WO2022174882A1 - Dérivés de carbamate hétérocyclyle à 5 chaînons en tant qu'inhibiteurs double du récepteur 1 de lpa et du récepteur 2 de lpa - Google Patents

Dérivés de carbamate hétérocyclyle à 5 chaînons en tant qu'inhibiteurs double du récepteur 1 de lpa et du récepteur 2 de lpa Download PDF

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WO2022174882A1
WO2022174882A1 PCT/EP2021/053707 EP2021053707W WO2022174882A1 WO 2022174882 A1 WO2022174882 A1 WO 2022174882A1 EP 2021053707 W EP2021053707 W EP 2021053707W WO 2022174882 A1 WO2022174882 A1 WO 2022174882A1
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compound
carbonyl
amino
ethoxy
methylisoxazol
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PCT/EP2021/053707
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Elisabetta Armani
Gabriele Amari
Mafalda PAGANO
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Chiesi Farmaceutici S.P.A.
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Priority to PCT/EP2021/053707 priority Critical patent/WO2022174882A1/fr
Publication of WO2022174882A1 publication Critical patent/WO2022174882A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/04—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
    • C07D249/06—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles with aryl radicals directly attached to ring atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C07D261/10—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D261/14—Nitrogen atoms

Definitions

  • the present invention generally relates to compounds inhibiting lysophosphatidic acid receptors (hereinafter LPA inhibitors); the invention relates to compounds that are 5-membered heterocyclyl carbamate derivatives, methods of preparing such compounds, pharmaceutical compositions containing them and therapeutic use thereof.
  • LPA inhibitors lysophosphatidic acid receptors
  • the compounds of the invention may be useful for instance in the treatment of many disorders associated with LPA receptors mechanisms.
  • Lysophosphatidic acid is a phospholipid mediator concentrated in serum that acts as a potent extracellular signaling molecule through at least six cognate G protein- coupled receptors (GPCRs) in numerous developmental and adult processes including cell survival, proliferation, migration, differentiation, vascular regulation, and cytokine release.
  • GPCRs G protein- coupled receptors
  • LPA-mediated processes involve nervous system function, vascular development, immune system function, cancer, reproduction, fibrosis, and obesity (see e.g. Yung etal, J Lipid Res. 2014 Jul;55(7): 1192-214).
  • the formation of an LPA species depends on its precursor phospholipid, which can vary typically by acyl chain length and degree of saturation.
  • the term LPA generally refers to 18:1 oleoyl-LPA (1 -acyl-2 - hydroxy-sn-glycero3 -phosphate), that is the most quantitatively abundant forms of LPA in human plasma with 16:0-, 18:2-, and 18: 1-LPA (see e.g. Sano et ah, J Biol Chem.
  • LPA lipoprotein A1
  • PLA1 phospholipase A1
  • PLA2 phospholipase A2
  • LCAT lecithin- cholesterol acyltransferase
  • A1 phospholipase A1
  • PLA2 phospholipase A2
  • LCAT lecithin- cholesterol acyltransferase
  • ATX Autotaxin
  • the second pathway first converts the phospholipids into phosphatidic acid by the action of phospholipase D.
  • PLA1 or PLA2 metabolize phosphatidic acid to the lysophosphatidic acids (see e.g. Riaz et al, Int J Mol Sci. 2016 Feb; 17(2): 215).
  • ATX activity is the maj or source of plasma extracellular LPA but the source of tissue LPA that contributes to signaling pools likely involves not only ATX but other enzymes as well.
  • the biological functions of LPA are mediated by at least six recognized cell- surface receptors.
  • LPA receptors are rhodopsin-like 7-TM proteins that signal through at least two of the four Ga subunit families (Gal2/13, Gaq/11, Gai/o and GaS). LPA receptors usually trigger response from multiple heterotrimeric G-proteins, resulting in diverse outcomes in a context and cell type dependent manner. Gal 2/ 13 -mediated LPA signaling regulates cell migration, invasion and cytoskeletal re-adjustments through activation of RHO pathway proteins. RAC activation downstream of Gai/o-PI3K also regulates similar processes, but the most notable function of LPA-induced Gai/o is mitogenic signaling through the R.AF- MEK-MAPK cascade and survival signaling through the PI3K-AKT pathway.
  • the LPA- coupled Gaq/11 protein primarily regulates Ca2+ homeostasis through PLC and the second messengers IP3 and DAG. Lastly, GaS can activate adenylyl cyclase and increase cAMP concentration upon LPA stimulation (see e.g. Riaz et ah, Int J Mol Sci. 2016 Feb; 17(2): 215).
  • LPA Long Term Evolution
  • LPA1 is a 41-kD protein that is widely expressed, albeit at different levels, in all human adult tissues examined and the importance of LPA1 signaling during development and adult life has been demonstrated through numerous approaches (see e.g. Ye at al, 2002, Neuroreport. Dec 3; 13(17) :2169-75). Wide expression of LPA1 is observed in adult mice, with clear presence in at least brain, uterus, testis, lung, small intestine, heart, stomach, kidney, spleen, thymus, placenta, and skeletal muscle.
  • LPA1 is also widely expressed in humans where the expression is more spatially restricted during embryonic development. LPA1 couples with and activates three types of G proteins: God/o, Gaq/11, and Gal2/13. LPA1 activation induces a range of cellular responses: cell proliferation and survival, cell migration, cytoskeletal changes, Ca2+ mobilization, adenylyl cyclase inhibition and activation of mitogen-activated protein kinase, phospholipase C, Akt, and Rho pathways (see e.g. Choi et al, Annu Rev Pharmacol Toxicol. 2010; 50:157-86).
  • LPA2 in humans is a 39-kD protein and shares -55% amino acid sequence homology with LPA1 (see e.g. Yung et al, J Lipid Res. 2014 Jul;55(7): 1192-214).
  • LPA2 is highly expressed in kidney, uterus, and testis and moderately expressed in lung; in human tissues, high expression of LPA2 is detected in testis and leukocytes, with moderate expression found in prostate, spleen, thymus, and pancreas.
  • LPA2 In terms of signaling activity, LPA2 mostly activates the same pathways as triggered by LPA1 with some exceptions that regards its unique cross-talk behavior. For example, LPA2 promotes cell migration through interactions with focal adhesion molecule TRIP6 (see e.g. Lai YJ, 2005, Mol.Cell.Biol. 25:5859 68), and several PDZ proteins and zinc finger proteins are also reported to interact directly with the carboxyl-terminal tail of LPA2 (see e.g. Lin FT, 2008, Biochim.Biophys.Acta 1781:558 62).
  • LPA3 Human LPA3 is a 40-kD protein and shares sequence homology with LPA1 (-54%) and LPA2 (-49%). In adult humans LPA3 is highly expressed in heart, pancreas, prostate and testis. Moderate levels of expression are also found in brain, lungs and ovary. Like LPA1 and LPA2 the signaling activity of LPA3 results from its coupling to God/o and Gaq/11 (see e.g Ishii et al, Mol Pharmacol 58:895 902, 2000). Each LPA has multiple important regulatory functions throughout the body.
  • LPA signaling has been strongly implicated in many disease states, great interest has been expressed in developing specific LPA inhibitors (see e.g. Stoddard et el, Biomol Ther (Seoul) 2015 Jan;23(l):l-ll).
  • PF pulmonary fibrosis
  • Different studies have demonstrated a positive role for LPA in the pathogenesis of pulmonary fibrosis (PF), a devastating disease characterized by alveolar epithelial cell injury, accumulation of myofibroblasts and deposition of extracellular matrix proteins leading to a loss of lung function and death (see e.g. Wilson MS, Wynn TA (2009), Mucosal Immunol 2: 103 121).
  • PF pulmonary fibrosis
  • mice lacking LPA1 or LPA2 are markedly protected from fibrosis and mortality in a mouse model of the bleomycin induced pulmonary fibrosis (see e.g. Huang et al, Am J Re spir Cell Mol Biol 2013 Dec; 49(6): 912 922 and Tager et al, Nat Med. 2008 Jan; 14(1) :45-54).
  • LPA1 is known to induce the proliferation and differentiation of lung fibroblasts (see e.g. Shiomi etal, Wound Repair Regen. 2011 Mar Apr; 19(2): 229 240), and to augment the fibroblast-mediated contraction of released collagen gels (see e.g. Mio etal, Journal of Laboratory and Clinical Medicine, Volume 139, Issue 1, January 2002, Pages 20-27).
  • the knockdown of LPA2 attenuated the LPA- induced expression of TGF-bI and the differentiation of lung fibroblasts to myofibroblasts, resulting in the decreased expression of different profibrotic markers such as FN, a-SMA, and collagen, as well as decreased activation of extracellular regulated kinase 1/2, Akt, Smad3, and p38 mitogen-activated protein kinase (see e.g. Huang et al, Am J Respir Cell Mol Biol. 2013 Dec; 49(6): 912 922).
  • LPA1/3 antagonist ameliorated irradiation-induced lung fibrosis (see e.g. Gan et al, 2011, Biochem Biophys Res Commun 409: 7 13).
  • LPA1 administration of an LPA1 antagonist suppressed renal interstitial fibrosis (see e.gPradere et al, J Am Soc Nephrol 2007; 18:3110 3118).
  • WO2019126086 and WO2019126087 disclose cyclohexyl acid isoxazole azines as LPA1 antagonist, useful for the treatment of disorder or condition associated with dysregulation of lysophosphatidic acid receptor 1.
  • WO2019126099 (Bristol-Myers Squibb) discloses isoxazole N-linked carbamoyl cyclohexyl acid as LPA1 antagonist for the treatment of disorder or condition associated with dysregulation of lysophosphatidic acid receptor 1.
  • W02019126090 discloses triazole N-linked carbamoyl cyclohexyl acids as LPA1 antagonists.
  • the compounds are selective LPA1 receptor inhibitors and are useful for the treatment of disorder or condition associated with dysregulation of lysophosphatidic acid receptor 1.
  • WO2017223016 discloses carbamoyloxymethyl triazole cyclohexyl acids as LPA1 antagonist for the treatment of fibrosis including idiopathic pulmonary fibrosis.
  • WO2012028243 discloses pyrazolopyridinone derivatives according to formula (I) and a process of manufacturing thereof as LPA2 receptor antagonists for the treatment of various diseases.
  • antagonizing the LPA receptors may be useful for the treatment of fibrosis and disease, disorder and conditions that result from fibrosis, and even more antagonizing both receptors LPA1 and LPA2 may be particularly efficacious in the treatment of the above-mentioned disease, disorder and conditions.
  • the invention refers to a compound of formula (I) wherein X is independently CH or N,
  • Ri is selected from the group consisting of aryl, (C 4 -C 6 )cycloalkyl and heteroaryl, wherein any of such aryl, heteroaryl and cycloalkyl is optionally substituted by one or more groups selected from (Ci-C 4 )alkyl, halo, (Ci-C 4 )haloalkyl, CN and R4O-;
  • R2 is H or (Ci-C 4 )alkyl
  • R is (Ci-C 4 )alkyl
  • R4 is (Ci-C 4 )alkyl.
  • the invention refers to pharmaceutical composition
  • the invention refers to a compound of formula (I) for the use as a medicament.
  • the invention refers to a compound of formula (I) or a stereoisomer, tautomer or pharmaceutically acceptable salt or solvate thereof for use in treating disease, disorder, or condition associated with dysregulation of lysophosphatidic acid receptor 1 (LPA1) and 2 (LPA2).
  • the invention refers to a compound of formula (I) or a stereoisomer, tautomer or pharmaceutically acceptable salt or solvate thereof for use in the prevention and/or treatment of fibrosis and/or diseases, disorders, or conditions that involve fibrosis.
  • the invention refers to a compound of formula (I) or a stereoisomer, tautomer or pharmaceutically acceptable salt or solvate thereof for use in the prevention and/or treatment idiopathic pulmonary fibrosis (IPF).
  • IPF idiopathic pulmonary fibrosis
  • the invention refers to a compound of formula VIII, XXI and
  • Ri is selected from the group consisting of aryl,(C4-C6)cycloalkyl and heteroaryl, wherein any of such aryl, heteroaryl and cycloalkyl is optionally substituted by one or more groups selected from (Ci-C4)alkyl, halo, (Ci-C4)haloalkyl, CN and R 4 O-; R2 is H or (Ci-C4)alkyl;
  • R4 is (Ci-C4)alkyl.
  • the invention refers to a process for the preparation of a compound of formula (I), wherein X is respectively CH or N, said process comprising the steps of i. reacting a compound of formula VIII or XXI with a compound of formula: to obtain compounds of formula IX and XXI respectively, according to the schemes: wherein Ri and R2 are as above described; ii. subjecting said compounds IX and XXII to hydrolysis, preferably in the presence of LiOH, to obtain compounds of formula (I) according to the schemes:
  • the invention refers to a process for the preparation of a compound of formula (I), wherein X is CH said process comprising the steps of i. reacting a compound of formula XXX with a compound of formula: to obtain compounds of XXXI according to the scheme: wherein Ri is as above defined; ii. subjecting said compound XXXI to Boc-deprotection, preferably in the presence of TFA, and followed by hydrolysis, preferably in the presence of LiOH, to obtain compound of formula (I) according to the scheme: xxxi xxxii (I)
  • pharmaceutically acceptable salts refers to derivatives of compounds of formula (I) wherein the parent compound is suitably modified by converting any of the free acid or basic group, if present, into the corresponding addition salt with any base or acid conventionally intended as being pharmaceutically acceptable.
  • Suitable examples of said salts may thus include mineral or organic acid addition salts of basic residues such as amino groups, as well as mineral or organic basic addition salts of acid residues such as carboxylic groups.
  • Cations of inorganic bases which can be suitably used to prepare salts comprise ions of alkali or alkaline earth metals such as potassium, sodium, calcium or magnesium.
  • Those obtained by reacting the main compound, functioning as a base, with an inorganic or organic acid to form a salt comprise, for example, salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methane sulfonic acid, camphor sulfonic acid, acetic acid, oxalic acid, maleic acid, fumaric acid, succinic acid and citric acid.
  • solvate means a physical association of a compound of this invention with one or more solvent molecules, whether organic or inorganic. This physical association includes hydrogen bonding. In certain instances, the solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid.
  • the solvate may comprise either a stoichiometric or nonstoichiometric amount of the solvent molecules.
  • stereoisomer refers to isomers of identical constitution that differ in the arrangement of their atoms in space. Enantiomers and diastereomers are examples of stereoisomers.
  • enantiomer refers to one of a pair of molecular species that are mirror images of each other and are not superimposable.
  • diastereomer refers to stereoisomers that are not mirror images.
  • racemate or “racemic mixture” refers to a composition composed of equimolar quantities of two enantiomeric species, wherein the composition is devoid of optical activity.
  • the symbols “R” and “ S” represent the configuration of substituents around a chiral carbon atom(s).
  • the isomeric descriptors “R” and “S” are used as described herein for indicating atom configuration(s) relative to a core molecule and are intended to be used as defined in the literature (IUP AC Recommendations 1996, Pure and Applied Chemistry, 68:2193-2222 (1996)).
  • tautomer refers to each of two or more isomers of a compound that exist together in equilibrium and are readily interchanged by migration of an atom or group within the molecule.
  • halogen or “halogen atoms” or “halo” as used herein includes fluorine, chlorine, bromine, and iodine atom.
  • 5-membered heterocyclyl refers to a mono satured or unsatured group containing one or more heteroatoms selected from N and O.
  • (C x -C y ) alkyl wherein x and y are integers, refers to a straight or branched chain alkyl group having from x to y carbon atoms.
  • x is 1 and y is 6, for example, the term includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl and n-hexyl.
  • (C x -C y )alkylene wherein x and y are integers, refers to a C x -C y alkyl radical having in total two unsatisfied valencies, such as a divalent methylene radical.
  • (C x -C y ) haloalkyl wherein x and y are integers, refer to the above defined “C x -C y alkyl” groups wherein one or more hydrogen atoms are replaced by one or more halogen atoms, which can be the same or different.
  • Examples of said “(C x -C y ) haloalkyl” groups may thus include halogenated, poly-halogenated and fully halogenated alkyl groups wherein all hydrogen atoms are replaced by halogen atoms, e.g. trifluorom ethyl.
  • (C x -C y ) cycloalkyl wherein x and y are integers, refers to saturated cyclic hydrocarbon groups containing the indicated number of ring carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl.
  • aryl refers to mono cyclic carbon ring systems which have 6 ring atoms wherein the ring is aromatic.
  • suitable aryl monocyclic ring systems include, for instance, phenyl.
  • heteroaryl refers to a mono- or bi-cyclic aromatic group containing one or more heteroatoms selected from S, N and O, and includes groups having two such monocyclic rings, or one such monocyclic ring and one monocyclic aryl ring, which are fused through a common bond.
  • a bond pointing to a wavy or squiggly line depicts the bond that is the point of attachment of the moiety or substituent to the core or backbone structure.
  • a dash that is not between two letters or symbols is meant to represent the point of attachment for a substituent.
  • physiologically acceptable anions may be present, selected among chloride, bromide, iodide, trifluoroacetate, formate, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate, p-toluenesulfonate, pamoate and naphthalene disulfonate.
  • acidic groups such as COOH groups
  • corresponding physiological cation salts may be present as well, for instance including alkaline or alkaline earth metal ions.
  • the present invention refers to a series of compounds represented by the general formula (I) as herein below described in details, which are endowed with a dual selectivity towards receptors LPA1 and LPA2.
  • the duality of action can be effective in the treatment of those diseases where the LPA receptors play a relevant role in the pathogenesis such as fibrosis and disease, disorder and condition from fibrosis.
  • the compounds of formula (I) of the present invention are able to act as antagonist of both LPA1 and LPA2 receptors in a substantive and effective way, particularly appreciated by the skilled person when looking at a suitable and efficacious compounds useful for the treatment of fibrosis, in particular idiopatic pulmonary fibrosis.
  • the counpounds of formual (I) of the invention have a dual activity as shown in Table 6, wherein for each compound is reported the potency expressed as half maximal inhibitory concentration (IC50) on both receptors.
  • IC50 half maximal inhibitory concentration
  • the compounds of the present invention according to Table 6 show a notable potency with respect to their inhibitory activity on both receptors LPA1 and LPA2 even below about 30 nM on LPA1 and even below about 200 nM on LPA2, confirming that they are able to antagonize the two isoforms of LPA receptor mainly involved in fibrosis and diseases that result from fibrosis.
  • the compounds of formula (I) of the present invention not only are able to act as dual antagonist for the LPA1 and LPA2 receptors, but they can be easily prepared by a convenient and synthetic process as detailed herein below.
  • the present invention relates to a compound of general formula (I) as dual LPA1 and LPA2 antagonist wherein X is independently CH or N, Ri is selected from the group consisting of aryl, (C4-C6)cycloalkyl and heteroaryl, wherein any of such aryl, heteroaryl and cycloalkyl is optionally substituted by one or more groups selected from (Ci-C4)alkyl, halo, (Ci-C4)haloalkyl, CN and R 4 O-; R2 is H or selected from the group consisting of (Ci-C4)alkyl;
  • R is (Ci-C4)alkyl, preferably methyl
  • R4 is (Ci-C4)alkyl, preferably methyl.
  • the invention further concerns the corresponding deuterated derivatives of compounds of formula (I).
  • the invention refers to at least one of the compounds listed in the Table 1 below and pharmaceutical acceptable salts thereof.
  • the invention refers to compound of formula (I) wherein X is independently CH or N, Ri is selected from the group consisting of aryl, preferably phenyl,
  • (C5-C6)cycloalkyl preferably cyclopentyl or cyclohexyl, wherein any of such aryl and cycloalkyl is optionally substituted by one or more groups selected from
  • (Ci-C4)alkyl preferably methyl, halo, preferably chlorine, fluorine or bromine,
  • (Ci-C4)haloalkyl preferably trifluorom ethyl
  • R2 is H or (Ci-C4)alkyl, preferably methyl
  • R is (Ci-C4)alkyl, preferably methyl.
  • the invention refers to at least one of the compounds listed in the Table 2 below and pharmaceutical acceptable salts thereof; those compounds are particularly active on both receptors LPA1 and LPA2, as shown in Table 6.
  • the invention refers to at least one of the compounds listed in the Table 3 below and pharmaceutical acceptable salts thereof; those compounds are particularly active on both receptors LPA1 and LPA2, as shown in Table 6.
  • Table 3 List of preferred compounds of Formula (I)
  • the invention is directed to compounds of formula (I) as defined above, wherein X is CH represented by the formula (la)
  • Ri is aryl, preferably phenyl, wherein any aryl is optionally substituted by one or more groups selected from (Ci-C4)alkyl, preferably methyl, halo, preferably chlorine, fluorine or bromine,
  • R2 is H
  • R is (Ci-C4)alkyl, preferably methyl.
  • the invention refers to at least one of the compound listed in the Table 4 below and pharmaceutical acceptable salts thereof; those compounds are even more particularly active on both receptors LPA1 and LPA2, as shown in Table 6.
  • Table 4 List of preferred compounds of Formula (la)
  • the invention is directed to compounds of formula
  • Ri is selected from the group consisting of aryl and (C 4 -C 6 )cycloalkyl, wherein any of such aryl and cycloalkyl is optionally substituted by one or more groups selected from (Ci-C 4 )alkyl, halo;
  • R2 is H or (Ci-C 4 )alkyl
  • R is (Ci-C 4 )alkyl.
  • the invention refers to compound of formula (lb) wherein
  • Ri is selected from the group consisting of aryl, preferably phenyl and
  • (C 4 -C 6 )cycloalkyl preferably cyclopentyl or cyclohexyl, wherein any of such aryl and cycloalkyl is optionally substituted by one or more groups selected from
  • (Ci-C 4 )alkyl preferably methyl, halo, preferably chlorine, fluorine or bromine, R2 is H or selected from the group consisting of (Ci-C4)alkyl, preferably methyl,
  • R3 1S (Ci-C4)alkyl preferably methyl.
  • the invention refers to at least one compound listed in the Table 5 below and pharmaceutical acceptable salts thereof.
  • the invention also relates to a process for the preparation of a compound of formula (I) as above described, wherein X is CH or N, and said process comprising the steps of: i. reacting a compound of formula VIII and XXI with a compound of formula to obtain compounds of formula IX and XXII respectively, according to the schemes: wherein Ri and R 2 are as above described; ii. subjecting said compounds IX and XXII to hydrolysis, preferably in the presence of LiOH, to obtain compounds of formula (I) according to the schemes:
  • the invention refers to a process for the preparation of a compound of formula (I) wherein
  • X is CH and said process comprising the steps of: i. reacting a compound of formula XXX with a compound of formula to obtain compounds of XXXI according to the scheme:
  • the compounds VIII, XXI, and XXX may be obtained via synthetic pathways known in the art, as e.g. exemplified in the scheme 1, 3 and 4 herein below.
  • Compound VI may be obtained by Mitsunobu reaction of compound V with methyl 3-hydroxycyclohexane-l-carboxylate (mixture of isomers or single enantiomers) in THF by means of PPh3 and DBAD at temperatures from 0°C to 60°C.
  • Compound VII may be obtained by total hydrolysis of compounds VI with an aqueous solution of LiOH and a solvent such as dioxane.
  • Compound VIII may be obtained by selective esterification of compound VII in MeOH with the addition of PTSA.
  • Compound IX may be obtained by Curtius rearrangement of compound VIII with an alcohol R 1 CHCH 3 OH in presence of ADDP and TEA in a solvent such as toluene at high temperatures.
  • compounds (I) may be obtained by hydrolysis of compound IX in an aqueous solution of LiOH and a solvent such as dioxane.
  • Compound X may be obtained by hydrolysis of compound V in an aqueous solution of LiOH and a solvent such as dioxane.
  • Compound XI may be obtained by acetylation of compound X with acetic anhydride in an aqueous solution of KOH.
  • Compound XII may be obtained by Curtius rearrangement of compound XI with an alcohol R 1 CHCH 3 OH in presence of ADDP and TEA in a solvent such as toluene at high temperatures.
  • Compound XIII may be obtained by hydrolysis of compound XII with an aqueous solution of LiOH and a solvent such as dioxane.
  • Compound IX may be obtained by Mitsunobu reaction of compound XIII with methyl 3 -hydroxy cyclohexane- 1- carboxylate (mixture of isomers or single enantiomers) in THF by means of PPh3 and DBAD at temperatures from 0°C to 60°C.
  • compounds of formula (I) may be obtained by hydrolysis of compound IX in an aqueous solution of LiOH and a solvent such as dioxane.
  • Compound XV may be obtained by reaction of compound XIV and oxalyl chloride in a solvent such as DCM with a catalytic amount of DMF at room temperature.
  • Compound XVI may be obtained by reaction of compound XV with compound III in pyridine and THF.
  • Compound XVII may be obtained by reaction of compound XVI with hydroxylamine hydrochloride in acetic acid at high temperatures.
  • Phenol XVIII may be obtained reacting compound XVII with bis(pinacolato)diboron, AcOK and Pd(dppf)Ch in THF at high temperatures, then treating the crude boronic intermediate (not isolated) with 30% H2O2 in EtOAc.
  • Compound XIX may be obtained under Mitsunobu conditions by reaction of compound XVIII with methyl 3-hydroxycyclohexane-l-carboxylate (mixture of isomers or single enantiomers) in THF by means of PPh3 and DBAD at temperatures from 0°C to 60°C.
  • Compound XX may be obtained by total hydrolysis of compound XIX in an aqueous solution of LiOH and a solvent such as dioxane.
  • Compound XXI may be obtained by selective esterification of compound XX in MeOH with the addition of PTSA.
  • Compound XXII may be obtained by Curtius rearrangement of compound XXI with an alcohol R1CHCH3OH in presence of ADDP and TEA in a solvent such as toluene at high temperatures.
  • compounds of formula (I) may be obtained by hydrolysis of compound XXII in an aqueous solution of LiOH and a solvent such as dioxane.
  • Compound XXIV may be obtained by reaction of 4-bromobenzaldehyde and methyl 2- cyanoacetate, NEt3.HCl, DMF, sodium azide in a solvent such as DCM with a catalytic amount of DMF at room temperature to 70°C.
  • Compound XXV may be obtained by reaction of compound XXIV with Mel with a base such as K2CO3 in a solvent such as CH3CN.
  • Compound XXVI may be obtained by hydrolysis of compound XXV with an aqueous 1M LiOH in a solvent such as THF.
  • Compound XXVII may be obtained by Curtius rearrangement of compound XXVI with an alcohol R1CHCH3OH in presence of ADDP and TEA in a solvent such as toluene at high temperatures.
  • Compound XXVIII may be obtained by reaction of compound XXVII with Boc anhydride in presence of DMAP in a solvent such as DCM.
  • Compound XXIX may be obtained by reaction of compound XXVIII with bis(pinacolato)diboron in presence of PdCh and CH3COOK in a solvent such as dioxane at high temperature.
  • Compound XXX may be obtained by reaction of compound XIX with NaBCb.IBC) in a solvent such as THF/H2O.
  • Compound XXXI may be obtained under Mitsunobu conditions by reaction of compound XXX with methyl 3-hydroxycyclohexane-l-carboxylate (mixture of isomers or single enantiomers) in a solvent such as THF in presence of PPh3 and DBAD at temperatures from 0°C to 60°C.
  • Compound XXXII may be obtained by Boc-deprotection of intermediate XXXI with TFA in a solvent such as THF.
  • compounds of formula (I) may be obtained by hydrolysis of compound XXXII in an aqueous solution of LiOH and a solvent such as dioxane.
  • the compound of formula (I) of the invention can conveniently be prepared by using common intermediates, represented by the compounds of formula VIII, XXI and XXX.
  • the invention refers to a compound of formula VIII
  • the invention refers to a compound of formula XXI XXI wherein R2 is H or (Ci-C4)alkyl, preferably methyl.
  • the invention refers to a compound of formula XXX XXX wherein Ri is selected from the group consisting of aryl and (C4-C6)cycloalkyl, heteroaryl, wherein any of such aryl, heteroaryl and cycloalkyl is optionally substituted by one or more groups selected from (Ci-C4)alkyl, halo, (Ci-C4)haloalkyl, CN, R 4 O-.
  • Ri in XXX is aryl substituted by halo, preferably chlorine.
  • the invention refers to the use of the compound VIII and XXI as intermediate for the preparation of a compound of formula (I) according to claim 1, wherein:
  • the invention refers to the use of VIII as above indicated, wherein said compound is subjected to Curtius rearrangement with R 1 CHCH 3 OH to give compound IX, followed by hydrolysis, preferably in presence of LiOH, to give compound o formula (I), according to the following scheme:
  • the invention refers to the use of XXI as above indicated, wherein said compound is subjected to Curtius rearrangement with R1CHCH3OH to give compound IX, followed by hydrolysis, preferably in presence of LiOH, to give a compound of formula (I) according to the following scheme:
  • the invention refers to the use of the compound XXX as intermediate for the preparation of a compound of formula (I) according to claim 1, wherein:
  • the invention refers to the use of XXX as above indicated, wherein said compound is subjected to Mitsunobu reaction, to give compound XXXI, followed by Boc-deprotection, preferably in the presence of TFA, to give compound XXXII, followed by hydrolysis, preferably in presence of LiOH, to give a compound of formula (I) according to the following scheme: wherein R1 is selected from the group consisting of aryl and (C4-C6)cycloalkyl, heteroaryl, wherein any of such aryl, heteroaryl and cycloalkyl is optionally substituted by one or more groups selected from (Ci-C4)alkyl, halo, (Ci-C4)haloalkyl, CN, R4O-.
  • the compounds of formula (I) of the present invention have surprisingly been found to effectively inhibit both receptors LPA1 and LPA2.
  • the inhibition of both receptors LPA1 and LPA2 may result in a more efficacious treatment of the diseases or condition wherein the LPA receptors are involved.
  • the compounds of formula (I) of the present invention have an antagonist drug potency expressed as half maximal inhibitory concentration (IC50) on LPA1 lesser or equal than 30 nM and an IC50 on LPA2 lesser or equal than 200 nM, as shown in the present experimental part.
  • IC50 half maximal inhibitory concentration
  • the compounds of the present invention have an IC50 on LPA1 lesser or equal than 30 nM and an IC50 on LPA2 lesser or equal than 150 nM.
  • the compounds of the present invention have an IC50 on LPA1 lesser or equal than 30 nM and an IC50 on LPA2 lesser or equal than 90 nM.
  • the compounds of the present invention have an IC50 on LPA1 lesser or equal than 20 nM and an IC50 on LPA2 lesser or equal than 90 nM.
  • the compounds of the present invention have an IC50 on LPA1 lesser or equal than 20 nM and an IC50 on LPA2 lesser or equal than 75 nM.
  • the compounds of the present invention have an IC50 on LPA1 lesser or equal than 15 nM and an IC50 on LPA2 lesser or equal than 45 nM.
  • the present invention refers to a compound of formula (I) or a stereoisomer, tautomer or pharmaceutically acceptable salt or solvate thereof for use as a medicament.
  • the invention refers to a compound of formula (I) in the preparation of a medicament, preferably for use in the treatment of disorders associated with LPA receptors mechanism.
  • the invention refers to a compound of formula (I) or a stereoisomer, tautomer or pharmaceutically acceptable salt or solvate thereof, for use in the treatment of disorders associated with LPA receptors mechanism.
  • the present invention refers to a compound of formula (I) for use in the treatment of a disease, disorder or condition associated with dysregulation of lysophosphatidic acid receptor 1 (LPA1) and receptor 2 (LPA2).
  • LPA1 lysophosphatidic acid receptor 1
  • LPA2 receptor 2
  • the present invention refers to a compound of formula (I) useful for the prevention and/or treatment of fibrosis and/or diseases, disorders, or conditions that involve fibrosis.
  • fibrosis refers to conditions that are associated with the abnormal accumulation of cells and/or fibronectin and/or collagen and/or increased fibroblast recruitment and include but are not limited to fibrosis of individual organs or tissues such as the heart, kidney, liver, joints, lung, pleural tissue, peritoneal tissue, skin, cornea, retina, musculoskeletal and digestive tract.
  • the compounds of formula (I) of the present invention are useful for the treatment and/or prevention of fibrosis such as pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), hepatic fibrosis, renal fibrosis, ocular fibrosis, cardiac fibrosis, arterial fibrosis and systemic sclerosis.
  • fibrosis such as pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), hepatic fibrosis, renal fibrosis, ocular fibrosis, cardiac fibrosis, arterial fibrosis and systemic sclerosis.
  • the compounds of formula (I) of the present invention are useful for the treatment of idiopathic pulmonary fibrosis (IPF).
  • IPF idiopathic pulmonary fibrosis
  • the duality of action can be particularly efficacious in the treatment of those diseases where the LPA1 and LPA2 receptors play a relevant role in the pathogenesis such as fibrosis and disease, disorder and condition from fibrosis, and more in particular for the treatment of IPF.
  • the invention also refers to a method for the prevention and/or treatment of disorders associated with LPA receptors mechanisms, said method comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula (I).
  • the invention refers to a method for the prevention and/or treatment of disorder or condition associated with dysregulation of lysophosphatidic acid receptor 1 (LPA1) and receptor 2 (LPA2) administering a patient in need of such treatment a therapeutically effective amount of a compound of formula (I).
  • LPA1 lysophosphatidic acid receptor 1
  • LPA2 receptor 2
  • the invention refers to the use of a compound of formula (I) according to the invention, or a pharmaceutically acceptable salt thereof, for the treatment of disorders associated with LPA receptors mechanism.
  • the present invention refers to the use of a compound of formula (I) for the treatment of a disease, disorder or condition associated with dysregulation of lysophosphatidic acid receptor 1 (LPA1) and receptor 2 (LPA2).
  • LPA1 lysophosphatidic acid receptor 1
  • LPA2 receptor 2
  • safety and effective amount in reference to a compound of formula (I) or a pharmaceutically acceptable salt thereof or other pharmaceutically-active agent means an amount of the compound sufficient to treat the patient's condition but low enough to avoid serious side effects and it can nevertheless be routinely determined by the skilled artisan.
  • the compounds of formula (I) or pharmaceutically acceptable salts thereof may be administered once or according to a dosing regimen wherein a number of doses are administered at varying intervals of time for a given period of time. Typical daily dosages may vary depending upon the route of administration chosen.
  • the present invention also refers to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof in admixture with at least one or more pharmaceutically acceptable carrier or excipient.
  • the invention refers to a pharmaceutical composition of compounds of formula (I) in admixture with one or more pharmaceutically acceptable carrier or excipient, for example those described in Remington’s Pharmaceutical Sciences Handbook, XVII Ed., Mack Pub., N.Y., U.S.A.
  • Administration of the compounds of the invention and their pharmaceutical compositions may be accomplished according to patient needs, for example, orally, nasally, parenterally (subcutaneously, intravenously, intramuscularly, intrastemally and by infusion) and by inhalation.
  • the compounds of the present invention are administered orally or by inhalation.
  • the compounds of the present invention are administered orally.
  • the pharmaceutical composition comprising the compound of formula (I) is a solid oral dosage form such as tablets, gelcaps, capsules, caplets, granules, lozenges and bulk powders.
  • the pharmaceutical composition comprising the compound of formula (I) is a tablet.
  • the compounds of the invention can be administered alone or combined with various pharmaceutically acceptable carriers, diluents (such as sucrose, mannitol, lactose, starches) and known excipients, including suspending agents, solubilizers, buffering agents, binders, disintegrants, preservatives, colorants, flavorants, lubricants and the like.
  • the pharmaceutical composition comprising a compound of formula (I) is a liquid oral dosage forms such as aqueous and non-aqueous solutions, emulsions, suspensions, syrups, and elixirs.
  • Such liquid dosage forms can also contain suitable known inert diluents such as water and suitable known excipients such as preservatives, wetting agents, sweeteners, flavorants, as well as agents for emulsifying and/or suspending the compounds of the invention.
  • suitable known inert diluents such as water and suitable known excipients such as preservatives, wetting agents, sweeteners, flavorants, as well as agents for emulsifying and/or suspending the compounds of the invention.
  • the pharmaceutical composition comprising the compound of formula (I) is an inhalable preparation such as inhalable powders, propellant-containing metering aerosols or propellant-free inhalable formulations.
  • the powder may be filled in gelatine, plastic or other capsules, cartridges or blister packs or in a reservoir.
  • a diluent or carrier chemically inert to the compounds of the invention e.g. lactose or any other additive suitable for improving the respirable fraction may be added to the powdered compounds of the invention.
  • Inhalation aerosols containing propellant gas such as hydrofluoroalkanes may contain the compounds of the invention either in solution or in dispersed form.
  • the propellant-driven formulations may also contain other ingredients such as co-solvents, stabilizers and optionally other excipients.
  • the propellant-free inhalable formulations comprising the compounds of the invention may be in form of solutions or suspensions in an aqueous, alcoholic or hydroalcoholic medium and they may be delivered by jet or ultrasonic nebulizers known from the prior art or by soft-mist nebulizers.
  • the compounds of the invention can be administered as the sole active agent or in combination with other pharmaceutical active ingredients.
  • the dosages of the compounds of the invention depend upon a variety of factors including among others the particular disease to be treated, the severity of the symptoms, the route of administration and the like.
  • the invention is also directed to a device comprising a pharmaceutical composition comprising a compound of Formula (I) according to the invention, in form of a single- or multi-dose dry powder inhaler or a metered dose inhaler.
  • MgSCE magnesium sulfate
  • Na2S2C> 3 Sodium thiosulfate
  • PPh3 triphenylphosphine pTLC: preparative thin layer chromatography
  • PTSA p-toluenesulfonic acid
  • TEA triethylamine
  • THF tetrahydrofuran
  • Flash chromatography was performed on Interchim PuriFlash 450 system. Preparative thin-layer chromatography (PTLC) with Uniplate 500 and 1000 micron silica gel plates or TLC silica gel RP-18 F254S (glass plates 5x10 cm).
  • PTLC Preparative thin-layer chromatography
  • the UPLC-MS was performed on apparatus Shimadzu LCMS-2020 Single Quadrupole Liquid Chromatograph Mass Spectrometer using a column Acquity UPLC 18pm C18 (2.1x50 mm), 100 A, a Mobile phase A: 0.1% formic acid in water and a Mobile phase B: 0.1% formic acid in acetonitrile.
  • UPLC conditions Wavelenght: 254 nm and 220 nm; Flow: 0.5 ml/min; Column temperature: 25 °C.
  • MS conditions Mass range: 50-1000 m/z; Ionization: alternate; Scan speed: 15000 u/sec.
  • the LCMS was performed on apparatus Dionex UHPLC Ultimate 3000 with DAD detector/Thermo Scientific MSQ Plus using a column Kinetex ® 2.6 pm XB-C18 (4.6x50 mm), 110 A, a mobile phase A: water and a mobile phase B: acetonitrile.
  • MS conditions Mass range: 100-1000 m/z; Ionization: alternate; Scan speed: 12000 u/sec.
  • the LCMS was performed on apparatus Dionex UHPLC Ultimate 3000 with DAD detector/Thermo Scientific MSQ Plus using a column: Kinetex ® 2.6 pm XB-C18 (4.6x50 mm), 110 A and mobile phase A: 0.1% formic acid in water and mobile phase B: 0.1% formic acid in acetonitrile.
  • MS conditions Mass range: 100-1000 m/z; Ionization: alternate; Scan speed: 12000 u/sec.
  • LCMS-method D The LCMS was performed on apparatus Dionex UHPLC Ultimate 3000 with DAD detector/Thermo Scientific MSQ Plus using a column Kinetex ® 2.6 pm XB-C18 (4.6.x50 mm), 110 A, a mobile phase A: 0.1% formic acid in water and a mobile phase B: 0.1% formic acid in acetonitrile.
  • the LCMS was performed on apparatus Dionex UHPLC Ultimate 3000 with DAD detector/Thermo Scientific MSQ Plus using a column Kinetex ® 2.6 pm XB-C18 (4.6.x50 mm), 110 A, a mobile phase A: 0.1% formic acid in water and a Mobile phase B: 0.1% formic acid in acetonitrile.
  • the LCMS was performed on apparatus Agilent Technologies 1260 Infinity II with DAD detector using a column Acquity UPLC BEH C18 (2.1x50 mm), 2.6 pm, a mobile phase A: 0.1% formic acid in water and a mobile phase B: 0.1% formic acid in acetonitrile.
  • HPLC conditions Wavelenght range: (190-4000) nm ⁇ 4 nm, Flow: 0.5 ml/min,
  • MS conditions Mass range: 100-1000 m/z, Ionization: alternate, Scan speed: 5200 u/sec.
  • the LCMS was performed on apparatus Dionex UHPLC Ultimate 3000 with DAD detector/Thermo Scientific MSQ Plus using a column Kinetex 2.6pm C18 (4.6x50 mm), 110 A, a Mobile phase A: water and a Mobile phase B: acetonitrile.
  • HPLC conditions Wavelenght range: (190-340) nm ⁇ 4 nm, Flow: 1.0 ml/min,
  • MS conditions Mass range: 100-1000 m/z, Ionization: alternate, Scan speed: 12000 u/sec.
  • the LCMS was performed on apparatus Dionex UHPLC Ultimate 3000 with DAD detector/Thermo Scientific MSQ Plus using a column Gemini-NX 3 pm C18 (4.6x50 mm), 110 A, a Mobile phase A: 0.1% formic acid in water and a Mobile phase B: 0.1% formic acid in acetonitrile.
  • MS conditions Mass range: 100-1000 m/z, Ionization: alternate, Scan speed: 12000 u/sec.
  • the LCMS was performed on apparatus Dionex UHPLC Ultimate 3000 with DAD detector/Thermo Scientific MSQ Plus using a column kinetex 2.6pm C18 (4.6x50 mm), 110 A, a Mobile phase A: 0.1% formic acid in water and a Mobile phase B: 0.1% formic acid in acetonitrile.
  • HPLC conditions Wavelenght range: (190-340) nm ⁇ 4 nm, Flow: 1.0 ml/min,
  • the LCMS was performed on apparatus Dionex UHPLC Ultimate 3000 with DAD detector/Thermo Scientific MSQ Plus using a column kinetex 2.6pm C18 (4.6x50 mm), 110 A, a Mobile phase A: 0.1% formic acid in water and a Mobile phase B: 0.1% formic acid in acetonitrile.
  • Methyl 3-oxobutanoate (40.00 g, 0.34 mol) was dissolved in MeOH (405 mL) then methylamine (30 mL, 0.34 mol) was added and the reaction mixture was stirred for 2 hours at RT. The solvent was evaporated to dryness, then toluene was added and the mixture was evaporated again to remove water. The white solid (42 g) was used in the next step without purification.
  • Step 2 preparation of methyl (lS,3R)-3-hydroxycyclohexane-l-carboxylate
  • Step 2bis preparation of methyl (lR,3R)-3-hydroxycyclohexane-l-carboxylate (intermediate 2bis) intermediate 2bis
  • MeOH 70 mL
  • p-toluenesulfonic acid monohydrate 0.068 g, 0.361 mmol
  • the solvent was removed under reduced pressure and the residue was dissolved in EtOAc and washed with aqueous sat. NaiCCb and brine.
  • the organic phase was dried over sodium sulfate, filtered and concentrated to dryness to afford 0.537 g of the title compound as a pale yellow oil that was used without purification.
  • Step 3 preparation of 4-(chlorocarbonyl)phenyl acetate (intermediate 3) intermediate 3
  • N,N-dimethylformamide (0.1 mL) was added to a solution of 4-(acetyloxy)benzoic acid (20.00 g, 0.11 mol) in DCM (555 mL) under argon.
  • Oxalyl chloride (27 mL, 0.14 mmol) was added dropwise to the reaction mixture at 0 ° C. The reaction was stirred for 3h at room temperture then the solvent was removed under vacuum to give a yellow oil. Crude was used in the next step without further purification.
  • Step 4 preparation of methyl 2-(4-acetoxybenzoyl)-3-(methylimino)butanoate (intermediate 4) intermediate 4
  • Methyl 3-(methylamino)but-2-enoate (12.00 g, 0.093 mol) was dissolved in anh.
  • THF (258 mL)
  • anh. pyridine 11.30 mL, 0.14 mol
  • the reaction mixture was cooled to 0°C and intermediate 3 (20.30 g, 0.10 mol) in anh.
  • THF 47 mL was slowly added to the solution.
  • the reaction mixture was warmed up to room temperature and stirred overnight.
  • Triphenyl phosphine (3.37 g, 0.013 mol) was dissolved in anh.
  • THF 54 mL
  • Di-tert-butyl azodicarboxylate (2.96 g, 0.013 mol) was added at 0°C.
  • the reaction mixture was stirred for 1 h at 0°C (white pulp was formed), then a solution of methyl (lS,3R)-3-hydroxycyclohexane-l-carboxylate (2.71 g, 0.017 mol) and intermediate 5 (1.00 g, 0.004 mol) in anh.
  • THF 33 mL
  • Step 7 preparation of 5-(4-(((lS,3S)-3-carboxycyclohexyl)oxy)phenyl)-3- methylisoxazole-4-carboxylic acid (intermediate 7) intermediate 7
  • Step 8 preparation -(4-(((lS,3S)-3-(methoxycarbonyl)cyclohexyl)oxy)phenyl)-3- methylisoxazole-4-carboxylic acid (intermediate 8) intermediate 8
  • Step 9 preparation of methyl (lS,3S)-3-(4-(3-methyl-4-((((R)-l-(2- (trifluoromethyl) phenyl)ethoxy)carbonyl)amino) isoxazol-5-yl)phenoxy)cyclohexane- 1-carboxylate (intermediate 9.1) intermediate 9.1
  • intermediates 9.2, 9.3, 9.4, 9.5 and 9.6 can be obtained using intermediate 8 and an alcohol as indicated in the table below in place of (R)-l-(2- (trifluoromethyl)phenyl)ethan- 1 -ol .
  • Step 10 preparation of (lS,3S)-3-(4-(3-methyl-4-((((R)-l-(2- (trifluoromethyl)phenyl)ethoxy) carbonyl)amino)isoxazol-5-yl)phenoxy)cyclohexane-l- carboxylic acid (Example 1)
  • a solution of 2M LiOH (0.11 mL, 0.22 mmol, 3.0 Eq) was added dropwise to a solution of intermediate 9.1 (0.04 g, 0.07 mmol) in dioxane (0.22 mL) at 0°C. The reaction mixture was stirred overnight at room temperature.
  • Step 2 preparation of 5-(4-acetoxyphenyl)-3-methylisoxazole-4-carboxylic acid (intermediate 11) intermediate 11
  • Intermediate 10 (1.43 g, 6.50 mmol) was dissolved in 2M KOH solution (9.45 mL,
  • intermediates 12.2 and 12.3 can be obtained using intermediate 11 and an alcohol as indicated in the following Table in place of (R)-l-(2- chlorophenyl)ethan- 1 -ol .
  • Step 4 preparation of (R)-l-(2-chlorophenyl)ethyl (5-(4-hydroxyphenyl)-3- methylisoxazol-4-yl)carbamate (intermediate 13.1) intermediate 13.1
  • Step 5 preparation of methyl (lS,3S)-3-(4-(4-((((R)-l-(2- chlorophenyl)ethoxy)carbonyl) amino)-3-methylisoxazol-5-yl)phenoxy)cyclohexane-l- carboxylate (intermediate intermediate 14.1
  • Di-tert-butyl azodi carboxyl ate (2.96 g, 12.90 mmol) and triphenylphosphine (3.37 g, 12.90 mmol) were dissolved in anhydrous THF (61.00 mL) in a closed vessel under argon atmosphere and stirred at room temperature for 0.5 h, then a solution of intermediate 13.1 (1.60 g, 4.30 mmol) and methyl (lS,3R)-3-hydroxycyclohexane-l- carboxylate (2.71 g, 17.20 mmol) in anhydrous THF (23.50 mL) was added dropwise under stirring The mixture was then
  • intermediates 14.2 and 14.3 may be obtained reacting respectively intermediate 13.2 and 13.3 with methyl (lS,3R)-3-hydroxycyclohexane-l-carboxylate (intermediate 2); intermediate 14.4 may be obtained reacting intermediate 13.1 with methyl (lR,3R)-3-hydroxycyclohexane-l-carboxylate (intermediate 2bis).
  • Step 6 preparation of (lS,3S)-3-(4-(4-((((R)-l-(2- chlorophenyl)ethoxy)carbonyl)amino)-3-methylisoxazol-5-yl)phenoxy)cyclohexane-l- carboxylic acid (Example 6)
  • Step 1 preparation of 5-bromo-6-methylpicolinoyl chloride (intermediate 15) intermediate 15
  • N,N-dimethylformamide (0.10 mL) was added to a solution of 5-bromo-6- methylpicolinic acid (1.00 g, 4.63 mmol) in DCM (23.15 mL) under argon.
  • Oxalyl chloride (1.13 mL, 6.02 mmol) was added dropwise at 0°C. The reaction was stirred for 3 h at room temperature then the mixture was eaporated to dryness to give a yellow oil that was used in the next step without further purification.
  • intermediate 15 may be obtained 5-bromopicolinoyl chloride starting from 5-bromopicolinic acid as reagent.
  • Step 2 preparation of methyl-2-(5-bromo-6-methylpicolinoyl)-3- (methylimino)butanoate (intermediate 16) intermediate 16
  • intermediate 16A Similarly may be obtained intermediate 16A starting from intermediate 15A as reagent.
  • the reaction was concentrated and diluted with EtOAc (50 mL)/10% KHSCri (50 mL). The phases were separated, the aqueous layer was washed with EtOAc (2x50 ml), then the combined organic layers were washed with water, saturated Na 2 C0 3 and brine, dried over Na 2 S0 4 and concentrated to dryness to obtain 3.70 g of the title compound as a brown oil. Crude was used in the next step without further purification.
  • Step 3 preparation of methyl 5-(5-bromo-6-methylpyridin-2-yl)-3- methylisoxazole-4-carboxylate (intermediate 17) intermediate 17
  • intermediate 17A may be obtained using intermediate 16A as reagent.
  • the crude was absorbed on SiCh (2 g/ 1 g of crude) and purified via column chromatography, eluting with 0-10% EtOAc in Hexane.
  • ESI (+)[M+H] + 298.95
  • Step 4 preparation of methyl 5-(5-hydroxy-6-methylpyridin-2-yl)-3- methylisoxazole-4-carboxylate (intermediate 18) intermediate 18
  • Intermediate 17 (1.25 g, 4.02 mmol), AcOK (1.18 g, 12.05 mmol) and bis(pinacolato)diboron (1.53 g, 6.03 mmol) were dissolved in anhydrous THF in a sealed tube under argon atmosphere.
  • the reaction mixture was degassed with argon then Pd(dppf)Ch (0.15 g, 0.20 mmol) was added.
  • the tube was moved to a pre-heated oil bath and stirred at 80°C for 16h.
  • the reaction mixture was cooled to room temperature, quenched with water (12.50 mL) and extracted with EtOAc (3x 35 mL).
  • the combined organic layers were dried over MgS0 4 , filtrated and evaporated to dryness under vacuum.
  • the crude product was dissolved in EtOAc (25.00 mL) then 30% H2O2 (4.63 mL, 40.17 mmol) was added dropwise.
  • intermediate 18A may be obtained using intermediate 17A as reagent.
  • the crude was purified via column chromatography, eluting with 5-40% EtOAc in hexane.
  • Step 5 preparation of methyl 5-(5-(((lS,3S)-3-(methoxycarbonyl)cyclohexyl)oxy)- 6-methylpyridin-2-yl)-3-methylisoxazole-4-carboxylate (intermediate 19) intermediate 19
  • the reaction mixture was cooled to 0°C, tributylphosphine (0.80 mL, 3.26 mmol) was added and the reaction mixture was stirred at 0°C for 0.5 h then left to warmed up to room temperature, moved into a pre-heated oil bath and stirred at 50°C overnight.
  • the solvent was evaporated to dryness to give 1.90 of crude.
  • the crude was absorbed on Si02 (2 g/ 1 g crude) and purified by flash chromatography (cartridge 40 g, Interchim Puriflash), eluting with 0-50% EtOAc in hexane to obtain 0.29 g of the title compound as a yellow oil.
  • Triphenyl phosphine (3.36 g, 12.80 mmol) was dissolved in anhydrous THF (53.00 mL) under argon athmosphere argon.
  • Di-tert-butyl azodicarboxylate (2.95 g, 12.80 mmol) was added at 0°C.
  • the reaction mixture was stirred for 1 h at 0°C then a solution of methyl (lS,3R)-3-hydroxycyclohexane-l-carboxylate (Intermediate 2) (2.70 g, 17.10 mmol) and intermediate 18A (1.00 g, 4.30 mmol) in anhydrous THF (32.90 mL) was added.
  • Step 6 preparation of 5-(5-(((lS,3S)-3-carboxycyclohexyl)oxy)-6-methylpyridin- 2-yl)-3-methylisoxazole-4-carboxylic acid (intermediate 20) intermediate 20
  • intermediate 20 A may be obtained starting from intermediate 19A as reagent.
  • Step 7 preparation of 5-(5-(((lS,3S)-3-(methoxycarbonyl)cyclohexyl)oxy)-6- methylpyridin-2-yl)-3-methylisoxazole-4-carboxylic acid (intermediate 21) intermediate 21
  • intermediate 21 A may be obtained using intermediate 20 A as reagent.
  • the crude product was purified via flash chromatography (cartridge puriflash 40 g) eluting with 0-70% EtOAc in hexane.
  • ESI (+)[M+H] + 361.05
  • Step 8 preparation of methyl (lS,3S)-3-((6-(4-((((R)-l-(2- chlorophenyl)ethoxy)carbonyl) amino)-3-methylisoxazol-5-yl)-2-methylpyridin-3- yl)oxy)cyclohexane-l-carboxylate (intermediate 22.1) intermediate 22.1
  • Intermediates 22.1 A may be obtained similarly to the preparation of intermediate 22.1, reacting intermediate 21 A with (R)-l-(2-(chlorophenyl)ethan-l-ol.
  • Intermediates 22.2 to 22.6 may be obtained similarly to intermediate 22.1, reacting intermediate 21 with a different alcohol as indicated in the following Table in place of (R)- 1 -(2-(chlorophenyl)ethan- 1 -ol .
  • Step 9 preparation of (lS,3S)-3-((6-(4-((((R)-l-(2- chlorophenyl)ethoxy)carbonyl)amino)-3-methylisoxazol-5-yl)-2-methylpyri din-3- yl)oxy)cyclohexane-l -carboxylic acid (Example 10)
  • Example 10
  • Step 1 preparation of methyl 4-(4-bromophenyl)-lH-l,2,3-triazole-5-carboxylate
  • intermediate 23 To a stirred mixture of 4-bromobenzaldehyde (2.00 g, 10.81 mmol), triethylamine hydrochloride (4.46 g, 32.4 mmol) and methyl 2-cyanoacetate (0.954 mL, 10.81 mmol) in DMF (40 mL) were added then sodium azide (2.249 g, 34.6 mmol) was added and the mixture was heated at 70°C for 14 h. The reaction was cooled to r.t., poured into water (200 mL) and extracted with EtOAc (2 x 100 mL). The aqueous phase was added with
  • Step 2 preparation of methyl 4-(4-bromophenyl)-l-methyl-lH-l,2,3-triazole-5- carboxylate (intermediate 24) To a suspension of intermediate 23 (0.780 g, 2.77 mmol) in acetonitrile (15 mL),
  • Step 3 preparation of 4-(4-bromophenyl)-l-methyl-lH-l,2,3-triazole-5- carboxylic acid (intermediate 25) intermediate 25
  • Step 4 preparation of (R)-l-(2-chlorophenyl)ethyl (4-(4-bromophenyl)-l-methyl- lH-l,2,3-triazol-5-yl)carbamate (intermediate 26)
  • Step 5 preparation of (R)-l-(2-chlorophenyl)ethyl (4-(4-bromophenyl)-l-methyl- lH-l,2,3-triazol-5-yl)(tert-butoxycarbonyl)carbamate (intermediate 27)
  • Step 6 preparation of (R)-l-(2-chlorophenyl)ethyl (tert-butoxycarbonyl)(l -methyl-
  • Step 7 preparation of (R)-l-(2-chlorophenyl)ethyl (tert-butoxycarbonyl)(4-(4- hydroxyphenyl)-l-methyl-lH-l,2,3-triazol-5-yl)carbamate (intermediate 29) intermediate 29
  • Step 9 preparation of methyl (lS,3S)-3-(4-(5-((((R)-l-(2- chlorophenyl)ethoxy)carbonyl)amino)- 1 -methyl- 1H- 1 ,2,3-triazol-4- yl)phenoxy)cyclohexane-l-carboxylate (intermediate 31) intermediate 31
  • Step 10 preparation of (lS,3S)-3-(4-(5-((((R)-l-(2- chlorophenyl)ethoxy)carbonyl)amino)- 1 -methyl- 1H- 1 ,2,3-triazol-4- yl)phenoxy)cyclohexane-l -carboxylic acid (Example 17)
  • Example 17
  • the effectiveness of compounds of the present invention as dual LPA1 and LPA2 antagonist can be determined at the human recombinant LPA1 or LPA2 expressed in CHO cells, using a FLIPR assay in 384 well format.
  • CHO-hLPAl and hLPA2 cell lines are cultured in a humidified incubator at 5% C02 in DMEM/F-12 (1:1) MIXTURE with 2mM Glutamax, supplemented with 10% of Foetal Bovine Serum, 1 mM Sodium Pyruvate, 11 mM Hepes and IX Penicillin/Streptomycin.
  • CHO hLPAl or hLPA2 cells are seeded into black walled clear- bottom 384-well plates (#781091, Greiner Bio-One GmbH) at a density of 7,500 cells per well in 50 m ⁇ culture media and grown overnight in a 37°C humidified C02-incubator.
  • the raw data obtained in unstimulated controls are set as “100% inhibition”, while the raw data obtained in negative controls, i.e. in the absence of compounds and stimulating with LPA EC80, are set as “0% inhibition”.
  • LPA1 IC50 comprised between about 20 nM and 40 nM ++: LPA1 IC50 comprised between about 10 nM and 20 nM +++: LPA1 IC50 less than about 10 nM LPA receptor 2 (LPA2)
  • LPA2 IC50 comprised between about 100 nM and 200 nM ++: LPA2 IC50 comprised between about 45 nM and 100 nm +++: LPA2 IC50 less than about 45 nM.
  • the Comparative Examples A-H do not show a remarkable activity on the receptor LPA2.
  • their inhibitory activity expressed as IC50 on LPA2 is comprised between 0.8 and 6 mM and therefore it is significantly lower in comparison with the inhibitory activity of the compound of the present invention.

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Abstract

La présente invention concerne des composés de formule générale (I) inhibant à la fois le récepteur 1 (LPA1) et le récepteur 2 (LPA2) de l'acide lysophosphatidique, en particulier l'invention concerne des composés qui sont des dérivés de carbamate hétérocyclyle à 5 chaînons, des procédés de préparation de ces composés, des compositions pharmaceutiques les contenant et leur utilisation thérapeutique. Les composés selon l'invention peuvent être utiles dans le traitement de maladies ou d'affections associées à une dysrégulation des récepteurs du LPA, en particulier la fibrose.
PCT/EP2021/053707 2021-02-16 2021-02-16 Dérivés de carbamate hétérocyclyle à 5 chaînons en tant qu'inhibiteurs double du récepteur 1 de lpa et du récepteur 2 de lpa WO2022174882A1 (fr)

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US11584738B2 (en) 2020-06-03 2023-02-21 Gilead Sciences, Inc. LPA receptor antagonists and uses thereof
US11702407B2 (en) 2020-06-03 2023-07-18 Gilead Sciences, Inc. LPA receptor antagonists and uses thereof
US11939318B2 (en) 2021-12-08 2024-03-26 Gilead Sciences, Inc. LPA receptor antagonists and uses thereof
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US11548871B2 (en) 2019-11-15 2023-01-10 Gilead Sciences, Inc. Triazole carbamate pyridyl sulfonamides as LPA receptor antagonists and uses thereof
US11999717B2 (en) 2019-11-15 2024-06-04 Gilead Sciences, Inc. Triazole carbamate pyridyl sulfonamides as LPA receptor antagonists and uses thereof
US11584738B2 (en) 2020-06-03 2023-02-21 Gilead Sciences, Inc. LPA receptor antagonists and uses thereof
US11702407B2 (en) 2020-06-03 2023-07-18 Gilead Sciences, Inc. LPA receptor antagonists and uses thereof
US11912686B2 (en) 2020-06-03 2024-02-27 Gilead Sciences, Inc. LPA receptor antagonists and uses thereof
US11980609B2 (en) 2021-05-11 2024-05-14 Gilead Sciences, Inc. LPA receptor antagonists and uses thereof
US11939318B2 (en) 2021-12-08 2024-03-26 Gilead Sciences, Inc. LPA receptor antagonists and uses thereof

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