Tetrahydrothieno pyridine derivatives as DDRS inhibitors
Inventors
Carzaniga, Laura • RANCATI, Fabio • Rizzi, Andrea • KNIGHT, Keith Christopher • KARAWAJCZYK, Anna • Wołek, Barbara Karolina • Mullins, Toby Matthew Grover • WHITTAKER, Ben Paul
Assignees
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Publication Number
US-12617801-B2
Publication Date
2026-05-05
Expiration Date
Abstract
The present invention relates to compounds of general formula (I) inhibiting Discoidin Domain Receptors (DDR inhibitors), methods of preparing such compounds, pharmaceutical compositions containing them and therapeutic use thereof. The compounds of the invention may be useful for instance in the treatment of many disorders associated with DDR mechanisms.
Core Innovation
The disclosure provides compounds of formula (I), or pharmaceutically acceptable salts thereof, built on a tetrahydrothieno[2,3-c]pyridine-3-carboxamide scaffold. The structural definition specifies L, Hy, R1, R2, R3, n, R4, and R5 with optional substitutions, and includes preferred sub-formulas Iaa′, Iaa″, Iab, and related formula (Ia) and formula (Iaa) variants.
The disclosure further describes specific substituted tetrahydrothieno[2,3-c]pyridine-3-carboxamide derivatives and related intermediates, including pharmaceutically acceptable salt forms such as HCl salts. Exemplified structures include substituted phenyl and heteroaryl side chains, including fluoro, trifluoromethyl, bromopyridyl, methoxy, amino-, aminomethyl-pyridines and pyrazines, together with analytical characterization of representative examples and intermediates.
The compounds are presented in therapeutic context for diseases, disorders, or conditions associated with dysregulation of Discoidin Domain Receptor and fibrosis, including pulmonary fibrosis and idiopathic pulmonary fibrosis (IPF). The invention motivates dual DDR1/DDR2 inhibition with lung activity and indicates therapeutic use in fibrotic conditions or fibrosis-related disease.
Claims Coverage
The independent claim is a compound of formula (I) or a pharmaceutically acceptable salt with detailed definitions of L, Hy, R1, R2, R3, n, R4, and R5. The consolidated claim coverage also includes dependent claims to specific compound embodiments, pharmaceutical compositions, inhalation administration, and therapeutic methods tied to Discoidin Domain Receptor dysregulation and fibrosis-related diseases.
A compound of formula (I) with defined substituent scope
A compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein L is selected from —C(O)— and —CH2—; Hy is a monocyclic heteroaryl with defined optional substitutions; R1 is selected from Het or aryl with optional substituents; R2 is selected from —O(C1-C4)haloalkyl, a halogen atom, —O(C3-C7)cycloalkyl, and —(C1-C4)haloalkyl; R3 is H or selected from halogen, cyano, —O(C1-C4)alkyl, —O(C1-C4)haloalkyl, heterocycloalkyl-(C1-C4)alkylene-, (C1-C4)alkylene-heterocycloalkyl-NR4R5, and heteroaryl optionally substituted; n is 0, 1 or 2; R4 is H or —(C1-C4)alkyl; and R5 is H or —(C1-C4)alkyl.
Preferred sub-formulas Iaa′, Iaa″, Iab, and related embodiments
Preferred sub-formulas are defined by selections for L, R2, R3, and Hy, including sub-formula-dependent structural choices referenced by the tables and specific compound lists.
Pharmaceutical composition with carriers or excipients
A pharmaceutical composition containing the compound or a pharmaceutically acceptable salt thereof mixed with one or more pharmaceutically acceptable carriers or excipients.
Pharmaceutical composition administered by inhalation
A pharmaceutical composition formulated to be administered by inhalation.
Method of treating dysregulation of Discoidin Domain Receptor
A method of treating a disease, disorder, or condition associated with dysregulation of Discoidin Domain Receptor by administering a specified compound or a pharmaceutically acceptable salt to a subject in need.
Method of treating fibrosis-related diseases or fibrotic conditions
A method that treats at least one selected fibrotic condition or fibrosis-related disease by administering the compound or a pharmaceutically acceptable salt to a subject in need.
Overall claim coverage centers on formula (I) tetrahydrothieno[2,3-c]pyridine-3-carboxamide compounds with defined L, Hy, R1, R2, R3, R4, R5, and n selections, and extends to preferred sub-formulas, pharmaceutical compositions including inhalation, and methods of treating diseases associated with Discoidin Domain Receptor dysregulation and selected fibrosis-related conditions.
Stated Advantages
Particularly active on Discoidin Domain Receptor 1 (DDR1).
Particularly active on Discoidin Domain Receptor 2 (DDR2).
High potency with stated Ki/IC50 values < ~80 nM.
DDR1/DDR2 selectivity versus other kinases.
Improved inhalatory profile and reduced systemic exposure.
Low metabolic stability.
Favorable safety/tolerability.
Inhibitory activity increases with changes in linker/substitution position.
Compounds inhibit DDR1 and DDR2 with Ki values less than 80 nM, preferably less than 50 nM, and more preferably less than 25 nM.
Provided compounds are medicaments for DDR dysregulation and fibrosis, including idiopathic pulmonary fibrosis (IPF).
Documented Applications
Treating a disease, disorder, or condition linked to dysregulation of Discoidin Domain Receptor by administering the compound or a pharmaceutically acceptable salt to a subject in need.
Treating at least one selected fibrotic condition or fibrosis-related disease by administering the compound or a pharmaceutically acceptable salt to a subject in need.
Therapeutic use in diseases associated with DDR dysregulation and fibrosis, including idiopathic pulmonary fibrosis (IPF).
Pharmaceutical composition formulated for administration by inhalation.
Assays and data for Discoidin Domain Receptor 1 (DDR1) and Discoidin Domain Receptor 2 (DDR2), including DDR1/DDR2 binding and cell-based assay potency trends.
Medicaments for DDR dysregulation and fibrosis, including idiopathic pulmonary fibrosis (IPF).
Fibrosis-related diseases and conditions, including pulmonary fibrosis, hepatic fibrosis, renal fibrosis, ocular fibrosis, cardiac fibrosis, arterial fibrosis, and systemic sclerosis.
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