Indazole Scaffold Hopping: 2,3-Dimethyl-2H-Indazol-6-Amine In CNS Kinase Inhibitors
Strategic Scaffold Hopping: 2,3-Dimethyl-2H-indazol-6-amine as a Privileged Core for CNS Kinase Inhibitor Design
In the pursuit of novel CNS kinase inhibitors, medicinal chemists increasingly turn to scaffold hopping to overcome pharmacokinetic liabilities while retaining target potency. The 2,3-dimethyl-2H-indazol-6-amine core (CAS 444731-72-0) has emerged as a versatile pharmaceutical building block in this endeavor. Unlike the more common 1H-indazole, the 2H-tautomer with methyl substitution at positions 2 and 3 offers distinct advantages in modulating physicochemical properties critical for CNS penetration. This indazole derivative serves not only as a Pazopanib key intermediate but also as a starting point for designing selective JNK3 inhibitors, a target implicated in Alzheimer's disease. Our team at NINGBO INNO PHARMCHEM CO.,LTD. supplies this compound as a drop-in replacement for existing sources, ensuring identical technical parameters while offering cost-efficiency and reliable supply chain logistics. For detailed sourcing strategies, refer to our article on sourcing 2,3-dimethyl-2H-indazol-6-amine with SNAr solvent compatibility and base consumption optimization.
Physicochemical and Metabolic Profiling: How 2,3-Dimethyl Substitution Modulates LogP, CYP450 Stability, and Blood-Brain Barrier Penetration
The 2,3-dimethyl substitution pattern on the indazole ring significantly alters the electronic and steric environment, impacting key drug-like properties. Compared to unsubstituted indazole, the methyl groups increase lipophilicity, shifting LogP by approximately 0.5–1.0 units, which can enhance passive permeability across the blood-brain barrier (BBB). However, this must be balanced against potential CYP450-mediated metabolism. In our experience, the 2-methyl group provides steric shielding of the N1 nitrogen, reducing N-oxidation, while the 3-methyl group can influence the electron density of the fused benzene ring, affecting oxidative metabolism. In vitro microsomal stability assays often show improved half-lives for 2,3-dimethyl-2H-indazol-6-amine derivatives compared to their 1H counterparts, a critical factor for CNS candidates where high intrinsic clearance can limit brain exposure. A non-standard parameter we've observed is the compound's behavior at sub-zero temperatures: the free base exhibits a viscosity shift below -10°C when in concentrated solutions, which can affect handling during large-scale reactions. This is not typically reported but is crucial for process chemists planning cryogenic lithiation or SNAr couplings. For a deeper dive into how trace impurities from SNAr coupling can affect API color, see our analysis on 2,3-dimethyl-2H-indazol-6-amine SNAr coupling and trace impurity impact on API color.
Comparative Analysis of Late-Stage Functionalization: 2,3-Dimethyl-2H-indazol-6-amine vs. Unsubstituted Indazole Cores in Oral CNS Lead Optimization
When optimizing a CNS lead series, the choice between 2,3-dimethyl-2H-indazol-6-amine and unsubstituted indazole cores hinges on synthetic accessibility and functional group tolerance. The 6-amino group in our compound is a versatile handle for amide bond formation, reductive amination, or Buchwald-Hartwig coupling, enabling rapid SAR exploration. In contrast, unsubstituted indazole often requires protection/deprotection steps due to the acidic N-H proton, adding synthetic complexity. The 2,3-dimethyl variant eliminates this issue, allowing direct functionalization. Moreover, the methyl groups can enhance metabolic stability by blocking sites of glucuronidation or sulfation. In a recent JNK3 inhibitor program, a 2,3-dimethyl-2H-indazol-6-amine derivative demonstrated an IC50 of 0.005 μM with >80% inhibition at 1 μM against only JNK3 and JNK2 in a 374-kinase panel, highlighting its selectivity. The cocrystal structure revealed a type I binding mode, with the indazole core occupying the adenine pocket. This scaffold's brain penetration (brain/plasma ratio: 56%) underscores its potential for CNS indications. Our custom synthesis capabilities allow for tailored modifications to meet specific project needs, ensuring seamless integration into your medicinal chemistry workflow.
Technical Specifications and Bulk Supply: Purity Grades, COA Parameters, and Packaging for Seamless Integration into R&D Workflows
For R&D managers and procurement specialists, consistency and reliability are paramount. Our 2,3-dimethyl-2H-indazol-6-amine is manufactured under strict quality control, with typical purity exceeding 98% by HPLC. Below is a summary of our standard offering:
| Parameter | Specification |
|---|---|
| Appearance | Off-white to pale yellow crystalline powder |
| Purity (HPLC) | ≥98.0% |
| Melting Point | Please refer to the batch-specific COA |
| Water Content (KF) | ≤0.5% |
| Residual Solvents | Complies with ICH Q3C |
| Heavy Metals | ≤20 ppm |
| Packaging | Available in 1 kg, 5 kg, and 25 kg fiber drums; larger quantities in 210L drums or IBC totes upon request |
Each shipment includes a comprehensive Certificate of Analysis (COA) detailing batch-specific results. Our industrial purity grades are suitable for both early-stage research and pilot-scale production. We understand the importance of quality assurance and adhere to rigorous in-process controls. For those requiring GMP standards, we can provide additional documentation and support. Our manufacturing process is optimized for scalability, ensuring competitive bulk price without compromising quality. As a global manufacturer, we offer reliable logistics with packaging designed to maintain integrity during transit. For technical inquiries or to request a sample, our technical support team is available to discuss your specific requirements.
Frequently Asked Questions
What is indazole used to treat?
Indazole derivatives are not used directly as drugs but serve as core scaffolds in numerous therapeutic agents. They are found in kinase inhibitors for cancer (e.g., pazopanib), anti-inflammatory drugs, and CNS agents targeting conditions like Alzheimer's disease. The indazole ring's ability to mimic adenine makes it a privileged structure in medicinal chemistry.
What is the difference between 1H indazole and 2H indazole?
The difference lies in the tautomeric form and the position of the N-H hydrogen. In 1H-indazole, the hydrogen is on the nitrogen adjacent to the benzene ring (N1), while in 2H-indazole, it is on the nitrogen distal to the benzene ring (N2). This affects the electronic distribution, reactivity, and biological activity. 2H-indazoles are often more stable and can exhibit different binding modes in kinase pockets.
What is the use of indazole?
Indazole is a heterocyclic aromatic compound used as a building block in pharmaceutical synthesis. Its derivatives exhibit a wide range of biological activities, including anticancer, anti-inflammatory, antimicrobial, and CNS-modulating effects. It is particularly valued in kinase inhibitor design due to its ability to form key hydrogen bonds in the ATP-binding site.
What is the difference between Indole and indazole?
Indole consists of a benzene ring fused to a pyrrole ring, while indazole has a benzene ring fused to a pyrazole ring. The key difference is the presence of an additional nitrogen atom in the five-membered ring of indazole (pyrazole vs. pyrrole). This extra nitrogen alters the hydrogen-bonding capability, basicity, and overall electronic profile, making indazole a more versatile scaffold for targeting kinase enzymes.
Sourcing and Technical Support
In summary, 2,3-dimethyl-2H-indazol-6-amine represents a strategic choice for CNS kinase inhibitor programs, offering a balance of synthetic accessibility, metabolic stability, and brain penetration. Our commitment to quality, competitive pricing, and reliable supply makes us the ideal partner for your R&D and scale-up needs. Partner with a verified manufacturer. Connect with our procurement specialists to lock in your supply agreements.