Imidazo[1,2-a]pyridines with potent activity against herpesviruses

Synthesis of a series of 2-aryl-3-pyrimidyl-imidazo[1,2-a]pyridines with potent activity against herpes simplex viruses is described. Synthetic approaches allowing for variation of the 2-aryl, 3-heteroaryl as well as other imidazopyridine substituents are outlined and resulting effects on antiviral activity are highlighted. Several compounds with in vitro antiviral activity similar or better than acyclovir are described.     

The identification of pyrazolo[1,5-a]pyridines as potent p38 kinase inhibitors

A series of pyrazolo[1,5-a]pyridine derivatives was designed and synthesized as novel potent p38 kinase inhibitors. Our approaches towards improving in vitro metabolism and in vivo pharmacokinetic properties of the series are described.     

Non-hinge-binding pyrazolo[1,5-a]pyrimidines as potent B-Raf kinase inhibitors

As part of our research effort to discover B-Raf kinase inhibitors, we prepared a series of C-3 substituted N-(3-(pyrazolo[1,5-a]pyrimidin-7-yl)phenyl)-3-(trifluoromethyl)benzamides. X-ray crystallography studies revealed that one of the more potent inhibitors (10n) bound to B-Raf kinase without forming a hinge-binding hydrogen bond. With basic amine residues appended to C-3 aryl residues, cellular activity and solubility were enhanced over previously described compounds of this class.     

Synthesis of novel substituted 2-phenylpyrazolopyridines with potent activity against herpesviruses

Herpesviruses are a significant source of human disease; amongst these herpes simplex virus 1 (HSV-1) and HSV-2 are very prevalent and cause recurrent infections. We recently identified a pyrazolo[1,5-a]pyridine scaffold that showed promising activity against HSV-1 and HSV-2 in Vero cell antiviral assays. Here, we describe the synthesis and anti-herpetic activity of several 3-pyrimidinyl-2-phenylpyrazolo[1,5-a]pyridines with differing 2-phenyl substitution patterns. Approaches to rapidly access a number of analogs with different 2-phenyl substitution patterns are outlined. Several of the compounds described have comparable activity to acyclovir against HSV-1 and HSV-2.     

The chemistry of [1,2,3]triazolo[1,5-a]pyridines

The reactivity of [1,2,3]triazolo[1,5-a]pyridines 1 is described. Triazolopyridines react with electrophiles in two contrasting ways, giving 3-substituted triazolopyridines 2, or products 3, resulting from triazolo ring opening with loss of molecular nitrogen. The triazolopyridines can be lithiated at -40 degrees C by lithium diisopropylamide in ether giving regiospecifically the 7-lithio derivative. Bromotriazolopyridines have activation towards nucleophilic substitution at position 5 and 7, and benzenoid inertness at position 6. The parent compound 1a is easily hydrogenated giving tetrahydrotriazolopyridine 11a in high yield; when the triazolopyridines have substituents, the hydrogenation reaction strongly depends on the position of the substituent. Triazolopyridinium ylides of type 18 and 26 react with acetylenic esters; these reactions are influenced by the nature of solvent and the acetylenic ester used, giving different types of adducts: stable disubstituted triazolopyridinium ylides of type 19 and 20, indolizines 21, or pyrroleninylpyrazolo[5,1-a] pyridines 22. Photochemistry, and photochemical reactions with MP and DMAD of these ylides are also described. A new way to 2,2'-bipyridines, in two steps from triazolopyridines is reported.     

Synthesis and SAR of substituted pyrazolo[1,5-a]quinazolines as dual mGlu2/mGlu3 NAMs

Herein we report the design and synthesis of a series of substituted pyrazolo[1,5-a]quinazolin-5(4H)-ones as negative allosteric modulators of metabotropic glutamate receptors 2 and 3 (mGlu₂ and mGlu₃, respectively). Development of this series was initiated by reports that pyrazolo[1,5-a]quinazoline-derived scaffolds can yield compounds with activity at group II mGlu receptors which are prone to molecular switching following small structural changes. Several potent analogues, including 4-methyl-2-phenyl-8-(pyrimidin-5-yl)pyrazolo[1,5-a]quinazolin-5(4H)-one (10b), were discovered with potent in vitro activity as dual mGlu₂/mGlu₃ NAMs, with excellent selectivity versus the other mGluRs.     

Synthesis and antiprotozoal activity of novel bis-benzamidino imidazo[1,2-a]pyridines and 5,6,7,8-tetrahydro-imidazo[1,2-a]pyridines

The key dinitrile intermediates 4a-d were synthesized by reaction of phenacyl bromide 1 and the appropriate 2-amino-5-bromopyridines to yield 3a-d. Suzuki coupling of 3a-d with 4-cyanophenylboronic acid yielded the 2,6-bis(4-cyanophenyl)-imidazo[1,2-a]pyridine derivatives 4a-d. The bis-amidoximes 5a-d, obtained from 4a-d by the action of hydroxylamine, were converted to the bis-O-acetoxyamidoximes which on catalytic hydrogenation in a mixture of ethanol/ethyl acetate gave the acetate salts of 2,6-bis[4-(amidinophenyl)]-imidazo[1,2-a]pyridines 7a-d. In contrast, catalytic hydrogenation of the bis-O-acetoxyamidoxime of 5a in glacial acetic acid gave the saturated analogue 2,6-bis[4-(amidinophenyl)]-5,6,7,8-tetrahydro-imidazo[1,2-a]pyridine 8. O-Methylation of the amidoximes 5a-d gave the N-methoxyamidines 6a-d. The diamidines showed strong DNA binding affinity, were very active in vitro against T. b. r. exhibiting IC(50) values between 7 and 38nM, but were less effective against P. f. with IC(50) values between 23 and 92nM. Two of the diamidines 7c and 7d were slightly more active than furamidine but less active than azafuramidine in the T. b. r. STIB900 mouse model. Only one prodrug 6b showed moderate activity in the same mouse model.     

Synthesis of pyrazolo[1,5-a]pyrimidine linked aminobenzothiazole conjugates as potential anticancer agents

A series of pyrazolo[1,5-a]pyrimidine linked 2-aminobenzothizole conjugates (6a–t) were synthesized and evaluated for their anticancer activity against five human cancer cell lines. Among them two compounds 6p and 6m showed significant anticancer activity with IC₅₀ values ranging from 2.01 to 7.07 and 1.94–3.46 μM, respectively. Moreover, cell cycle arrest in G₂/M and reduction in Cdk1 expression level were observed upon treatment of these compounds and they also induced caspase-3 dependent apoptosis. This was further confirmed by staining as well as DNA fragmentation analysis.     

Synthesis and antiproliferative evaluation of pyrazolo[1,5-a]-1,3,5-triazine myoseverin derivatives

Pyrazolo[1,5-a]-1,3,5-triazine myoseverin derivatives 1a–c were prepared from 4-(N-methyl-N-phenylamino)-2-methylsulfanylpyrazolo[1,5-a]-1,3,5-triazine 2. Their cytotoxic activity, inhibition of tubulin polymerization, and cell cycle effects were evaluated. Compounds 1a and 1c are potent tubulin inhibitors and displayed specific antiproliferative activity in colorectal cancer cell lines at micromolar concentrations.     

2-Amino-[1,2,4]triazolo[1,5-a]pyridines as JAK2 inhibitors

The advancement of a series of ligand efficient 2-amino-[1,2,4]triazolo[1,5-a]pyridines, initially identified from high-throughput screening, to a JAK2 inhibitor with pharmacodynamic activity in a mouse xenograft model is disclosed.

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In vitro and in vivo anti-tumoral activities of imidazo[1,2-a]quinoxaline, imidazo[1,5-a]quinoxaline, and pyrazolo[1,5-a]quinoxaline derivatives

Imidazoquinoxaline and pyrazoloquinoxaline derivatives, analogues of imiquimod, were synthesized, and their in vitro cytotoxic and pharmacodynamic activities were evaluated. In vitro cytotoxicity studies were assessed against melanoma (A375, M4Be, RPMI-7591), colon (LS174T), breast (MCF7), and lymphoma (Raji) human cancer cell lines. In vivo studies were carried out in M4Be xenografted athymic mice. EAPB0103, EAPB0201, EAPB0202, and EAPB0203 showed significant in vitro activities against A375 compared to fotemustine and imiquimod used as references. These compounds were 6-110 and 2-45 times more active than fotemustine and imiquimod, respectively. EAPB0203 bearing phenethyl as substituent at position 1 and methylamine at position 4 showed the highest activity. EAPB0203 has also a more potent cytotoxic activity than imiquimod and fotemustine in M4Be and RPMI-7591 and interesting cytotoxic activity in other tumor cell lines tested. In vivo, EAPB0203 treatment schedules caused a significant decrease in tumor size compared to vehicle control and fotemustine treatments.     

Pyrrolo[1,2-a]pyrazine and pyrazolo[1,5-a]pyrazine: Novel,potent, and selective series of Vasopressin1b receptor antagonists

Novel series of pyrrole-pyrazinone and pyrazole-pyrazinone have been identified as potent and selective Vasopressin_1b receptor antagonists. Exploration of the substitution pattern around the core of these templates allowed generation of compounds with high inhibitory potency at the Vasopressin_1b receptor, including examples that showed good selectivity with respect to Vasopressin_1a, Vasopressin₂, and Oxytocin receptor subtypes.     

Discovery of novel pyrazolo[1,5-a]pyrimidines as potent pan-Pim inhibitors by structure- and property-based drug design

Pim kinases are promising targets for the development of cancer therapeutics. Among the three Pim isoforms, Pim-2 is particularly important in multiple myeloma, yet is the most difficult to inhibit due to its high affinity for ATP. We identified compound 1 via high throughput screening. Using property-based drug design and co-crystal structures with Pim-1 kinase to guide analog design, we were able to improve potency against all three Pim isoforms including a significant 10,000-fold gain against Pim-2. Compound 17 is a novel lead with low picomolar potency on all three Pim kinase isoforms.     

Synthesis and SAR of 3-arylsulfonyl-pyrazolo[1,5-a]pyrimidines as potent serotonin 5-HT6 receptor antagonists

Syntheses of a series of novel 3-sulfonyl-pyrazolo[1,5-a]pyrimidines and their 5-HT(6) receptor antagonistic structure-activity relationship are disclosed. The nature and position of substituents, which affect their receptor antagonistic activity, are analyzed. Among all synthesized derivatives, {3-(3-chlorophenylsulfonyl)-5,7-dimethyl-pyrazolo[1,5-a]pyrimidin-2-yl}-methyl-amine 33 (K(i)=190 pM), (3-phenylsulfonyl-7-methyl-pyrazolo[1,5-a]pyrimidin-2-yl)-methyl-amine 44 (K(i)=240 pM), (3-phenylsulfonyl-5-metoxymethyl-7-methyl-pyrazolo[1,5-a]pyrimidin-2-yl)-methyl-amine 50 (K(i)=270 pM), and (3-phenylsulfonyl-5-methyl-7-metoxymethyl-pyrazolo[1,5-a]pyrimidin-2-yl)-methyl-amine 52 (K(i)=280 pM) are the most potent antagonists of the 5-HT(6) receptors.     

Identification of pyrazolo[1,5-a]pyrimidine-3-carboxylates as B-Raf kinase inhibitors

B-Raf kinase plays a critical role in the Raf-MEK-ERK signaling pathway and inhibitors of B-Raf could be used in the treatment of melanomas, colorectal cancer, and other Ras related human cancers. We have identified novel small molecule pyrazolo[1,5-a]pyrimidine derivatives as B-Raf kinase inhibitors. Structure–activity relationship was generated for various regions of the scaffold to improve the biochemical profile.     

Discovery of pyrazolo[1,5-a]pyrimidine-based Pim inhibitors: A template-based approach

The synthesis and hit-to-lead SAR development from a pyrazolo[1,5-a]pyrimidine-derived hit 5 to the identification of a series of potent, pan–Pim inhibitors such as 11j are described.     

Synthesis and antitumor activity of substituted triazolo[4,3-a]pyrimidin-6-sulfonamide with an incorporated thiazolidinone moiety

Chlorosulfonation of 3-methyl[1,2,4]triazolo[4,3-a]pyrimidine with chlorosulfonic acid in the presence of thionyl chloride was studied. When triazolo[4,3-a]pyrimidines are used as substrates, the substitution occurs at C-6. Also the reactivity of the hydrazides (7) towards aldehydes, thioglycolic acid and amines were studies. The newly prepared compounds 10a,d and 11a,d demonstrated inhibitory effects on the growth of a wide range of cancer cell lines generally at 10^?5 M level and in some cases at 10^?7 M concentrations.     

Synthesis and antibacterial activity of substituted 1,2,3,4-tetrahydropyrazino [1,2-a] indoles

A series of substituted 1,2,3,4-tetrahydropyrazino [1,2-a] indole derivatives have been synthesized and tested against the Gram positive and Gram negative strains of bacteria namely Staphylococcus aureus (MTCCB 737), Salmonella typhi (MTCCB 733), Pseudomonas aeruginosa (MTCCB 741), Streptomyces thermonitrificans (MTCCB 1824) and Escherichia coli (MTCCB 1652). All synthesized compounds showed mild to moderate activity. However, compounds 4d-f were found to have potent activity against pathogenic bacteria used in the study. Their MIC ranged from 3.75 to 60 microg/disc. In vitro toxicity tests demonstrated that toxicity of 4d-f was not significantly different than that of gentamycin. However, at higher concentration (1000-4000 microg/ml) difference was highly significant.     

Pyrazolopyrimidines and pyrazolotriazines with potent activity against herpesviruses

Synthesis of several pyrazolo[1,5-c]pyrimidines, pyrazolo[1,5-a]pyrimidines and pyrazolo[1,5-a][1,3,5]triazines with potent activity against herpes simplex viruses is described. Synthetic approaches allowing for variation of the substitution pattern are outlined and resulting changes in antiviral activity are highlighted. Several compounds with in vitro antiviral activity similar or better than acyclovir are described.     

Hit to lead optimization of pyrazolo[1,5-a]pyrimidines as B-Raf kinase inhibitors

Our continued effort towards optimization of the pyrazolo[1,5-a]pyrimidine scaffold as B-Raf kinase inhibitors is described. Structure guided design was utilized to introduce kinase hinge region interacting groups in the 2-position of the scaffold. This strategy led to the identification of lead compound 9 with enhanced enzyme and cellular potency, while maintaining good selectivity over a number of kinases.