ALK5 inhibitors
Inventors
Kulyk, Svitlana • Owens, Christina • Sullivan, Steven D. E. • Kozak, Jennifer • Hughes, Adam D.
Assignees
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Publication Number
US-11730720-B2
Publication Date
2023-08-22
Expiration Date
Abstract
The present disclosure provides inhibitors of activin receptor-like kinase 5 (ALK5). Also disclosed are methods to modulate the activity of ALK5 and methods of treatment of disorders mediated by ALK5.
Core Innovation
The disclosure provides ALK5-inhibiting heteroaryl compounds of Formula (II), (III), or (VII), or pharmaceutically acceptable salts thereof, alongside an enumerated group of specific substituted 1,5-naphthyridine derivatives. Disclosed structures feature selections for R2, R5, and R6 substituents, encompassing 1,5-naphthyridine and quinoline scaffolds linked to pyrazole, imidazole, or triazole heterocycles, as well as stereoisomer-enriched forms. These compounds and associated pharmaceutical compositions are prepared for administration, including formulation for inhaled delivery.
The disclosure addresses adverse effects associated with systemic ALK5 inhibition by providing lung-selective inhibition with reduced systemic exposure. Certain embodiments provide ester-based soft ALK5 inhibitors designed for local lung activity followed by hydrolysis to less-active carboxylic-acid metabolites. Disclosed examples demonstrate ALK5 target modulation, elevated lung-to-plasma exposure ratios, and minimized systemic target engagement.
The disclosure further describes therapeutic methods and combination regimens utilizing ALK5 inhibitors with antifibrotic or immunotherapeutic agents. Formulations and treatment protocols address conditions such as various forms of fibrosis and oncology indications. Sequential or simultaneous administration regimens provide lung selectivity and rapid clearance while monitoring and adjusting treatment for pulmonary fibrosis and related ALK5-mediated conditions.
Claims Coverage
The claims identify two independent claims encompassing two inventive features: a broad genus of ALK5 inhibitor compounds defined by Formula (II), (III), or (VII) and an enumerated set of specific substituted 1,5-naphthyridine compounds, or pharmaceutically acceptable salts thereof.
Formula-defined ALK5 inhibitor compounds
Claim 1 covers a compound of Formula (II), (III), or (VII), or a pharmaceutically acceptable salt thereof, with specified substituent selections for R2, R5, and R6, including amino-linked groups, cyclic groups, substituted or unsubstituted nitrogen heterocycles, and bicyclic or fused rings.
Enumerated 1,5-naphthyridine compounds
Claim 6 covers an enumerated list of specific substituted 1,5-naphthyridine compounds bearing pyrazolyl or imidazolyl groups and diverse amine, piperazine, piperidine, bicyclic, cycloalkenyl, or fused heterocyclic substituents, or a pharmaceutically acceptable salt thereof.
The two independent claims cover a broad formula-defined compound genus and an enumerated list of specific 1,5-naphthyridine compounds, including pharmaceutically acceptable salts thereof, with dependent claims extending to pharmaceutical compositions, inhalation formulations, and methods of treating ALK5-mediated diseases including fibroses and cancers.
Stated Advantages
Ester-based soft ALK5 inhibitors reduce systemic exposure through hydrolysis to less-active carboxylic-acid metabolites.
The compounds provide potent, long-acting, lung-selective ALK5 inhibition by inhalation with rapid clearance to address adverse effects associated with systemic ALK5 inhibition.
The description proposes potential synergistic effects for ALK5-inhibitor combination therapies.
Documented Applications
Pharmaceutical compositions comprising a claimed compound or pharmaceutically acceptable salt and a pharmaceutically acceptable carrier, including compositions formulated for inhalation for local lung activity.
Treatment of ALK5-mediated fibrosis, including idiopathic pulmonary fibrosis, as well as cardiac, kidney, pulmonary, liver, portal vein, skin, bladder, intestinal, peritoneal, myeloid, oral submucous, and retinal fibrosis.
Treatment of ALK5-mediated cancer, including non-small cell lung cancer, breast, colon, prostate, lung cancer, hepatocellular carcinoma, glioblastoma, melanoma, and pancreatic cancer.
Sequential or simultaneous combination therapies of ALK5 inhibitors with radiation, antifibrotic agents (such as nintedanib or pirfenidone), or immunotherapeutic agents (such as PD-1 and CTLA-4 inhibitors).
Treatment of ALK5-mediated alopecia, neurodegenerative disease, and aging-related symptoms.
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