et towards al. optimized cyclin-dependent the structure kinase of 2compound (CDK2) and 4. Aurora Comprehensive B enzymes modification [24]. Johanne of et the al. optimizedsubstituent the at structurethe C6 position of compound of the4 imidazop. Comprehensiveyridine ring modiﬁcation has led to of theobtaining substituent a derivative at the C6 6 positioncharacterized of the imidazopyridineby higher potency ring to has inhibit led to obtainingboth kinases a derivative [25]. NF-6 characterizedκB could also by be higher activated potency by κ tomitogen inhibit bothand kinasesstress activated [25]. NF- proteinB could kinase also be 1 activated(MSK1) byprotein. mitogen Among and stress the activatedMSK1 inhibitors, protein imidazopyridine (7) (Figure 4) with a nanomolar value of IC50 (3 nM) has been found [26]. Imidazopyridine derivatives indicated inhibitory impact on inhibitors of apoptosis proteins (IAPs) family and myeloid cell leukemia 1 (Mcl-1) protein [27,28]. Imidazopyridine derivatives have been examined by Puskullu for cytotoxic activity on the human breast adenocarcinoma cell line MCF-7. Compound 8 (Figure 4) with the N-hydroxycarboximidamide group at the phenyl ring demonstrated the highest cytotoxic activity (IC50 0.082 µM). Substitution of the hydroxycarboximidamide group nitrogen atom by an alkyl chain significantly reduced the activity [29]. In the treatment of breast cancer poly(ADP-ribose) polymerase (PARP) inhibitors were also examined. Zhu et al. obtained the series of imidazo[4,5-c]pyridines with moderate to good PARP inhibitory activity. PARP inhibitors increase the sensitivity of tumor cells to chemotherapy. The best potency was demonstrated by compound 9 with an IC50 value of 8.6 nM. The obtained compound was also tested in the combination with temozolomide on three human tumor cell lines MDA-MB-468, SW-620 and A549. Research revealed an appreciable increase in the potency of growth inhibition of tumor cells in comparison with the application of only temozolomide [30].

Molecules 2017, 22, 399 4 of 25 kinase 1 (MSK1) protein. Among the MSK1 inhibitors, imidazopyridine (7) (Figure4) with a nanomolar value of IC50 (3 nM) has been found [26]. Imidazopyridine derivatives indicated inhibitory impact on inhibitorsMolecules 2017 of, 22 apoptosis, 399 proteins (IAPs) family and myeloid cell leukemia 1 (Mcl-1) protein [27,284]. of 24

Figure 4. Azolopyridines with antiproliferative activity.

Angiogenesis is the formation process of a blood network necessary for the proper functioning Imidazopyridine derivatives have been examined by Puskullu for cytotoxic activity on the human of the body. In healthy subjects, this process is regulated by a plurality of inhibitors and stimulants. breast adenocarcinoma cell line MCF-7. Compound 8 (Figure4) with the N-hydroxycarboximidamide Excessive angiogenesis, which is essential for further growth of tumor cells, is observed in the late group at the phenyl ring demonstrated the highest cytotoxic activity (IC 0.082 µM). Substitution stages of cancer. The JAK/STAT-3 signaling pathway is involved in the50 angiogenesis process. of the hydroxycarboximidamide group nitrogen atom by an alkyl chain signiﬁcantly reduced the Vasbinder attempted to synthesize a selective inhibitor of Januse kinase 1 (JAK-1). Research selected activity [29]. In the treatment of breast cancer poly(ADP-ribose) polymerase (PARP) inhibitors were compound 10 with good potency towards JAK-1 (IC50 0.022 µM) and without significant impact on also examined. Zhu et al. obtained the series of imidazo[4,5-c]pyridines with moderate to good PARP the other isoforms [31]. One of the assignments of the MET pathway in cancer development is the inhibitory activity. PARP inhibitors increase the sensitivity of tumor cells to chemotherapy. The best formation of new vessels. Inhibitors of c-MET kinases with an imidazopyridine core may be useful potency was demonstrated by compound 9 with an IC value of 8.6 nM. The obtained compound for stopping carcinogenesis [32]. 50 was also tested in the combination with temozolomide on three human tumor cell lines MDA-MB-468, SW-620 and A549. Research revealed an appreciable increase in the potency of growth inhibition of 2.2. Antimicrobial Activity tumor cells in comparison with the application of only temozolomide [30]. AngiogenesisIn the past few is the years formation a large process number of a bloodof bact networkerial strains necessary resistant for the to proper previously functioning used ofchemotherapeutics the body. In healthy agents subjects, have thisemerged. process Methicillin is regulated resistant by a plurality Staphylococcus of inhibitors aureus and (MRSA) stimulants. and Excessivevancomycin-resistant angiogenesis, Enterococcus which is faecalis essential (VRE) for cause further a serious growth problems of tumor during cells,is hospitalization observed inthe [33,34]. late stagesAlso, ofin cancer.the case The of JAK/STAT-3 tuberculosis, signaling an increase pathway in isthe involved prevalence in the of angiogenesis MDR-TB process.and XDR-TB Vasbinder was attemptedobserved. toMerely synthesize 50% aof selective patients inhibitor with MDR-TB of Januse and kinase 26% 1 of (JAK-1). patients Research with XDR-TB selected compoundcompleted 10treatmentwith good successfully potency towards[35]. The JAK-1crisis of (IC microbial50 0.022 µ resistanceM) and without is a serious signiﬁcant public impacthealth issue on the around other isoformsthe world. [31 Obtaining]. One of thenew assignments drugs with ofnew the mechanisms MET pathway of actions in cancer is developmentnecessary. is the formation of new vessels.Arridos Inhibitorset al. combined of c-MET 2,6-diarylpiperidin-4-one kinases with an imidazopyridine core to the imidazo[4,5- core may beb]pyridine useful for ring. stopping Both carcinogenesisstructures have [ 32been]. widely described in the literature as antimicrobial agents. They observed an increase in activity against Gram positive (Staphylococcus aureus and Bacillus subtilis) and Gram 2.2.negative Antimicrobial (Escherichia Activity coli, Pseudomonas aeruginosa and Klebsiella pneumonia) bacteria in the presence of the chlorineIn the pastatom fewat the years para position a large of number the phenyl of bacterial groups of strains compound resistant 11 and to 12 previously (Figure 5). used The chemotherapeuticspresence of the methyl agents group have at the emerged. C5 position Methicillin enhanced resistantactivity againstStaphylococcus the tested aureus bacteria(MRSA) strains. andThe vancomycin-resistantintroduction of anotherEnterococcus methyl group faecalis at the(VRE) C3 position cause a results serious in problems a further during increment hospitalization in activity [36]. [33, 34]. Also, in the case of tuberculosis, an increase in the prevalence of MDR-TB and XDR-TB was observed. Merely 50% of patients with MDR-TB and 26% of patients with XDR-TB completed treatment successfully [35]. The crisis of microbial resistance is a serious public health issue around the world. Obtaining new drugs with new mechanisms of actions is necessary.

Figure 5. Antibacterial imidazo[4,5-b]pyridines.

Molecules 2017, 22, 399 4 of 24

Figure 4. Azolopyridines with antiproliferative activity.

Angiogenesis is the formation process of a blood network necessary for the proper functioning of the body. In healthy subjects, this process is regulated by a plurality of inhibitors and stimulants. Excessive angiogenesis, which is essential for further growth of tumor cells, is observed in the late stages of cancer. The JAK/STAT-3 signaling pathway is involved in the angiogenesis process. Vasbinder attempted to synthesize a selective inhibitor of Januse kinase 1 (JAK-1). Research selected compound 10 with good potency towards JAK-1 (IC50 0.022 µM) and without significant impact on the other isoforms [31]. One of the assignments of the MET pathway in cancer development is the formation of new vessels. Inhibitors of c-MET kinases with an imidazopyridine core may be useful for stopping carcinogenesis [32].

2.2. Antimicrobial Activity In the past few years a large number of bacterial strains resistant to previously used chemotherapeutics agents have emerged. Methicillin resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecalis (VRE) cause a serious problems during hospitalization [33,34].

Also,Molecules in2017 the, 22 case, 399 of tuberculosis, an increase in the prevalence of MDR-TB and XDR-TB 5was of 25 observed. Merely 50% of patients with MDR-TB and 26% of patients with XDR-TB completed treatment successfully [35]. The crisis of microbial resistance is a serious public health issue around the world.Arridos Obtaining et al. combinednew drugs 2,6-diarylpiperidin-4-onewith new mechanisms of actions core to is the necessary. imidazo[4,5- b]pyridine ring. BothArridos structures et al. have combined been widely 2,6-diarylpiperidin-4-one described in the literature core to as the antimicrobial imidazo[4,5- agents.b]pyridine They ring. observed Both structuresan increase have in activity been widely against described Gram positive in the (literStaphylococcusature as antimicrobial aureus and Bacillusagents. subtilisThey observed) and Gram an increasenegative in (Escherichia activity against coli, Pseudomonas Gram positive aeruginosa (Staphylococcusand Klebsiella aureus pneumonia and Bacillus) bacteria subtilis in the) and presence Gram negativeof the chlorine (Escherichia atom coli, at the Pseudomonas para position aeruginosa of the and phenyl Klebsiella groups pneumonia of compound) bacteria11 andin the12 presence(Figure5 of). Thethe chlorine presence atom of the at methylthe para group position at theof the C5 phenyl position groups enhanced of compound activity against 11 andthe 12 (Figure tested bacteria 5). The presencestrains. Theof the introduction methyl group of anotherat the C5 methylposition group enhanced at the activity C3 position against resultsthe tested in abacteria further strains. increment The introductionin activity [36 of]. another methyl group at the C3 position results in a further increment in activity [36].

Figure 5. Antibacterial imidazo[4,5-b]pyridines. Figure 5. Antibacterial imidazo[4,5-b]pyridines. Molecules 2017, 22, 399 5 of 24

Glucosamine-6-phosphate synthase synthase could could be be a potential molecular target for new imidazo[4,5-cc]pyridine]pyridine derivativesderivatives in in the the treatment treatment of of fungal fungal infections. infections. This This enzyme enzyme is responsibleis responsible for thefor synthesisthe synthesis of fungal of fungal cell walls cell walls and regulation and regula oftion sugar of metabolism. sugar metabolism. The ﬁnal The product final ofproduct catalysis of iscatalysis uridine is diphosphate uridine diphosphateN-acetylglucosamine N-acetylglucosamine (UDP-GlcNAc) (UDP-GlcNAc) which is which liable foris liable synthesis for synthesis of cell wall of componentscell wall components [37,38]. Compounds [37,38]. Compounds13–17 (Figure 13–617) exhibited(Figure 6) good exhibited antimicrobial good antimicrobial activity in comparison activity in withcomparison the reference with the drugs reference streptomycin drugs streptomycin and ﬂuconazole. and Thefluconazole. molecular The docking molecular studies docking showed studies that derivativesshowed that containing derivatives halogen containing atoms halogen possess atom goods docking possess energy,good docking oral absorption, energy, skinoral penetrationabsorption, andskin membranepenetration permeability and membrane [39]. 3-Deazapurines permeability with[39]. good3-Deazapurines tuberculostatic with activity good were tuberculostatic disclosed by Khoje.activity Compounds were disclosed18 and by19 Khoje.(Figure Compounds7) exhibited activity18 and against 19 (FigureMycobacterium 7) exhibited tuberculosis activity withagainst the valueMycobacterium of MIC below tuberculosis 1 µM[ with40]. the value of MIC below 1 µM [40].

Figure 6. Antifungal imidazo[4,5- c]pyridines.

Certain imidazo[4,5-b]pyridine derivatives demonstrated activity inhibiting the growth of Trypanosoma brucei. T brucei causes in humans the fatal disease African trypanosomiasis [41]. Methionyl-tRNA synthetase of T. brucei is an extensively used molecular target in the process of antitrypanosomal drugs development. This enzyme fulfills an essential role in the proper creation of the peptide chain due to the influence on translation [42,43]. Imidazopyridine 20 (Figure 7) exhibited a good inhibitory effect on methionyl-tRNA synthase (IC50 < 50 nM, EC50 39 nM).

Figure 7. Antimicrobial imidazo[4,5-b]pyridines and imidazo[4,5-c]pyridines.

The pharmacokinetic parameters have been also examined. Although compound 20 demonstrated remarkable pharmacokinetic parameters after oral administration at 50 mg/kg (Cmax 37.6 µM, and AUC 6223 min·µmol/L) it poorly penetrates into the brain. The brain’s permeability to drugs is extremely important due to the ability of T. brucei to cerebrospinal fluid penetration. Structural modifications have led to obtaining derivative 21 with improved brain permeability in mice and inhibition potency (IC50 < 50 nM, EC50 22 nM) and moderate pharmacokinetic properties (Cmax 9.7 mM, AUC 952 min·mmol/L) [44].

Molecules 2017, 22, 399 5 of 24

Glucosamine-6-phosphate synthase could be a potential molecular target for new imidazo[4,5-c]pyridine derivatives in the treatment of fungal infections. This enzyme is responsible for the synthesis of fungal cell walls and regulation of sugar metabolism. The final product of catalysis is uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) which is liable for synthesis of cell wall components [37,38]. Compounds 13–17 (Figure 6) exhibited good antimicrobial activity in comparison with the reference drugs streptomycin and fluconazole. The molecular docking studies showed that derivatives containing halogen atoms possess good docking energy, oral absorption, skin penetration and membrane permeability [39]. 3-Deazapurines with good tuberculostatic activity were disclosed by Khoje. Compounds 18 and 19 (Figure 7) exhibited activity against Mycobacterium tuberculosis with the value of MIC below 1 µM [40].

Figure 6. Antifungal imidazo[4,5-c]pyridines.

Certain imidazo[4,5-b]pyridine derivatives demonstrated activity inhibiting the growth of Trypanosoma brucei. T brucei causes in humans the fatal disease African trypanosomiasis [41]. Methionyl-tRNA synthetase of T. brucei is an extensively used molecular target in the process of antitrypanosomal drugs development. This enzyme fulfills an essential role in the proper creation Moleculesof the peptide2017, 22, 399chain due to the influence on translation [42,43]. Imidazopyridine 20 (Figure6 of 7) 25 exhibited a good inhibitory effect on methionyl-tRNA synthase (IC50 < 50 nM, EC50 39 nM).

Molecules 2017, 22, 399 6 of 24

2.3. Anti-Inflammatory Figure 7. Antimicrobial imidazo[4,5-b]pyridines and imidazo[4,5-c]pyridines.]pyridines. Inflammation is a defensive reaction of the body caused by chemical, physical or biological agents.The The pharmacokinetic inflammatory response parameters begins havewith thebeen activation also examined. of the immune Although system andcompound production 20 Certain imidazo[4,5-b]pyridine derivatives demonstrated activity inhibiting the growth of demonstratedof inflammatory remarkable mediators. pharmacokinetic Chronic inflammation parameters can leadafter tooral harmful administration effects on at the 50 mg/kgbody and (Cmax the Trypanosoma brucei. T brucei causes in humans the fatal disease African trypanosomiasis [41]. 37.6development µM, and AUCof other 6223 diseases min·µmol/L) such it as poorly cancer penetr andates neuropathy. into the brain. Retinal The ischemiabrain’s permeability is caused byto Methionyl-tRNA synthetase of T. brucei is an extensively used molecular target in the process of drugsinsufficient is extremely blood supply important in the due retina. to theSustained ability ischemiaof T. brucei leads to to cerebrospinal the activation fluid of inflammatory penetration. antitrypanosomal drugs development. This enzyme fulﬁlls an essential role in the proper creation of Structuralmediators, modificationsfurther degeneration have led of tothe obtaining retina and derivative impaired 21vision. with Tumor improved necrosis brain factor- permeabilityα (TNF- αin), the peptide chain due to the inﬂuence on translation [42,43]. Imidazopyridine 20 (Figure7) exhibited a miceinterleukin-6 and inhibition (IL-6), andpotency adhesion (IC50

Figure 8. Anti-inflammatoryAnti-inﬂammatory imidazo[4,5-b]pyridines.

2.4. Antiviral Activity Viruses have the ability to attack all living organisms, plants, animals and humans. An extremely dangerous phenomenon is their high mutation rate. For this reason, researchers around the world are looking for new antiviral drugs among pyridine derivatives. Human immunodeficiency virus (HIV) is one of the most serious and deadly communicable diseases. Li performed a series of in vitro anti-HIV assays on MT-4 cell culture infected by the HIV-1 IIIB strain, the HIV-1 mutant strain RES056, and the HIV-2 strain ROD. Synthesized compounds demonstrated moderate to good activity. The assays revealed that amide (compound 25, Figure 9) and sulfamide (compound 26) groups are preferable in the para position of the anilide moiety. The presence of electron-withdrawing group in the ortho position of the anilide moiety is likewise relevant for

Molecules 2017, 22, 399 7 of 25

Nitric oxide synthase (NOS) is the enzyme that produces nitric oxide(II) which performs many biological functions in human body. One of the inducible NOS isoforms is involved in the immune response. iNOS is activated by proinflamatory factors. However, overexpression of iNOS may lead to adverse reactions such as stroke. The main issue is to achieve a compound which selectively inhibits only iNOS [50,51]. Compound 23 (Figure8) was characterized by selectivity for iNOS with a pIC 50 value of 7.09 (nNOS pIC50 4.86; eNOS pIC50 3.95) and good pharmacological parameters. The method of binding compound 23 with L-arginine of isoform iNOS was determined by X-ray crystallography. The methoxy group is essential for selectivity. The 4-methoxy group is nested in a hydrophobic pocket formed by Val346 and Phe363 (murine iNOS numbering) [52]. Cyclooxygenase (COX) is the protein engaged in the formation of prostaglandins, thromboxane and prostacyclin. Cyclooxygenase is part of the inflammatory response. The majority of nonsteroidal anti-inflammatory drugs inhibit the activity of both isoforms COX-1 and COX-2. Numerous side effects are related to the inhibition of COX-1, therefore selective inhibitors of COX-2 are eligible [53,54]. Kirwen et al. investigated the selective COX-2 inhibitors with imidazopyridine Molecules 2017, 22, 399 7 of 24 moiety. The imidazopyridines obtained contain diaryl pharmacophore which is a key building element anti-HIVof many chemicalactivity. moleculesDerivatives with 25 and anti-inflammatory 26 were characterized activityThe by highesthigher potency activity andthan selectivity the reference was drugsdemonstrated nevirapine by compoundand delaviridine24 (COX-1 [56]. IC50 21,8 µmol/L; COX-2 IC50 9,2 µmol/L) (Figure8)[55]. Puerstinger et al. developed the series of imidazo[4,5-c]pyridines and tested them against the 2.4. Antiviral Activity Bovine Viral Diarrhea Virus (BVDV). As a result of extensive modification, highly active and selective againstViruses BVDV have molecule the ability 27 to(Figure attack 9) all was living obtained. organisms, A plants,decrease animals of activity and humans. in the presence An extremely of a fluorinedangerous atom phenomenon on the phenyl is their ring high located mutation in rate.the 2-position For this reason, was observed. researchers The around presence the world of large are substituentslooking for new on antiviralthe benzyl drugs group among was pyridine associated derivatives. with the Human reduction immunodeficiency of activity. The virus received (HIV) is compoundone of the most interacted serious andwith deadly viral communicableRNA-dependent diseases. RNA Lipolymerase. performed aThe series derivatives of in vitro anti-HIVdid not demonstrateassays on MT-4 activity cell cultureagainst infectedthe Hepatitis by the C Virus HIV-1 (HCV) IIIB strain, which thehas HIV-1a similar mutant organizational strain RES056, structure and tothe BVDV. HIV-2 As strain a second ROD. Synthesizedstep, compounds compounds selective demonstrated against HCV moderate were searched. to good Only activity. a couple The assaysof the testedrevealed compounds that amide (28 (compound, 29) showed25 selectivity, Figure9) (SI and > 595) sulfamide and high (compound activity (EC2650) groups0.10–0.20 are µM) preferable [57,58]. in theA parapluralityposition of modifications of the anilide in moiety. the benzyl The presencegroup have of electron-withdrawingled to obtaining compound group 30 in (Figure the ortho 9) whichposition is ofhighly the anilide potent moiety(EC50 0.004 is likewise µM) and relevant selective for against anti-HIV HCV. activity. The Derivativesaction mechanism25 and of26 thesewere compoundscharacterized is bythe higher inhibition potency of replication than the reference of a genotype drugs 2a nevirapine cell culture and infectious delaviridine HCVcc [56 ].[59].

Figure 9. AntiviralAntiviral imidazo[4,5- imidazo[4,5-bb]pyridines]pyridines and and imidazo[4,5- imidazo[4,5-c]pyridine derivatives.

2.5. Autoimmune Disorders Puerstinger et al. developed the series of imidazo[4,5-c]pyridines and tested them against the BovineCathepsin Viral Diarrhea S (CTSS) Virus belong(BVDV). to Asthe a family result ofof extensive cysteine modiﬁcation,proteases. Cathepsin highly active S is produced and selective by immuneagainst BVDV cells presenting molecule 27 antigen,(Figure9 which) was obtained.are activated A decrease by inflammatory of activity in mediators. the presence The of distinctive a ﬂuorine propertiesatom on the of phenyl this protein ring located from inother the 2-position cathepsins was are observed. the stability The presencebeyond ofthe large lysosome substituents and the on catalyticthe benzyl activity group at was neutral associated pH [60,61]. with theInhibition reduction of this of activity.enzyme Thecan receivedbe effective compound in the treatment interacted of immunewith viral RNA-dependentrelated diseases RNA such polymerase. as rheumati The derivativessm or didpsoriasis. not demonstrate Cai et activityal. obtained against 9H-purine-6-carbonitrile 31 (Figure 10) as a good CTSS inhibitor and pyridine-2-carbonitrile 32 which was characterized by the selectivity towards CTSS but with less potency.

Figure 10. Anti-autoimmune azines 31–33.

Subsequently, they obtained 1H-imidazo[4,5-c]pyridine-4-carbonitrile hybrids of these two compounds in order to improve their properties. Among the obtained derivatives compound 33 possessing the ethoxy group showed the highest activity (CTSS IC50 25 nM) while maintaining good selectivity (CTSK IC50 8310 nM). The longer chain or moiety without the oxygen atom indicated a lower activity [62].

Molecules 2017, 22, 399 7 of 24 anti-HIV activity. Derivatives 25 and 26 were characterized by higher potency than the reference drugs nevirapine and delaviridine [56]. Puerstinger et al. developed the series of imidazo[4,5-c]pyridines and tested them against the Bovine Viral Diarrhea Virus (BVDV). As a result of extensive modification, highly active and selective against BVDV molecule 27 (Figure 9) was obtained. A decrease of activity in the presence of a fluorine atom on the phenyl ring located in the 2-position was observed. The presence of large substituents on the benzyl group was associated with the reduction of activity. The received compound interacted with viral RNA-dependent RNA polymerase. The derivatives did not demonstrate activity against the Hepatitis C Virus (HCV) which has a similar organizational structure to BVDV. As a second step, compounds selective against HCV were searched. Only a couple of the tested compounds (28, 29) showed selectivity (SI > 595) and high activity (EC50 0.10–0.20 µM) [57,58]. A plurality of modifications in the benzyl group have led to obtaining compound 30 (Figure 9) which is highly potent (EC50 0.004 µM) and selective against HCV. The action mechanism of these compounds is the inhibition of replication of a genotype 2a cell culture infectious HCVcc [59].

Molecules 2017, 22, 399 8 of 25 the Hepatitis C Virus (HCV) which has a similar organizational structure to BVDV. As a second step, compounds selective against HCV were searched. Only a couple of the tested compounds (28, 29) showed selectivity (SI > 595) and high activity (EC50 0.10–0.20 µM) [57,58]. A plurality of modiﬁcations in the benzyl group have led to obtaining compound 30 (Figure9) which is highly potent (EC50 0.004 µM) and selective against HCV. The action mechanism of these compounds isFigure the inhibition 9. Antiviral of imidazo[4,5- replicationb]pyridines of a genotype and imidazo[4,5- 2a cell culturec]pyridine infectious derivatives. HCVcc [59].

2.5. Autoimmune Disorders Cathepsin SS (CTSS) (CTSS) belong belong to theto the family family of cysteine of cysteine proteases. proteases. Cathepsin Cathepsin S is produced S is produced by immune by immunecells presenting cells presenting antigen, whichantigen, are which activated are byactivated inﬂammatory by inflammatory mediators. mediators. The distinctive The distinctive properties propertiesof this protein of this from protein other cathepsins from other are cathepsins the stability are beyond the stability the lysosome beyond and the the lysosome catalytic and activity the catalyticat neutral activity pH [60 at,61 neutral]. Inhibition pH [60,61]. of this Inhibition enzyme can of this be effective enzyme incan the be treatment effective in of the immune treatment related of immunediseases suchrelated as rheumatism diseases orsuch psoriasis. as Cairheumati et al. obtainedsm or 9Hpsoriasis.-purine-6-carbonitrile Cai et al.31 (Figureobtained 10) 9asH a-purine-6-carbonitrile good CTSS inhibitor 31 and (Figure pyridine-2-carbonitrile 10) as a good CTSS32 which inhibitor was characterizedand pyridine-2-carbonitrile by the selectivity 32 whichtowards was CTSS characterized but with less by potency.the selectivity towards CTSS but with less potency.

Figure 10. Anti-autoimmune azines 31–33. Figure 10. Anti-autoimmune azines 31–33.

Subsequently, they obtained 1H-imidazo[4,5-c]pyridine-4-carbonitrile hybrids of these two compoundsSubsequently, in order theyto improve obtained their 1 Hproperti-imidazo[4,5-es. Amongc]pyridine-4-carbonitrile the obtained derivatives hybrids compound of these 33 two compounds in order to improve their properties. Among the obtained derivatives compound 33 possessing the ethoxy group showed the highest activity (CTSS IC50 25 nM) while maintaining good possessing the ethoxy group showed the highest activity (CTSS IC 25 nM) while maintaining good selectivity (CTSK IC50 8310 nM). The longer chain or moiety without50 the oxygen atom indicated a lowerselectivity activity (CTSK [62]. IC 50 8310 nM). The longer chain or moiety without the oxygen atom indicated a lower activity [62].

2.6. Antidiabetic Activity Diabetes is one of the most frequently occurring non-communicable diseases. The World Health Organization created the program for the years 2013–2030 which aims to reduces morbidity from diabetes and improvement of pharmacotherapies [63]. Hypoglycemic treatment in the early stages is relatively simple. It requires lifestyle changes and the introduction of monotherapy. Unfortunately, diabetes is a progressive disease and over time it requires the implementation of combination therapy. The most commonly used drugs include sulfonylureas, GLP-1 receptor agonists, PPAR-α agonists, DPP-IV inhibitors and the recently introduced glinides [64,65]. Novel glycogen synthase kinase 3 (GSK-3) inhibitors have been developed. 7-Hydroxybenzimidazole initially obtained by Lee showed good inhibitory activity to the enzyme GSK-3. Physicochemical properties including polar surface area (PSA) have been insufﬁcient. Compounds having the phenol scaffold are metabolized by glucuronidation to ether O-glucuronides [66]. Accordingly, the author exchanged the 7-hydroxybenzimidazole moiety for an imidazopyridine which can also be metabolized by glucuronidation. The results revealed that the newly synthesized derivatives have a stronger inhibitory effect on GSK-3 (IC50 1–12 nM) than their 7-hydroxybenzimidazole analogues. X-ray crystallography demonstrated that the imidazopyridine interacted with a carbonyl and an amino group of Val135 as a hydrogen-bonding donor and as a hydrogen-bonding acceptor. In contrast, 7-hydroxybenzimidazoles interacted with Asp133 and Pro136. Microsomal mouse stability studies were performed for received Molecules 2017, 22, 399 8 of 24

2.6. Antidiabetic Activity Diabetes is one of the most frequently occurring non-communicable diseases. The World Health Organization created the program for the years 2013–2030 which aims to reduces morbidity from diabetes and improvement of pharmacotherapies [63]. Hypoglycemic treatment in the early stages is relatively simple. It requires lifestyle changes and the introduction of monotherapy. Unfortunately, diabetes is a progressive disease and over time it requires the implementation of combination therapy. The most commonly used drugs include sulfonylureas, GLP-1 receptor agonists, PPAR-α agonists, DPP-IV inhibitors and the recently introduced glinides [64,65]. Novel glycogen synthase kinase 3 (GSK-3) inhibitors have been developed. 7-Hydroxybenzimidazole initially obtained by Lee showed good inhibitory activity to the enzyme GSK-3. Physicochemical properties including polar surface area (PSA) have been insufficient. Compounds having the phenol scaffold are metabolized by glucuronidation to ether O-glucuronides [66]. Accordingly, the author exchanged the 7-hydroxybenzimidazole moiety for an imidazopyridine which can also be metabolized by glucuronidation. The results revealed that the newly synthesized derivatives have a stronger inhibitory effect on GSK-3 (IC50 1–12 nM) than their 7-hydroxybenzimidazole analogues. X-ray crystallography demonstrated that the imidazopyridine interacted with a carbonyl and an amino

Moleculesgroup of2017 Val135, 22, 399 as a hydrogen-bonding donor and as a hydrogen-bonding acceptor. In contrast,9 of 25 7-hydroxybenzimidazoles interacted with Asp133 and Pro136. Microsomal mouse stability studies were performed for received compounds. Compound 34 (Figure 11) was characterized by good compounds.stability (70%), Compound high potency34 (Figure(IC50 8 nM)11) wasbut also characterized good physicochemical by good stability properties (70%), such high as potency cLogP (IC(2.73)50 8 and nM) a butPSA also (83.56 good Ĺ2) physicochemical [67]. properties such as cLogP (2.73) and a PSA (83.56 ´L2) [67].

Figure 11. Imidazo[4,5-Imidazo[4,5-b]pyridine derivative with antidiabetic activity.

2.7. Miscellaneous Activities Sharma etet al. al. reported reported the the series series of imidazopyridine of imidazopyridine derivatives derivatives like 35 likeas angiotensin35 as angiotensin II receptor II antagonistsreceptor antagonists (Figure 12 (Figure). ARBs act12). by ARBs inhibiting act by the in angiotensinhibiting the typeangiotensin I receptor type thereby I receptor preventing thereby the actionMoleculespreventing of 2017 angiotensin ,the 22, 399action IIof and angiotensin consequently II and reduce consequently blood pressure reduce [blood68]. pressure [68]. 9 of 24 The Maillard reaction is a common reaction occurring between amino acids and reducing sugars. The reaction leads to Amadori products which may accumulate in the human body and cause chronic diseases [69,70]. Following the merger of imidazopyridine and benzohydrazide, compounds with antiglycation and antioxidative potential were obtained. The tendency to an increase in both activities with the increasing number of the hydroxyl group was observed. It is related to high redox potential and the ability to donate electrons. Compound 36 is characterized by the highest antioxidant (EC50 26.12 µM) and an antiglycation (IC50 140.16 µM) activity even higher than for references compounds gallic acid and rutin [71,72]. Frohn reported the synthesis of compound 37 with excellent inhibitory activity towards prolyl hydroxylase domain-2 (PHD2) with the value of IC50 0.003 µM. PHD2 is critical for the regulation of hypoxia-inducible factor (HIF), whereas the hypoxia-inducible factor is engaged in the process of erythropoiesisFigure 12. Imidazo[4,5-Imidazo[4,5-[73,74]. b]pyridine]pyridine and imidazo[4,5- c]pyridine derivatives with a variety of activities.

3. Synthetic Routes to Imidazo[4,5-b]pyridines and Imidazo[4,5-c]pyridines The Maillard reaction is a common reaction occurring between amino acids and reducing sugars. The reactionWhile many leads strategies to Amadori are productsavailable whichfor imidazo[4,5- may accumulateb]pyridine in theand human imidazo[4,5- body andc]pyridine cause chronicsynthesis, diseases the most [69,70 popular]. Following approaches the merger involv of imidazopyridinee both condensation–deh and benzohydrazide,ydration reactions compounds of withpyridine-2,3-diamine antiglycation and or antioxidative pyridine-3,4-diamine potential werewith obtained.carboxylic The acids tendency (or their to an equivalents) increase in bothand activitiescondensation with with the increasingaldehydes numberunder oxidative of the hydroxyl conditions. group Carboxylic was observed. acids or It istheir related equivalents to high redox(nitriles, potential amidates, and and the orthoesters) ability to donate are usually electrons. reacted Compound under strongly36 is characterized acidic or harsh by dehydrating the highest antioxidantconditions that (EC 50often26.12 requireµM) and high an antiglycationtemperatures (ICor 50the140.16 use µofM) reagents activity such even higheras phosphorus than for referencesanhydride. compounds The reaction gallic can acidalso and be rutinperformed [71,72 ].stepwise via intermediate amides. In the case of aldehydes,Frohn reportedthe reaction the proceeds synthesis through of compound an imidaz37 witholidine-pyridine, excellent inhibitory and this activity requires towards an oxidative prolyl hydroxylasestep for conversion domain-2 to the (PHD2) corresponding with the value imidazopy of IC50ridine.0.003 Recently,µM. PHD2 a number is critical of for modifications the regulation of ofknown hypoxia-inducible methods were factor described (HIF), whereasthat may the signific hypoxia-inducibleantly accelerate factor the is engaged reactions in theand process increase of erythropoiesistheir yields. [73,74]. According to the classical method of benzimidazole synthesis, Dymińska et al. proposed the 3.synthesis Synthetic of Routesimidazo[4,5- to Imidazo[4,5-b]pyridineb 38]pyridines from 2,3-diaminopyridine and Imidazo[4,5-c ]pyridinesand formic acid (Scheme 1) [75]. The firstWhile successful many strategies lithium bromide are available mediated for imidazo[4,5- solvent freeb ]pyridinecondensation and of imidazo[4,5- arylenediaminec]pyridine and synthesis,esters to obtain the most2-substitu popularted imidazopyridines approaches involve (e.g., both 39) in condensation–dehydration good to excellent yields at reactions 110–115 °C of pyridine-2,3-diaminewas described by Dekhane or pyridine-3,4-diamine et al. [76]. Mladenova with carboxylic performed acids (orthe their reaction equivalents) of methyl and condensation4-((benzyloxy)methyl)tetrahydrofuran-2-carbimidate with aldehydes under oxidative conditions. hydrochloride– Carboxyliccis acids or theirtrans equivalents with (nitriles,2,3-diaminopyridine amidates, and in orthoesters)MeOH resulting are usually in the reactedcorresponding under strongly1H-imidazo[4,5- acidic orb]pyridine harsh dehydrating 40, cis or conditionstrans in a yield that of often 40% require [77]. high temperatures or the use of reagents such as phosphorus anhydride. The reaction can also be performed stepwise via intermediate amides. In the case of aldehydes, the reaction proceeds through an imidazolidine-pyridine, and this requires an oxidative step for conversion

Scheme 1. Synthesis of imidazo[4,5-b]pyridines from 2,3-diaminopyridine and carboxylic acids or their functional derivatives.

Dymińska also obtained 7-methyl-3H-imidazo[4,5-c]pyridine from 5-methyl-3,4-diamino-pyridine in 100% formic acid (Scheme 2). The reaction mixture was boiled

Molecules 2017, 22, 399 9 of 24

Figure 12. Imidazo[4,5-b]pyridine and imidazo[4,5-c]pyridine derivatives with a variety of activities.

3. Synthetic Routes to Imidazo[4,5-b]pyridines and Imidazo[4,5-c]pyridines While many strategies are available for imidazo[4,5-b]pyridine and imidazo[4,5-c]pyridine synthesis, the most popular approaches involve both condensation–dehydration reactions of pyridine-2,3-diamine or pyridine-3,4-diamine with carboxylic acids (or their equivalents) and condensation with aldehydes under oxidative conditions. Carboxylic acids or their equivalents (nitriles, amidates, and orthoesters) are usually reacted under strongly acidic or harsh dehydrating conditions that often require high temperatures or the use of reagents such as phosphorus anhydride.Molecules 2017 ,The22, 399 reaction can also be performed stepwise via intermediate amides. In the case10 of of 25 aldehydes, the reaction proceeds through an imidazolidine-pyridine, and this requires an oxidative step for conversion to the corresponding imidazopyridine. Recently, a number of modifications of knownto the corresponding methods were imidazopyridine. described that Recently, may signific a numberantly ofaccelerate modifications the ofreactions known methodsand increase were theirdescribed yields. that may significantly accelerate the reactions and increase their yields. According to the classical method of benzimidazolebenzimidazole synthesis, DymińskaetDymińska et al. proposed the synthesis of imidazo[4,5- bb]pyridine]pyridine 3838 fromfrom 2,3-diaminopyridine 2,3-diaminopyridine and and formic formic acid acid (Scheme (Scheme 11))[ [75].75]. The first first successful successful lithium lithium bromide bromide mediated mediated solvent solvent free free condensation condensation of arylenediamine of arylenediamine and estersand estersto obtain to obtain2-substitu 2-substitutedted imidazopyridines imidazopyridines (e.g., 39) in (e.g., good39 to) excellent in good yields to excellent at 110–115 yields °C ◦ wasat 110–115 describedC wasby Dekhane described et by al. Dekhane [76]. Mladenova et al. [76]. performed Mladenova the performed reaction theof reactionmethyl 4-((benzyloxy)methyl)tetrahydrofuran-2-carbimidateof methyl 4-((benzyloxy)methyl)tetrahydrofuran-2-carbimidate hydrochloride– hydrochloride–cis or cis ortranstrans with 2,3-diaminopyridine in in MeOH resulting in the corresponding 1H-imidazo[4,5-bb]pyridine]pyridine 4040,, ciscis or trans in a yield of 40% [77]. [77].

Scheme 1. SynthesisSynthesis ofof imidazo[4,5- imidazo[4,5-b]pyridinesb]pyridines from from 2,3-diaminopyridine 2,3-diaminopyridine and and carboxylic carboxylic acids acids or their or theirfunctional functional derivatives. derivatives.

Dymińska also obtained 7-methyl-3H-imidazo[4,5-c]pyridine from Dymi´nskaalso obtained 7-methyl-3H-imidazo[4,5-c]pyridine from 5-methyl-3,4-diamino-pyridine 5-methyl-3,4-diamino-pyridineMolecules 2017, 22, 399 in 100% formic acid (Scheme 2). The reaction mixture was boiled10 of 24 in 100% formic acid (Scheme2). The reaction mixture was boiled under reﬂux for 6 h and was recommendedunder reflux for as a6 methodh and forwas the recommended preparation ofas derivativesa method substitutedfor the preparation with a methyl of derivatives group at varioussubstituted positions with a of methyl the pyridine group at ring various [78]. positions of the pyridine ring [78].

Scheme 2. Synthesis of methyl-substituted imidazo[4,5-c]pyridines.

A typical reaction for the preparation of imidazopyridines seems to be the synthesis from A typical reaction for the preparation of imidazopyridines seems to be the synthesis from carboxylic acid and 2,3-diaminepyridine or 3,4-diaminopyridine in polyphosphoric acid (PPA) as a carboxylic acid and 2,3-diaminepyridine or 3,4-diaminopyridine in polyphosphoric acid (PPA) as a dehydrating agent at an elevated temperature (Scheme 3). The method is simple, convenient and dehydrating agent at an elevated temperature (Scheme3). The method is simple, convenient and rather good yielded (~75%), particularly when microwave irradiation is used [79]. rather good yielded (~75%), particularly when microwave irradiation is used [79].

Scheme 3. Synthesis of functionalized imidazo[4,5-c]pyridine.

The condensation reaction of 2-amino-3-hydroxypyridine with different carboxylic acids by microwave-assisted heating is a fast method for producing libraries based on fused 2-substituted imidazo[4,5-b]pyridines in moderate to good yields (Scheme 4). The best results (yields 71%–92%) were obtained by using silica gel as a support and equimolecular quantities of the both reactants at 100 W [80,81].

H NH 2 MW, 170-250 C N RCOOH Y or silica gel Y R N N NH2 MW, 120 C N

R: Me, long alkyl chain, Ph, 3-Cl-Ph, 4-Cl-Ph, 4-OMe-Ph, 3-OH-Ph, 4-CN-Ph, 4-CF3-Ph, cyclo-C6H11 Y: H, Me, Cl Scheme 4. Microwave assisted synthesis of imidazo[4,5-b]pyridines.

Rene et al. reported an efficient one-step route to fluoroalkyl-azabenzimidazoles via the condensation of fluorinated carboxylic acids and pyridinediamines (Scheme 5). This method is high-yielding (54%–99%) with a broad scope and is operationally simple with potential application to parallel synthesis [82].

Scheme 5. Synthesis of fluoroalkyl-imidazo[4,5-b]pyridines.

Imidazo[4,5-b]pyridine and imidazo[4,5-c]pyridine derivatives were also synthesized from 4-phenylpicolinothioamide (Scheme 6), which was obtained from starting carbonitrile via methyl carbimidate in the reaction with DBU and ammonium polysulfide. Then, upon treatment of appropriate diamines in ethylene glycol, 4-phenylpicolinothioamide gave the corresponding imidazopyridines [83].

Molecules 2017, 22, 399 10 of 24 Molecules 2017, 22, 399 10 of 24 Molecules 2017, 22, 399 10 of 24 under reflux for 6 h and was recommended as a method for the preparation of derivatives substitutedunder reflux with for a methyl6 h and gr oupwas at recommended various positions as ofa methodthe pyridine for thering preparation[78]. of derivatives undersubstituted reflux with for a 6methyl h and gr oupwas atrecommended various positions as aof methodthe pyridine for thering preparation [78]. of derivatives substituted with a methyl group at various positions of the pyridine ring [78].

Scheme 2. Synthesis of methyl-substituted imidazo[4,5- c]pyridines. Scheme 2. Synthesis of methyl-substituted imidazo[4,5-c]pyridines. Scheme 2. Synthesis of methyl-substituted imidazo[4,5-c]pyridines. A typical reaction for the preparation of imidazopyridines seems to be the synthesis from carboxylicA typical acid reactionand 2,3-diaminepyridine for the preparation or 3,4-di of imidazopyridinesaminopyridine in seems polyphosphoric to be the acidsynthesis (PPA) from as a A typical reaction for the preparation of imidazopyridines seems to be the synthesis from dehydratingcarboxylic acid agent and at 2,3-diaminepyridine an elevated temperature or 3,4-di (Schemeaminopyridine 3). The methodin polyphosphoric is simple, convenientacid (PPA) andas a Moleculescarboxylic2017 acid, 22, 399and 2,3-diaminepyridine or 3,4-diaminopyridine in polyphosphoric acid (PPA)11 ofas 25a ratherdehydrating good yielded agent at (~75%), an elevated particularly temperature when microwave (Scheme 3). irradiation The method is used is simple, [79]. convenient and dehydratingrather good yieldedagent at (~75%), an elevated particularly temperature when microwave (Scheme 3). irradiation The method is used is simple, [79]. convenient and rather good yielded (~75%), particularly when microwave irradiation is used [79].

Scheme 3. Synthesis of functionalized imidazo[4,5-c]pyridine. Scheme 3. Synthesis of functionalized imidazo[4,5-c]pyridine. Scheme 3. Synthesis of functionalized imidazo[4,5-c]pyridine. Scheme 3. Synthesis of functionalized imidazo[4,5-c]pyridine. The condensation reaction of 2-amino-3-hydroxypyridine with different carboxylic acids by microwave-assistedThe condensationcondensation heating reactionreaction is a ofoffast 2-amino-3-hydroxypyridine2-amino-3-hydroxypyridine method for producing librar withies differentbased on carboxylicfused 2-substituted acids by The condensation reaction of 2-amino-3-hydroxypyridine with different carboxylic acids by microwave-assistedimidazo[4,5-b]pyridines heating in moderate is a fastfast methodtomethod good foryieldsfor producingproducing (Scheme librarieslibrar 4). Theies best basedbased results onon fusedfused (yields 2-substituted2-substituted 71%–92%) microwave-assisted heating is a fast method for producing libraries based on fused 2-substituted imidazo[4,5-wereimidazo[4,5- obtainedb]pyridines by using silicain moderate gel as a tosupport good yieldsyieldsand equimolecular (Scheme(Scheme4 4).). TheThe quantities bestbest resultsresults of the (yields(yields both reactants 71%–92%)71%–92%) at imidazo[4,5-b]pyridines in moderate to good yields (Scheme 4). The best results (yields 71%–92%) were100were W obtainedobtained [80,81]. byby usingusing silicasilica gelgel asas aa supportsupport andand equimolecularequimolecular quantitiesquantities of thethe bothboth reactantsreactants at 100were100 WW obtained [[80,81].80,81]. by using silica gel as a support and equimolecular quantities of the both reactants at 100 W [80,81]. H NH 2 MW, 170-250 C NH Y NH2 RCOOH R MW,or 170-250 silica gel C Y HN NH2 RCOOH N Y N NH MW,MW,or 170-250 silica 120 gelCC Y N N R Y 2 RCOOH N NH orMW, silica 120 gelC Y N N R 2 N N R:NH Me,2 long alkyl chain, Ph,MW, 3-Cl-Ph, 120 C 4-Cl-Ph, 4-OMe-Ph,N R:3-OH-Ph, Me, long 4-CN-Ph, alkyl chain, 4-CF Ph,3-Ph, 3-Cl-Ph, cyclo-C 4-Cl-Ph,6H11 Y: 4-OMe-Ph, H, Me, Cl R: Me, long alkyl chain, Ph, 3-Cl-Ph, 4-Cl-Ph, 4-OMe-Ph, 3-OH-Ph, 4-CN-Ph, 4-CF3-Ph, cyclo-C6H11 Y: H, Me, Cl Scheme 4. Microwave3-OH-Ph, 4-CN-Ph,assisted4-CF synthesis3-Ph, cyclo-C of imidazo[4,5-6H11 Y: H, Me,b]pyridines. Cl Scheme 4. Microwave assisted synthesis of imidazo[4,5-bb]pyridines.]pyridines. Scheme 4. Microwave assisted synthesis of imidazo[4,5-b]pyridines. Rene et al. reported an efficient one-step route to fluoroalkyl-azabenzimidazoles via the Rene et al. reported an efficient one-step route to fluoroalkyl-azabenzimidazoles via the condensationRene et al.of fluorinated reported an carboxylic efficient one-stepacids and route pyridinediamines to fluoroalkyl-azabenzimidazoles (Scheme 5). This method via the is condensationRene et al.of fluorinatedreported an carboxylic efficient one-stepacids an droute pyridinediamines to fluoroalkyl-azabenzimidazoles (Scheme 5). This method via the is condensationhigh-yielding (54%–99%) of fluorinated with carboxylic a broad scope acids and and is pyridinediamines operationally simple (Scheme with 5potential). This methodapplication is condensationhigh-yielding (54%–99%)of fluorinated with carboxylic a broad scope acids and an dis pyridinediaminesoperationally simple (Scheme with potential 5). This applicationmethod is high-yieldingto parallel synthesis (54%–99%) [82]. with a broad scope and is operationally simple with potential application to high-yieldingto parallel synthesis (54%–99%) [82]. with a broad scope and is operationally simple with potential application parallelto parallel synthesis synthesis [82 [82].].

Scheme 5. Synthesis of fluoroalkyl-imidazo[4,5-b]pyridines. Scheme 5. Synthesis of fluoroalkyl-imidazo[4,5-b]pyridines. Scheme 5. Synthesis of fluoroalkyl-imidazo[4,5-b]pyridines. Imidazo[4,5-b]pyridineScheme and 5. Synthesis imidazo[4,5- of ﬂuoroalkyl-imidazo[4,5-c]pyridine derivativesb]pyridines. were also synthesized from 4-phenylpicolinothioamideImidazo[4,5-b]pyridine (Schemeand imidazo[4,5- 6), whichc ]pyridinewas obtained derivatives from starting were carbonitrilealso synthesized via methyl from 4-phenylpicolinothioamideImidazo[4,5-b]pyridine (Schemeand imidazo[4,5- 6), whichc ]pyridinewas obtained derivatives from starting were carbonitrilealso synthesized via methyl from carbimidateImidazo[4,5- in theb]pyridine reaction andwith imidazo[4,5- DBU and cammo]pyridinenium derivatives polysulfide. were Then, also upon synthesized treatment from of 4-phenylpicolinothioamidecarbimidate in the reaction (Scheme with DBU 6), which and ammowas obtainednium polysulfide. from starting Then, carbonitrile upon treatment via methyl of 4-phenylpicolinothioamideappropriate diamines in ethylene (Scheme 6glycol,), which 4-ph wasenylpicolinothioamide obtained from starting gave carbonitrile the corresponding via methyl carbimidateappropriate indiamines the reaction in ethylene with DBU glycol, and 4-ph ammoenylpicolinothioamidenium polysulfide. Then,gave uponthe corresponding treatment of carbimidateimidazopyridines in the reaction[83]. with DBU and ammonium polysulﬁde. Then, upon treatment of appropriate appropriateimidazopyridines diamines [83]. in ethylene glycol, 4-phenylpicolinothioamide gave the corresponding diaminesimidazopyridinesMolecules 2017 in, ethylene22, 399 [83]. glycol, 4-phenylpicolinothioamide gave the corresponding imidazopyridines11 [of83 24].

Scheme 6. Imidazopyridine synthesis from carbonitrile via picolinothioamide.

The cyclization to the imidazo[4,5-b]pyridine ring system was also effected by refluxing The cyclization to the imidazo[4,5-b]pyridine ring system was also effected by reﬂuxing 2,3-diaminopyridine in triethyl orthoformate or triethyl orthoacetate followed by chlorohydric acid 2,3-diaminopyridine in triethyl orthoformate or triethyl orthoacetate followed by chlorohydric acid treatment to obtain, respectively, imidazo[4,5-b]pyridine its 2-methyl derivative in yield 83% and treatment to obtain, respectively, imidazo[4,5-b]pyridine its 2-methyl derivative in yield 83% and 78% 78% (Scheme 7) [84]. (Scheme7)[84].

Scheme 7. Imidazopyridine synthesis using orthoesters.

A facile synthesis of imidazo[4,5-b]pyridines was described by Rosenberg et al. using a Pd-catalyzed amide coupling reaction. 3-Alkyl and 3-arylamino-2-chloropyridines reacted with simple primary amides in good yields (51%–99%) when refluxing in t-butanol in the presence of tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct, di-tert-butyl(2′,4′,6′-triisopropyl-3,6- dimethoxy-[1,1′-biphenyl]-2-yl)phosphine as a ligand and potassium phosphate (Scheme 8). That reaction provided quick access to products with substitution at N1 and C2 [85].

Scheme 8. Pd-catalyzed amide coupling reaction produces imidazo[4,5-b]pyridines.

Al-duaij et al. [86] described an interesting method of imidazo[4,5-b]pyridine synthesis using malononitrile. First, heating diaminomaleonitrile 41 with triethyl orthoformate in dioxane afforded ethyl [2-amino-1,2-dicyanovinyl]imidoformate 42. Treatment of 42 with the appropriate amines, namely 4-methoxybenzylamine and 4-methylbenzylamine catalyzed by aniline hydrochloride, formed (substituted benzyl)-N-(2-amino-1,2-dicyanovinyl)formimidine 43 which underwent intramolecular cyclization in the presence of 1,8-diazabicyclo(5.4.0)undec-7-ene (DBU) to form 5-amino-1-(substituted benzyl)-4-cyanoformimidoyl imidazole derivative 44 (Scheme 9).

Molecules 2017, 22, 399 11 of 24 Molecules 2017, 22, 399 11 of 24

Scheme 6. Imidazopyridine synthesis from carbonitrile via picolinothioamide. Scheme 6. Imidazopyridine synthesis from carbonitrile via picolinothioamide. The cyclization to the imidazo[4,5-b]pyridine ring system was also effected by refluxing The cyclization to the imidazo[4,5-b]pyridine ring system was also effected by refluxing 2,3-diaminopyridine in triethyl orthoformate or triethyl orthoacetate followed by chlorohydric acid 2,3-diaminopyridine in triethyl orthoformate or triethyl orthoacetate followed by chlorohydric acid treatment to obtain, respectively, imidazo[4,5-b]pyridine its 2-methyl derivative in yield 83% and Moleculestreatment2017 to, 22 obtain,, 399 respectively, imidazo[4,5-b]pyridine its 2-methyl derivative in yield 83%12 ofand 25 78% (Scheme 7) [84]. 78% (Scheme 7) [84].

Scheme 7. ImidazopyridineImidazopyridine synthesis synthesis using using orthoesters. orthoesters. Scheme 7. Imidazopyridine synthesis using orthoesters. A facile synthesis of imidazo[4,5-b]pyridines was described by Rosenberg et al. using a A facile synthesis of imidazo[4,5- bb]pyridines]pyridines was was described described by by Rosenberg Rosenberg et et al. al. using using a Pd-catalyzed amide coupling reaction. 3-Alkyl and 3-arylamino-2-chloropyridines reacted with aPd-catalyzed Pd-catalyzed amide amide coupling coupling reaction. reaction. 3-Alkyl 3-Alkyl and and3-arylamino-2-chloropyridines 3-arylamino-2-chloropyridines reacted reacted with simple primary amides in good yields (51%–99%) when refluxing in t-butanol in the presence of withsimple simple primary primary amides amides in good in yields good (51%–99%) yields (51%–99%) when refluxing when in reﬂuxing t-butanol in int -butanolthe presence in the of tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct, di-tert-butyl(2′,4′,6′-triisopropyl-3,6- presencetris(dibenzylideneacetone)dipalladium(0)-chloroform of tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct, di-tert-butyl(2 adduct,′,4 di-tert-butyl(2′,6′-triisopropyl-3,6-0,40,60- dimethoxy-[1,1′-biphenyl]-2-yl)phosphine as a ligand and potassium phosphate (Scheme 8). That triisopropyl-3,6-dimethoxy-[1,1dimethoxy-[1,1′-biphenyl]-2-yl)phosphine0-biphenyl]-2-yl)phosphine as a ligand and potassium as a ligand phosphate and potassium (Scheme phosphate 8). That reaction provided quick access to products with substitution at N1 and C2 [85]. (Schemereaction 8provided). That reaction quick access provided to products quick access with to substitution products with at N1 substitution and C2 [85]. at N1 and C2 [85].

Scheme 8. Pd-catalyzed amide coupling reaction produces imidazo[4,5-b]pyridines. Scheme 8. Pd-catalyzed amide coupling reaction produces imidazo[4,5-b]pyridines. Scheme 8. Pd-catalyzed amide coupling reaction produces imidazo[4,5-b]pyridines. Al-duaij et al. [86] described an interesting method of imidazo[4,5-b]pyridine synthesis using Al-duaij et al. [86] described an interesting method of imidazo[4,5-b]pyridine synthesis using malononitrile. First, heating diaminomaleonitrile 41 with triethyl orthoformate in dioxane afforded malononitrile.Al-duaij et First, al. [ 86heating] described diaminomaleonitrile an interesting method 41 with oftriethyl imidazo[4,5- orthoformateb]pyridine in dioxane synthesis afforded using ethyl [2-amino-1,2-dicyanovinyl]imidoformate 42. Treatment of 42 with the appropriate amines, malononitrile.ethyl [2-amino-1,2-dicyanovinyl]imidoformate First, heating diaminomaleonitrile 4241. Treatmentwith triethyl of orthoformate42 with the appropriate in dioxane affordedamines, namely 4-methoxybenzylamine and 4-methylbenzylamine catalyzed by aniline hydrochloride, ethylnamely [2-amino-1,2-dicyanovinyl]imidoformate 4-methoxybenzylamine and 4-methylbenzylamine42. Treatment catalyzed of 42 with by theaniline appropriate hydrochloride, amines, formed (substituted benzyl)-N-(2-amino-1,2-dicyanovinyl)formimidine 43 which underwent namelyformed 4-methoxybenzylamine(substituted benzyl)- andN-(2-amino-1,2-dicyanovinyl)formimidine 4-methylbenzylamine catalyzed by aniline 43 hydrochloride, which underwent formed intramolecular cyclizationN in the presence of 1,8-diazabicyclo(5.4.0)undec-7-ene (DBU) to form (substitutedintramolecular benzyl)- cyclization-(2-amino-1,2-dicyanovinyl)formimidine in the presence of 1,8-diazabicyclo(5.4.0)undec-7-ene43 which underwent (DBU) intramolecular to form 5-amino-1-(substituted benzyl)-4-cyanoformimidoyl imidazole derivative 44 (Scheme 9). cyclization5-amino-1-(substituted in the presence benzyl)-4-cyanoformimidoyl of 1,8-diazabicyclo(5.4.0)undec-7-ene imidazole (DBU)derivative to form 44 (Scheme 5-amino-1-(substituted 9). Moleculesbenzyl)-4-cyanoformimidoyl 2017, 22, 399 imidazole derivative 44 (Scheme9). 12 of 24

Scheme 9. Synthesis ofof 5-amino-1-(substituted5-amino-1-(substituted benzyl)-4-cyanoformimidoyl benzyl)-4-cyanoformimidoyl imidazole imidazole derivative derivative as anas aninterediate interediate for for imidazole[4,5- imidazole[4,5-b]pyridines.b]pyridines.

Next 1-aryl-5-amino-4-(cyanoformimidoyl)imidazoles 44 were reacted with malononitrile Next 1-aryl-5-amino-4-(cyanoformimidoyl)imidazoles 44 were reacted with malononitrile under under mild experimental conditions and led to 3-aryl-5,7-diamino-6-cyano-3H-imidazo[4,5-b] mild experimental conditions and led to 3-aryl-5,7-diamino-6-cyano-3H-imidazo[4,5-b]pyridines 45, pyridines 45, when the reaction was carried out in the presence of DBU, or to when the reaction was carried out in the presence of DBU, or to 3-aryl-5-amino-6,7-dicyano-3H- 3-aryl-5-amino-6,7-dicyano-3H-imidazo[4,5-b]pyridines 46, in its absence. Both reactions evolved imidazo[4,5-b]pyridines 46, in its absence. Both reactions evolved from the adduct formed by a from the adduct formed by a nucleophilic attack of the malononitrile anion to the carbon of the cyanoformimidoyl substituent (Scheme 10) [86,87].

Scheme 10. Synthesis of functionalized imidazo[4,5-b]pyridines from 1-aryl-5-amino-4-(cyanoformimidoyl)imidazoles.

A new environmentally-benign, convenient, and facile methodology for the synthesis of 2-substituted-1H-imidazo[4,5-b]pyridine was elaborated by Kale et al. [88]. The reaction of 2,3-diaminopyridine with substituted aryl aldehydes in water under thermal conditions without the use of any oxidative reagent has been studied. The reaction has yielded 1H-imidazo[4,5-b]pyridine derivatives (Scheme 11) by an air oxidative cyclocondensation reaction in one step in an excellent yield (83%–87%). Ivanova et al. described similar preparation of substituted 2-(1,2,4-triazol-3-yl)imidazopyridines from diaminopyridines and triazole aldehydes. In that case also, good yields were obtained 37%–71% [89].

Scheme 11. Classical synthesis from 2,3-diaminopyridine and aldehydes.

A set of 3H-imidazo[4,5-b]pyridines was also readily prepared from (hetero)aromatic ortho-diamines and aldehydes using chlorotrimethylsilane in DMF as a promoter and water-acceptor agent, followed by oxidation with air oxygen (Scheme 12). The authors obtained products with very good yields 79%–80% [90].

Scheme 12. Modification with chlorotrimethylsilane as apromoter and water-acceptor.

Molecules 2017, 22, 399 12 of 24 Molecules 2017, 22, 399 12 of 24 Molecules 2017, 22, 399 12 of 24

Scheme 9. Synthesis of 5-amino-1-(substituted benzyl)-4-cyanoformimidoyl imidazole derivative as Scheme 9. Synthesis of 5-amino-1-(substituted benzyl)-4-cyanoformimidoyl imidazole derivative as Schemean interediate 9. Synthesis for imidazole[4,5- of 5-amino-1-(substitutedb]pyridines. benzyl)-4-cyanoformimidoyl imidazole derivative as an interediate for imidazole[4,5-b]pyridines. an interediate for imidazole[4,5-b]pyridines. Next 1-aryl-5-amino-4-(cyanoformimidoyl)imidazoles 44 were reacted with malononitrile underNext mild 1-aryl-5-amino-4-(cyanoformimidoyl)imidazoles experimental conditions and led to 3-aryl-5,7-diamino-6-cyano-3 44 were reacted withH -imidazo[4,5-malononitrileb] Moleculesunder mild2017, 22 experimental, 399 conditions and led to 3-aryl-5,7-diamino-6-cyano-3H-imidazo[4,5-13 of 25b] under mild experimental conditions and led to 3-aryl-5,7-diamino-6-cyano-3H-imidazo[4,5-b] pyridines 45, when the reaction was carried out in the presence of DBU, or to pyridines 45, when the reaction was carried out in the presence of DBU, or to 3-aryl-5-amino-6,7-dicyano-3H-imidazo[4,5-b]pyridines 46, in its absence. Both reactions evolved nucleophilic3-aryl-5-amino-6,7-dicyano-3 attack of the malononitrileH-imidazo[4,5- anionb]pyridines to the carbon 46, in ofits the absence. cyanoformimidoyl Both reactions substituent evolved from the adduct formed by a nucleophilic attack of the malononitrile anion to the carbon of the (Schemefrom the 10 adduct)[86,87 formed]. by a nucleophilic attack of the malononitrile anion to the carbon of the cyanoformimidoyl substituent (Scheme 10) [86,87]. cyanoformimidoyl substituent (Scheme 10) [86,87].

Scheme 10. Synthesis of functionalized imidazo[4,5-b]pyridines from Scheme 10. 10. SynthesisSynthesis of functionalizedof functionalized imidazo[4,5- b]pyridinesimidazo[4,5- fromb]pyridines 1-aryl-5-amino-4- from Scheme1-aryl-5-amino-4-(cyanoformimidoyl)imidazoles. 10. Synthesis of functionalized imidazo[4,5-b]pyridines from (cyanoformimidoyl)imidazoles.1-aryl-5-amino-4-(cyanoformimidoyl)imidazoles. 1-aryl-5-amino-4-(cyanoformimidoyl)imidazoles. A new environmentally-benign, convenient, and facile methodology for the synthesis of A new environmentally-benign,environmentally-benign, convenient, an andd facile methodology for the synthesis of 2-substituted-1A new environmentally-benign,H-imidazo[4,5-b]pyridine convenient, was elaborated and facile by Kalemethodology et al. [88]. for theThe synthesisreaction of 2-substituted-1H-imidazo[4,5--imidazo[4,5-bb]pyridine]pyridine was was elaborated by KaleKale etet al.al. [88[88].]. The The reaction of 2-substituted-12,3-diaminopyridineH-imidazo[4,5- with substitutedb]pyridine aryl was aldehyde elaborateds in water by underKale thermalet al. [88].conditions The reactionwithout theof 2,3-diaminopyridine with with substituted substituted aryl aryl aldehyde aldehydess in inwater water under under thermal thermal conditions conditions without without the 2,3-diaminopyridineuse of any oxidative withreagent substituted has been aryl studied. aldehyde The sreaction in water has under yielded thermal 1H-imidazo[4,5- conditions withoutb]pyridine the theuse useof any of any oxidative oxidative reagent reagent has has been been studied. studied. The The reaction reaction has has yielded yielded 1 1HH-imidazo[4,5--imidazo[4,5-b]pyridine]pyridine usederivatives of any oxidative (Scheme reagent11) by an has air been oxidative studied. cyclocon The reactiondensation has reaction yielded in1H one-imidazo[4,5- step in anb ]pyridineexcellent derivatives (Scheme 11)11) by an air oxidative cyclocondensationcyclocondensation reaction in one step in an excellent derivativesyield (83%–87%). (Scheme 11)Ivanova by an air etoxidative al. cyclocondescribeddensation similar reaction preparation in one step of in ansubstituted excellent yield (83%–87%).(83%–87%). Ivanova Ivanova et al.et described al. described similar preparationsimilar ofpreparation substituted 2-(1,2,4-triazol-3-of substituted yield2-(1,2,4-triazol-3-yl)imidazopyridines (83%–87%). Ivanova et fromal. diaminopyridinesdescribed similar and triazolepreparation aldehydes. of Insubstituted that case yl)imidazopyridines2-(1,2,4-triazol-3-yl)imidazopyridines from diaminopyridines from diaminopyridines and triazole aldehydes. and triazole In that aldehydes. case also, In good that yields case 2-(1,2,4-triazol-3-yl)imidazopyridinesalso, good yields were obtained 37%–71% from [89]. diaminopyridines and triazole aldehydes. In that case werealso, good obtained yields 37%–71% were obtained [89]. 37%–71% [89]. also, good yields were obtained 37%–71% [89].

Scheme 11. Classical synthesis from 2,3-diaminopyridine and aldehydes. Scheme 11. Classical synthesis from 2,3-diaminopyridine and aldehydes. Scheme 11. Classical synthesis from 2,3-diaminopyridine and aldehydes. A set of 3H-imidazo[4,5-b]pyridines was also readily prepared from (hetero)aromatic A set of 33HH-imidazo[4,5--imidazo[4,5-b]pyridines was also readily prepared from (hetero)aromatic(hetero)aromatic ortho-diamines and aldehydes using chlorotrimethylsilane in DMF as a promoter and water-acceptor ortho-diamines and aldehydes using chlorotrimethylsilane in DMF as a promoter and water-acceptor agent, followed by oxidation with air oxygen (Scheme 12). The authors obtained products with very agent, followed by oxidation with air oxygen (Scheme(Scheme 1212).). The authors obtained products with very good yields 79%–80% [90]. good yields 79%–80% [[90].90].

Scheme 12. Modification with chlorotrimethylsilane as apromoter and water-acceptor. Scheme 12. Modification with chlorotrimethylsilane as apromoter and water-acceptor. Scheme 12. ModificationModiﬁcation with chlorotrimethylsilane as apromoter and water-acceptor.

Reduction of 6-methoxy-3-nitropyridin-2-amine 47 was achieved catalytically (using Pd/C as a catalyst under hydrogen gas) to give the compound 6-methoxypyridine-2,3-diamine (48). This diamino analog was instable and immediately used in the next step reaction without further puriﬁcation (Scheme 13). Subsequent imidazole ring compound 49 was formed from compound 48 by treating with CS2 and KOH in 63% yield [91]. Molecules 2017, 22, 399 13 of 24 Molecules 2017, 22, 399 13 of 24 Molecules 2017, 22, 399 13 of 24 Reduction of 6-methoxy-3-nitropyridin-2-amine 47 was achieved catalytically (using Pd/C as a catalystReduction under ofhydrogen 6-methoxy- gas)3-nitropyridin-2-amine to give the compound 47 was6-methoxypyridine-2,3-diamine achieved catalytically (using Pd/C(48). Thisas a catalystReduction under ofhydrogen 6-methoxy- gas)3-nitropyridin-2-amine to give the compound 47 was6-methoxypyridine-2,3-diamine achieved catalytically (using (Pd/C48). Thisas a diamino analog was instable and immediately used in the next step reaction without further diaminocatalyst underanalog hydrogen was instable gas) andto give immediately the compound used in6-methoxypyridine-2,3-diamine the next step reaction without (48 further). This Moleculespurification2017, 22(Scheme, 399 13). Subsequent imidazole ring compound 49 was formed from compound14 of 48 25 purificationdiamino analog (Scheme was 13).instable Subsequent and immediately imidazole ring used compound in the next 49 was step formed reaction from without compound further 48 by treating with CS2 and KOH in 63% yield [91]. bypurification treating with (Scheme CS2 and 13). KOH Subsequent in 63% imidazoleyield [91]. ring compound 49 was formed from compound 48 by treating with CS2 and KOH in 63% yield [91].

Scheme 13.13. Synthesis of imidazo[4,5-bb]pyridine-2-thione.]pyridine-2-thione. Scheme 13. Synthesis of imidazo[4,5-b]pyridine-2-thione. Scheme 13. Synthesis of imidazo[4,5-b]pyridine-2-thione. Enhancing the reactivity of the catalytic system by using a palladium catalyst with sterically Enhancing the reactivity of the catalytic system by using a palladium catalyst with sterically demandingEnhancing and the electron reactivity rich ligandsof the catalytic attached system to it has by often using been a palladium shown as catalystan appropriate with sterically way of demandingEnhancing and theelectron reactivity rich ligands of the catalyticattached systemto it has by often using been a palladium shown as catalyst an appropriate with sterically way of performing the copper-free Sonogashira reaction. Sajith et al. [92] reported PdCl2(PCy3)2 (Scheme 14) performingdemanding theand copper-free electron rich Sonogashira ligands attached reaction. to Sajithit has etoften al. [ 92been] reported shown PdClas an (PCyappropriate) (Scheme way 14 of) performingas an efficient the copper-freecatalyst for Sonogashira the copper reaction.and amine-free Sajith et al.Sonogashira [92] reported cross PdCl coupling22(PCy33)2 (Schemereactions 14) of asperforming an efﬁcient the copper-free catalyst for Sonogashira the copper reaction. and amine-free Sajith et Sonogashiraal. [92] reported cross PdCl coupling2(PCy3)2 reactions(Scheme 14) of as2-halo-3-alkyl an efficient imidazo[4,5- catalyst forb ]pyridinesthe copper (I, and Br, Cl)amine-free using tetrabutyl Sonogashira ammonium cross couplingacetate as reactionsan activator of 2-halo-3-alkylas an efficient imidazo[4,5- catalyst forb]pyridines the copper (I, Br,and Cl) amine-free using tetrabutyl Sonogashira ammonium cross acetate coupling as an reactions activator of in 2-halo-3-alkylin N-methylpyrrolidone imidazo[4,5- (NMP)b]pyridines under (I,microwave Br, Cl) using enhanced tetrabutyl conditions ammonium (yields acetate 70%–95%). as an activator inN2-halo-3-alkyl-methylpyrrolidone N-methylpyrrolidone imidazo[4,5- (NMP) (NMP)b]pyridines under under microwave microwave(I, Br, Cl) enhanced using enhanced tetrabutyl conditions conditions ammonium (yields (yields 70%–95%). acetate 70%–95%). as an activator in N-methylpyrrolidone (NMP) under microwave enhanced conditions (yields 70%–95%).

Scheme 14. Synthesis of 2-halo-3-alkyl imidazo[4,5-b]pyridines. Scheme 14. Synthesis of 2-halo-3-alkyl imidazo[4,5- b]pyridines. Scheme 14. Synthesis of 2-halo-3-alkyl imidazo[4,5-b]pyridines. The same authors described the synthesis of imidazo[4,5-b]pyridines in the reaction with The same authors described the synthesis of imidazo[4,5-b]pyridines in the reaction with 1,1′-carbonyldiimidazoleThe same authors described (CDI) and thethen synthesis with phosphoryl of imidazo[4,5- chlorideb]pyridines or with formic in the acid reaction followed with by 1,1′-carbonyldiimidazoleThe same authors described(CDI) and thethen synthesis with phosphoryl of imidazo[4,5- chlorideb ]pyridinesor with formic in the acid reaction followed with by 1,1halogenation0-carbonyldiimidazole with carbon (CDI)tetrabromide and then or withN-iodosuccinimide phosphoryl chloride (NIS) (Scheme or with 15) formic [93]. acid followed halogenation1,1′-carbonyldiimidazole with carbon (CDI) tetrabromide and then or with N-iodosuccinimide phosphoryl chloride (NIS) or(Scheme with formic 15) [93]. acid followed by byhalogenation halogenation with with carbon carbon tetrabromide tetrabromide or N or-iodosuccinimideN-iodosuccinimide (NIS) (NIS) (Scheme (Scheme 15) 15 [93].)[93 ].

Scheme 15. Synthesis of 2-halo-imidazo[4,5-b]pyridines. Scheme 15. Synthesis of 2-halo-imidazo[4,5-b]pyridines. Scheme 15. Synthesis of 2-halo-imidazo[4,5-b]pyridines. They also proposedScheme a modified 15. Synthesis approach of 2-halo-imidazo[4,5- for the synthesisb]pyridines. of 3-substituted 2-aryl/heteroaryl imidazo[4,5-They alsob]pyridines proposed awith modified excellent approach yields. for thThee synthesis method ofutilizing 3-substituted palladium 2-aryl/heteroaryl catalysed They also proposed a modified approach for the synthesis of 3-substituted 2-aryl/heteroaryl imidazo[4,5-cross-couplingThey alsob]pyridines proposedreactions awith modiﬁed underexcellent approachmicrowave yields. for theThe synthesis enhancedmethodof utilizing 3-substitutedconditions. palladium 2-aryl/heteroarylUtilization catalysed of cross-couplingimidazo[4,5-b]pyridines reactions with underexcellent microwave yields. Theenhanced method utilizingconditions. palladium Utilization catalysed of imidazo[4,5-(A-taphos)2PdClb]pyridines2-catalysed with Suzuki-Miyayura excellent yields. The cross-coupling method utilizing reactions palladium enables catalysed rapid cross-couplingderivatization (A-cross-couplingtaphos)2PdCl 2-catalysedreactions Suzuki-Miyayura under microwave cross-coupling enhanced reactions conditions. enablesta rapid Utilization derivatization of reactionsof this imidazo[4,5- under microwaveb]pyridine enhancedpharmaceutically conditions. relevant Utilization core (Scheme of (A-16). Thisphos) catalytic2PdCl2-catalysed system is (A-taphos)2PdCl2-catalysed Suzuki-Miyayura cross-coupling reactions enables rapid derivatization ofSuzuki-Miyayuracompatible this imidazo[4,5- with cross-couplingab ]pyridinebroad spectrum pharmaceutically reactions of enables arylboronic relevant rapid derivatization acidscore (Schemeelectron of 16). thisrich, This imidazo[4,5- electron catalytic poor,b system]pyridine and is of this imidazo[4,5-b]pyridine pharmaceutically relevant core (Scheme 16). This catalytic system is pharmaceuticallycompatibleheteroarylboronic with relevantacidsa broad [92]. core Inspectrum another (Scheme paperof 16arylboronic). the This same catalytic authorsacids system electronreported is therich, compatible regioisomeric electron with poor, synthesis a broad and compatible with a broad spectrum of arylboronic acids electron rich, electron poor, and heteroarylboronicspectrum of arylboronic acids [92]. acids In electron another rich, paper electron the same poor, authors and heteroarylboronic reported the regioisomeric acids [92]. In synthesis another heteroarylboronic acids [92]. In another paper the same authors reported the regioisomeric synthesis paper the same authors reported the regioisomeric synthesis of fully decorated imidazopyridines employing a C-H activation protocol with a wide range of aryl/heteroaryl/alkyl boronic acids in aqueous DMF. The use of a copper catalyst and bathophenanthroline as a ligand were found to be Molecules 2017, 22, 399 14 of 24 Molecules 20172017,, 2222,, 399399 1414 ofof 2424 of fully decorated imidazopyridines employing a C-H activation protocol with a wide range of of fully decorated imidazopyridines employing a C-H activation protocol with a wide range of aryl/heteroaryl/alkylMolecules 2017, 22, 399 boronic acids in aqueous DMF. The use of a copper catalyst15 and of 25 aryl/heteroaryl/alkyl boronic acids in aqueous DMF. The use of a copper catalyst and bathophenanthroline as a ligand were found to be instrumental in driving these reactions to bathophenanthroline as a ligand were found to be instrumental in driving these reactions to bathophenanthrolinecompletion. The optimized as a ligand protocol were was found further to be extended instrumental to alkyl/aryl/heteroaryl in driving these reactions potassium to completion.instrumental The in driving optimized these reactionsprotocol towas completion. further Theextended optimized to alkyl/aryl/heteroaryl protocol was further extendedpotassium to organotrifluoroborates [94]. organotrifluoroboratesalkyl/aryl/heteroaryl potassium [94]. organotriﬂuoroborates [94].

Scheme 16. Synthesis of 3-substituted 2-aryl/heteroaryl imidazo[4,5-b]pyridines. Scheme 16.16. SynthesisSynthesis of of 3-substituted 3-substituted 2-aryl/heteroaryl imidazo[4,5-imidazo[4,5- imidazo[4,5-bb]pyridines.]pyridines.]pyridines. Baladi et al. described the first C-2 direct alkenylation of the valuable Baladi et al. described the first C-2 direct alkenylation of the valuable 3H-imidazo[4,5-Baladi et al.b described]pyridine thepromoted ﬁrst C-2 directby microwave-assisted alkenylation of the valuable Pd/Cu 3Hco-catalysis.-imidazo[4,5- Byb]pyridine using 3H-imidazo[4,5--imidazo[4,5-b]pyridine]pyridine promotedpromoted byby microwave-assistedmicrowave-assisted Pd/CuPd/Cu co-catalysis.co-catalysis. ByBy usingusing promotedPd(OAc)2, byCuI, microwave-assisted phenanthroline, and Pd/Cu tBuOLi co-catalysis. in dioxane By under using microwave Pd(OAc)2, CuI,irradiation phenanthroline, conditions and at Pd(OAc)22,, CuI,CuI, phenanthroline,phenanthroline, andand ttBuOLi in dioxane under microwave◦ irradiation conditions at 120tBuOLi °C infor dioxane 30 min, under both microwave electron-rich irradiation and conditionselectron-deficient at 120 Cβ for-bromostyrenes 30 min, both electron-richreacted at andthe 120 °C for 30 min, both electron-rich and electron-deficient β-bromostyrenes reacted at the 120C-2electron-deﬁcient °Cposition for 30 of min,imidazo[4,5-β-bromostyrenes both electron-richb]pyridine reacted inand at moderate the electron-deficient C-2 position to good of imidazo[4,5- yieldsβ-bromostyrenes (Schemeb]pyridine 17). reacted A in variety moderate at the of C-2 position of imidazo[4,5-b]pyridine]pyridine inin moderatemoderate toto goodgood yieldsyields (Scheme(Scheme 17).17). AA varietyvariety ofof functionalto good yields groups (Scheme including 17). A halides, variety ofacetals, functional ethers groups and cyano including moieties halides, were acetals, well etherstolerated and under cyano functionalfunctional groupsgroups includingincluding halides,halides, acetals,acetals, ethersethers andand cyanocyano moietiesmoieties werewere wellwell toleratedtolerated underunder themoieties reaction were conditions; well tolerated and under more the importantly, reaction conditions; such groups and more can importantly,be used for such further groups chemical can be thethe reactionreaction conditions;conditions; andand moremore importantly,importantly, such groups can be used for further chemical transformationsused for further chemical[95]. transformations [95]. transformationstransformations [95].[95].

Scheme 17. Synthesis of 2-styrene-imidazo[4,5- b]pyridines. Scheme 17. SynthesisSynthesis ofof 2-styrene-imidazo[4,5-2-styrene-imidazo[4,5-b]pyridines.]pyridines. A rapid and facile access to C2-substituted imidazo[4,5-b]pyridine analogues utilizing palladium A rapidrapid andand facilefacile accessaccess toto C2-substitutedC2-substituted imidazo[4,5-imidazo[4,5-bb]pyridine]pyridine analoguesanalogues utilizingutilizing palladiumpalladium mediated Buchwald–Hartwig cross-coupling reactions has been reported by Khader et al. [96]. The use mediated Buchwald–Hartwig Buchwald–Hartwig cross-coupling cross-coupling reactions reactions has been has reported been reported by Khader by etKhader al. [96]. et The al. [use96]. of enolizable heterocycles as cross-coupling partners resulted in a wide range of ofThe enolizable use of enolizable heterocycles heterocycles as cross-couplin as cross-couplingg partners partners resulted resulted in ina awide wide range range of imidazo[4,5-b]pyridine analogues which are prone to have medicinal relevance. XantPhos imidazo[4,5-imidazo[4,5-bb]pyridine]pyridine]pyridine analoguesanalogues which which areareare proneproneprone tototo havehavehave medicinalmedicinalmedicinal relevance.relevance.relevance. XantPhos XantPhos (4,5-bis(diphenylphosphino)-9,9-dimethylxanthene) and Pd(OAc)2 were found to be more effective (4,5-bis(diphenylphosp(4,5-bis(diphenylphosphino)-9,9-dimethylxanthene)(4,5-bis(diphenylphosphino)-9,9-dimethylxanthene) and and Pd(OAc) Pd(OAc)22 werewerewere foundfound found toto to bebe moremore effective effective for the coupling of 2-halo imidazo[4,5-b]pyridines with pyridone2 nucleophiles (Scheme 18). A for the the coupling coupling of of 2-halo 2-halo imidazo[4,5- imidazo[4,5-b]pyridinesb]pyridines with with pyridone pyridone nucleophiles nucleophiles (Scheme (Scheme 18). 18 A). forregioselective the coupling approach of 2-halo for imidazo[4,5- the synthesisb]pyridines of 2-substituted with pyridone 3H nucleophiles-imidazo[4,5- b(Scheme]pyridine 18). and A regioselectiveAregioselective regioselective approachapproach approach forfor for thethe the synthesissynthesis synthesis ofof of 2-substituted2-substituted 2-substituted 33 H-imidazo[4,5--imidazo[4,5-bb]pyridine]pyridine]pyridine and and 1H-imidazo[4,5-b]pyridine has been also reported. The authors obtained products with yields from 1H-imidazo[4,5--imidazo[4,5-bb]pyridine]pyridine]pyridine hashas has beenbeen alsoalso reported.reported. TheThe authauth authorsors obtained obtained products products with with yields from medium to excellent (49%–95%). The overall efficiency of a cross-coupling process is significantly medium to excellent (49%–95%). The The overall overall efficiency efficiency of of a a cross-coupling process process is significantly significantly affected by the structure of the ligand (BINAP, XantPhos) and the catalyst. Therefore, the use of a affected by the structure of the ligand (BINAP, XantPhos)XantPhos) andand thethe catalyst.catalyst. Therefore, Therefore, the the use use of a ligand with appropriate steric and electronic properties is very crucial in dealing with problematic ligandligand withwithwith appropriateappropriateappropriate steric stericsteric and andand electronic electronicelectronic properties propertiesproperties is veryisis veryvery crucial crucialcrucial in dealinginin dealingdealing with withwith problematic problematicproblematic and and specific substrates in this area. andspecific specific substrates substrates in this in area.this area.

Scheme 18. Fuctionalization of imidazo[4,5-b]pyridines at the C-2 position using 2-hydroxypyridine Scheme 18. FuctionalizationFuctionalization ofof imidazo[4,5-imidazo[4,5-b]pyridines]pyridines atat thethe C-2C-2 positionposition usingusing 2-hydroxypyridine2-hydroxypyridine withScheme XantPhos 18. Fuctionalization and Pd(OAc)2of imidazo[4,5-b]pyridines at the C-2 position using 2-hydroxypyridine with XantPhos and Pd(OAc)2 with XantPhos and Pd(OAc)2 .

A facile rearrangement of N-(hetero)aryl 2-imidazolines into diversely substituted imidazo[4,5-b]pyridines, under Bechamp reduction conditions has been discovered by

Molecules 2017, 22, 399 15 of 24 Molecules 2017, 22, 399 15 of 24 Molecules 2017, 22, 399 16 of 25 A facile rearrangement of N-(hetero)aryl 2-imidazolines into diversely substituted A facile rearrangement of N-(hetero)aryl 2-imidazolines into diversely substituted imidazo[4,5-b]pyridines, under Bechamp reduction conditions has been discovered by Mujumdar et imidazo[4,5-b]pyridines, under Bechamp reduction conditions has been discovered by Mujumdar et Mujumdaral. [97]. Combined et al. [97] . Combinedwith the withearlier the reported earlier reported protocol protocol for Pd-catalyzed for Pd-catalyzed (hetero)arylation (hetero)arylation of al. [97]. Combined with the earlier reported protocol for Pd-catalyzed (hetero)arylation of of2-imidazolines, 2-imidazolines, it provides it provides a simple a simple two-step two-step access access to a torange a range of compounds of compounds based based on this on core. this core.The 2-imidazolines, it provides a simple two-step access to a range of compounds based on this core. The Themethod method uses uses the Pd(OAc) the Pd(OAc)2/BINAP2/BINAP catalytic catalytic system system in the in firs thet ﬁrststep stepto the to theimidazoline imidazoline structure structure 50, method uses the Pd(OAc)2/BINAP catalytic system in the first step to the imidazoline structure 50, 50which, which when when subjected subjected to the to modified the modiﬁed Bechamp Bechamp reduction reduction conditions conditions (Fe/NH (Fe/NH4Cl in aqueous4Cl in aqueous EtOH), which when subjected to the modified Bechamp reduction conditions (Fe/NH4Cl in aqueous EtOH), EtOH),converted converted to a more to polar a more imidazopyridine polar imidazopyridine 51 (Scheme51 (Scheme 19). 19). converted to a more polar imidazopyridine 51 (Scheme 19).

Scheme 19. Pd-catalyzed (hetero)arylation of 2-imidazolines. Scheme 19. Pd-catalyzed (hetero)arylation of 2-imidazolines. A practical strategy for the preparation of imidazopyridine derivatives from A practical strategy for the preparation of imidazopyridineimidazopyridine derivatives from ortho-haloaminopyridines utilizing a two-step C-N coupling/cyclization reaction sequence has been ortho-haloaminopyridines utilizing a two-steptwo-step C-NC-N coupling/cyclizationcoupling/cyclization reaction reaction sequence has been developed by Li et al. [98]. Their procedure provides rapid and efficient access to many medicinally developed by Li et al. [[98].98]. Their procedure provid provideses rapid and efficient efﬁcient accessaccess to many medicinally interesting imidazopyridine compounds and related imidazopyrazine/purine heterocycles. They interesting imidazopyridine imidazopyridine compounds compounds and and related related imidazopyrazine/purine imidazopyrazine/purine heterocycles. heterocycles. They began the investigation by screening conditions for C-N coupling of 4-amino-3-bromopyridine with Theybegan began the investigation the investigation by screening by screening conditions conditions for C-N for coupling C-N coupling of 4-amino-3-bromopyridine of 4-amino-3-bromopyridine with benzylamine (Scheme 20). The best catalyst and base were BrettPhos and LiHMDS (82% yield). withbenzylamine benzylamine (Scheme (Scheme 20). 20The). Thebest best catalyst catalyst and and base base were were Br BrettPhosettPhos and and LiHMD LiHMDSS (82% (82% yield). yield). Alternative catalysts (such as tBuXPhos, XPhos, RuPhos or XantPhos) did not afford the desired Alternative catalysts (such as tBuXPhos, XPhos, RuPhos or Xant XantPhos)Phos) did not afford the desired product in useful yield. Surprisingly, the BrettPhos G1 precatalyst outperformed the BrettPhos G3 product in useful yield. Surprisingly, the BrettPhosBrettPhos G1 precatalyst outperformed the BrettPhos G3 precatalyst (45% yield) and Pd(OAc)2/BrettPhos (12% yield). The choice of LiHMDS as a base was precatalyst (45% yield) andand Pd(OAc)Pd(OAc)22/BrettPhos (12% (12% yield). yield). The The choice choice of of LiHMDS LiHMDS as as a base was found to be critical for achieving high yield while none of the other bases (NaHMDS, KHMDS, found to be critical for achieving high yield while none of the other bases (NaHMDS, KHMDS, NaOtBu, LiOtBu, Cs2CO3) examined gave more than a 35% yield. Additional variables including NaOtBu, LiOtBu, Cs2COCO33)) examined examined gave gave more more than a 35%35% yield.yield. Additional variables includingincluding solvent, concentration, catalyst loading, equivalents of base, and temperatures were also examined. solvent, concentration, catalyst loading, equivale equivalentsnts of of base, base, and and temperatures were were also also examined. They concluded the following reaction conditions as optimal for the C-N coupling: BrettPhos G1 They concluded the following reaction conditions as optimal for the C-NC-N coupling:coupling: BrettPhos G1 precatalyst (6 mol%), LiHMDS (2.5 equiv), THF (0.4 M), 40 ◦°C. In addition, we also examined precatalyst (6 mol%), LiHMDS (2.5 equiv), THF (0.4 M), 40 °C.C. In addition, we also examined 4-amino-3-iodopyridine and 4-amino-3-chloropyridine as the halide coupling partner and found 4-amino-3-iodopyridine andand 4-amino-3-chloropyridine4-amino-3-chloropyridine as as the the halide halide coupling coupling partner partner and and found found that that the former showed comparable reactivity (85% yield) while the chloride had inferior thethat formerthe former showed showed comparable comparable reactivity reactivity (85% yield) (85% while yield) the chloridewhile the had chloride inferior performancehad inferior performance (47% yield). (47%performance yield). (47% yield).

Scheme 20. C-N coupling of 4-amino-3-bromopyridine with benzylamine. Scheme 20. C-N coupling of 4-amino-3-bromopyridine with benzylamine. Salome et al. has presented a very straightforward method for preparing differently substituted Salome et al. has presented a very straightforward method for preparing differently substituted imidazo[4,5-Salomeb et]pyridines. al. has presented The target a very compounds straightforward mainly method result from for preparing direct amidation differently of substitutedthe highly imidazo[4,5-b]pyridines. The target compounds mainly result from direct amidation of the highly imidazo[4,5-electrophilic b2-chloro-3-nitropyridine]pyridines. The target compounds with variou mainlys amides result including from directprimary, amidation secondary of theand highly cyclic electrophilic 2-chloro-3-nitropyridine with various amides including primary, secondary and cyclic electrophilicamides using 2-chloro-3-nitropyridine Pd-coupling reactions (Scheme with various 21). Despite amides the including poor nucleophilic primary, secondary character of and amides, cyclic amides using Pd-coupling reactions (Scheme 21). Despite the poor nucleophilic character of amides, amideswhen reacted using Pd-couplingwith aryl halides, reactions the (Schemereaction 21 coul). Despited be extended the poor to nucleophilic sulfonamides, character carbamates of amides, and when reacted with aryl halides, the reaction could be extended to sulfonamides, carbamates and whenureas reactedby means with of aryl XanthPhos halides, theas reactiona ligand couldand Cs be2 extendedCO3 as the to base sulfonamides, in dioxane carbamates in the presence and ureas of ureas by means of XanthPhos as a ligand and Cs2CO3 as the base in dioxane in the presence of byPd(OAc) means2 ofor XanthPhosPd2(dba)3. The as a ligandnitro intermediates and Cs2CO3 as52 thewere base quantitatively in dioxane in reduced the presence by means of Pd(OAc) of iron2 orin Pd(OAc)2 or Pd2(dba)3. The nitro intermediates 52 were quantitatively reduced by means of iron in Pdthe (dba)presence. The of nitroammonium intermediates chloride52 inwere a mixture quantitatively of ethanol reduced and water. by means The ofresulting iron in crude the presence amino the2 presence3 of ammonium chloride in a mixture of ethanol and water. The resulting crude amino ofintermediate ammonium 53 chloride was further in a mixturesubmitted of ethanolto cyclization and water. usingThe SiCl resulting4 as an efficient crude aminoLewis intermediatecatalyst. The intermediate 53 was further submitted to cyclization using SiCl4 as an efficient Lewis catalyst. The 53 was further submitted to cyclization using SiCl4 as an efﬁcient Lewis catalyst. The reaction can be

Molecules 2017, 22, 399 17 of 25 Molecules 2017, 22, 399 16 of 24 Molecules 2017, 22, 399 16 of 24 Molecules 2017, 22, 399 16 of 24 reaction can be performed 10 min after exposure to microwave◦ irradiation at 180 °C. The overall reactionperformed can 10 be min performed after exposure 10 min to microwaveafter exposure irradiation to microwave at 180 C. irradiation The overall atyields 180 °C. (reduction The overall and yields (reduction and cyclization) were satisfactory to excellent (55%–90%) [99]. yieldscyclization)reaction (reduction can were be performed and satisfactory cyclization) 10 to min excellent were after satisfactory (55%–90%)exposure to [ 99excellentmicrowave]. (55%–90%) irradiation [99]. at 180 °C. The overall yields (reduction and cyclization) were satisfactory to excellent (55%–90%) [99].

Scheme 21. Synthesis of differently substituted imidazo[4,5-b]pyridines from Scheme 21. Synthesis of differently substituted imidazo[4,5-b]pyridines from Scheme2-chloro-3-nitropyridine. 21. Synthesis of differently substituted imidazo[4,5-b]pyridines from 2-chloro-3-nitropyridine. 2-chloro-3-nitropyridine.Scheme 21. Synthesis of differently substituted imidazo[4,5-b]pyridines from 2-chloro-3-nitropyridine. The two-step procedure procedure using using Fe Fe and and acetic acetic acid acid in in ethanol ethanol to toreduce reduce 3-nitropyridin-4-amine 3-nitropyridin-4-amine 55 The two-step procedure using Fe and acetic acid in ethanol to reduce 3-nitropyridin-4-amine 55 55(Scheme(Scheme 22) 22 followed) followed by by Ytterbium Ytterbium triflate triﬂate cataly catalyzedzed condensation condensation with with triethyl triethyl orthoformate to (SchemeThe 22)two-step followed procedure by Ytterbium using Fe triflate and acetic cataly acidzed in condensation ethanol to reduce with 3-nitropyridin-4-amine triethyl orthoformate 55to imidazo[4,5-cc]pyridine]pyridine 5757by by 3,4-diaminopyridine 3,4-diaminopyridine56 was56 was reported reported by Wang by etWang al. [100 et]. al. The [100]. optimum The imidazo[4,5-(Scheme 22)c ]pyridinefollowed by57 Ytterbiumby 3,4-diaminopyridine triflate catalyzed 56 condensationwas reported with by Wangtriethyl et orthoformate al. [100]. The to stoichiometryoptimum stoichiometry of each component of each component is highlighted is highlighted and the broad and utilitythe broad was utility demonstrated was demonstrated with high optimumimidazo[4,5- stoichiometryc]pyridine 57of eachby 3,4-diaminopyridine component is highlighted 56 was and reported the broad by utility Wang was et demonstratedal. [100]. The compatibilitywith high compatibility to numerous to functionalnumerous groups.functional The groups. use of theThe optimal use of the conditions optimal resulted conditions in obtaining resulted withoptimum high stoichiometrycompatibility toof numerouseach component functional is highlighted groups. The and use the of broadthe optimal utility conditions was demonstrated resulted thein obtaining desired products the desired in yields products of 32%–99%. in yields of 32%–99%. inwith obtaining high compatibility the desired productsto numerous in yields functional of 32%–99%. groups. The use of the optimal conditions resulted in obtaining the desired products in yields of 32%–99%.

Scheme 22. Synthesis of imidazo[4,5-c]pyridine from 3,4-diaminopyridine and orthoformate by c Scheme 22. Synthesis of imidazo[4,5- cc]pyridine]pyridine from from 3,4-diaminopyr 3,4-diaminopyridineidine and and orthoformate orthoformate by by c ytterbium triflate catalyzed condensation. ytterbiumScheme 22. triflate triﬂate Synthesis catalyzed of imidazo[4,5- condensation.c]pyridine from 3,4-diaminopyridine and orthoformate by c ytterbium triflate catalyzed condensation. Harer et al. discovered a one-step synthesis of 3H-imidazo[4,5-b]pyridines from aldehydes and Harer et et al. al. discovered discovered a one-step a one-step synthesis synthesis of 3 ofH-imidazo[4,5- 3H-imidazo[4,5-b]pyridinesb]pyridines from from aldehydes aldehydes and 2-nitro-3-aminopyridine through reductive cyclization using Na2S2O4 [101]. Aqueous paste of 2-nitro-3-aminopyridineand 2-nitro-3-aminopyridineHarer et al. discovered through a throughone-step reductive reductivesynthesis cyclization cyclizationof 3H-imidazo[4,5- using using Na Na2bS]pyridines2OS24O [101].4 [101 from].Aqueous Aqueous aldehydes paste paste and of Na2S2O4 was prepared as 1M in H2O and added in 3 equivalent proportions to the reaction mixture Na2-nitro-3-aminopyridine2SS22OO4 4waswas prepared prepared as as 1Mthrough 1M in in H H 22OreductiveO and and added added cyclization in in 3 3 equivalent equivalent using proportions proportionsNa2S2O4 [101]. to to the theAqueous reaction pastemixture of (Scheme 23). (SchemeNa2S2O4 was23).23). prepared as 1M in H2O and added in 3 equivalent proportions to the reaction mixture (Scheme 23).

Scheme 23. Synthesis of 3H-imidazo[4,5-b]pyridines from aldehydes and 2-nitro-3-aminopyridine Scheme 23. Synthesis of 3H-imidazo[4,5-b]pyridines from aldehydes and 2-nitro-3-aminopyridine Scheme 23. Synthesis of 3H-imidazo[4,5-b]pyridines from aldehydes and 2-nitro-3-aminopyridine TheScheme second 23. Synthesisreaction offor 3 Hone-step-imidazo[4,5- synthesisb]pyridines of 1 fromH-imidazo[4,5- aldehydes andb]pyridines 2-nitro-3-aminopyridine. was obtained from The second reaction for one-step synthesis of 1H-imidazo[4,5-b]pyridines was obtained from ketones and 2-nitro-3-aminopyridine through reductive cyclization using SnCl2×2H2O as a reductive ketonesThe and second 2-nitro-3-aminopyridine reaction for one-step through synthesis reductive of 1H-imidazo[4,5- cyclization usingb]pyridines SnCl2×2H was2O obtainedas a reductive from catalyst.The Imidazopyridine second reaction forscaffolds one-step were synthesis visited ofafter 1H -imidazo[4,5-treatment of bthe]pyridines substituted was acetophenones obtained from catalyst.ketones andImidazopyridine 2-nitro-3-aminopyridine scaffolds were through visited reductive after treatment cyclization of using the substituted SnCl2×2H2O acetophenones as a reductive ketonesand 2-nitro-3-aminopyridine and 2-nitro-3-aminopyridine with the through addition reductive of SnCl2 cyclization×H2O in the using presence SnCl of2× formic2H2O asacid a reductive (Scheme andcatalyst. 2-nitro-3-aminopyridine Imidazopyridine scaffolds with the were addition visited of SnClafter2 ×Htreatment2O in the of presence the substituted of formic acetophenones acid (Scheme catalyst.24). It is Imidazopyridinepresumably formed scaffolds through were visitedformylation after treatmentof the aniline of the nitrogen, substituted nitro acetophenones reduction and 24).and 2-nitro-3-aminopyridineIt is presumably formed with through the addition formylation of SnCl of2×H the2O anilinein the presence nitrogen, of nitroformic reduction acid (Scheme and 2-nitro-3-aminopyridinecyclization. Formylation withof the the aniline addition nitrogen of SnCl is believed×H O in to the assist presence nitro reduction of formic [101]. acid (Scheme 24). cyclization.24). It is presumably Formylation formed of the anilinethrough nitrogen formylation is believed2 of2 the to assistaniline nitro nitrogen, reduction nitro [101]. reduction and It is presumably formed through formylation of the aniline nitrogen, nitro reduction and cyclization. cyclization. Formylation of the aniline nitrogen is believed to assist nitro reduction [101]. Formylation of the aniline nitrogen is believed to assist nitro reduction [101].

Scheme 24. Synthesis of 1H-imidazo[4,5-b]pyridines from ketones and 2-nitro-3-aminopyridine. Scheme 24. Synthesis of 1H-imidazo[4,5-b]pyridines from ketones and 2-nitro-3-aminopyridine. Scheme 24. Synthesis of 1H-imidazo[4,5-b]pyridines from ketones and 2-nitro-3-aminopyridine.

Molecules 2017, 22, 399 16 of 24 reaction can be performed 10 min after exposure to microwave irradiation at 180 °C. The overall yields (reduction and cyclization) were satisfactory to excellent (55%–90%) [99].

Scheme 21. Synthesis of differently substituted imidazo[4,5-b]pyridines from 2-chloro-3-nitropyridine.

The two-step procedure using Fe and acetic acid in ethanol to reduce 3-nitropyridin-4-amine 55 (Scheme 22) followed by Ytterbium triflate catalyzed condensation with triethyl orthoformate to imidazo[4,5-c]pyridine 57 by 3,4-diaminopyridine 56 was reported by Wang et al. [100]. The optimum stoichiometry of each component is highlighted and the broad utility was demonstrated with high compatibility to numerous functional groups. The use of the optimal conditions resulted in obtaining the desired products in yields of 32%–99%.

Scheme 22. Synthesis of imidazo[4,5-c]pyridine from 3,4-diaminopyridine and orthoformate by c ytterbium triflate catalyzed condensation.

Harer et al. discovered a one-step synthesis of 3H-imidazo[4,5-b]pyridines from aldehydes and 2-nitro-3-aminopyridine through reductive cyclization using Na2S2O4 [101]. Aqueous paste of Na2S2O4 was prepared as 1M in H2O and added in 3 equivalent proportions to the reaction mixture (Scheme 23).

Scheme 23. Synthesis of 3H-imidazo[4,5-b]pyridines from aldehydes and 2-nitro-3-aminopyridine

The second reaction for one-step synthesis of 1H-imidazo[4,5-b]pyridines was obtained from ketones and 2-nitro-3-aminopyridine through reductive cyclization using SnCl2×2H2O as a reductive catalyst. Imidazopyridine scaffolds were visited after treatment of the substituted acetophenones and 2-nitro-3-aminopyridine with the addition of SnCl2×H2O in the presence of formic acid (Scheme Molecules24). It is2017 presumably, 22, 399 formed through formylation of the aniline nitrogen, nitro reduction18 ofand 25 cyclization. Formylation of the aniline nitrogen is believed to assist nitro reduction [101].

Scheme 24. Synthesis of 1 H-imidazo[4,5-b]pyridines from ketones and 2-nitro-3-aminopyridine. Molecules 2017, 22, 399 17 of 24 Molecules 2017, 22, 399 17 of 24 A series of imidazopyridineimidazopyridine derivativesderivatives has been synthesizedsynthesized efficientlyefficiently via intramolecularintramolecular A series of imidazopyridine derivatives3+ has been synthesized efficiently via intramolecular3+ cyclization in in excellent excellent yields yields using using Al Al3+-exchanged-exchanged on on K10 K10 montmorillonite montmorillonite clay clay (Al3+ (Al-K10-K10 clay) clay) as a 3+ 3+ ascyclizationreusable a reusable heterogeneous in excellent heterogeneous yields catalyst using catalyst by AlSuresh by-exchanged Suresh et al. et[102]. on al. K10 [The102 montmorillonite]. authors The authors report clay reportwas (Al the was -K10first the clay)to firstutilize as to a utilizereusableAl3+-K10 Al heterogeneousas3+-K10 a catalyst as a catalyst for catalyst imidazopyridine for by imidazopyridine Suresh etsynthesi al. [102]. synthesiss (Scheme The (Schemeauthors 25). Many report25). Manyfunctional was functionalthe first groups to groupsutilize were 3+ wereAltolerated-K10 tolerated asduring a catalyst during the synthesis thefor synthesisimidazopyridine of targeted of targeted synthesicomp compoundsoundss (Scheme and and the25). the yields Many yields obtainedfunctional obtained were were groups excellentexcellent were (80%–93%).tolerated during TheThe catalyst catalystthe synthesis was was reused reused of attargeted leastat least five comp five times oundstimes with withand a slight thea slight decrease yields decrease obtained in the yield.in thewere This yield. excellent catalyst This was(80%–93%).catalyst environmentally was The environmentally catalyst benign, was cost-effective, reusedbenign, atcost-effective, least and five also times providedand withalso otherprova slightided advantages decrease other advantages such in the as nontoxicity,yield. such This as operational/experimentalcatalystnontoxicity, was operational/experimentalenvironmentally simplicity, benign, and simplicity, cost-effective, mild reaction and mildand conditions. alsoreaction prov conditions.ided other advantages such as nontoxicity, operational/experimental simplicity, and mild reaction conditions.

Scheme 25.25. Intramolecular cyclizationcyclization usingusing AlAl3+3+-exchanged-exchanged on on K10 K10 montmorillonite montmorillonite clay. clay. Scheme 25. Intramolecular cyclization using Al3+-exchanged on K10 montmorillonite clay. A one-step versatile method for the synthesis of 1H-imidazo[4,5-b]pyridines (Scheme 26) from A one-step versatile method for the synthesis of 1H-imidazo[4,5-b]pyridines (Scheme 26) from quinoxalinonesA one-step versatileand their method aza-analogues for the synthesis has been of 1developedH-imidazo[4,5- on bthe]pyridines basis of (Scheme the novel 26) fromring quinoxalinones and their aza-analogues has been developed on the basis of the novel ring contractions quinoxalinonescontractions of 3-aroyl-quinoxalinonesand their aza-analogues and hastheir been aza-analogues developed with on 1,2-arylenediaminesthe basis of the novel in boiling ring of 3-aroyl-quinoxalinones and their aza-analogues with 1,2-arylenediamines in boiling acetic acid contractionsacetic acid solution of 3-aroyl-quinoxalinones with rather good yields and oftheir 41%–84% aza-analogues [103]. with 1,2-arylenediamines in boiling solutionacetic acid with solution rather with good rather yields good of 41%–84% yields of [ 10341%–84%]. [103].

Scheme 26. Synthesis of 1H-imidazo[4,5-b]pyridines from quinoxalinones and their aza-analogues. Scheme 26. Synthesis of 1 H-imidazo[4,5--imidazo[4,5-b]pyridines from quinoxalinon quinoxalinoneses and their aza-analogues. The reactions between N-aryl amidines 58 and 4-phenylsulfonyl tetrafluoropyridine 59 were The reactions between N-aryl amidines 58 and 4-phenylsulfonyl tetrafluoropyridine 59 were reportedThe reactionsby Poorfreidoni between et al.N-aryl [104]. amidines Reactants58 weandre stirred 4-phenylsulfonyl at room temperature tetraﬂuoropyridine in the presence59 were of reported by Poorfreidoni et al. [104]. Reactants were stirred at room temperature in the presence of reportedNaHCO3 byin acetonitrile Poorfreidoni and et al.corresponding [104]. Reactants polyfuncti were stirredonal heteroaromatic at room temperature imidazopyridine in the presence systems of NaHCO3 in acetonitrile and corresponding polyfunctional heteroaromatic imidazopyridine systems NaHCO60 via anin intramolecular acetonitrile and nucleophilic corresponding aromatic polyfunctional substitution heteroaromatic process (Scheme imidazopyridine 27). The systemsproducts’60 60 via an3 intramolecular nucleophilic aromatic substitution process (Scheme 27). The products’ viastructure an intramolecular was the result nucleophilic of substitution aromatic at substitution the 2-position process of (Schemethe pyridine 27). The ring products’ by the structureamidine structure was the result of substitution at the 2-position of the pyridine ring by the amidine wassecondary the result nitrogen, of substitution followed at theby 2-positionintramolecular of the pyridinering closure ring by at the the amidine geometrically secondary accessible nitrogen, secondary nitrogen, followed by intramolecular ring closure at the geometrically accessible followed3-position by of intramolecular the pyridine ring ring by closure the amidine at the geometricallyprimary nitrogen. accessible 3-position of the pyridine ring 3-position of the pyridine ring by the amidine primary nitrogen. by the amidine primary nitrogen.

Scheme 27. Synthesis of 5,6-difluoro-imidazo[4,5-b]pyridines from N-aryl amidines and Scheme4-phenylsulfonyl 27. Synthesis tetrafluoropyridine. of 5,6-difluoro-imidazo[4,5- b]pyridines from N-aryl amidines and 4-phenylsulfonyl tetrafluoropyridine. Recently, methods for the use of solid-phase to obtain imidazopyridines have been described. A novelRecently, route for methods the solid-phase for the use synthesis of solid-phase of 1,2,5-substituted to obtain imidazopyridines 7-azabenzimidazole have been derivatives described. has A novelbeen developed route for bythe Farrant solid-phase et al. (Schemesynthesis 28) of [105]. 1,2,5-substituted In this method 7-azabenzimidazole primary amines are derivatives attached to has an beenaldehyde developed resin bythen Farrant coupled et al. to (Scheme 6-chloro-5-nitro-nicotinyl 28) [105]. In this method chloride. primary Subsequent amines are alkylation attached towith an aldehyde resin then coupled to 6-chloro-5-nitro-nicotinyl chloride. Subsequent alkylation with

Molecules 2017, 22, 399 17 of 24

A series of imidazopyridine derivatives has been synthesized efficiently via intramolecular cyclization in excellent yields using Al3+-exchanged on K10 montmorillonite clay (Al3+-K10 clay) as a reusable heterogeneous catalyst by Suresh et al. [102]. The authors report was the first to utilize Al3+-K10 as a catalyst for imidazopyridine synthesis (Scheme 25). Many functional groups were tolerated during the synthesis of targeted compounds and the yields obtained were excellent (80%–93%). The catalyst was reused at least five times with a slight decrease in the yield. This catalyst was environmentally benign, cost-effective, and also provided other advantages such as nontoxicity, operational/experimental simplicity, and mild reaction conditions.

Scheme 25. Intramolecular cyclization using Al3+-exchanged on K10 montmorillonite clay.

A one-step versatile method for the synthesis of 1H-imidazo[4,5-b]pyridines (Scheme 26) from quinoxalinones and their aza-analogues has been developed on the basis of the novel ring contractions of 3-aroyl-quinoxalinones and their aza-analogues with 1,2-arylenediamines in boiling acetic acid solution with rather good yields of 41%–84% [103].

Scheme 26. Synthesis of 1H-imidazo[4,5-b]pyridines from quinoxalinones and their aza-analogues.

The reactions between N-aryl amidines 58 and 4-phenylsulfonyl tetrafluoropyridine 59 were reported by Poorfreidoni et al. [104]. Reactants were stirred at room temperature in the presence of NaHCO3 in acetonitrile and corresponding polyfunctional heteroaromatic imidazopyridine systems 60 via an intramolecular nucleophilic aromatic substitution process (Scheme 27). The products’ structure was the result of substitution at the 2-position of the pyridine ring by the amidine

Moleculessecondary2017 ,nitrogen,22, 399 followed by intramolecular ring closure at the geometrically accessible19 of 25 3-position of the pyridine ring by the amidine primary nitrogen.

Scheme 27.27. SynthesisSynthesis of of 5,6-difluoro-imidazo[4,5- 5,6-diﬂuoro-imidazo[4,5-b]pyridinesb]pyridines from from NN-aryl-aryl amidines amidines and 4-phenylsulfonyl tetraﬂuoropyridine.tetrafluoropyridine.

Recently, methods for the use of solid-phase to obtain imidazopyridines have been described. A Recently, methods for the use of solid-phase to obtain imidazopyridines have been described. novel route for the solid-phase synthesis of 1,2,5-substituted 7-azabenzimidazole derivatives has A novel route for the solid-phase synthesis of 1,2,5-substituted 7-azabenzimidazole derivatives has been developed by Farrant et al. (Scheme 28) [105]. In this method primary amines are attached to an been developed by Farrant et al. (Scheme 28)[105]. In this method primary amines are attached to an aldehydeMolecules 2017 resin, 22, 399 then coupled to 6-chloro-5-nitro-nicotinyl chloride. Subsequent alkylation18 with of 24 aldehyde resin then coupled to 6-chloro-5-nitro-nicotinyl chloride. Subsequent alkylation with amines, reduction amines, reduction of the nitro of group the andnitro cyclization group and with cycli aldehydeszation giveswith 1,2,5-substitutedaldehydes gives 7-azabenzimidazole 1,2,5-substituted derivatives7-azabenzimidazole with yields derivatives of 50%–94%. with yields of 50%–94%.

Scheme 28. The solid-phase synthesis of 1,2,5-substituted 7-azabenzimidazole derivatives. Scheme 28. The solid-phase synthesis of 1,2,5-substituted 7-azabenzimidazole derivatives.

4. Conclusions 4. Conclusions Numerous compounds derived from the imidazopyridine nucleus are used in the clinic for the Numerous compounds derived from the imidazopyridine nucleus are used in the clinic for treatment of many diseases. Most of them are imidazo[1,2-a]pyridine derivatives. However, the treatment of many diseases. Most of them are imidazo[1,2-a]pyridine derivatives. However, imidazo[4,5-b]pyridines and imidazo[4,5-c]pyridines, despite the similar activity, exhaustive and imidazo[4,5-b]pyridines and imidazo[4,5-c]pyridines, despite the similar activity, exhaustive and target target based research on development of many compounds as antitumor, antimicrobial, based research on development of many compounds as antitumor, antimicrobial, anti-inflammatory, anti-inflammatory, antiviral, immunomodulatory, antidiabetic modulators have not made their way antiviral, immunomodulatory, antidiabetic modulators have not made their way to the market and to the market and clinic. This is probably due to lack of a comprehensive compilation of various clinic. This is probably due to lack of a comprehensive compilation of various research reports in each research reports in each activity capable of providing insights into the SAR of the compounds. The activity capable of providing insights into the SAR of the compounds. The present review covering present review covering more than 100 the most recent references on activity and chemical synthesis more than 100 the most recent references on activity and chemical synthesis is expected to provide a is expected to provide a closer look at the imidazo[4,5-b]pyridine and closer look at the imidazo[4,5-b]pyridine and imidazo[4,5-c]pyridine-derived compounds for a versatile imidazo[4,5-c]pyridine-derived compounds for a versatile and target oriented information to and target oriented information to develop clinically viable molecules. develop clinically viable molecules. Acknowledgments: This work was carried out with the support of The Leading National Research Centre (KNOW).Acknowledgments: This work was carried out with the support of The Leading National Research Centre (KNOW). Author Contributions: Henryk Foks collected the literature. Katarzyna Gobis and Malwina Krause wrote the manuscript.Author Contributions: All the authors Henryk have Foks read collected and approved the literature. the final manuscript.Katarzyna Gobis and Malwina Krause wrote the Conflictsmanuscript. of Interest:All the authorThe authorss have read declare and no approved conflict ofthe interest. final manuscript. Conflicts of Interest: The authors declare no conflict of interest.

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