WO2022174883A1 - Dérivés hétérocyclyle à 5 chaînons servant d'inhibiteurs double du récepteur 1 de lpa et du récepteur 2 de lpa 2 - Google Patents

Dérivés hétérocyclyle à 5 chaînons servant d'inhibiteurs double du récepteur 1 de lpa et du récepteur 2 de lpa 2 Download PDF

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WO2022174883A1
WO2022174883A1 PCT/EP2021/053708 EP2021053708W WO2022174883A1 WO 2022174883 A1 WO2022174883 A1 WO 2022174883A1 EP 2021053708 W EP2021053708 W EP 2021053708W WO 2022174883 A1 WO2022174883 A1 WO 2022174883A1
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alkyl
group
alkylene
compound
formula
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PCT/EP2021/053708
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English (en)
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Gabriele Amari
Elisabetta Armani
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Chiesi Farmaceutici S.P.A.
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Priority to PCT/EP2021/053708 priority Critical patent/WO2022174883A1/fr
Publication of WO2022174883A1 publication Critical patent/WO2022174883A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom 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
    • C07D333/30—Hetero atoms other than halogen
    • C07D333/36—Nitrogen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D275/00—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings
    • C07D275/02—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings not condensed with other rings
    • C07D275/03—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings not condensed with other rings 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

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 derivatives, methods of preparing such compounds, pharmaceutical compositions containing them and therapeutic use thereof.
  • LPA inhibitors lysophosphatidic acid receptors
  • 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 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.
  • WO2012028243 discloses pyrazolopyridinone derivatives according to formula (I) and a process of manufacturing thereof as LPA2 receptor antagonists for the treatment of various diseases.
  • R2 is H or an (Ci-C 4 )alkyl group
  • R3 is H or selected from the group consisting of (Ci-C 4 )alkyl, (Ci-C 4 )haloalkyl, (C 3 - C8)cycloalkyl and (C 3 -C 8 )heterocycloalkyl;
  • R4 and R5 may form together with the nitrogen atom to which they are attached a 5 or 6 membered saturated heterocyclic ring system optionally containing a further heteroatom selected from N, S or O, said heterocyclic ring system may be optionally substituted by one or more groups selected from (Ci-C4)alkyl, -CN, (Ci-Ce) haloalkyl, (Ci-Ce) hydroxyalkyl,
  • the invention refers to pharmaceutical composition comprising a compound of formula (I) or a stereoisomer, tautomer or pharmaceutically acceptable salt or solvate thereof, in admixture with one or more pharmaceutically acceptable carrier or excipient.
  • the invention refers to a compound of formula (I) for 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 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
  • 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.
  • 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.
  • 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)).
  • 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.
  • 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.
  • Said heterocycloalkyl may be further optionally substituted on the available positions in the ring, namely on a carbon atom, or on an heteroatom available for substitution.
  • Substitution on a carbon atom includes spiro di substitution as well as substitution on two adjacent carbon atoms, in both cases thus form additional condensed 5 to 6 membered heterocyclic ring.
  • (C x -C y ) hydroxyalkyl wherein x and y are integers, refers to the above defined “(Ci-Ce) alkyl” groups wherein one or more hydrogen atoms are replaced by one or more hydroxy (OH) group.
  • (C x -C y ) alkoxy or “(C x -C y ) alkoxyl” wherein x and y are integers, refer to a straight or branched hydrocarbon of the indicated number of carbons, attached to the rest of the molecule through an oxygen bridge.
  • a dash that is not between two letters or symbols is meant to represent the point of attachment for a substituent.
  • L 3 is a bond or an (Cl-C6)alkylene group wherein said alkylene may be optionally substituted by one or more group selected from (Ci-C4)alkyl, -OR3, -NR4R5, -(Ci-C4)alkylene-OR 3 , -(Ci-C4)alkylene-NR4R5, halo and oxo;
  • the invention further concerns the corresponding deuterated derivatives of compounds of formula (I).
  • Li is a bond or an (Ci-C 4 )alkylene group;
  • L2 is selected from the group consisting of wherein Li and L 3 indicate the attachment of L 2 to these groups;
  • L 3 is a bond or an (Ci-C6)alkylene group wherein said alkylene may be optionally substituted by one or more group selected from (Ci-C 4 )alkyl, -OR 3 , -NR 4 R 5 , -(Ci-C4)alkylene-OR3, -(Ci-C4)alkylene-NR4R5, halo and oxo;
  • Rs is H or selected from the group consisting of (Ci-C 4 )alkyl, (Ci-C 4 )haloalkyl, (C 3 -C 8 )cycloalkyl and (C 3 -C 8 )heterocycloalkyl;
  • R4 and Rs are at each occurrence independently H or selected from the group consisting of (Ci-C 4 )alkyl, (C 3 -C 8 )cycloalkyl, (Ci-Ce) haloalkyl, (Ci-Ce) hydroxyalkyl, (C1-C 6 ) aminoalkyl, (Ci-Ce) alkoxyl, (Ci-Ce) alkoxy-(Ci-C 6 ) alkyl, (C 3 -C 6 ) heterocycloalkyl-(Ci-C 6 ) alkyl, aryl, heteroaryl and (C 3 -C 6 ) heterocycloalkyl; or R 4 and R 5 may form together with the nitrogen atom to which they are attached a 5 or 6 membered saturated heterocyclic ring system optionally containing a further heteroatom selected from N, S or O, said heterocyclic ring system may be optionally substituted by one or more groups selected from (Ci-C 4 )alky
  • Re is H or selected from the group consisting of (Ci-C 4 )alkyl, (Ci-Ce) haloalkyl, (Ci-Ce) hydroxyalkyl, (Ci-Ce) aminoalkyl and (Ci-Ce) alkoxyl,
  • Q is H or selected from the group consisting of (C3-C8)cycloalkyl, (C3- C 8 )heterocycloalkyl, aryl and 5-6 membered heteroaryl, wherein each of said cycloalkyl, heterocycloalkyl, aryl and heteroaryl may be optionally substituted by one or more group selected from (Ci-C4)alkyl, -NR4R5, -(Ci-C4)alkylene-OR 3 , -(Ci-C4)alkylene-NR4R5, halo, -NR 2 C(0)R 6 , -NR 2 C(0)0R 6 , -(Ci-C4)alkylene-NR 2 C(0)R 6 and
  • Re is H or selected from the group consisting of (Ci-C 4 )alkyl, (Ci-Ce) haloalkyl, (Ci-Ce) hydroxyalkyl, (Ci-Ce) aminoalkyl and (Ci-Ce) alkoxyl;
  • the invention refers to compound of formula (I) wherein Xi is S, X 5 , Xr, and X 7 are CH, X 4 , X 2 and X 3 are C;
  • Q is aryl, wherein said aryl may be optionally substituted by halo, preferably chlorine, R is H or selected from (Ci-C4)alkyl and halo.
  • the invention refers to the compound in the Table 1 below and pharmaceutical acceptable salts thereof.
  • Example 4 In a further aspect, the invention refers to a compound of formula V In a further aspect, the invention refers to the use of the compound V as intermediate for the preparation of Example 1.
  • the invention refers to a compound of formula XVI In a further aspect, the invention refers to the use of the compound XVI as intermediate for the preparation of Example 3.
  • the invention refers to a compound of formula XIX
  • the invention refers to the use of the compound XIX as intermediate for the preparation of Example 4.
  • the compounds of the present invention have an IC50 on LPA1 and LPA2 lesser or equal than 100 nM. More preferably, the compounds of the present invention have an IC50 on LPA1 and 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) 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 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 the use of a compound of formula (I) in the preparation of a medicament for the treatment of disorders associated with LPA receptors mechanism.
  • 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).
  • 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.
  • 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.
  • 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.
  • 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.
  • diluents such as sucrose, mannitol, lactose, starches
  • excipients including suspending agents, solubilizers, buffering agents, binders, disintegrants, preservatives, colorants, flavorants, lubricants and the like.
  • 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.
  • Na2S2C> 3 Sodium thiosulfate
  • NMR characterization 1H-NMR spectra were performed on a Varian MR-400 spectrometer operating at 400 MHZ (proton frequency), equipped with: a self-shielded Z-gradient coil 5 mm lH/nX broadband probe head for reverse detection, deuterium digital lock channel unit, quadrature digital detection unit with trans mitter offset frequency shift, or on AgilentVNMRS-500 or on a Bruker Avance 400 spectrometers. Chemical shift are reported as 6 values in ppm relative to trimethylsilane (TMS) as an internal standard.
  • TMS trimethylsilane
  • Ionization mode alternate Positive/Negative Electrospray (ES+/ES-)
  • Step 2 Synthesis of 2-[4-(methoxymethoxy)phenyl]thiophene-3-carboxylic acid (intermediate 2) intermediate 2
  • Ethyl 2-[4-(methoxymethoxy)phenyl]thiophene-3-carboxylate (489.0 mg, 1.44 mmol) was dissolved in THF (3 mL), Water (3 mL) and Methanol (3 mL).
  • lithium hydroxide (68.9 mg, 2.88 mmol) was then added and the mixture was stirred at rt overnight. The solvents were removed under vacuum, then HC1 1 M was added to slightly acidic pH and the mixture was extracted with ethyl acetate (3x).
  • Step 5 Synthesis of methyl (IS, 3S)-3-[4-[3-[[(lR)-l-(2- chlorophenyl)ethoxy]carbonylamino]thiophen-2-yl]phenoxy]cyclohexane-l-carboxylate (intermediate 5) intermediate 5
  • Triphenylphosphine (701.59 mg, 2.67 mmol) was dissolved in dry THF (2 mL). The mixture was cooled down to 0 °C and a solution of (NE)-N-[(2-methylpropan-2- yl)oxy-oxomethyl]iminocarbamic acid tert-butyl ester (615.92 mg, 2.67 mmol) (DBAD) in dry THF (2 mL) was added dropwise. The mixture was stirred at 0 °C. After 5min the formation of an abundant white solid was observed.
  • Step 2 Preparation of ethyl 5-chloro-2-[4-(methoxymethoxy)phenyl]thiophene-3- carboxylate (Intermediate 7) intermediate 7
  • Step 3 Preparation of 5-chloro-2-[4-(methoxymethoxy)phenyl]thiophene-3- carboxylic acid (Intermediate 8) intermediate 8
  • Step 4 Preparation of [(lR)-l-(2-chlorophenyl)ethyl] N-[5-chloro-2-[4- (methoxymethoxy)phenyl] thiophen-3-yl]carbamate (Intermediate 9)
  • Step 6 Preparation of methyl (lS,3S)-3-[4-[5-chloro-3-[[(lR)-l-(2- chlorophenyl)ethoxy] carbonylamino]thiophen-2-yl]phenoxy]cy clohexane- 1 - carboxylate (Intermediate 11) intermediate 11
  • Step 2 Preparation of methyl 5-[4-(methoxymethoxy)phenyl]-3-methyl-l,2- thiazole-4-carboxylate (Intermediate 13) intermediate 13
  • Step 6 Preparation of methyl (lS,3S)-3- ⁇ 4-[4-( ⁇ [(lR)-l-(2- chlorophenyl)ethoxy]carbonyl ⁇ amino)-3-methyl-l,2-thiazol-5- yljphenoxy ⁇ cyclohexane- 1-carboxylate (Intermediate 17) intermediate 17 Title compound was prepared following the procedure used for the synthesis of
  • Step 7 Preparation of (lS,3S)-3- ⁇ 4-[4-( ⁇ [(lR)-l-(2- chlorophenyl)ethoxy]carbonyl ⁇ amino)-3-methyl-l,2-thiazol-5- yljphenoxy ⁇ cyclohexane- 1 -carboxylic acid (Example 3) (Example 3)
  • Step 3 Preparation of methyl (lS,3S)-3-(4-(4-((((R)-l-(2-chloropyridin-3- yl)ethoxy)carbonyl)amino)-3-methylisothiazol-5-yl)phenoxy)cyclohexane-l- carboxylate (Intermediate 20) intermediate 20
  • Step 4 Preparation of (lS,3S)-3-(4-(4-((((R)-l-(2-chloropyridin-3- yl)ethoxy)carbonyl)amino)-3-methylisothiazol-5-yl)phenoxy)cyclohexane-l -carboxylic acid (Example 4) (Example 4) To a solution of methyl (lS,3S)-3-(4-(4-((((R)-l-(2-chloropyridin-3- yl)ethoxy)carbonyl)amino)-3-methylisothiazol-5-yl)phenoxy)cyclohexane-l- carboxylate (0.037 g, 0.070 mmol) in THF (1 mL) cooled to 0°C, aqueous 1M LiOH (0.279 mL, 0.279 mmol) was added and the resulting mixture was left to warm to r.t.
  • 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
  • the compounds are diluted 1:50 prior to the experiment with Assay Buffer (20 mM HEPES, 145 mM NaCl, 5 mM KC1, 5.5 mM glucose, 1 mM MgC12 and 2 mM CaC12, pH 7.4 containing 0.01% Pluronic F-127) to obtain a solution corresponding to 5-fold the final concentration in the assay (4X, 2% DMSO).
  • the final concentration of DMSO in the assay will be 0.5% in each well.
  • 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 100 nM and 200 nM ++: LPA1 IC50 comprised between about 45 nM and 100 nm +++: LPA1 IC50 less than about 45 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. Comparative Examples A-H

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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 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/EP2021/053708 2021-02-16 2021-02-16 Dérivés hétérocyclyle à 5 chaînons servant d'inhibiteurs double du récepteur 1 de lpa et du récepteur 2 de lpa 2 WO2022174883A1 (fr)

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11548871B2 (en) 2019-11-15 2023-01-10 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
US11939318B2 (en) 2021-12-08 2024-03-26 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
US11999717B2 (en) 2022-12-05 2024-06-04 Gilead Sciences, Inc. Triazole carbamate pyridyl sulfonamides as LPA receptor antagonists and uses thereof

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US20060194850A1 (en) * 2003-08-05 2006-08-31 Ajinomoto Co. Inc Novel azole compound
WO2012028243A1 (fr) 2010-09-02 2012-03-08 Merck Patent Gmbh Dérivés de pyrazolopyridinone en tant qu'antagonistes de récepteur de lpa
WO2017223016A1 (fr) 2016-06-21 2017-12-28 Bristol-Myers Squibb Company Acides carbamoyloxyméthyl triazole cyclohexyliques en tant qu'antagonistes de lpa
WO2019126086A1 (fr) 2017-12-19 2019-06-27 Bristol-Myers Squibb Company Azines isoxazole d'acide de cyclohexyle en tant qu'antagonistes de lpa
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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
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