Quinazoline derivatives as LPA receptor 2 inhibitors
Inventors
Amari, Gabriele • Armani, Elisabetta • PAGANO, Mafalda • Raveglia, Luca • GIULIANI, Marta • Beato, Claudia
Assignees
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Publication Number
US-12404270-B2
Publication Date
2025-09-02
Expiration Date
Abstract
The present invention relates to a compounds of general formula (I) inhibiting lysophosphatidic acid receptor 2 (LPA2), particularly the invention relates to compounds that are quinazoline derivatives, 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 LPA receptors, in particular fibrosis.
Core Innovation
The invention relates to compounds of formula (I) defined by a quinazoline-4-amine core and multiple variable substituents including R, R1, R2, R3, A, Rc, and RA/RB, with optional fused or formed ring systems. The general definition permits heteroaryl, aryl, alkyl, halo, haloalkyl, nitro, ether/alkoxy, ester, carbamate, amine, and carbonyl-containing groups, and includes the proviso that when R2 is H, R is not H.
The disclosure characterizes exemplified members of the claimed chemical series by providing specific quinazoline-based piperazine sulfonamide compounds with heteroaryl substituents such as thiazole, oxazole, furan, thiophene, pyridinyl, phenyl, and 1,3,4-oxadiazol-2-yl. The examples include trifluoromethyl, trifluoromethoxy, difluoromethoxy, and nitro substituted quinazoline variants, together with carbamate, acetamide, amine, carboxamide, cyclopropylmethanone, and sulfonamide forms.
The document also provides chemical structures and analytical characterization, including LC-MS and 1H NMR data, for specific examples and intermediates within the series. The described examples connect the general formula (I) to concrete compounds bearing quinazoline-piperazine-linked motifs and related stereodefined substituent patterns, and the compounds are described as active LPA2 antagonists.
Claims Coverage
The independent claim family covers compounds of formula (I) defined by detailed substituent and ring constraints, including a proviso relating R and R2. Dependent coverage narrows A to selected heteroaryl rings, includes explicit example compounds, and extends to pharmaceutical compositions and methods for treating diseases linked to LPA2 dysregulation.
Compound of formula (I) with defined substituent constraints
A compound of formula (I) wherein R, R1, R2, R3, A, Rc, and RA/RB are defined by specific allowable substituent classes, ring-formation rules, optional fused ring system formation when A is aryl, and a proviso that when R2 is H, R is not H.
Selected heteroaryl for A
A compound of formula (I) wherein A is a 5-6 membered heteroaryl selected from thiazole, thiophene, or furan.
Selected specific example compounds within the formula (I) scaffold
A compound of formula (I) selected from a listed group of specific methyl carbamates, acetamides, amine/carboxamide derivatives, and other explicitly named substituted quinazoline and piperazine-linked sulfonyl motifs.
Pharmaceutical composition containing formula (I) compound
A pharmaceutical composition that contains a compound of formula (I) mixed with one or more pharmaceutically acceptable carriers or excipients.
Method of treating LPA2 dysregulation disease conditions
A method of treating a disease, disorder, or condition linked to dysregulation of lysophosphatidic acid receptor 2 (LPA2) by administering the pharmaceutical composition to a subject in need.
Overall, the claim coverage centers on a formula (I) quinazoline-4-amine scaffold with tightly defined substituent and ring constraints, including the R2/H proviso, narrowed by selected heteroaryl choice for A and by explicit listed example compounds. It further extends to pharmaceutical compositions containing the claimed compounds and to therapeutic methods for diseases linked to LPA2 dysregulation.
Stated Advantages
Compounds are described as active LPA2 antagonists with reported IC50 potency values.
Improved LPA2 potency compared with referenced prior examples.
Potential lower dosing to reduce adverse events.
Enables treatment or prevention of LPA receptor-associated disorders, including disorders involving dysregulation of LPA2.
Targets fibrosing disorders associated with LPA2 dysregulation, including pulmonary, hepatic, renal, ocular, cardiac, arterial fibrosis, systemic sclerosis, and idiopathic pulmonary fibrosis.
The invention unexpectedly yields active LPA2 antagonists.
Documented Applications
Treatment or prevention of LPA receptor-associated disorders involving dysregulation of lysophosphatidic acid receptor 2 (LPA2).
Treatment or prevention of fibrosing disorders associated with LPA2 dysregulation, including pulmonary, hepatic, renal, ocular, cardiac, arterial fibrosis, systemic sclerosis, and idiopathic pulmonary fibrosis.
Treating a disease, disorder, or condition linked to dysregulation of lysophosphatidic acid receptor 2 (LPA2), with fibrosis emphasis including idiopathic pulmonary fibrosis (IPF).
Use of the disclosed compounds in pharmaceutical compositions and medicament contexts, including oral and inhalation administration routes and inhalable dry powder and aerosol formulations.
In vitro CHO-hLPA2 FLIPR assay classification of IC50 values for multiple examples.
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