[go: up one dir, main page]

WO2024249867A1 - Composés pour le traitement de maladies fibrotiques - Google Patents

Composés pour le traitement de maladies fibrotiques Download PDF

Info

Publication number
WO2024249867A1
WO2024249867A1 PCT/US2024/032008 US2024032008W WO2024249867A1 WO 2024249867 A1 WO2024249867 A1 WO 2024249867A1 US 2024032008 W US2024032008 W US 2024032008W WO 2024249867 A1 WO2024249867 A1 WO 2024249867A1
Authority
WO
WIPO (PCT)
Prior art keywords
methyl
compound
alkyl
phenyl
optionally substituted
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/US2024/032008
Other languages
English (en)
Inventor
Nakcheol Jeong
Misun Lee
Jung-Hee Kim
Petpiboon Prasit
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Am Sciences
Original Assignee
Am Sciences
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Am Sciences filed Critical Am Sciences
Publication of WO2024249867A1 publication Critical patent/WO2024249867A1/fr
Anticipated expiration legal-status Critical
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • This disclosure relates to the fields of chemistry and biology. More particularly, this disclosure provides compounds and pharmaceutically acceptable salts thereof, that inhibit lysophosphatidic acid receptor 1 (LPA1). These compounds are useful, e.g., for treating a disease associated with LPA1 activity. This disclosure also provides compositions containing the same as well as methods of using and making the same.
  • LPA1 lysophosphatidic acid receptor 1
  • Lysophospholipids are bioactive lipids that regulate various cellular signaling pathways by binding to the 7-transmembrane domain G protein-coupled (GPCR) receptors.
  • the LPAs have long been known as precursors of phospholipid biosynthesis in both eukaryotic and prokaryotic cells, but the LPAs have emerged only recently as signaling molecules that are rapidly produced and released by activated cells, notably platelets, to influence target cells by acting on specific cell-surface receptors.
  • LPA receptor-mediated effects have been described in numerous cell types and model systems, both in vitro and in vivo, through gain- and loss-of-function studies. These studies have revealed physiological and pathophysiological influences on virtually every organ system and developmental stage of an organism. These include the nervous, cardiovascular, reproductive, and pulmonary systems. Disturbances in normal LPA signaling may contribute to a range of diseases, including neurodevelopmental and neuropsychiatric disorders, pain, cardiovascular disease, bone disorders, fibrosis, cancer, infertility, and obesity.
  • Some embodiments provide a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as described herein.
  • the compound of Formula (I) is: or pharmaceutically acceptable salts thereof, wherein:
  • R A is hydrogen, C1-C6 alkyl, or C1-C6 alkoxy
  • Ring B is 3-7 membered heterocyclylene or 5-6 membered heteroarylene;
  • Ring C is phenylene or 5-6 membered heteroarylene; m is 0 or 1; n is 0, 1, 2, or 3; each R 1 is independently selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkoxyalkyl, 3-7 membered heterocyclyl, and 5-6 membered heteroaryl; or two R 1 together with the atoms to which they are attached forms a 5-8 membered heterocyclyl or 5-6 membered heteroaryl; each R 2 is independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and halogen;
  • R 3 is selected from:
  • each R E is independently selected from: (i) hydroxyl
  • phenyl optionally substituted with 1-3 substituents selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxyalkyl, C1-C6 alkoxy, hydroxyl, cyano, and halogen,
  • Q is selected from:
  • R A1 and R B1 are independently selected from hydrogen and C1-C6 alkyl optionally substituted with hydroxyl;
  • R c and R D are independently selected from hydrogen and C1-C6 alkyl
  • R F is selected from:
  • R A3 and R B3 are independently selected from hydrogen and C1-C6 alkyl
  • R G is H or C1-C3 alkyl; and x is 0 or 1.
  • Some embodiments provide a method of treating a fibrotic disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein.
  • Some embodiments provide a method for reducing LPA1 activation in a cell comprising LPA1, the method comprising contacting the cell with a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • pharmaceutically acceptable carrier means a pharmaceutically-acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent,, solvent, or encapsulating material.
  • a pharmaceutically-acceptable material such as a liquid or solid filler, diluent,, solvent, or encapsulating material.
  • Remington The Science and Practice of Pharmacy, 21st ed , Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 6th ed. Rowe et al., Eds.; The Pharmaceutical Press and the American Pharmaceutical Association: 2009; Handbook of Pharmaceutical Additives, 3rd ed. Ash and Ash Eds.; Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, 2nd ed. Gibson Ed.; CRC Press LLC: Boca Raton, FL, 2009.
  • pharmaceutically acceptable salt refers to a formulation of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound.
  • pharmaceutically acceptable salts are obtained by reacting a compound described herein, with acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.
  • pharmaceutically acceptable salts are obtained by reacting a compound having acidic group described herein with a base to form a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamine, A-methyl-D-glucamine, tris(hydroxymethyl)methylamine, and salts with amino acids such as arginine, lysine, and the like, or by other methods previously determined.
  • a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamine, A-methyl-D-glucamine, tris(hydroxymethyl)methylamine, and salts with amino acids such as arginine, lysine, and the like, or by other methods previously determined.
  • Examples of a salt that the compounds described hereinform with a base include the following: salts thereof with inorganic bases such as sodium, potassium, magnesium, calcium, and aluminum; salts thereof with organic bases such as methylamine, ethylamine and ethanolamine; salts thereof with basic amino acids such as lysine and ornithine; and ammonium salt.
  • the salts may be acid addition salts, which are specifically exemplified by acid addition salts with the following: mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid:organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, and ethanesulfonic acid; acidic amino acids such as aspartic acid and glutamic acid.
  • mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid
  • organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tart
  • pharmaceutical composition refers to a mixture of a compound described herein with other chemical components (referred to collectively herein as “pharmaceutically acceptable excipients”), such as carriers, stabilizers, diluents, dispersing agents, suspending agents, and/or thickening agents.
  • pharmaceutically acceptable excipients such as carriers, stabilizers, diluents, dispersing agents, suspending agents, and/or thickening agents.
  • the pharmaceutical composition facilitates administration of the compound to an organism. Multiple techniques of administering a compound exist in the art including, but not limited to: rectal, oral, intravenous, aerosol, parenteral, ophthalmic, pulmonary, and topical administration.
  • subject refers to an animal, including, but not limited to, a primate (e.g., human), monkey, cow, pig, sheep, goat, horse, dog, cat, rabbit, rat, or mouse.
  • primate e.g., human
  • monkey cow, pig, sheep, goat
  • horse dog, cat, rabbit, rat
  • patient are used interchangeably herein in reference, for example, to a mammalian subject, such as a human.
  • treat or “treatment” refer to therapeutic or palliative measures.
  • Beneficial or desired clinical results include, but are not limited to, alleviation, in whole or in part, of symptoms associated with a disease or disorder or condition, diminishment of the extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state (e.g., one or more symptoms of the disease), and remission (whether partial or total), whether detectable or undetectable.
  • Treatment can also mean prolonging survival as compared to expected survival if not receiving treatment.
  • terapéuticaally effective amount means an amount of compound that, when administered to a subject in need of such treatment, is sufficient to (i) treat a disease or disorder described herein (e.g., a fibrotic disease), (ii) attenuate, ameliorate, or eliminate one or more symptoms of the particular disease, condition, or disorder, or (iii) delay the onset of one or more symptoms of the particular disease, condition, or disorder described herein.
  • a disease or disorder described herein e.g., a fibrotic disease
  • halogen refers to fluoro (F), chloro (Cl), bromo (Br), or iodo (I).
  • hydroxyl refers to an -OH radical.
  • cyano refers to a -CN radical.
  • alkyl refers to a saturated acyclic hydrocarbon radical that may be a straight chain or branched chain, containing the indicated number of carbon atoms.
  • Ci-io indicates that the group may have from 1 to 10 (inclusive) carbon atoms in it.
  • Alkyl groups can either be unsubstituted or substituted with one or more substituents. Non-limiting examples include methyl, ethyl, iso-propyl, Zc/7-butyl, w-hexyl.
  • saturated as used in this context means only single bonds present between constituent carbon atoms and other available valences occupied by hydrogen and/or other substituents as defined herein.
  • alkenyl refers to an alkyl group having at least one double-bond between constituent carbon atoms.
  • Non-limiting examples include ethenyl, zz-propenyl, zso-propenyl, n- butenyl, ec-butenyl.
  • haloalkyl refers to an alkyl, in which one or more hydrogen atoms is/are replaced with an independently selected halogen.
  • hydroxy alkyl refers to an alkyl, in which one or more hydrogen atoms is/are replaced with hydroxyl.
  • alkoxy refers to an -O-alkyl radical (e.g., -OCH3).
  • alkoxyalkyl refers to an alkyl, in which one or more hydrogen atoms is/are replaced with an independently selected alkoxy.
  • aryl refers to a 6-20 carbon mono-, bi-, tri- or polycyclic group wherein at least one ring in the system is aromatic (e g., 6-carbon monocyclic, 10-carbon bicyclic, or 14-carbon tricyclic aromatic ring system); and wherein 0, 1, 2, 3, or 4 atoms of each ring may be substituted by a substituent.
  • aryl groups include phenyl, naphthyl, tetrahydronaphthyl, and the like.
  • aryloxy refers to an -O-aryl radical (e g., phenoxy).
  • cycloalkyl refers to cyclic saturated hydrocarbon groups having, e.g., 3 to 20 ring carbons, preferably 3 to 16 ring carbons, and more preferably 3 to 12 ring carbons or 3-10 ring carbons or 3-6 ring carbons, wherein the cycloalkyl group may be optionally substituted.
  • cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • Cycloalkyl may include multiple fused and/or bridged rings.
  • Non-limiting examples of fused/bridged cycloalkyl includes: bicyclo[EEO]butane, bicyclo[2. E0]pentane, bicyclo[E El]pentane, bicyclo[3.E0]hexane, bicyclo[2.E l]hexane, bicyclo[3.2.0]heptane, bicyclo[4.E0]heptane, bicyclo[2.2.1]heptane, bicyclo[3.1.1]heptane, bicyclo[4.2.0]octane, bicyclo[3.2. l]octane, bicyclo[2.2.2]octane, and the like.
  • Cycloalkyl also includes spirocyclic rings (e.g., spirocyclic bicycle wherein two rings are connected through just one atom).
  • spirocyclic cycloalkyls include spiro[2.2]pentane, spiro[2.5]octane, spiro[3.5]nonane, spiro[3.5]nonane, spiro[3.5]nonane, spiro[4.4]nonane, spiro[2.6]nonane, spiro[4.5]decane, spiro[3.6]decane, spiro[5.5]undecane, and the like.
  • heteroaryl as used herein, means a mono-, bi-, tri- or polycyclic group having 5 to 20 ring atoms, alternatively 5, 6, 9, 10, or 14 ring atoms; wherein at least one ring in the system contains one or more heteroatoms independently selected from the group consisting of N, O, and S and at least one ring in the system is aromatic (but does not have to be a ring which contains a heteroatom, e.g. tetrahydroisoquinolinyl, e.g., tetrahydroquinolinyl).
  • Heteroaryl groups can either be unsubstituted or substituted with one or more substituents.
  • heteroaryl include thienyl, pyridinyl, furyl, oxazolyl, oxadiazolyl, pyrrolyl, imidazolyl, triazolyl, thiodiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolyl, benzothienyl, benzoxadiazolyl, benzofuranyl, benzimidazolyl, benzotriazolyl, cinnolinyl, indazolyl, indolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, purinyl, thienopyridinyl, pyrido[2,3-t/]
  • the heteroaryl is selected from thienyl, pyridinyl, furyl, pyrazolyl, imidazolyl, isoindolinyl, pyranyl, pyrazinyl, and pyrimidinyl.
  • heteroaryl also includes aromatic lactams, aromatic cyclic ureas, or vinylogous analogs thereof, in which each ring nitrogen adjacent to a carbonyl is tertiary (i.e., all three valences are occupied by non-hydrogen substituents), such as one or more N_
  • imidazolone (e g., ’ ), wherein each ring nitrogen adjacent to a carbonyl is tertiary (i.e., the oxo group (i.e., “ O”) herein is a constituent part of the heteroaryl ring).
  • imidazolone e g., ’
  • heterocyclyl refers to a mono-, bi-, tri-, or polycyclic saturated or partially unsaturated ring system with 3-16 ring atoms (e.g., 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system) having 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic or polycyclic, said heteroatoms selected from O, N, or S (e.g., carbon atoms and 1-3, 1-6, or 1-9 heteroatoms of N, O, or S if monocyclic, bicyclic, or tricyclic, respectively), wherein one or more ring atoms may be substituted by 1-3 oxo (forming, e.g., a lactam) and one or more N or S atoms may be substituted by 1-2 oxido (forming, e.g., an N-oxide, an S-oxid
  • heterocyclyl groups include piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, tetrahydrofuranyl, tetrahydropyridyl, dihydropyrazinyl, dihydropyridyl, dihydropyrrolyl, dihydrofuranyl, dihydrothiophenyl, and the like.
  • Heterocyclyl may include multiple fused and bridged rings.
  • fused/bridged heteorocyclyl includes: 2-azabicyclo[1.1.0]butane, 2-azabicyclo[2.1.0]pentane, 2- azabicyclo[ 1.1.1 Jpentane, 3 -azabicyclo[3.
  • Heterocyclyl also includes spirocyclic rings (e.g., spirocyclic bicycle wherein two rings are connected through just one atom).
  • Non-limiting examples of spirocyclic heterocyclyls include 2-azaspiro[2.2]pentane, 4- azaspiro[2.5]octane, l-azaspiro[3.5]nonane, 2-azaspiro[3.5]nonane, 7-azaspiro[3.5]nonane, 2- azaspiro[4.4]nonane, 6-azaspiro[2.6]nonane, l,7-diazaspiro[4.5]decane, 7-azaspiro[4.5]decane 2,5-diazaspiro[3.6]decane, 3-azaspiro[5.5]undecane, 2-oxaspiro[2.2]pentane, 4- oxaspiro[2.5]octane, l-oxaspiro[3.5]nonane, 2-oxaspiro[3.5]nonane, 7-oxaspiro[3.5]nonane, 2-
  • aromatic rings include: benzene, pyridine, pyrimidine, pyrazine, pyndazine, pyndone, pyrrole, pyrazole, oxazole, thiazole, isoxazole, isothiazole, and the like.
  • heterocyclyloxy refers to an -O-heterocylyl radical.
  • saturated as used in this context means only single bonds present between constituent atoms.
  • a ring when a ring is described as being “partially unsaturated”, it means said ring has one or more additional degrees of unsaturation (in addition to the degree of unsaturation attributed to the ring itself; e.g., one or more double or tirple bonds between constituent ring atoms), provided that the ring is not aromatic.
  • additional degrees of unsaturation in addition to the degree of unsaturation attributed to the ring itself; e.g., one or more double or tirple bonds between constituent ring atoms
  • examples of such rings include: cyclopentene, cyclohexene, cycloheptene, dihydropyridine, tetrahydropyridine, dihydropyrrole, dihydrofuran, dihydrothiophene, and the like.
  • rings and cyclic groups e.g., aryl, heteroaryl, heterocyclyl, cycloalkyl, and the like described herein
  • rings and cyclic groups encompass those having fused rings, including those in which the points of fusion are located (i) on adjacent ring atoms
  • ring systems e.g., [x.x.O] ring systems, in which 0 represents a zero atom bridge (e.g., single ring atom (spiro-fused ring systems) ( r (iii) a contiguous array of ring atoms (bridged ring systems having all bridge lengths > 0) (e.g., [x.x.O] ring systems, in which 0 represents a zero atom bridge (e.g., single ring atom (spiro-fused ring systems) ( r (iii) a contiguous array of ring atoms (bridged ring systems having all bridge lengths > 0) (e.g.,
  • atoms making up the compounds of the present embodiments are intended to include all isotopic forms of such atoms.
  • Isotopes include those atoms having the same atomic number but different mass numbers.
  • isotopes of hydrogen include tritium and deuterium
  • isotopes of carbon include 13 C and 14 C.
  • the compounds generically or specifically disclosed herein are intended to include all tautomeric forms.
  • a compound containing the moiety: encompasses the tautomeric form containing the moiety: .
  • a pyridinyl or pyrimidinyl moiety that is described to be optionally substituted with hydroxyl encompasses pyridone or pyrimidone tautomeric forms.
  • the compounds provided herein may encompass various stereochemical forms.
  • the compounds also encompass enantiomers (e.g., R and S isomers), diastereomers, as well as mixtures of enantiomers (e.g., R and S isomers) including racemic mixtures and mixtures of diastereomers, as well as individual enantiomers and diastereomers, which arise as a consequence of structural asymmetry in certain compounds.
  • enantiomers e.g., R and S isomers
  • diastereomers e.g., R and S isomers
  • mixtures of enantiomers e.g., R and S isomers
  • a disclosed compound is named or depicted by a structure that specifies the stereochemistry (e.g., a structure with “wedge” and/or “dashed” bonds) and has one or more chiral centers, it is understood to represent the indicated stereoisomer of the compound.
  • LPA signaling promotes normal wound healing and collagen deposition, including fibroblast activation, proliferation, and migration.
  • increased LPA levels and activation of LPA1 can promote fibrosis, the result of an uncontrolled tissue healing process which leads to excessive accumulation and insufficient resorption of extracellular matrix (ECM) which ultimately results in end-organ failure.
  • ECM extracellular matrix
  • This disclosure provides compounds of Formula (I), and pharmaceutically acceptable salts thereof, that are antagonists of LPA1. These chemical entities are useful, e.g., for treating a disease in which increased (e.g., excessive) LPA1 activation contributes to the pathology and/or symptoms and/or progression of the disease (e.g., a fibrotic disease in a subject (e.g., a human). This disclosure also provides compositions containing the same as well as methods of using and making the same.
  • Some embodiments provide a compound of Formula (I): or pharmaceutically acceptable salts thereof, wherein:
  • R A is hydrogen, C1-C6 alkyl, or C1-C6 alkoxy
  • Ring B is 3-7 membered heterocyclylene or 5-6 membered heteroarylene;
  • Ring C is phenylene or 5-6 membered heteroarylene; m is 0 or 1; n is 0, 1, 2, or 3; each R 1 is independently selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkoxyalkyl, 3-7 membered heterocyclyl, and 5-6 membered heteroaryl; or two R 1 together with the atoms to which they are attached forms a 5-8 membered heterocyclyl or 5-6 membered heteroaryl; each R 2 is independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and halogen;
  • R 3 is selected from:
  • each R E is independently selected from:
  • phenyl optionally substituted with 1-3 substituents selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxyalkyl, C1-C6 alkoxy, hydroxyl, cyano, and halogen,
  • Q is selected from:
  • R A1 and R B1 are independently selected from hydrogen and C1-C6 alkyl optionally substituted with hydroxyl;
  • R c and R D are independently selected from hydrogen and C1-C6 alkyl
  • R F is selected from: (i) C1-C6 alkyl optionally substituted with 1-3 substituents selected from:
  • R A3 and R B3 are independently selected from hydrogen and C1-C6 alkyl
  • R G is H or C1-C3 alkyl; and x is 0 or 1 .
  • Formula (I) is Formula (I-I): or pharmaceutically acceptable salts thereof, wherein:
  • R A is hydrogen, C1-C6 alkyl, or C1-C6 alkoxy
  • Ring B is 3-7 membered heterocyclylene or 5-6 membered heteroarylene;
  • Ring C is phenylene or 5-6 membered heteroarylene; m is 0 or 1; n is 0, 1, 2, or 3; each R 1 is independently selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkoxyalkyl, 3-7 membered heterocyclyl, and 5-6 membered heteroaryl; or two R 1 together with the atoms to which they are attached forms a 5-8 membered heterocyclyl or 5-6 membered heteroaryl; each R 2 is independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and halogen;
  • R 3 is selected from
  • each R E is independently selected from
  • Q is selected from:
  • R A1 and R B1 are independently selected from hydrogen and C1-C6 alkyl optionally substituted with hydroxyl;
  • R c and R D are independently selected from hydrogen and C1-C6 alkyl
  • R F is selected from:
  • R A is hydrogen
  • R A is C1-C6 alkyl. In some embodiments, R A is methyl.
  • R A is C1-C6 alkoxy. In some embodiments, R A is methoxy.
  • each of R A2 and R B2 is hydrogen.
  • one of R A2 and R B2 is hydrogen and the other one of R A2 and R B2 is C1-C6 alkyl substituted with hydroxyl.
  • Q is C1-C6 haloalkyl substituted with hydroxyl.
  • Q is unsubstituted C1-C6 haloalkyl.
  • Q is 5-6 membered heteroaryl optionally substituted with hydroxyl.
  • Q is 6 membered heteroaryl optionally substituted with hydroxyl.
  • Q is selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazinyl.
  • Q is 5 membered heteroaryl optionally substituted with hydroxyl.
  • Q is selected from the group consisting of pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thiophenyl, oxazolyl, isoxazolyl, isothiazolyl, thiazolyl, furzanyl, oxadiazolyl, thiadiazolyl, oxatriazolyl, and thiatriazolyl.
  • R F is CN .
  • R F is selected from the group consisting an j
  • R F is unsubstituted C3-C6 cycloalkyl.
  • each of R A1 and R B1 is hydrogen.
  • one of R A1 and R B1 is hydrogen and the other one of R A1 and R B1 is methyl.
  • each of R A1 and R B1 is independently selected C1-C6 alkyl optionally substituted with hydroxyl.
  • each of R A1 and R B1 is independently selected unsubstituted C 1- C6 alkyl.
  • R F is -NR A3 R B3 .
  • each of R A3 and R B3 is hydrogen.
  • one of R A3 and R B3 is hydrogen and the other one of R A3 and R B3
  • R B3 is C1-C6 alkyl.
  • one of R A3 and R B3 is hydrogen and the other one of R A3 and R B3 is C1-C3 alkyl.
  • one of R A3 and R B3 is hydrogen and the other one of R A3 and R B3 is methyl.
  • each of R A3 and R B3 is independently selected C1-C6 alkyl. In some embodiments, each of R A3 and R B3 is independently selected unsubstituted Cl - C6 alkyl.
  • Ring B is 3-7 membered heterocyclylene.
  • Ring B is selected from the group consisting of azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuryl, thiolanyl, pyrazolinyl, oxathiolanyl, isoxazolidinyl, isothiazolidinyl, pyrrolinyl, pyrrolidinonyl, pyrazolidinyl, imidazolinyl, dioxolanyl, sulfolanyl, thiazolidedionyl, succinimidyl, dihydrofuranonyl, pyrazolidinonyl, oxazolidinyl, isoxazolidinonyl, hydantionyl, thiohydantionyl, imidazolidinonyl, oxazolidinonyl, thiazolidinonyl, oxathiolanonyl, diox
  • Ring B is selected from the group consisting of azetidinyl, pyrrolidinyl, dihydropyrrolyl, piperidinyl, piperazinyl, and azaspiro[3.3]heptanyl.
  • Ring B is selected from the group consisting of wherein indicates the attachment point to Ring A.
  • Ring B is , wherein indicates the attachment point to Ring A.
  • Ring B is 5-6 membered heteroarylene.
  • Ring B is 5 membered heteroarylene selected from the group consisting of pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thiophenyl, oxazolyl, isoxazolyl, isothiazolyl, thiazolyl, furzanyl, oxadiazolyl, thiadiazolyl, oxatriazolyl, and thiatriazolyl.
  • Ring B is 6 membered heteroarylene selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazinyl.
  • Ring B is pyridyl
  • Ring B is
  • Ring C is phenylene
  • Ring C is 5-6 membered heteroarylene.
  • Ring C is 5 membered heteroarylene selected from the group consisting of pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thiophenyl, oxazolyl, isoxazolyl, isothiazolyl, thiazolyl, furzanyl, oxadiazolyl, thiadiazolyl, oxatriazolyl, and thiatriazolyl.
  • Ring C is selected from the group consisting of isoxazolyl, pyrazolyl, triazolyl, thiophenyl, and isothiazolyl.
  • Ring C is selected from the group consisting wherein
  • Ring wherein * indicates the attachment point to Ring B.
  • Ring wherein “ ” indicates the attachment point to Ring B.
  • Ring C is 6 membered heteroarylene selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazinyl.
  • Ring C is pyrimidinyl
  • each R 1 is an independently selected C1-C6 alkyl.
  • each R 2 is independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and halogen.
  • At least one R 2 is halogen.
  • At least one R 2 is chloro.
  • At least one R 2 is C1-C6 alkyl.
  • At least one R 2 is methyl.
  • At least one R 2 is C 1-C6 haloalkyl.
  • At least one R 2 is C1-C6 alkoxy.
  • At least one R 2 is methoxy.
  • R G is C1-C3 alkyl. In some embodiments, R G is methyl.
  • x is 0.
  • x is 1.
  • X is -CH(OH)-.
  • R 3 is hydrogen
  • R 3 is C1-C6 alkyl optionally substituted with 1-2 R E .
  • At least one R E is hydroxyl
  • At least one R E is C1-C6 alkoxy. In some embodiments, at least one R E is phenyl optionally substituted with 1 -3 substituents selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxyalkyl, C1-C6 alkoxy, hydroxyl, cyano, or halogen.
  • At least one R E is 5-10 membered heteroaryl optionally substituted with C1-C6 alkyl.
  • At least one R E is C3-C10 cycloalkyl.
  • R 3 is selected from the group consisting of ** ,
  • R 3 is , wherein R E is phenyl optionally substituted with 1-3 substituents selected from C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxyalkyl, C1-C63 alkoxy, hydroxyl, cyano, or halogen.
  • R 3 is , wherein R E is phenyl substituted with 1-2 substituents selected from the group consisting of methyl, ethyl, isopropyl, chloro, fluoro, cyano, methoxy, and trifluoromethyl.
  • R 3 is , wherein R E is 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl.
  • R 3 is , wherein R E is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • R 3 is C6-C10 aryl optionally substituted with hydroxyl.
  • R 3 is phenyl substituted with hydroxyl.
  • R 3 is C5-C10 cycloalkyl. In some embodiments, R 3 is 5-6 membered heteroaryl optionally substituted with phenyl.
  • R 3 is 5 membered heteroaryl optionally substituted with phenyl.
  • R 3 is selected from the group consisting of pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thiophenyl, oxazolyl, isoxazolyl, isothiazolyl, thiazolyl, furzanyl, oxadiazolyl, thiadiazolyl, oxatriazolyl, and thiatri azolyl, each optionally substituted with phenyl.
  • R 3 is pyrazolyl, oxazolyl, or oxadiazolyl, each optionally substituted with phenyl.
  • R 3 is selected from the group consisting of
  • R 3 is 6 membered heteroaryl optionally substituted with phenyl.
  • R 3 is selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazinyl, each optionally substituted with phenyl.
  • R 3 is pyridyl optionally substituted with phenyl.
  • R 3 is unsubstituted 5-6 membered heteroaryl.
  • R 3 is 5-6 membered heterocyclyl optionally substituted with phenyl.
  • R 3 is 5 membered heterocyclyl optionally substituted with phenyl.
  • R 3 is 6 membered heterocyclyl optionally substituted with phenyl.
  • R 3 is unsubstituted 5-6 membered heterocyclyl. In some embodiments, R c is hydrogen.
  • R c is C1-C6 alkyl.
  • one of R c and R D is hydrogen and the other one of R c and R D is C1-C6 alkyl.
  • R D is C1-C3 alkyl.
  • R D is methyl
  • n 0.
  • n 1
  • n is 2.
  • n 3.
  • Formula (I) is Formula (I-a): or pharmaceutically acceptable salts thereof.
  • Formula (I) is Formula (I-b):
  • Formula (I) is Formula (I-c): or pharmaceutically acceptable salts thereof, wherein Z is CH, N, O, or S; V is C or N; and wherein Z is O or S when V is C.
  • Formula (I) is Formula (I-e):
  • the compound is selected from the group consisting of the compounds in Examples 1-31, or a pharmaceutically acceptable salt thereof.
  • the compound is selected from the group consisting of the compounds delineated in Table A, or a pharmaceutically acceptable salt thereof.
  • Table A
  • composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • LPA1 lysophosphatidic acid receptor 1
  • LPA1 antagonists useful for treating a fibrotic in a subject.
  • Some embodiments provide a method of treating a fibrotic disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein.
  • Some embodiments provide a method of treating a fibrotic disease in a subject previously determined to have a fibrotic disease, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein.
  • the subject is suspected of having a fibrotic disease.
  • the subject is at risk of developing a fibrotic disease.
  • the fibrotic disease is associated with one or more of the liver, lung, kidney, heart, eyes, skin, pancreas, intestines, or bladder. In some embodiments, the fibrotic disease is associated with cell proliferative disease such as cancer. In some embodiments, the fibrotic disease is associated with nerve injury. In some embodiments, the fibrotic disease is associated with tissue repair.
  • the fibrotic disease comprises liver fibrosis.
  • the liver fibrosis is associated with, for example, acute hepatitis, chronic hepatitis, liver cirrhosis, alcohol and drug induced liver fibrosis, fatty liver (NAFLD), non-alcoholic steatohepatitis (NASH), viral hepatitis, hepatic blood flow disorder, and/or portal hypertension.
  • the fibrotic disease is liver fibrosis.
  • the fibrotic disease comprises lung fibrosis.
  • the lung fibrosis is associated with, for example, idiopathic pulmonary fibrosis, interstitial lung disease (ILD), radiation induced lung injury, and/or acute respiratory distress syndrome (ARDS).
  • the fibrotic disease is lung fibrosis.
  • the fibrotic disease comprises skin fibrosis.
  • the skin fibrosis is associated with, for example, scleroderma, keloids, and/or Dupuytren’s contracture.
  • the fibrotic disease is skin fibrosis.
  • the fibrotic disease comprises kidney fibrosis.
  • the kidney fibrosis is associated with, for example, chronic kidney disease, Alport syndrome, and/or hypertension.
  • the fibrotic disease is kidney fibrosis.
  • the fibrotic disease comprises nerve injury.
  • the nerve injury is associated with, for example, neuropathic pain and/or multiple sclerosis, demyelination, or fetal hydrocephalus.
  • the fibrotic disease is nerve injury.
  • the fibrotic disease comprises a cell proliferative disorder.
  • the cell proliferative disorder is, for example, a hematological or solid tumor, including cancer metastases.
  • the fibrotic disease is a cell proliferative disorder.
  • the fibrotic disease comprises intestinal fibrosis. In some embodiments, the fibrotic disease comprises head and neck fibrosis. In some embodiments, the fibrotic disease comprises bladder fibrosis. In some embodiments, the fibrotic disease comprises biliary cirrhosis. In some embodiments, the fibrotic disease is intestinal fibrosis. In some embodiments, the fibrotic disease is head and neck fibrosis. In some embodiments, the fibrotic disease is bladder fibrosis. In some embodiments, the fibrotic disease is biliary cirrhosis.
  • Some embodiments provide a method for reducing LPA1 activation in a subject, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • Some embodiments provide a method for reducing LPA1 activation in a cell comprising LPA1, the method comprising contacting the cell with a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • the contacting is in vitro.
  • the contacting is in vivo.
  • the contacting comprises administering to a subject having the cell a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • test compounds to act as LPA1 antagonists may be demonstrated by assays known in the art.
  • the activity of the compounds and compositions provided herein as LPA1 antagonists can be assayed in vitro, in vivo, or in a cell line.
  • Potency of an LPA1 antagonist as provided herein can be determined by EC50 or IC50 values.
  • a compound with a lower EC 50 or IC50 value, as determined under substantially similar conditions, is a more potent antagonist relative to a compound with a higher EC50 or IC50 value.
  • the compounds of Formula (I), including pharmaceutically acceptable salts thereof can be administered in the form of pharmaceutical compositions as described herein.
  • the compounds disclosed herein can be prepared in a variety of ways using commercially available starting materials, compounds known in the literature, or from readily prepared intermediates, by employing standard synthetic methods and procedures either known to those skilled in the art, or in light of the teachings herein.
  • the synthesis of the compounds disclosed herein can be achieved by generally following the schemes provided herein, with modification for specific desired substituents.
  • Standard synthetic methods and procedures for the preparation of organic molecules and functional group transformations and manipulations can be obtained from the relevant scientific literature or from standard textbooks in the field. Although not limited to any one or several sources, classic texts such as R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); Smith, M. B., March, J., March' s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th edition, John Wiley & Sons: New York, 2001; and Greene, T.W., Wuts, P.G.
  • the synthetic processes disclosed herein can tolerate a wide variety of functional groups; therefore, various substituted starting materials can be used.
  • the processes generally provide the desired final compound at or near the end of the overall process, although it may be desirable in certain instances to further convert the compound to a pharmaceutically acceptable salt thereof.
  • the reaction mixture was partitioned between EtOAc (130 mL) and NH4CI (80 mL), washed with brine (90 mL), dried over Na2SC>4, filtered and evaporated under reduced pressure to give the crude product.
  • Step 4 Preparation of methyl 2-methyl-2-[[l-[4-[4-[3-methyl-4-[[(lR)-l- phenylethoxy]carbonylamino]isoxazol-5-yl]-l- piperidyl /phenyl /cyclopropanecarbonyl /sulfamoyl /propanoate
  • the crude product was purified by Prep-HPLC (UniSil 3-100 Ci8 Ultra (150*25 mm*3um) ;mobile phase: [water (FA) -ACN];B%: 47%-77%, 7min) and lyophilized to give the methyl 2-methyl-2-[[l-[4-[4-[3-methyl-4-[[(lR)-l- phenylethoxy]carbonylamino]isoxazol-5-yl]-l- piperidyl]phenyl]cyclopropanecarbonyl]sulfamoyl]propanoate (5.7 mg, 8.56 pmol, 5.24% yield, 98% purity) as a yellow solid.
  • reaction mass was cooled to room temperature and fdtered through celite, and concentrated then diluted with water (20 mL) and washed with ethyl acetate, then Aq.
  • Step 3 Preparation of methyl (R)-l-(3-methoxy-4-(4-(3-methyl-4-(((l-phenylethoxy) carbonyl)amino)isoxazol-5-yl)piperidin-l-yl)phenyl)cyclopropane-l-carboxylate
  • reaction mass was diluted with water (20 mL) extracted with ethyl acetate (2 x 25mL). The combined organic layer was washed with water (2 x 20 mL), brine solution (20 mL), dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure to get crude product.
  • reaction mixture was concentrated, diluted with water (10 mL), washed with diethyl ether (2 x 5 mL), pH was adjusted with 10% Aq. citric acid up to 3 to 4, white solid was precipitated, filtered on Buchner funnel, solid was washed with water (2 x 5 mL), pentane (2 x 5 mL) and dried under vacuum to get crude product (30 mg).
  • reaction mixture was concentrated, diluted with water (15 mL) extracted with ethyl acetate (2 x 15 mL). The combined organic layer was washed with water (2 x 10 mL), 10% NaHCO3 solution (2 x 7 mL) and brine solution (5 mL), dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure to afford methyl l-(4- bromo-3-methoxyphenyl)cyclopropane-l -carboxylate (0.8 g and 76% Yield ) as colorless liquid MS (ES) mY 285.0 (M+H) + .
  • reaction mass was cooled to room temperature and fdtered through celite, and concentrated then diluted with water (20 mL) and washed with ether, then Aq. layer was acidified with 10% citric acid until pH is acidic, then extracted with ethyl acetate (2 x 20 mL), washed with water (20 mL), brine solution (20 mL), dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure to get crude.
  • Step 3 Preparation of methyl l-(3-methoxy-4- ⁇ 6-[3-methyl-4-( ⁇ [(lR)-l- phenylethoxy]carbonyl ⁇ amino)-l, 2-oxazol-5-yl]-2-azaspiro[3.3 ]heptan-2- yl ⁇ phenyl)cyclopropane-l-carboxylate
  • Step 4 Preparation of l-(3-methoxy-4- ⁇ 6-[3-methyl-4-( ⁇ [(lR)-l- phenylethoxy]carbonyl ⁇ amino)-l, 2-oxazol-5-yl]-2-azaspiro[3.3 ]heptan-2- yl ⁇ phenyl)cyclopropane-l-carboxylic acid
  • Step 8 Preparation of methyl l-[4-[3-[3-methyl-4-[[(lR)-l-phenylethoxy] carbonylamino]isoxazol-5-yl] azetidin-l-yl] phenyl] cyclopropanecarboxylate
  • Step 9 Preparation of l-[4-[3-[3-methyl-4-[[(lR)-l-phenylethoxy]carbonylamino] isoxazol-5-ylJazetidin-l-ylJphenylJcyclopropanecarboxylic acid
  • [M+H + ] 490.3.
  • (400 MHz, CD3OD) 8 7.44 - 7.19 (m, 7H), 7.17 - 7.05 (m, 2H), 5.87 - 5.70 (m, 1H), 4.15 - 3.95 (m, 2H), 3.10 - 2.90 (m, 2H), 2.77 - 2.56 (m, 1H), 2.03 (s, 3H), 1.81 - 1.41 (m, 9H), 1.20 - 1.05 (m, 2H).
  • Reaction was progressed by TLC & LCMS. Reaction mixture was quenched with Imol/L hydrochloric acid (50 mL) under ice cooling, extracted with ethyl acetate (2 x 150 mL). The combined organic layer was washed with water (2 x 100 mL), sodium bicarbonate solution (50 mL) and brine solution (50 mL), dried over anhydrous sodium sulphate, fdtered and evaporated under reduced pressure to get crude product.
  • reaction mass was diluted with water (80 mL) extracted with ethyl acetate (3 x 50 mL). The combined organic layer was washed with water (2 x 50 mL), brine solution (50 mL), dried over anhydrous sodium sulphate, filtered and evaporated to get crude.
  • reaction mass was concentrated, washed with pentane, dried under vacuum to obtain 5- ⁇ 2-azaspiro[3.3]heptan-6-yl ⁇ -3-methyl-l,2-oxazole-4-carboxylic acid hydrochloride ( Yield: 275 mg, 84% ) as white solid, MS (ES) m/z 221.1 (M+H) + .
  • reaction mass was cooled to room temperature and filtered through celite, and concentrated then diluted with water (20 mL) and washed with ethyl acetate, then Aq.
  • Step 7 Preparation of methyl l-(4- ⁇ 6-[3-methyl-4-( ⁇ [(lR)-l- phenylethoxy]carbonyl ⁇ amino)-l, 2-oxazol-5-yl]-2-azaspiro[3.3 ]heptan-2- yl ⁇ phenyl)cyclopropane-l-carboxylate
  • Step 8 Preparation of l-(4- ⁇ 6-[3- ethyl-4-( ⁇ [(lR)-l-phenylethoxy]carbonyl ⁇ amino)-l,2- oxazol-5-yl]-2-azaspiro[ 3.3 ]heptan-2-yl ⁇ phenyl)cyclopropane-l -carboxylic acid
  • Example 9 Preparation of l-(4-((2S,4S)-2-methyl-4-(3-methyl-4-((((R) -1- phenylethoxy)carbonyl)amino)isoxazol-5-yl)piperidin-l-yl)phenyl)cyclopropane-l- carboxylic acid (Compound 10) & l-(4-((2R,4R)-2-methyl-4-(3-methyl-4-((((R)-l- phenylethoxy) carbonyl)amino)isoxazol-5-yI)piperidin-l-yl)phenyl)cyclopropane-l- carboxylic acid (Compound 21)
  • Step 7 Preparation of methyl 5- [l-[4-(l -ethoxycarbonylcyclopropyl) phenyl] -2-methyl-4- piperidyl]-3-methyl-isoxazole-4-carboxylate
  • Step 8 Preparation of 5-[l-[4-(l -ethoxy carbonylcyclopropyl) phenyl] -2-methyl- 4- piperidyl ]-3-methyl-isoxazole-4-carboxylic acid
  • Step 9 Preparation of l-[4-[4-[4-(l-hydroxy-4-phenyl-butyl)-3-methyl- isoxazol-5-yl]-l- piperidyl /phenyl / cyclopropanecarboxylic acid
  • Step 10 Preparation of l-[4-[(2S,4S)-2-methyl-4-[3-methyl-4-[[(lR) -1 -phenylethoxy] carbonylamino ]isoxazol-5-yl ]-l -piperidyl Jphenyl cyclopropanecarboxylic acid and l-[ 4- [(2R, 4R)-2-methyl-4-[3-methyl-4-[[( I R)-l -phenylethoxy] carbonylamino] isoxazol-5-yl ]-l- piperidyl] phenyl] cyclopropanecarboxylic acid
  • Step 1 Preparation of methyl !-(4- ⁇ 6-[3-methyl-4-( ⁇ [(lR)-l-(2- methylphenyl)ethoxy ] carbonyl ⁇ amino)-l, 2-oxazol-5-yl ]-2-azaspiro[ 3.3 ]heptan-2- yl ⁇ phenyl)cyclopropane-l-carboxylate
  • Step 7 Preparation of 1 - [4- [4-[4-methoxy-2-[](lR)-l -phenylethoxy] carbonylamino] phenyl]-! -piperidyl] phenyl] cyclopropanecarboxylic acid
  • ethyl carb onochlori date (4.77 mL, 3.7 eq., 50.1 mmol) in THF ( 50 mL) was added at -78 °C, and the reaction mixture was allowed to room temperature and continued to stir for 8 h. Progress of the reaction was monitored by TLC and LCMS. After completion of reaction, the resulting mixture was quenched ice cold water (lOOmL), and extracted with Ethyl acetate (2 x 100 mL). The extract was washed with brine, dried and evaporated.
  • Residue was purified by combiflash MPLC using ethyl acetate in n-hexane (1% to 25%) to afford tert-butyl 4-[5-(ethoxycarbonyl)-l-methyl-lH-
  • reaction mass was concentrated, washed with pentane, dried under vacuum to obtain product l-methyl-4-(piperidin-4-yl)-lH-l,2,3-triazole-5-carboxylic acid hydrochloride (450 mg, crude) as white solid; MS (ES) m/z 211.1 (M+H) + .
  • Step 7 Preparation of 4-(l-(4-(l-(methoxycarbonyl)cyclopropyl)phenyl)piperidin-4-yl)-l- methyl-lH-1, 2, 3-lriazole-5-carboxylic acid
  • reaction mass was cooled to room temperature and filtered through celite, and concentrated then diluted with water (20 mL) and washed with ethyl acetate, then Aq.
  • Step 8 Preparation of methyl (R)-l-(4-(4-(l-methyl-5-(((l-phenylethoxy)carbonyl)amino)- 1H-1,2, 3-triazol-4-yl)piperidin-l-yl)phenyl)cyclopropane-l -carboxylate
  • reaction mass was diluted with water (20 mL) extracted with ethyl acetate (2 x 25mL). The combined organic layer was washed with water (2 x 20 mL), brine solution (20 mL), dried over anhydrous sodium sulphate, fdtered and evaporated under reduced pressure to get crude product.
  • reaction mass was concentrated to get the crude product. Obtained crude was acidified with 10% citric acid solution and stirred for lOminutes. Product was precipitated, filtered and washed with pentane(10 mL) to yield product l-(4- ⁇ 4-[l-methyl-5-( ⁇ [(lR)-l-phenylethoxy]carbonyl ⁇ amino)-lH-l,2,3-triazol-4- yl]piperidin-l-yl ⁇ phenyl)cyclopropane-l-carboxylic acid (55 mg, crude) as off white solid; MS (ES) m/z 430.3 (M+1H) + .
  • Residue was purified by combiflash MPLC using ethyl acetate in n-hexane (1% to 25%) to afford tert-butyl 4-[5-(ethoxy carbonyl)- 1- methyl-lH-l,2,3-triazol-4-yl]piperidine-l-carboxylate (120 mg, yield 45%) as a yellow gummy solid; MS (ES) m/z 339 (M+H)+ but deboc mass MS (ES) m/z 283.2 (M-56) + was observed in LCMS.
  • reaction mass was concentrated, washed with pentane, dried under vacuum to obtain product l-methyl-4-(piperidin-4-yl)-lH-l,2,3-triazole-5-carboxylic acid hydrochloride (220 mg, yield 92%) as a white solid; MS (ES) m/z 211.1 (M+H) + .
  • Step 7 Preparation of4-(l-(4-(l-(methoxycarbonyl)cyclopropyl)phenyl)piperidin-4-yl)-l- methyl-lH-1,2, 3-triazole-5-carboxylic acid
  • reaction mass was cooled to room temperature and filtered through celite, and concentrated then diluted with water (20 mL) and washed with ethyl acetate, then Aq.
  • Step 8 Preparation of methyl !-(4- ⁇ 4-[5-( ⁇ [(lR)-l-(2- chlorophenyl)ethoxy]carbonyl ⁇ amino)-l -methyl- 1H-1, 2, 3-triazol-4-yl ]piperidin-l- yl ⁇ phenyl)cyclopropane-l-carboxylate
  • reaction mass was diluted with water (10 mL) extracted with ethyl acetate (2 x 20 mL). The combined organic layer was washed with water (2 x 10 mL), brine solution (10 mL), dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure to got crude.
  • Step 9 Preparation of l-(4- ⁇ 4-[5-( ⁇ [(lR)-l-(2-chlorophenyl)ethoxy]carbonyl ⁇ amino)-l- methyl-lH-l,2,3-triazol-4-yl]piperidin-l-yl ⁇ phenyl)cyclopropane-l-carboxylic acid
  • reaction mixture was purified by prep-HPLC (Phenomenex luna Cis 150*25 mm* 10um;mobile phase: [water (FA) -ACN];gradient:29%-59% B over 10 min) and lyophilized to give the l-[4-[4-[5-[l-[2-(methoxymethyl)phenyl] ethoxy carbonylamino]-l-methyl-triazol-4-yl]-l- piperidyl]phenyl]cyclopropanecarboxylic acid (90 mg, 165.29 pmol, 61.89% yield, 98% purity) as a white solid.
  • Step 5 Preparation of l-[4-[4-[5-[[(lS)-l- [2-(methoxymethyl)phenyl]ethoxy] carbonylamino ]-l-methyl-triazol-4-yl] -1 -piperidyl] phenyl ] cyclopropanecarboxylic acid l-[4-[4-[5-[l-[2-(methoxymethyl)phenyl]ethoxy carbonylamino]- 1-methyl-tri azol -4-yl]- 1- piperidyl] phenyl] cyclopropanecarboxylic acid(6) (80 mg, 149.92 pmol, 1 eq) was separated by SFC (column: DAICEL CHIRALPAK IC (250 mm*30 mm, lOum); mobile phase: [CCh-i-PrOH (0.1%NH3H2O)]; B%:50%, isocratic elution mode)
  • reaction mass was concentrated, washed with pentane, dried under vacuum to obtain product l-methyl-4-(piperidin-4-yl)-lH-l,2,3-triazole-5-carboxylic acid hydrochloride (Yield: 380 mg, 98% ) as white solid; MS (ES) m/z 211.1 (M+H) + .
  • reaction mass was cooled to room temperature and filtered through celite, and concentrated then diluted with water (20 mL) and washed with ethyl acetate, then Aq.
  • Step 3 Preparation of methyl l-(4- ⁇ 4-[5-( ⁇ [(lR)-l-cyclohexylethoxy]carbonyl ⁇ amino)-l- methyl-lH-l,2,3-triazol-4-yl]piperidin-l-yl ⁇ phenyl)cyclopropane-l-carboxylate
  • reaction mass was concentrated to get the crude product. Obtained crude was acidified with 10% citric acid solution and stirred for 10 minutes. Product got precipitated, precipitated product was filtered, washed with water and pentane. Dried under vacuum to obtain product l-(4- ⁇ 4-[3-methyl-4-( ⁇ [(lR)-l-phenylethoxy]carbonyl ⁇ amino)- l,2-oxazol-5-yl]piperi din- l-yl ⁇ phenyl)cyclopropane-l -carboxylic acid (48 mg, 88% yield) as off white solid; MS (ES) m z 490.0 (M+H)+; LC purity: 99.5%
  • reaction mass was cooled to room temperature and filtered through celite, and concentrated then diluted with water (20 mL) and washed with ethyl acetate, then Aq.
  • Step 1 Preparation of methyl (R)-l-(4-(4-(4-(((l-(2-chlorophenyl)ethoxy)carbonyl) ammo)-3-methyUsoxazol-5-yl)piperidm-l-yl)phenyl)cyclopropane-l -carboxylate
  • Step 1 Preparation of methyl l-(4- ⁇ 4-[3-methyl-4-( ⁇ [(lR)-l-phenylethoxy] carbonyl ⁇ amino)-l,2-oxazol-5-yl]piperidin-l-yl ⁇ phenyl)cyclopropane-l-carboxylate
  • reaction mass was diluted with water (20 mb) extracted with ethyl acetate (2 x 25mL). The combined organic layer was washed with water (2 x 20 mL) and brine solution (20 mb), dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure to get crude product.
  • reaction mass was concentrated to get the crude product. Obtained crude was acidified with 10% citric acid solution and stirred for 10 minutes. Product got precipitated, precipitate was filtered, washed with water and pentane. Dried under vacuum to obtain product l-(4- ⁇ 4-[3-methyl-4-( ⁇ [(lR)-l-phenylethoxy]carbonyl ⁇ amino)- l,2-oxazol-5-yl]piperidin-l-yl ⁇ phenyl)cyclopropane-l-carboxylic acid (950 mg, 88% yield) as an off white solid; MS (ES) m/z 490.2 (M+1H) + ;
  • Step 3 Preparation of (1R)-1 -phenyl ethyl N- ⁇ 3-methyl-5-[l-(4- ⁇ l-[(prop-2-ene-l- sulfonyl)carbamoyl]cyclopropyl ⁇ phenyl)piperidin-4-yl]-l,2-oxazol-4-yl ⁇ carbamate
  • Step 2 Preparation of l-[( ⁇ [l-(4- ⁇ 4-[3-methyl-4-( ⁇ [(lR)-l-phenylethoxy] carbonyl ⁇ amino)-l,2-oxazol-5-yl]piperidin-l-yl ⁇ phenyl)cyclopropyl]formamido ⁇ sulfonyl)methyl ] cyclopropane- 1 -carboxylic acid
  • reaction mixture was concentrated, diluted with water (10 mL), washed with diethyl ether (2 x 10 mL), pH was adjusted with 10% Aq. citric acid up to 3 to 4, white solid was precipitated, fdtered on Buckner funnel, solid was washed with water (2 x 10 mL), pentane (2 x 10 mL) and dried under vacuum to afford crude.
  • Step 1 Preparation of methyl (R)-l-(4-(4-(4-(4-(((l-(2-ethylphenyl)ethoxy)carbonyl)amino)- 3-methylisoxazol-5-yl)piperidin-l-yl)phenyl)cyclopropane-l-carboxylate
  • Step 2 Preparation of l-(4- ⁇ 4-[4-( ⁇ [(lR)-l-(2-ethylphenyl)ethoxy]carbonyl ⁇ amino)-3- methyl-1, 2-oxazol-5-yl ]piperidin-l-yl ⁇ phenyl)cyclopropane-l -carboxylic acid
  • reaction mixture was stirred at room temperature for 16 hours. Progress of the reaction was monitored by TLC and LCMS. After completion of reaction, reaction mass was concentrated to get the crude product. Obtained crude was acidified with 10 % citric acid solution and stirred for 10 minutes. Product was precipitated. It was filtered, washed with water and pentane.
  • Step 3 Preparation of methyl 3-( ⁇ [l-(4- ⁇ 4-[4-( ⁇ [(lR)-l-(2- ethylphenyl)ethoxy ] car bony l ⁇ amino)-3-methyl-l , 2-oxazol-5-yl lpiperidin-1- yl ⁇ phenyl)cyclopropyl]formamido ⁇ sulfonyl) propanoate
  • Step 4 Preparation of 3-( ⁇ [l-(4- ⁇ 4-[4-( ⁇ [(lR)-l-(2-ethylphenyl)ethoxy]carbonyl ⁇ amino)- 3-methyl-l,2-oxazol-5-yl piperidin-l-yl ⁇ phenyl)cyclopropyllformamido ⁇ sulfonyl)propanoic acid
  • reaction mixture was stirred at room temperature for 16 hours. Progress of the reaction was monitored by TLC and LCMS. After completion of reaction, reaction mass was concentrated to get the crude product. Obtained crude was acidified with 10 % citric acid solution and stirred for 10 minutes. Product was precipitated. The precipitate was filtered, washed with water and pentane dried under vacuum to yield crude product. The obtained crude was purified by preparative HPLC using method Mobile Phase (A) :0.1% Formic Acid in water and Mobile Phase (B) : ACN to yield
  • Step 1 Preparation of methyl l-(([l-(4- ⁇ 4-[3-methyl-4-( ⁇ [(lR)-l-phenylethoxy] carbonyl ⁇ amino)-l ,2-oxazol-5-yl]piperidin-l-yl ⁇ phenyl)cyclopropyl] formami do ⁇ sulfonyl) cyclopropane- 1- carboxylate
  • reaction mixture was cooled to rt, Finally added methyl 2-methyl-3-sulfamoylpropanoate (204 mg, 1.1 eq., 1.12 mmol) and DBU (610 pL, 4 eq., 4.09 mmol) at 0°C stirred at rt for 16 hours. Progress of the reaction was monitored by TLC & LCMS. After completion of reaction, reaction mass was quenched with ice cold water, extracted with ethyl acetate (2 x 10 mL).
  • Example 25 Preparation of l-[[l-[4-[4-[l-methyl-5-[[(lR)-l- phenylethoxy]carbonylainino]triazol-4-yl]-l-piperidyl]phenyl]cyclopropanecarbonyl] sulfamoyljcyclopropanecarboxylic acid (Compound 57)
  • reaction mixture was purified by prep-HPLC (Phenomenex luna Cis 150*25 mm* 10um;mobile phase: [water (FA) -ACN];B%: 29%-59%, lOmin) and lyophilized to give l-[[l-[4-[4-[l-methyl-5-[[(lR) -1- phenylethoxy]carbonylamino]triazol-4-yl] -l-piperidyl]phenyl]cyclopropanecarbonyl]sulfamoyl] cyclopropanecarboxylicacid (70 mg, 109.94 pmol, 85.98% yield, 100% purity) as a white solid.
  • the crude product was purified by prep-HPLC (Unisil 3-100 Cis Ultra 150*50 mm*3 um;mobile phase: [water (FA) -ACN];B%: 24%-54%, 7min) to give 2-[[l-[4-[4-[l-methyl- 5-[[(lR) -l-phenylethoxy]carbonylamino]triazol-4-yl]-l- piperidyl]phenyl]cyclopropanecarbonyl]sulfamoyl]acetic acid (2.7 mg, 4.29 pmol, 10.72% yield, 97% purity) as a white solid.
  • prep-HPLC Unisil 3-100 Cis Ultra 150*50 mm*3 um;mobile phase: [water (FA) -ACN];B%: 24%-54%, 7min
  • Step 1 Preparation of methyl 3-( ⁇ [l-(4- ⁇ 6-[3-methyl-4-( ⁇ [(lK)-l-(2- methylphenyl)ethoxy ]carbonyl ⁇ amino)-l , 2-oxazol-5-yl]-2-azaspiro[ 3.3 ] heptaneyl) phenyl) cyclopropyl Jformamido ⁇ sulfonyl)propanoate stirred solution l-(4- ⁇ 6-[3-methyl-4-( ⁇ [(lR)-l-(2- methylphenyl)ethoxy]carbonyl (amino)- l,2-oxazol-5-yl]-2-azaspiro[3.3]heptan-2-yl (phenyl) cyclopropane- 1 -carboxylic acid (130 mg, 252 pmol) in DCM (2 mL) were added Tri ethylamine (105 pL, 3 eq.
  • Step 2 Preparation of 3-( ⁇ [l-(4- ⁇ 6-[3-methyl-4-( ⁇ [(lR)-l-(2- methylphenyl)ethoxy ]carbonyl ⁇ amino)-l , 2-oxazol-5-yl]-2-azaspiro[3.3 ]heptan-2- yl ⁇ phenyl)cyclopropyl]formamido ⁇ sulfonyl)propanoic acid
  • Step 4 Preparation of methyl l-]3-methoxy-4-[4-[3-methyl-4-[](lR)-l- phenylethoxy]carbonylamino] isoxazol -5-yl]-l -piperidyl] phenyl] cyclopropane- carboxylate
  • Step 7 Preparation of 3-[[l-[3-methoxy-4-[4-[3-methyl-4-[[(lR)-l- phenylethoxy]carbonylamino]isoxazol-5-yl]-l-piperidyl]phenyl]cyclopropanecarbonyl] sulfamoyl]propanoic acid
  • reaction mixture was purified by prep-HPLC (Phenomenex luna C18 150*25 mm* 10um;mobile phase: [water (FA) -ACN];B%: 26%-56%, 10 min) to give the 3-[[l-[3-methoxy-4-[4-[3-methyl-4-[[(lR) -1- phenylethoxy]carbonylamino]isoxazol-5-yl] -l-piperidyl]phenyl] cyclopropanecarbonyl] sulfamoyl] propanoic acid (11.29 mg, 17.24 pmol, 28.83% yield, 100% purity) as a white solid.
  • the reaction mixture was purified by prep-HPLC (Unisil 3-100 Cis Ultra 150*50 mm*3 unpmobile phase: [water (FA) -ACN];B%: 46%-76%, 7min) to give the 2-methyl-2-[[l-[4-[4-[3-methyl-4- [ [( 1 R) - 1 -phenyl ethoxy ] carb ony 1 amino] i soxazol -5 -y 1 ] - 1 - piperidyl]phenyl]cyclopropanecarbonyl]sulfamoyl]propanoicacid (15.1 mg, 23.64 pmol, 30.86% yield, 100% purity) as a white solid.
  • B103 cells stably expressing hLPARl were seeded at a density of 1.0 x 10 3 cells per well in clear flat-bottom black 96-well plates and incubated overnight in complete media. The following day, the cells were pre-incubated in serum-free media for 2 hours prior to ensure cellular equilibration.
  • a calcium-sensitive fluorescent dye the cells were treated with a concentration of 5 pM Fura-2 AM dye (Sigma, F1225) in Hank’s buffered salt solution (HBSS) supplemented with 20 mM HEPES, 1 M probenecid, and 0.3% fatty-acid-free bovine serum albumin for 40 minutes at room temperature (RT).
  • Test compounds prepared in DMSO, were then added to each well and incubated for 20 minutes at RT. To induce calcium release, a concentration of 5 pM LPA in HBSS supplemented with 20 mM HEPES, and 0.3% fatty-acid-free bovine serum albumin was introduced. Intracellular calcium mobilization was subsequently quantified by monitoring the fluorescence intensity using the Spark® multimode microplate reader (TEC AN).
  • TEC AN Spark® multimode microplate reader
  • Neuroprobe ChemoTx® System plates (10 mm pore size, 5.7 mm diameter sites; Gaithersburg, MD, USA) were utilized. To induce cell migrations, a concentration of 5 pM LPA or vehicle in DMEM were loaded to the bottom chamber. A total of 15,000 A2058 cells, which were starved for 24 hr following treated with test compounds or vehicle, were then applied to the upper membrane coated with 0.001% fibronectin. The plate was incubated for 4 to 8 hours to allow cell migration. Following incubation, the plate was dissembled, and the migrated cells were visualized by crystal violet staining. The stained area with crystal violet was quantified by measuring the absorbance at 590 nm and the relative percentage of the control was calculated.
  • a stock solution was prepared with the test article (Sponsor compound) in DMSO.
  • BSA Bovine Serum Albumin
  • BSEP Assay Uptake Buffer (10 mM HEPES-Tris pH 7.4, 0.1 M KN0 3 , 12.5 mM Mg(NOs)2, 50 mM sucrose)
  • BSEP Wash Buffer (10 mM Tris-HCl pH 7.4, 0.1 M KNO3, 50 mM sucrose)
  • BSEP Blocking Buffer (BSEP Wash Buffer + 0.5 mg/mL BSA)
  • Test system a. 96-well flat bottom plate containing a suspension of vesicles and a corresponding 96-well glass fiber filtration plate. b. Transport experiments were conducted in the Assay Uptake Buffer. c. Transport experiment was initiated with the addition of Mg- ATP or AMP to appropriate wells. d. Each condition was run in triplicate wells.
  • the Assay Uptake Buffer contained vesicles, the reference inhibitor and the probe substrate at the specified concentration in Table 1. iii.
  • Assay Uptake Buffer contained vesicles, the test article and the probe substrate at the specified concentration in Table 1.
  • Mg-ATP or AMP was added to test wells of flat bottom assay plate to a final concentration of 5 mM.
  • the amount of substrate was quantified with radiometric detection on a 1450 Microbeta (Perkin-Elmer).
  • V ATP-dependent substrate transport rate

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Pulmonology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des composés et des sels pharmaceutiquement acceptables de ceux-ci, qui inhibent le récepteur 1 de l'acide lysophosphatidique (LPA1). Ces composés sont utiles, par exemple, pour traiter une maladie associée à l'activité LPA1. La présente invention concerne également des compositions les contenant ainsi que leurs procédés d'utilisation et de fabrication.
PCT/US2024/032008 2023-06-02 2024-05-31 Composés pour le traitement de maladies fibrotiques Pending WO2024249867A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US202363470603P 2023-06-02 2023-06-02
US63/470,603 2023-06-02

Publications (1)

Publication Number Publication Date
WO2024249867A1 true WO2024249867A1 (fr) 2024-12-05

Family

ID=91585775

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2024/032008 Pending WO2024249867A1 (fr) 2023-06-02 2024-05-31 Composés pour le traitement de maladies fibrotiques

Country Status (2)

Country Link
TW (1) TW202513559A (fr)
WO (1) WO2024249867A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2470833A (en) * 2009-06-03 2010-12-08 Amira Pharmaceuticals Inc Isoxazolyl antagonists of lysophosphatidic acid receptors
US20110082164A1 (en) * 2009-10-01 2011-04-07 Amira Pharmaceuticals, Inc. Polycyclic compounds as lysophosphatidic acid receptor antagonists
WO2019041340A1 (fr) * 2017-09-04 2019-03-07 Eli Lilly And Company Composés inhibiteurs du récepteur 1 de l'acide lysophosphatidique (lpar1)

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2470833A (en) * 2009-06-03 2010-12-08 Amira Pharmaceuticals Inc Isoxazolyl antagonists of lysophosphatidic acid receptors
US20110082164A1 (en) * 2009-10-01 2011-04-07 Amira Pharmaceuticals, Inc. Polycyclic compounds as lysophosphatidic acid receptor antagonists
WO2019041340A1 (fr) * 2017-09-04 2019-03-07 Eli Lilly And Company Composés inhibiteurs du récepteur 1 de l'acide lysophosphatidique (lpar1)

Non-Patent Citations (8)

* Cited by examiner, † Cited by third party
Title
"Handbook of Pharmaceutical Additives", 2007, GOWER PUBLISHING COMPANY
"Pharmaceutical Preformulation and Formulation", 2009, THE PHARMACEUTICAL PRESS AND THE AMERICAN PHARMACEUTICAL ASSOCIATION
"Remington: The Science and Practice of Pharmacy", 2005, LIPPINCOTT WILLIAMS & WILKINS
GREENE, T.W.WUTS, P.G. M.: "Protective Groups in Organic Synthesis", 1999, JOHN WILEY & SONS
L. FIESERM. FIESER: "Fieser and Fieser's Reagents for Organic Synthesis", 1994, JOHN WILEY AND SONS
R. LAROCK: "Comprehensive Organic Transformations", 1989, VCH PUBLISHERS
SMITH, M. B.MARCH, J.: "March' s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure", 2001, JOHN WILEY & SONS
YIMIN QIAN ET AL: "Discovery of Highly Selective and Orally Active Lysophosphatidic Acid Receptor-1 Antagonists with Potent Activity on Human Lung Fibroblasts", vol. 55, no. 17, 13 September 2012 (2012-09-13), pages 7920 - 7939, XP002711399, ISSN: 0022-2623, Retrieved from the Internet <URL:http://pubs.acs.org/doi/abs/10.1021/jm301022v> [retrieved on 20120815], DOI: 10.1021/JM301022V *

Also Published As

Publication number Publication date
TW202513559A (zh) 2025-04-01

Similar Documents

Publication Publication Date Title
AU2015205374B2 (en) Bicyclic heterocyclyl derivatives as IRAK4 inhibitors
AU2003293129B2 (en) 3-aminopyrrolidine derivatives as modulators of chemokine receptors
JP6262885B2 (ja) オレキシン受容体拮抗剤としてのピペリジン誘導体
WO2011025774A1 (fr) Nouveaux agonistes de récepteurs adrénergiques bêta 3 dérivés de pyrrolidine
WO2011025690A1 (fr) Nouveaux agonistes de récepteurs adrénergiques bêta 3 dérivés de pyrrolidine
KR20110036044A (ko) 벤즈아제핀 유도체들 및 히스타민 ｈ3 길항제로서 이들의 용도
TW202309051A (zh) 食慾素受體促效劑及其用途
CN102015636A (zh) 作为组胺h3受体拮抗剂的氮杂环丁烷类和环丁烷类化合物
WO2022152852A1 (fr) Antagonistes de mrgx2
JP2016514709A (ja) ヤヌスキナーゼ阻害剤としてのジェミナル置換シアノエチルピラゾロピリドン
JPWO2007040166A1 (ja) 新規な縮合ピロール誘導体
WO2024249867A1 (fr) Composés pour le traitement de maladies fibrotiques
TW202530183A (zh) Ｒａｓ－ｐ１３ｋ抑制劑及其用途
CN102369196B (zh) 作为组胺h3受体拮抗剂的氮杂环丁烷
EP2832728A1 (fr) Composé triazinone et inhibiteur des canaux calciques de type t
TWI631120B (zh) Acridine derivative as an appetite hormone receptor antagonist
WO2024261327A1 (fr) Composés de 2-(hétéroaryl-thio)-1-(hétéroaryl)éthanone et leur utilisation en tant qu&#39;inhibiteurs de hdac6
WO2025136811A1 (fr) Composés chimiques et leurs utilisations
TW202530205A (zh) 經取代之芳基磺醯胺及其組合物及用途

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 24734765

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 2024734765

Country of ref document: EP

ENP Entry into the national phase

Ref document number: 2024734765

Country of ref document: EP

Effective date: 20251107