Amido cyclohexane acid derivatives as LPA receptor inhibitors
Inventors
Armani, Elisabetta • Amari, Gabriele • Rizzi, Andrea • PAGANO, Mafalda • Raveglia, Luca • Beato, Claudia
Assignees
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Publication Number
US-12454530-B2
Publication Date
2025-10-28
Expiration Date
Abstract
The present invention relates to compounds of general formula (I) inhibiting lysophosphatidic acid receptor 1 (LPA1), particularly the invention relates to compounds that are Ami do cyclohexane acid 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) having a defined core scaffold and variable substituent pattern. X is CR5, —CH—, or N, and A is selected from a specified group of ring systems, with further constraints on substituents R1 through R7. Substituent options include aryl, (C3-C6)cycloalkyl, heterocycloalkyl, heteroaryl, and (C1-C4)alkyl, with optional substitutions including (C1-C4)alkyl, halo, (C1-C4)haloalkyl, CN, —O(C1-C4)alkyl, and —NR6R7.
The structural definition includes a proviso tied to the selection of A and X, and R6 and R7 may optionally form together with the nitrogen atom to generate a 4-6 membered saturated heterocyclic ring system that may optionally include a further heteroatom selected from N, S, and O. The disclosure further describes stereoisomeric cyclohexane-1-carboxylic acid embodiments, including cis/trans and (1S,2S) single-diastereomer compounds with thiophene, aryl, pyridine, triazole, and isoxazole-like motifs together with an (R)-1-(2-chlorophenyl)ethoxycarbonyl amide side chain.
The disclosed compounds are described as LPA1 receptor antagonists and are associated with pharmaceutically acceptable salts, pharmaceutical compositions, and fibrosis-related therapeutic context. The content further references analytical characterization of stereodefined chiral carbamate intermediates and compounds, including cyclohexane carboxylate and carbamate scaffolds with heteroaryl motifs.
Claims Coverage
The provided claim set centers on one independent claim directed to a compound of formula (I), with dependent claims refining the structural definition and adding pharmaceutical composition and treatment use elements. Across the independent scope, the claim family focuses on a core formula definition with constraints on X, A, and substituents R1-R7, including a proviso for the A/X relationship.
Compound of formula (I) with constrained X and A
A compound of formula (I) wherein X is CR5, —CH—, or N; A is selected from a defined group of ring moieties; R1 through R7 are limited to specified group options including aryl, (C3-C6)cycloalkyl, heterocycloalkyl, heteroaryl, and (C1-C4)alkyl with optional substitutions including (C1-C4)alkyl, halo, (C1-C4)haloalkyl, CN, —O(C1-C4)alkyl, and —NR6R7; and R6 and R7 may optionally form a 4-6 membered saturated heterocyclic ring system optionally containing N, S, or O, with a proviso tied to the A/X selection.
Specified stereoisomeric embodiments
A compound selected from multiple named stereoisomeric cyclohexane-1-carboxylic acid embodiments with fused heteroaryl substituents and an (R)-1-(2-chlorophenyl)ethoxycarbonyl amide-linked side chain.
Pharmaceutical composition with pharmaceutically acceptable carriers or excipients
A pharmaceutical composition comprising the compound and one or more pharmaceutically acceptable carriers or excipients.
Treatment of fibrosis-related diseases or disorders
A method for treating fibrosis-related diseases or disorders including pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), hepatic fibrosis, renal fibrosis, ocular fibrosis, cardiac fibrosis, arterial fibrosis, or systemic sclerosis.
Coverage is anchored in the formula (I) definition with constrained choices for X, A, and R1-R7, including optional ring formation by R6 and R7 and a proviso for the A/X case. Dependent claims further narrow to enumerated stereoisomeric embodiments and extend to pharmaceutical composition and fibrosis-related treatment uses.
Stated Advantages
The disclosed compounds are described as LPA1 receptor antagonists with IC50 values referenced as less than 600 nM, preferably 250 nM or less, and more preferably 50 nM or less.
The disclosed compounds are described as showing BSEP inhibition at 50 μM of 50% or more.
The disclosed compounds are described as having passive permeability of 15 nm/sec or less.
Unexpectedly good BSEP inhibition and Caco-2 permeability for an LPA1-active scaffold, suitable for oral bioavailability.
Documented Applications
Medicinal use as a medicament for fibrosis-related diseases, including pulmonary, idiopathic pulmonary, hepatic, renal, ocular, cardiac, and arterial fibrosis, and systemic sclerosis.
Use in a method for treating fibrosis-related diseases or disorders including pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), hepatic fibrosis, renal fibrosis, ocular fibrosis, cardiac fibrosis, arterial fibrosis, and systemic sclerosis.
A pharmaceutical composition containing the compound with pharmaceutically acceptable carriers or excipients.
LPA1 antagonism based on in vitro FLIPR assay results using CHO-hLPA1.
Evaluation of BSEP inhibition and Caco-2 permeability to support oral bioavailability suitability.
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