Processes for preparing modulators of alpha-1 antitrypsin
Inventors
Bligh, Cavan McKeon • GIACOMETTI, Robert Daniel • Harrison, Cristian • LAWS, Stephen W. • Looker, Adam • Roeper, Stefanie
Assignees
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Publication Number
US-12673952-B2
Publication Date
2026-07-07
Expiration Date
Abstract
This disclosure provides large-scale processes for preparing a modulator of alpha-1 antitrypsin (AAT) activity that may be useful for treating alpha-1 antitrypsin deficiency (AATD), such as 4-(5-(4-fluorophenyl)-6-(tetrahydro-2H-pyran-4-yl)-1,5-dihydropyrrolo[2,3-f]indazol-7-yl)benzoic acid (Compound 1), 3-[5-(4-fluorophenyl)-6-isopropyl-1H-pyrrolo[2,3-f]indazol-7-yl]propanoic acid (Compound 2), or a pharmaceutically acceptable salt of any of the foregoing.
Core Innovation
The disclosure describes an alternative process for preparing a solid form of Compound 1 or a pharmaceutically acceptable salt thereof. The process forms ester C58B from intermediates B1 and D1, or precursors such as S4 or S6 and ester-substituted phenylboronic acids, and de-esterifies C58B to yield the solid form, including conversion to Form A or isolation as a THF solvate. The independent claim centers on this sequence, while dependent claims describe optional upstream reactions for preparing intermediates.
The described process route involves up to four reaction steps, compared with up to seven in earlier processes, and supports scalable GMP-compliant production at approximately 100 kg or greater. The disclosure further describes the preparation of intermediates C13 and C58B, synthetic routes to Compound 2 targeting production at a scale of at least 100 kg to about 300 kg, and a telescoped preparation of D1. Compound 1 and Compound 2 are also described as modulators in AAT-related functional assays.
Claims Coverage
The claims identify one independent claim directed to one inventive feature for preparing a solid form of Compound 1 or a pharmaceutically acceptable salt thereof.
Preparation of a solid form of Compound 1
The independent claim covers reacting B1 with D1 to form C58B, or a pharmaceutically acceptable salt thereof, and de-esterifying C58B to yield a solid form of Compound 1 or a pharmaceutically acceptable salt thereof. Dependent claims add specified reagents, conditions, and optional upstream reactions for preparing intermediates.
The independent claim covers the two-stage sequence of forming C58B and de-esterifying it to yield the solid form of Compound 1 or a pharmaceutically acceptable salt thereof, supplemented by dependent claims covering reagents, conditions, and intermediate preparation.
Stated Advantages
The process is described as scalable and intended to support GMP-compliant production at approximately 100 kg or greater.
The route is described as involving up to four reaction steps, compared with up to seven in earlier processes.
The disclosure identifies potential cost, time, and energy efficiencies.
Documented Applications
Preparation of a solid form of Compound 1, including Compound 1 Form A.
Preparation of Compound 2, with the description stating intended production at a scale of at least 100 kg to about 300 kg.
Assessment of Compound 1 and Compound 2 as modulators in AAT-related functional assays, including a Z-AAT elastase-activity assay.
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