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Research Brief on 3-bromo-4-fluoro-1H-indazole-6-carboxylic acid (CAS: 885521-65-3) in Chemical Biology and Pharmaceutical Applications

The compound 3-bromo-4-fluoro-1H-indazole-6-carboxylic acid (CAS: 885521-65-3) has recently emerged as a key intermediate in the synthesis of biologically active molecules, particularly in the development of kinase inhibitors and anticancer agents. This heterocyclic scaffold combines the structural features of indazole with strategically placed halogen substitutions, offering unique opportunities for medicinal chemistry optimization. Recent studies highlight its role as a versatile building block for targeted drug discovery programs.

Structural analysis reveals that the bromo and fluoro substituents at the 3- and 4-positions respectively contribute to enhanced binding affinity through halogen bonding interactions with protein targets. The carboxylic acid moiety at position 6 provides a convenient handle for further derivatization, enabling the creation of amide or ester analogs. This molecular architecture has shown particular promise in the development of ATP-competitive inhibitors targeting various oncogenic kinases.

In a 2023 study published in the Journal of Medicinal Chemistry, researchers utilized 3-bromo-4-fluoro-1H-indazole-6-carboxylic acid as a core scaffold to develop novel FGFR (fibroblast growth factor receptor) inhibitors. The team reported that derivatives of this compound exhibited nanomolar potency against FGFR1-3 isoforms while maintaining excellent selectivity profiles. X-ray crystallography studies confirmed the critical role of the bromo substituent in occupying a hydrophobic pocket of the kinase domain.

Another significant application appears in recent patent literature (WO2023056421), where this indazole derivative serves as a precursor for PARP (poly ADP-ribose polymerase) inhibitors. The synthetic routes described demonstrate efficient conversion of the carboxylic acid to various pharmacophores, highlighting the compound's versatility. Importantly, scale-up processes have been optimized to produce multi-kilogram quantities with >99% purity, addressing previous challenges in large-scale synthesis.

Emerging research also explores the compound's potential in PROTAC (proteolysis targeting chimera) development. A 2024 ACS Chemical Biology publication detailed its incorporation as the warhead in CRBN-recruiting PROTACs targeting BRD4. The electron-withdrawing effects of the halogens were found to enhance protein-ligand binding kinetics while maintaining appropriate physicochemical properties for cellular permeability.

From a safety perspective, recent toxicological assessments indicate favorable preliminary profiles for derivatives of 3-bromo-4-fluoro-1H-indazole-6-carboxylic acid. In vitro studies using hepatocyte models showed minimal CYP450 inhibition, and early ADME evaluations suggest good metabolic stability. However, researchers note that the bromine atom may present potential metabolic liabilities that require careful monitoring in lead optimization programs.

The commercial availability of this compound from major chemical suppliers (listed at $380-420/g for research quantities as of Q2 2024) reflects growing demand in both academic and industrial settings. Market analysis suggests increasing adoption in fragment-based drug discovery campaigns, particularly for challenging kinase targets where traditional scaffolds have shown limitations.

Future research directions likely include exploration of this scaffold in covalent inhibitor design (leveraging the reactive bromine center) and further investigation of its physicochemical properties through computational modeling. The compound's unique combination of halogen substitutions and hydrogen bond donor/acceptor capabilities positions it as a valuable tool for addressing current challenges in targeted therapy development.

• 447-44-9(4-Fluoro-1H-indazole-6-carboxylic acid)
• 885522-53-2(3-Bromo-4-fluoro-6-methyl-1H-indazole)
• 885521-41-5(Methyl 3-bromo-4-fluoro-1H-indazole-6-carboxylate)
• 885522-01-0(3-Bromo-6-fluoro-1H-indazole-4-carboxylic acid)
• 114086-30-5(3-Bromo-1H-indazole-6-carboxylic acid)
• 1363382-97-1(3-Bromo-1H-indazole-4-carboxylic acid)
• 885521-49-3(3-Bromo-1H-indazole-5-carboxylic acid)
• 885523-51-3(3,4-Dibromo-1H-indazole-6-carboxylic acid)
• 885522-87-2(3-BROMO-6-FLUORO-4-INDAZOLECARBOXYLIC ACID METHYL ESTER)
• 885523-75-1(3,6-DIBROMO-4-(1H)INDAZOLE CARBOXYLIC ACID)