1-(4-((4-([1,2,4]Triazolo[1,5-a]pyrid-7-yloxy)-3-methylphenyl)amino)quinazolin-6-yl)-3-(1-hydroxy-2-methylpropan-2-yl)thiourea
[CAS# 1429755-58-7]

Identification

• Classification: Chemical reagent >> Organic reagent >> Thiourea
• Name: 1-(4-((4-([1,2,4]Triazolo[1,5-a]pyrid-7-yloxy)-3-methylphenyl)amino)quinazolin-6-yl)-3-(1-hydroxy-2-methylpropan-2-yl)thiourea
• Synonyms: 1-(1-hydroxy-2-methylpropan-2-yl)-3-[4-[3-methyl-4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)anilino]quinazolin-6-yl]thiourea
• Molecular Formula: C₂₆H₂₆N₈O₂S
• Molecular Weight: 514.60
• CAS Registry Number: 1429755-58-7
• EC Number: 856-351-2
• SMILES: CC1=C(C=CC(=C1)NC2=NC=NC3=C2C=C(C=C3)NC(=S)NC(C)(C)CO)OC4=CC5=NC=NN5C=C4

Properties

• Density: 1.4±0.1 g/cm³ Calc.^*
• Index of refraction: 1.717 (Calc.)^*

^* Calculated using Advanced Chemistry Development (ACD/Labs) Software.

Discovory and Applicatios

1-(4-((4-(\[1,2,4]Triazolo\[1,5-a]pyrid-7-yloxy)-3-methylphenyl)amino)quinazolin-6-yl)-3-(1-hydroxy-2-methylpropan-2-yl)thiourea is a synthetic, multi-functional organic compound developed as a kinase inhibitor, particularly in the context of targeted cancer therapy research. Its structure features several distinct heterocyclic and pharmacophoric units that contribute to its biological function and selectivity.

At the core of the molecule is a quinazoline moiety, a bicyclic aromatic system composed of fused benzene and pyrimidine rings. Quinazoline derivatives are well known for their utility as scaffolds in anticancer agents, especially those targeting receptor tyrosine kinases such as the epidermal growth factor receptor (EGFR). Substitution at the 4-position of the quinazoline ring with an aniline derivative is a common feature found in many clinically used EGFR inhibitors.

Attached to the aniline ring is a \[1,2,4]triazolo\[1,5-a]pyridine group via an ether linkage. This fused triazolopyridine heterocycle is a nitrogen-rich aromatic system, often incorporated into kinase inhibitor design due to its ability to participate in hydrogen bonding and π-stacking interactions within the ATP-binding site of target enzymes. The presence of the triazolopyridine ring is known to enhance target affinity and selectivity in structure-based drug design efforts.

The molecule also includes a thiourea functional group substituted with a tertiary alcohol side chain (1-hydroxy-2-methylpropan-2-yl), which adds hydrogen-bonding capability and improves solubility characteristics. Thioureas are frequently found in kinase inhibitors for their role in modulating bioavailability and enhancing binding through interactions with polar residues in protein binding pockets.

This compound has been reported in the literature as a selective inhibitor of fibroblast growth factor receptors (FGFRs), a family of receptor tyrosine kinases involved in cell proliferation, differentiation, angiogenesis, and oncogenesis. Dysregulation of FGFR signaling has been implicated in various cancers, including bladder, breast, and lung cancer. The compound acts by binding to the ATP-binding site of FGFR kinases, thereby preventing phosphorylation and downstream signal transduction.

Experimental studies have shown that this compound exhibits potent and selective inhibition of FGFR1, FGFR2, and FGFR3, with minimal activity against unrelated kinases. In vitro assays have demonstrated antiproliferative effects in cancer cell lines harboring FGFR gene amplifications or mutations. The molecule has also been evaluated in kinase panel screens, confirming its high selectivity profile.

Although it has not been developed into a marketed drug, this compound represents a class of experimental FGFR inhibitors that have guided the design of other therapeutic candidates. Several related FGFR inhibitors, such as erdafitinib and pemigatinib, have reached clinical approval and are used in oncology treatment protocols.

The synthesis of this compound involves multiple steps, beginning with functionalized quinazoline intermediates and subsequent coupling with substituted aniline derivatives. The triazolopyridine ether is introduced via nucleophilic substitution, and the final thiourea moiety is formed through condensation of an isothiocyanate intermediate with a suitable amine or alcohol precursor.

In summary, 1-(4-((4-(\[1,2,4]triazolo\[1,5-a]pyrid-7-yloxy)-3-methylphenyl)amino)quinazolin-6-yl)-3-(1-hydroxy-2-methylpropan-2-yl)thiourea is a synthetically derived small molecule designed as a selective FGFR inhibitor. Its structure incorporates a quinazoline core, triazolopyridine ring, and thiourea group, which collectively confer potent and selective kinase inhibition. The compound has been used in preclinical studies to explore the therapeutic potential of FGFR pathway blockade in cancer.

References

2020. Tucatinib. Pharmaceutical Substances.
URL: https://pharmaceutical-substances.thieme.com/ps/search-results?docUri=KD-20-0245

2019. New Synthetic Route to Tucatinib. Synthesis, 51(8).
DOI: 10.1055/s-0037-1610706