Substituted pyrimidines and methods of use
Inventors
LOO, Mandy • Kulyk, Svitlana • Bailey, Christopher • Kozak, Jennifer • Soellner, Matthew B. • Hughes, Adam D.
Assignees
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Publication Number
US-11673879-B2
Publication Date
2023-06-13
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 relates to compounds of Formula (I-A) and pharmaceutically acceptable salts thereof possessing a substituted pyrimidine-2,4-diamine scaffold. Exemplary compounds predominantly feature a 2-(6-methylpyridin-2-yl)pyrimidin-4-yl motif and display varied aryl or heteroaryl substituents, such as piperazine, azetidine, pyrrolidine, morpholine, piperidine, and bicyclic amine groups, as well as ester, amide, and sulfonamide functionalities.
The compounds function as ALK5 inhibitors that modulate ALK5 activity and suppress TGF-beta signaling, including the inhibition of TGF-beta-stimulated SMAD3 phosphorylation. The independent claim defines the structural genus of Formula (I-A), specifying group A as phenyl or a 5- to 6-membered heteroaryl, alongside defined selections for R_A, R_1, R_2, R_3, and integer m. In specified embodiments, R_2 and R_3 are taken together with their attached nitrogen atom to form an optionally substituted heterocycle.
The description further encompasses soft ALK5 inhibitors, including ester prodrugs designed to inhibit ALK5 locally, such as in pulmonary tissue, before hydrolyzing into less active carboxylic-acid metabolites upon systemic entry. Embodiments also describe antibody constructs and targeting moieties joined via linkers for cell-specific delivery to target cells, such as T cells in cancer or cells associated with fibrosis. Inhaled, lung-selective administration featuring rapid systemic clearance is described to achieve localized target engagement while mitigating systemic exposure.
Claims Coverage
The claims identify one independent claim directed to compounds of Formula (I-A) and pharmaceutically acceptable salts thereof, characterized by one inventive feature.
Formula (I-A) compounds and pharmaceutically acceptable salts
Claim 1 covers a compound of Formula (I-A), or a pharmaceutically acceptable salt thereof, wherein A is selected from phenyl and 5- to 6-membered heteroaryl; R_A and R_1 are selected from designated functional groups, optionally substituted alkyl groups, carbocycles, and heterocycles; R_2 and R_3 are taken together with the attached nitrogen atom to form an optionally substituted heterocycle; and m is 0, 1, or 2.
The claim coverage centers on the structurally defined Formula (I-A) compound genus and its pharmaceutically acceptable salts, with additional embodiments addressing pharmaceutical compositions and methods of treating ALK5-mediated diseases.
Stated Advantages
Ester prodrug and soft-drug embodiments are intended to inhibit ALK5 locally, including in the lung, and hydrolyze into less active carboxylic-acid metabolites in systemic circulation, potentially reducing systemic exposure and side effects.
Inhaled, long-acting, lung-selective delivery with rapid clearance is presented as a strategy to limit systemic exposure and potential cardiac remodeling effects.
Documented Applications
Treatment of ALK5-mediated diseases or conditions, specifically including fibrosis and cancers.
Treatment of specific fibrosis indications, including cardiac, kidney, pulmonary, idiopathic pulmonary, liver, portal vein, skin, bladder, intestinal, peritoneal, myelofibrosis, oral submucous, retinal, and viral-infection-associated fibrosis.
Local ALK5 inhibition in the lung, including administration via inhalation as a pharmaceutical composition formulated with a carrier, or for use in combination therapy with a second therapeutic agent such as an antifibrotic agent or cancer immunotherapy.
Targeted delivery of ALK5 inhibitors to selected cells, including T cells in cancer and cells associated with fibrosis, using antibody constructs or targeting moieties with linkers.
Treatment of aging-related effects and anticipated application in pulmonary hypertension models.
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