(S)-1-(4-Fluoro-1-methyl-1H-indazol-5-yl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazol-2-one hydrochloride
[CAS# 2212022-57-4]

Identification

• Classification: Organic raw materials >> Heterocyclic compound >> Imidazoles
• Name: (S)-1-(4-Fluoro-1-methyl-1H-indazol-5-yl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazol-2-one hydrochloride
• Synonyms: 1-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]-3-(4-fluoro-1-methylindazol-5-yl)imidazol-2-one;hydrochloride
• Molecular Formula: C₂₆H₂₆ClF₂N₇O
• Molecular Weight: 525.98
• CAS Registry Number: 2212022-57-4
• SMILES: C[C@H]1C2=C(N(N=C2CCN1)C3=CC(=C(C(=C3)C)F)C)N4C=CN(C4=O)C5=C(C6=C(C=C5)N(N=C6)C)F.Cl

Safety Data

• Hazard Symbols: GHS07 Warning
• Hazard Statements: H302-H315-H319
• Precautionary Statements: P501-P270-P264-P280-P302+P352-P337+P313-P305+P351+P338-P362+P364-P332+P313-P301+P312+P330

Discovory and Applicatios

(S)-1-(4-Fluoro-1-methyl-1H-indazol-5-yl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazol-2-one hydrochloride is a stereodefined, complex heterocyclic small molecule that appears in the medicinal chemistry literature and supplier catalogues as an advanced synthetic intermediate and as the isolated stereochemical form related to the clinical candidate iptacopan (LNP023), a selective oral inhibitor of complement factor B. The structure contains multiple heterocyclic elements (an indazole, a pyrazolo[4,3-c]pyridine, and an imidazolone core), two para-substituted aryl rings bearing fluoro and methyl substituents, and defined stereochemistry at the substituted piperidine/pyrazolopyridine junction. The compound is typically encountered as the hydrochloride salt and is handled and stored as a crystalline solid for use in downstream synthetic transformations and biological testing.

The origin of this molecule is traceable to modern structure-guided drug discovery campaigns aimed at identifying potent, selective, and orally bioavailable inhibitors of complement factor B. During the lead-optimization phase investigators explored variations in the aryl substituents, heterocyclic linkers, ring fusion patterns, and stereochemistry to balance biochemical potency, selectivity, and drug-like pharmacokinetic properties. The compound named above represents one of the stereodefined intermediates or analogues that were synthesised, resolved and profiled as part of the medicinal chemistry effort that produced iptacopan. Analytical and preparative procedures described in medicinal-chemistry disclosures document its preparation, stereochemical assignment and use in subsequent coupling or deprotection steps en route to final clinical candidates.

In practice the molecule has two complementary roles in a drug-discovery setting. First, as an advanced intermediate it allows chemists to explore structure-activity relationships by permitting late-stage variation of peripheral substituents (for example introduction or removal of protecting groups, installation of solubilising moieties, or generation of polar handles). Second, as an isolated stereochemical variant it serves in biological profiling to determine the impact of absolute configuration on target binding, cellular activity and in vitro ADME parameters. Published structural biology accompanying the LNP023 programme demonstrated that defined stereochemistry was important for optimal binding into the factor B active site, and stereodefined intermediates such as the present compound were used to confirm stereochemical hypotheses by co-crystallisation and biochemical testing.

From the synthetic viewpoint the compound embodies common medicinal-chemistry strategies: convergent assembly of heterocyclic fragments, use of orthogonal protecting groups (for example N-Cbz or N-alkyl motifs on indazole/imidazole rings), and stereoselective formation or resolution of chiral centres. Typical operations in its preparation include cross-coupling of aryl fragments, heterocycle construction (such as pyrazolopyridine formation), installation of the imidazolone motif, and salt formation to afford a crystalline hydrochloride amenable to handling and purification. Characterisation data reported in supporting information for the LNP023 series include NMR, mass spectrometry and chiral chromatography to confirm identity, purity and enantiomeric excess.

The principal application of the compound is therefore within discovery and preclinical development rather than as a therapeutic itself. Its presence in experimental sequences was instrumental to identification and optimisation of iptacopan, which progressed to clinical trials and later regulatory submissions. As an intermediate it enabled iterative medicinal chemistry that refined potency and pharmacokinetic properties, and as a stereochemical probe it contributed to structure–activity and structure–based design work that validated the final clinical candidate.

References

Schubart A, Anderson K, Mainolfi N et al. (2019) Small-molecule factor B inhibitor for the treatment of complement-mediated diseases. Proceedings of the National Academy of Sciences of the United States of America 116(16) 7926–7931. DOI: 10.1073/pnas.1820892116

Mainolfi N, Ehara T, Karki R G et al. (2020) Discovery of 4-((2S,4S)-4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)benzoic acid (LNP023), a Factor B inhibitor specifically designed to be applicable to treating a diverse array of complement mediated diseases. Journal of Medicinal Chemistry 63(11) 5697–5722. DOI: 10.1021/acs.jmedchem.9b01870

Jang J H, Wong L, Ko B S et al. (2022) Iptacopan monotherapy in patients with paroxysmal nocturnal haemoglobinuria: a 2-cohort open-label proof-of-concept study. Blood Advances 6(15) 4450–4460. DOI: 10.1182/bloodadvances.2022006960