Pyridazinyl amino derivatives as ALK5 inhibitors
Inventors
Pizzirani, Daniela • Biagetti, Matteo • RONCHI, Paolo • BRUNO, PAOLO • GUARIENTO, Sara • Bertani, Barbara • PALA, Daniele • BARILLI, Alessio
Assignees
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Publication Number
US-12479826-B2
Publication Date
2025-11-25
Expiration Date
Abstract
The present invention relates to a compound of general formula (I) inhibiting the transforming growth factor-β (TGF-β) type I receptor (ALK5), methods of preparing such compounds, pharmaceutical compositions containing them and therapeutic use thereof. The compounds of the invention may be useful in the treatment of diseases or conditions associated with a dysregulation of ALK5 signaling pathway in a mammal.
Core Innovation
The invention relates to compounds of formula (I) and pharmaceutically acceptable salts thereof. The compounds are defined by an aryl R1 optionally substituted by halogen atoms, (C1-C6)alkyl and (C1-C6)haloalkyl, with A selected from A1, A2 and A3 and R2 selected from —NR5C(O)R6 and —NR5R6. Additional structural control is provided through X1, R3, R3′, R4, R5, R6, R7, R8, RA, RB and Rc, with multiple heterocycloalkyl and heteroaryl substitution patterns.
The compounds further define substituent variability through carbonyl-, oxy-, amide-, alkoxy-, hydroxy- and heterocycle-containing options. R3 and R3′ include groups such as —C(O)NR5R7, —C(O)OR7, —OC(O)R7, —OR7, and —C(O)NH-heterocycloalkyl, while R4 and R6 include —C(O)NR5R7, —C(O)heterocycloalkyl, —(C1-C6)alkylene-NRARB, and —NH—(C1-C6)alkylene-heterocycloalkyl, with optional substitution by groups such as —OH, halogen, —(C1-C6)alkyl, —(C1-C6)alkoxy, —CN, —(C1-C6)haloalkyl, and sulfonyl or carboxy-related groups.
The document also describes preferred embodiments and examples within the formula (I) class, including substituted quinazolin, pyridazinyl, quinoline, and pyridinyl motifs with 5-chloro-2-fluorophenyl groups and variable piperazine, piperidine, morpholine, thiomorpholine, diazaspiro, and diazabicyclo substituents. The disclosed compounds are positioned as ALK5 inhibitors and are associated with therapeutic use for ALK5 signaling pathway mediated diseases, including fibrosis and fibrosis-related conditions.
Claims Coverage
The provided material identifies one independent compound claim directed to formula (I) and dependent claim coverage for pharmaceutical composition and therapeutic use. The independent claim defines a broad genus through the R1, A, R2, X1, R3, R3′, R4, R5, R6, R7, R8, RA, RB and Rc selections, and the dependent claims add formulation and inhalation-based treatment features.
Compound of formula (I) with defined substituent groups
A compound of formula (I) wherein R1 is aryl optionally substituted by halogen atoms, —(C1-C6)alkyl and —(C1-C6)haloalkyl; A is selected from A1, A2 and A3; R2 is selected from —NR5C(O)R6 and —NR5R6; X1 is C, CH or N; and R3, R3′, R4, R5, R6, R7, R8, RA, RB and Rc are selected from the specified functional-group and heterocycloalkyl/heteroaryl options, together with pharmaceutically acceptable salts thereof.
Pharmaceutical composition with carriers or excipients
A pharmaceutical composition comprising the compound or its pharmaceutically acceptable salt and one or more pharmaceutically acceptable carriers or excipients.
Inhalation administration of the pharmaceutical composition
The pharmaceutical composition is adapted for administration by inhalation.
Treatment of ALK5-signaling-pathway-mediated disease in mammals
A method of treating a disease, disorder, or condition in mammals mediated by the ALK5 signaling pathway by administering the inhalation-adapted pharmaceutical composition.
Treatment of fibrosis and fibrosis-related conditions
The method wherein the disease, disorder, or condition includes fibrosis and/or a fibrosis-related disease, disorder, or condition.
The claim coverage is centered on a broadly defined class of formula (I) compounds with extensive substituent selections and pharmaceutically acceptable salts, and extends to pharmaceutical compositions, inhalation administration, and treatment of ALK5-signaling-pathway-mediated diseases in mammals, including fibrosis and fibrosis-related conditions.
Stated Advantages
The compounds inhibit ALK5.
In vitro ALK5 inhibition potency is unexpectedly increased for compounds containing the pyridinyl/pyridinyl-condensed group and pyridine substituents versus comparative intermediates, as reflected by reported IC50 values.
Potent ALK5 inhibition.
Improved inhalatory profile.
Low metabolic stability.
Low systemic exposure.
Good kinome selectivity.
Documented Applications
A pharmaceutical composition including the compound or its salt mixed with one or more pharmaceutically acceptable carriers or excipients.
Administration of the pharmaceutical composition by inhalation.
Treatment of a disease, disorder, or condition in mammals mediated by the ALK5 signaling pathway.
Treatment of fibrosis and/or a fibrosis-related disease, disorder, or condition.
Use as medicaments for ALK5-signaling pathway diseases, particularly fibrosis.
Treatment indications explicitly include pulmonary fibrosis, idiopathic pulmonary fibrosis, hepatic fibrosis, renal fibrosis, ocular fibrosis, cardiac fibrosis, arterial fibrosis, and systemic sclerosis.
In vitro ALK5 inhibition using an ADP-Glo kinases assay.
Prevention and/or treatment of ALK5-signaling-pathway-mediated diseases in mammals, with emphasis on fibrosis and fibrosis-related conditions.
Prevention and/or treatment of fibrosis and/or fibrosis-related diseases, disorders, or conditions.
Idiopathic pulmonary fibrosis (IPF).
Systemic sclerosis.
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