US20210032213A1 - Modulators of mas-related g-protein receptor x4 and related products and methods - Google Patents

Modulators of mas-related g-protein receptor x4 and related products and methods Download PDF

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US20210032213A1
US20210032213A1 US16/831,638 US202016831638A US2021032213A1 US 20210032213 A1 US20210032213 A1 US 20210032213A1 US 202016831638 A US202016831638 A US 202016831638A US 2021032213 A1 US2021032213 A1 US 2021032213A1
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agonist
heterocycle
carbocycle
alkyl
ppar
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Adam YEAGER
Brandon Selfridge
Marcos Sainz
Esther Martinborough
Marcus Boehm
Liming Huang
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Escient Pharmaceuticals Inc
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Escient Pharmaceuticals Inc
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Priority to US16/831,638 priority Critical patent/US20210032213A1/en
Publication of US20210032213A1 publication Critical patent/US20210032213A1/en
Priority to US17/531,660 priority patent/US11643399B2/en
Priority to US17/858,840 priority patent/US11840521B2/en
Priority to US18/497,891 priority patent/US20240300907A1/en
Assigned to ESCIENT PHARMACEUTICALS, INC. reassignment ESCIENT PHARMACEUTICALS, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: MARTINBOROUGH, ESTHER, YEAGER, Adam, BOEHM, MARCUS, HUANG, LIMING, SAINZ, Marcos, SELFRIDGE, Brandon
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Definitions

  • the invention relates to modulators of the Mas-related G-protein coupled receptor X4, to products containing the same, as well as to methods of their use and preparation.
  • MRGPRs Mas-related G protein receptors
  • MRGPR D, E, F and G The other four receptors (MRGPR X1, X2, X3 and X4) have no counterpart, based on homology, in species other than human.
  • mice MRGPR A1 corresponds, at least in part, to the human MRGPR X4.
  • These receptors mediate disorders including chronic itch (e.g., pruritus), inflammation disorders, autoimmunity, skin disorders, cardiovascular disease, lung inflammation/COPD, and adverse skin reactions to drugs. More specifically, both MRGPR A1 and MRGPR X4 are expressed in sensory neurons, skin melanocytes, dendritic cells, polymorphonuclear cells, macrophages, bronchial epithelial cells, lung smooth muscle and dorsal root ganglia.
  • MRGPR A1 and MRGPR X4 are receptors for (or sensitive to activation by) circulating bilirubin and its metabolites, and thus are important for itch sensation in conditions of elevated bilirubin such as cholestatic pruritus.
  • MRGPR X4 is activated by multiple additional components of bile including bile acids and metabolites thereof and heme metabolites including bilirubin and urobilin.
  • Bile acids and bilirubin are highly elevated in cholestatic pruritus while urobilin, which is a potent mediator of itch induction in mouse model, and thus may be important for itch sensation in conditions of elevated urobilin such as uremic pruritus.
  • modulating MRGPR X4 allows for treatment of autoimmune diseases such as psoriasis, multiple sclerosis, Steven Johnson's Syndrome, and other chronic itch conditions as explained in more detail below.
  • methods are provided for modulating a MRGPR X4 by contacting the MRGPR X4 with an effective amount of a compound having the structure of Formula (I):
  • n, x, A, Q 1 , Q 2 , Z, R, R 1 , R 2 , R 3 , R 4 and R 5 are as defined below.
  • methods for treating a MRGPR X4 dependent condition by administering to a subject in need thereof an effective amount of a compound having the structure of Formula (I), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof.
  • the MRGPR X4 dependent condition is one or more of an itch associated condition, a pain associated condition, an inflammation-associated condition, or an autoimmune disorder.
  • compositions comprising a compound having the structure of Formula (I), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, in combination with a pharmaceutically acceptable excipient.
  • compounds are provided having one or more of the structures disclosed herein, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof.
  • prodrugs and/or metabolites of a compound having the structure of Formula (I) are also provided.
  • a compound i.e., prodrug
  • a compound having the structure of Formula (I) may be administered to a subject which is then converted in vivo to a compound having the structure of Formula (I).
  • metabolites following administration to a subject of a compound having the structure of Formula (I) such compound may be converted in vivo to an active metabolite.
  • FIG. 1 shows in vitro activation of MRGPR X4 by heme metabolites bilirubin, biliverdin, urobilin, urobilinogen, and stercobilin.
  • FIGS. 2A-2B show induction of itch in wild type mice by urobilin compared to vehicle (VEH) ( FIG. 2A ) and by urobilin, bilirubin, and deoxycholic acid ( FIG. 2B ).
  • FIGS. 3A-3B show bilirubin stability ( FIG. 3A ) and bilirubin agonism of MRGPRX4 ( FIG. 3B ) after 24 hours storage under various temperature and light storage conditions (time zero (freshly prepared), room temperature dark, ⁇ 20° C. dark, room temperature lab light, and room temperature 400 nm blue light).
  • FIGS. 4A-4B show urobilin stability ( FIG. 4A ) and urobilin agonism of MRGPRX4 ( FIG. 4B ) after 24 hours storage under various temperature and light storage conditions (time zero (freshly prepared), room temperature dark, ⁇ 20° C. dark, room temperature lab light, and room temperature blue light).
  • the invention relates to modulators of the MRGPR X4, to products containing the same, as well as to methods of their use and preparation.
  • This invention is based, in part, on the identification that in mice MRGPR A1 functionally corresponds to the human MRGPR X4.
  • These receptors mediate disorders including chronic and intermittent itch (e.g., pruritus), inflammation disorders, autoimmunity, skin disorders, and adverse skin reactions to drugs and infectious diseases. More specifically, both MRGPR A1 and MRGPR X4 are expressed in sensory neurons and dorsal root ganglia.
  • MRGPR A1 and MRGPR X4 are receptors for (or sensitive to activation by) circulating bilirubin and its metabolites, and thus are important for itch sensation in conditions of elevated bilirubin such as cholestatic pruritus and end-stage renal failure.
  • MRGPR X4 is also activated by bile acids and metabolites thereof, which are also elevated in cholestatic pruritus.
  • urobilin an oxidative product of the heme metabolite urobilinogen solely excreted by the kidney, is a potent agonist of MRGPRX4 and pruritogen, and thus may be important for itch sensation in conditions of elevated urobilin such as uremic pruritus, kidney disease and end-stage renal failure.
  • modulating MRGPR X4 allows for treatment of autoimmune diseases such as psoriasis, multiple sclerosis, Steven Johnson's Syndrome, atopic disorders such as atopic dermatitis and other chronic itch conditions as explained in more detail below.
  • MRGPRs appear to be sensory receptors that recognize their external environment to exogenous or endogenous signals/chemicals. These receptors likely respond to multiple chemical ligands/agonists.
  • MRGPR X4 recognizes bilirubin, bile acids, and urobilin as agonist signals.
  • molecules of this invention modulate MRGPR X4 by functioning as inverse agonists that are capable of blocking multiple chemical entities, and/or as competitive antagonists that can specifically block individual ligands. In one embodiment, such modulations are selective against other MRGPRs, such as MRGPR X1, X2 and/or X3.
  • methods for modulating a MRGPR X4 comprising contacting the MRGPR X4 with an effective amount of compound having the structure of Formula (I):
  • Modulating MRGPR X4 means that the compound interacts with the MRGPR X4 in a manner such that it functions as an inverse agonist to the receptor, and/or as a competitive antagonist to the receptor. In one embodiment, such modulation is partially or fully selective against other MRGPRs, such as MRGPR X1, X2 and/or X3.
  • MRGPR refers to one or more of the Mas-related G protein coupled receptors, which are a group of orphan receptors with limited expression in very specialized tissues (e.g., in sensory neurons and dorsal root ganglia) and barrier tissues. There are eight related receptors in this class expressed in humans, only 4 of which have readily identifiable orthologs in other species (i.e., MRGPR D, E, F and G). The other four receptors (MRGPR X1, X2, X3 and X4) have no counterpart, based on homology, in non-human species.
  • Effective amount refers to a quantity of a specified agent sufficient to achieve a desired effect in a subject being treated with that agent. Ideally, an effective amount of an agent is an amount sufficient to inhibit or treat the disease without causing substantial toxicity in the subject. The effective amount of an agent will be dependent on the subject being treated, the severity of the affliction, and the manner of administration of the pharmaceutical composition. Methods of determining an effective amount of the disclosed compound sufficient to achieve a desired effect in a subject will be understood by those of skill in the art in light of this disclosure.
  • Alkyl means a saturated or unsaturated straight chain or branched alkyl group having from 1 to 8 carbon atoms, in some embodiments from 1 to 6 carbon atoms, in some embodiments from 1 to 4 carbon atoms, and in some embodiments from 1 to 3 carbon atoms.
  • saturated straight chain alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl-, n-hexyl, n-heptyl, and n-octyl groups.
  • branched alkyl groups include, but are not limited to, isopropyl, iso-butyl, sec-butyl, t-butyl, neopentyl, isopentyl, and 2,2-dimethylpropyl groups.
  • An unsaturated alkyl includes alkenyl and alkynyl as defined below.
  • Alkenyl means a straight chain or branched alkenyl group having from 2 to 8 carbon atoms, in some embodiments from 2 to 6 carbon atoms, in some embodiments from 2 to 4 carbon atoms, and in some embodiments from 2 to 3 carbon atoms. Alkenyl groups are unsaturated hydrocarbons that contain at least one carbon-carbon double bond. Examples of lower alkenyl groups include, but are not limited to, vinyl, propenyl, butenyl, pentenyl, and hexenyl.
  • Alkynyl means a straight chain or branched alkynyl group having from 2 to 8 carbon atoms, in some embodiments from 2 to 6 carbon atoms, in some embodiments from 2 to 4 carbon atoms, and in some embodiments from 2 to 3 carbon atoms. Alkynyl groups are unsaturated hydrocarbons that contain at least one carbon-carbon triple bond.
  • alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, and hexynyl.
  • Halo or “halogen” refers to fluorine, chlorine, bromine, and iodine.
  • Haldroxy refers to —OH.
  • Cyano refers to —CN.
  • Amino refers to —NH 2 , —NHalkyl or N(alkyl) 2 , wherein alkyl is as defined above.
  • Examples of amino include, but are not limited to —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , and the like.
  • Haloalkyl refers to alkyl as defined above with one or more hydrogen atoms replaced with halogen.
  • Examples of lower haloalkyl groups include, but are not limited to, —ClF 3 , —CHF 2 , and the like.
  • Alkoxy refers to alkyl as defined above joined by way of an oxygen atom (i.e., —O-alkyl).
  • alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, n-butoxy, isopropoxy, sec-butoxy, tert-butoxy, and the like.
  • Haloalkoxy refers to haloalkyl as defined above joined by way of an oxygen atom (i.e., —O-haloalkyl).
  • oxygen atom i.e., —O-haloalkyl
  • lower haloalkoxy groups include, but are not limited to, —OCF 3 , and the like.
  • Cycloalkyl refers to alkyl groups forming a ring structure, which can be substituted or unsubstituted, wherein the ring is either completely saturated, partially unsaturated, or fully unsaturated, wherein if there is unsaturation, the conjugation of the pi-electrons in the ring do not give rise to aromaticity.
  • Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups.
  • the cycloalkyl group has 3 to 8 ring members, whereas in other embodiments the number of ring carbon atoms range from 3 to 5, 3 to 6, or 3 to 7.
  • Cycloalkyl groups further include polycyclic cycloalkyl groups such as, but not limited to, norbornyl, adamantyl, bornyl, camphenyl, isocamphenyl, and carenyl groups, and fused rings such as, but not limited to, decalinyl, and the like.
  • Aryl groups are cyclic aromatic hydrocarbons that do not contain heteroatoms.
  • Representative aryl groups include, but are not limited to, phenyl, azulenyl, heptalenyl, biphenyl, indacenyl, fluorenyl, phenanthrenyl, triphenylenyl, pyrenyl, naphthacenyl, chrysenyl, biphenylenyl, anthracenyl, and naphthyl groups.
  • aryl groups contain 6-14 carbons in the ring portions of the groups.
  • aryl and aryl groups include fused rings wherein at least one ring, but not necessarily all rings, are aromatic, such as fused aromatic-aliphatic ring systems (e.g., indanyl, tetrahydronaphthyl, and the like).
  • aryl is phenyl or naphthyl, and in another embodiment aryl is phenyl.
  • Carbocycle refers to alkyl groups forming a ring structure, which can be substituted or unsubstituted, wherein the ring is either completely saturated, partially unsaturated, or fully unsaturated, wherein if there is unsaturation, the conjugation of the pi-electrons in the ring may give rise to aromaticity.
  • carbocycle includes cycloalkyl as defined above.
  • carbocycle includes aryl as defined above.
  • Heterocycle refers to aromatic and non-aromatic ring moieties containing 3 or more ring members, of which one or more is a heteroatom such as, but not limited to, N, O, S, or P.
  • heterocyclyl include 3 to 20 ring members, whereas other such groups have 3 to 15 ring members.
  • At least one ring contains a heteroatom, but every ring in a polycyclic system need not contain a heteroatom.
  • a dioxolanyl ring and a benzdioxolanyl ring system are both heterocyclyl groups within the meaning herein.
  • Heterocyclyl groups also include fused ring species including those having fused aromatic and non-aromatic groups.
  • a heterocyclyl group also includes polycyclic ring systems containing a heteroatom such as, but not limited to, quinuclidyl, and also includes heterocyclyl groups that have substituents, including but not limited to alkyl, halo, amino, hydroxy, cyano, carboxy, nitro, thio, or alkoxy groups, bonded to one of the ring members.
  • a heterocyclyl group as defined herein can be a heteroaryl group or a partially or completely saturated cyclic group including at least one ring heteroatom.
  • Heterocyclyl groups include, but are not limited to, pyrrolidinyl, furanyl, tetrahydrofuranyl, dioxolanyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, thiophenyl, benzothiophenyl, benzofuranyl, dihydrobenzofuranyl, indolyl, dihydroindolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, purinyl, xanthinyl,
  • Heteroaryl refers to aromatic ring moieties containing 5 or more ring members, of which, one or more is a heteroatom such as, but not limited to, N, O, and S.
  • Heteroaryl groups include, but are not limited to, groups such as pyrrolyl, pyrazolyl, pyridinyl, pyridazinyl, pyrimidyl, pyrazyl, pyrazinyl, pyrimidinyl, thienyl, triazolyl, tetrazolyl, triazinyl, thiazolyl, thiophenyl, oxazolyl, isoxazolyl, benzothiophenyl, benzofuranyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridin
  • heteroaryl and “heteroaryl groups” include fused ring compounds such as wherein at least one ring, but not necessarily all rings, are aromatic, including tetrahydroquinolinyl, tetrahydroisoquinolinyl, indolyl, and 2,3-dihydro indolyl.
  • Carboxylic acid isostere refers to a group that serves as a surrogate to a carboxylic acid group (i.e., —COOH).
  • a carboxylic acid isostore may be preferable to a carboxylic acid group for a number or reasons, including greater selectivity, reduced side effects, decreased toxicity, improved pharmacokinetics, increased stability, and/or simplified synthesis.
  • Carboxylic acid isosteres include hydroxamic acids, acylcyanamides, sulfonamides, phosphonic acids, phosphinc acids, cyanoacetamides, sulfonates, sulfonamides, acylsulfonamides, arylsulfonamides, sulfonylureas, tetrazoles, thiazolidinediones, oxazolidinediones, isoxazoles, isothiazoles, squaric acids, 3-hydroxyquinolin-2-ones, 4-hydroxyquinolin-2-ones, 5-oxo-1,2,4-oxadiazoles, 5-oxo-1,2,4-thiadiazoles, 5-thioxo-1,2,4-oxadiazoles, hydroxyisoxazoles, phenols, tetramic acids, tetronic acids, cyclopentane-1,3-diones, 6-
  • a carboxylic acid isostere may be acyclic and have one of the following structures (wherein R a is alkyl, carbocycle, or heterocycle, wherein each of carbocycle and heterocycle may be singly or multiply substituted with R 2 ):
  • a carboxylic acid isostere may be cyclic and have one of the following structures:
  • Racemic and diastereomeric mixtures, as well as the individual optical isomers can be synthesized so as to be substantially free of their enantiomeric or diastereomeric partners, and these are all within the scope of certain embodiments of the invention.
  • the isomers resulting from the presence of a chiral center comprise a pair of nonsuperimposable-isomers that are called “enantiomers.”
  • Single enantiomers of a pure compound are optically active (i.e., they are capable of rotating the plane of plane polarized light and designated R or S).
  • isolated optical isomer means a compound which has been substantially purified from the corresponding optical isomer(s) of the same formula.
  • the isolated isomer may be at least about 80%, at least 80% or at least 85% pure by weight. In other embodiments, the isolated isomer is at least 90% pure or at least 98% pure, or at least 99% pure by weight.
  • substantially enantiomerically or diastereomerically pure means a level of enantiomeric or diastereomeric enrichment of one enantiomer with respect to the other enantiomer or diastereomer of at least about 80%, and more specifically in excess of 80%, 85%, 90%, 95%, 98%, 99%, 99.5% or 99.9%.
  • racemate and “racemic mixture” refer to an equal mixture of two enantiomers.
  • a racemate is labeled “( ⁇ )” because it is not optically active (i.e., will not rotate plane-polarized light in either direction since its constituent enantiomers cancel each other out).
  • All compounds with an asterisk (*) adjacent to a tertiary or quaternary carbon are optically active isomers, which may be purified from the respective racemate and/or synthesized by appropriate chiral synthesis.
  • a “hydrate” is a compound that exists in combination with water molecules.
  • the combination can include water in stoichiometric quantities, such as a monohydrate or a dihydrate, or can include water in random amounts.
  • a “hydrate” refers to a solid form; that is, a compound in a water solution, while it may be hydrated, is not a hydrate as the term is used herein.
  • a “solvate” is similar to a hydrate except that a solvent other that water is present.
  • a solvent other that water For example, methanol or ethanol can form an “alcoholate”, which can again be stoichiometric or non-stoichiometric.
  • a “solvate” refers to a solid form; that is, a compound in a solvent solution, while it may be solvated, is not a solvate as the term is used herein.
  • “Isotope” refers to atoms with the same number of protons but a different number of neutrons, and an isotope of a compound of Formula (I) includes any such compound wherein one or more atoms are replaced by an isotope of that atom.
  • carbon 12 the most common form of carbon, has six protons and six neutrons, whereas carbon 13 has six protons and seven neutrons, and carbon 14 has six protons and eight neutrons.
  • Hydrogen has two stable isotopes, deuterium (one proton and one neutron) and tritium (one proton and two neutrons). While fluorine has a number of isotopes, fluorine-19 is longest-lived.
  • an isotope of a compound having the structure of Formula (I) includes, but not limited to, compounds of Formula (I) wherein one or more carbon 12 atoms are replaced by carbon-13 and/or carbon-14 atoms, wherein one or more hydrogen atoms are replaced with deuterium and/or tritium, and/or wherein one or more fluorine atoms are replaced by fluorine-19.
  • Salt generally refers to an organic compound, such as a carboxylic acid or an amine, in ionic form, in combination with a counter ion.
  • acids in their anionic form and cations
  • bases in the cationic form and anions
  • pharmaceutically acceptable refers an agent that has been approved for human consumption and is generally non-toxic.
  • pharmaceutically acceptable salt refers to nontoxic inorganic or organic acid and/or base addition salts (see, e.g., Lit et al., Salt Selection for Basic Drugs, Int. J. Pharm., 33, 201-217, 1986) (incorporated by reference herein).
  • Pharmaceutically acceptable base addition salts of compounds of the invention include, for example, metallic salts including alkali metal, alkaline earth metal, and transition metal salts such as, for example, calcium, magnesium, potassium, sodium, and zinc salts.
  • Pharmaceutically acceptable base addition salts also include organic salts made from basic amines such as, for example, N,N′dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), and procaine.
  • Pharmaceutically acceptable acid addition salts may be prepared from an inorganic acid or from an organic acid.
  • inorganic acids include hydrochloric, hydrobromic, hydriodic, nitric, carbonic, sulfuric, and phosphoric acids.
  • Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, aromatic aliphatic, heterocyclic, carboxylic, and sulfonic classes of organic acids, examples of which include formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, 4-hydroxybenzoic, phenylacetic, mandelic, hippuric, malonic, oxalic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic,
  • salts may be useful, for example as intermediates in the synthesis of compounds having the structure of Formula I, for example in their purification by recrystallization.
  • a method of treating a subject having a MRGPR X4 dependent condition comprising administering to the subject a pharmaceutically effective amount of a compound having the structure of Formula (I):
  • MRGPR X4 dependent condition means a condition where the activation, over sensitization, or desensitization of MRGPR X4 by a natural or synthetic ligand initiates, mediates, sustains, or augments a pathological condition.
  • MRGPR X4 is sensitive to (or activated by) bilirubin and its metabolites, including urobilin, or bile acids. Without limited by theory, it is to be understood that by modulating MRGPR X4, the itch or pain sensations can be eased.
  • the MRGPR X4 dependent condition is a condition that is caused by the activation of MRGPR X4 by a bile acid.
  • bile acid includes primary bile acids (e.g., cholic acid, chenodeoxycholic acid), conjugated bile acids, also referred to as bile salts (e.g., taurocholic acid, glycocholic acid, taurochenodeoxycholic acid, glycochenodeoxycholic acid), secondary bile acids (e.g., deoxycholic acid, lithocholic acid), and bile acid analogs.
  • a bile acid analog is a farnesoid X-receptor (FXR) agonist.
  • FXR farnesoid X-receptor
  • the compounds of the present disclosure may be used for treating an MRGPR X4 dependent condition caused by activation of MRGPR X4 by a bile acid and that would benefit from modulating MRGPR X4.
  • the MRGPR X4 dependent condition is an itch associated condition, a pain associated condition, an autoimmune condition, or an autoimmune or inflammatory disorder.
  • itch associated condition means pruritus (including acute and chronic pruritus) associated with any condition.
  • the itch sensation can originate, e.g., from the peripheral nervous system (e.g., dermal or neuropathic itch) or from the central nervous system (e.g., neuropathic, neurogenic or psychogenic itch).
  • the method of present invention is provided to treat an itch associated condition, such as chronic itch; cholestatic pruritus; contact dermatitis; Allergic blepharitis; Anemia; Atopic dermatitis; Bullous pemphigoid; Candidiasis; Chicken pox; Cholestasis; end-stage renal failure; hemodialysis; Contact dermatitis, Atopic Dermatitis; Dermatitis herpetiformis; Diabetes; Drug allergy, Dry skin; Dyshidrotic dermatitis; Ectopic eczema; Erythrasma; Folliculitis; Fungal skin infection; Hemorrhoids; Herpes; HIV infection; Hodgkin's disease; Hyperthyroidism; Iron deficiency anemia; Kidney disease; Leukemia, porphyrias; Liver disease, including primary biliary cholangitis, primary sclerosing cholangitis, Alagille syndrome, Progressive familial intrahepatic cholest
  • the phrase “pain associated condition” means any pain due to a medical condition.
  • a pain associated condition such as Acute Pain, Advanced Prostate Cancer, AIDS-Related Pain, Ankylosing Spondylitis, Arachnoiditis, Arthritis, Arthrofibrosis, Ataxic Cerebral Palsy, Autoimmune Atrophic Gastritis, Avascular Necrosis, Back Pain, Behcet's Disease (Syndrome), Burning Mouth Syndrome, Bursitis, Cancer Pain, Carpal Tunnel, Cauda Equina Syndrome, Central Pain Syndrome, Cerebral Palsy, Cervical Stenosis, Charcot-Marie-Tooth (CMT) Disease, Chronic Fatigue Syndrome (CFS), Chronic Functional Abdominal Pain (CFAP), Chronic Pain, Chronic Pancreatitis, Collapsed Lung (Pneumothorax), Complex Regional Pain Syndrome (RSD), Corneal Neuropathic Pain, Crohn's Disease, De
  • CMT Charcot-Marie-Tooth
  • CFS Chronic Fatigue
  • autoimmune disorder means a disease or disorder arising from and/or directed against an individual's own tissues or organs, or a co-segregate or manifestation thereof, or resulting condition therefrom.
  • various clinical and laboratory markers of autoimmune diseases may exist including, but not limited to, hypergammaglobulinemia, high levels of autoantibodies, antigen-antibody complex deposits in tissues, clinical benefit from corticosteroid or immunosuppressive treatments, and lymphoid cell aggregates in affected tissues.
  • the method of present invention is provided to treat an autoimmune disorder, such as chronic inflammation, Multiple Sclerosis, Steven Johnson's Syndrome, appendicitis, bursitis, colitis, cystitis, dermatitis, phlebitis, reflex sympathetic dystrophy/complex regional pain syndrome (rsd/crps), rhinitis, tendonitis, tonsillitis, acne vulgaris, reactive airway disorder, asthma, airway infection, autoinflammatory disease, celiac disease, chronic prostatitis, diverticulitis, glomerulonephritis, hidradenitis suppurativa, hypersensitivities, intestinal disorder, epithelial intestinal disorder, inflammatory bowel disease, irritable bowel syndrome, colitis, interstitial cystitis, otitis, pelvic inflammatory disease, endometrial pain, reperfusion injury, rheumatic fever, rheumatoid arthritis, sarcoidosis, transplant rejection, psorias
  • the term “administration” refers to providing a compound, or a pharmaceutical composition comprising the compound as described herein.
  • the compound or composition can be administered by another person to the subject or it can be self-administered by the subject.
  • routes of administration are oral, parenteral (e.g., intravenous), or topical.
  • treatment refers to an intervention that ameliorates a sign or symptom of a disease or pathological condition.
  • treatment also refers to any observable beneficial effect of the treatment.
  • the beneficial effect can be evidenced, for example, by a delayed onset of clinical symptoms of the disease in a susceptible subject, a reduction in severity of some or all clinical symptoms of the disease, a slower progression of the disease, a reduction in the number of relapses of the disease, an improvement in the overall health or well-being of the subject, or by other parameters well known in the art that are specific to the particular disease.
  • a prophylactic treatment is a treatment administered to a subject who does not exhibit signs of a disease or exhibits only early signs, for the purpose of decreasing the risk of developing pathology.
  • a therapeutic treatment is a treatment administered to a subject after signs and symptoms of the disease have developed.
  • the term “subject” refers to an animal (e.g., a mammal, such as a human).
  • a subject to be treated according to the methods described herein may be one who has been diagnosed with a MRGPR X4 dependent condition, such as an itch associated condition, a pain associated condition, or an autoimmune disorder. Diagnosis may be performed by any method or technique known in the art.
  • a subject to be treated according to the present disclosure may have been subjected to standard tests or may have been identified, without examination, as one at risk due to the presence of one or more risk factors associated with the disease or condition.
  • the method of treating a subject having a MRGPR X4 dependent condition further comprises administering to the subject a pharmaceutically effective amount of a second therapeutic agent.
  • a MRGPR X4 dependent condition e.g., an itch associated condition, a pain associated condition, an autoimmune condition, or an autoimmune disorder
  • the itch associated condition is a liver disease.
  • the second therapeutic agent is a liver disease therapeutic agent.
  • the liver disease therapeutic agent is ursodeoxycholic acid (UDCA), norUrsodeoxycholic acid, cholestyramine, stanozolol, naltrexone, rifampicin, Alisol B 23-acetate (AB23A), curcumin, dihydroartemisinin, fenofibrate, bezafibrate, metronidazole, methotrexate, colchicine, metformin, betaine, glucagon, naltrexone, a farnesoid X-receptor (FXR) agonist, a peroxisome proliferator-activated receptor (PPAR) agonist, a thyroid hormone receptor beta (TR ⁇ ) agonist, or any combination thereof.
  • UDCA ursodeoxycholic acid
  • norUrsodeoxycholic acid cholestyramine
  • stanozolol cholestyramine
  • stanozolol naltrexone
  • FXR agonists examples include obeticholic acid, Turofexorate isopropyl (WAY-362450), 3-(2,6-dichlorophenyl)-4-(3′-carboxy-2-chlorostilben-4-yl)oxymethyl-5-isopropylisoxazole (GW4064), PX20606 (PX-102), PX-101, INT-767, INT-787, TERN-101, alternativeusin, tropifexor (LJN452), nidufexor, turofexorate isopropyl, fexaramine, silymarin, silybin, hedragonic acid, cafestol, Cilofexor (GS-9674 or Px-104), EDP-305, BAR704, BAR502, EYP-001, RDX-023, AGN-242266, HPG-1860, MET-409, AGN-242256, EP-024297,
  • a FXR agonist is a bile acid or analog thereof (e.g., obeticholic acid, INT-767, INT-787, BAR502, hedragonic acid or BAR704) or a non-bile acid agonist (e.g., EDP-305, tropifexor, nidufexor, cilofexor, GW4064, Turofexorate isopropyl, fexaramine, PX20606 (PX-102), TERN-101, alternativeusin, silymarin, silybin, EYP-001, RDX023-2, AGN-242266, HPG-1860, MET-409, EP-024297, M-480, or cafestol).
  • a bile acid or analog thereof e.g., obeticholic acid, INT-767, INT-787, BAR502, hedragonic acid or BAR704
  • a non-bile acid agonist e.g.
  • a PPAR agonist is a PPAR-alpha agonist, a PPAR-gamma agonist, a PPAR-delta agonist, a PPAR-alpha/gamma dual agonist, a PPAR alpha/delta dual agonist, a PPAR gamma/delta dual agonist, or PPAR alpha/gamma/delta pan agonist.
  • Examples of PPAR alpha agonists that may be used in the methods described herein include fenofibrate, ciprofibrate, pemafibrate, gemfibrozil, clofibrate, binifibrate, clinofibrate, clofibric acid, nicofibrate, pirifibrate, plafibride, ronifibrate, theofibrate, tocofibrate, and SRI 0171.
  • PPAR gamma agonists examples include rosiglitazone, pioglitazone, deuterium-stabilized R-pioglitazone, efatutazone, ATx08-001, OMS-405, CHS-131, THR-0921, SER-150-DN, KDT-501, GED-0507-34-Levo, CLC-3001, and ALL-4.
  • Examples of PPAR delta agonists that may be used in the methods described herein include GW501516 (endurabol or ( ⁇ 4-[( ⁇ 4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl ⁇ methyl)sulfanyl]-2-methylphenoxy ⁇ acetic acid)), MBX8025 (seladelpar or ⁇ 2-methyl-4-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethylsylfanyl]-phenoxy ⁇ -acetic acid), GW0742 ([4-[[[2-[3-fluoro-4-(trifluoromethyl)phenyl]-4-methyl-5-thiazolyl]methyl]thio]-2-methyl phenoxy] acetic acid), L165041, HPP-593, and NCP-1046.
  • GW501516 endurabol or ( ⁇ 4-[( ⁇ 4-methyl-2-[
  • PPAR alpha/gamma agonists examples include saroglitazar, aleglitazar, muraglitazar, tesaglitazar, and DSP-8658.
  • PPAR alpha/delta agonists examples include elafibranor and T913659.
  • Examples of PPAR gamma/delta agonists that may be used in the methods described herein include a conjugated linoleic acid (CLA) and T3D-959.
  • CLA conjugated linoleic acid
  • T3D-959 conjugated linoleic acid
  • Examples of PPAR alpha/gamma/delta agonists that may be used in the methods described herein include IVA337 (lanifibranor), TTA (tetradecylthioacetic acid), bavachinin, GW4148, GW9135, bezafibrate, lobeglitazone, 2-(4-(5,6-methylenedioxybenzo[d]thiazol-2-yl)-2-methylphenoxy)-2-methylpropanoic acid (MHY2013), and CS038.
  • thyroid hormone receptor beta agonists examples include sobetirome, eprotirome, GC-24, MGL-3196, MGL-3745, VK-2809, KB141 [3,5-dichloro-4-(4-hydroxy-3-isopropylphenoxy) phenylacetic acid], and MB07811 (2R,4S)-4-(3-chlorophenyl)-2-[(3,5-dimethyl-4-(4′-hydroxy-3′-isopropylbenzyl)phenoxy)methyl]-2-oxido-[1,3,2]-dioxaphosphonane).
  • the second therapeutic agent may be administered simultaneously, separately, or sequentially with the compounds of the present disclosure. If administered simultaneously, the second therapeutic agent and compound of the present disclosure may be administered in separate dosage forms or in the same dosage form.
  • a method of treating a subject having an itch associated condition comprising administering to the subject a pharmaceutically effective amount of a compound having the structure of Formula (I) or pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof, or a pharmaceutical composition thereof.
  • the itch associated condition is cholestatic pruritus, uremic pruritus, atopic dermatitis, dry skin, psoriasis, contact dermatitis, or eczema.
  • n is 1, R 1 is H, Z is 0, R is —C( ⁇ O)OR 12 , and the compound has the structure of Formula (II):
  • n 0, Z is O and the compound has the structure of Formula (III):
  • x is 1 and the compound has the structure of Formula (V):
  • x is 1 and the compound has the structure of Formula (VII):
  • n is 1, R 1 is H, Z is O, R is —(C ⁇ O)NHR 15 , —CH 2 OH, —CH 2 NH 2 or —CN, and the compound has the structure of Formula (VIII), (IX), (X) or (XI), respectively:
  • n is 0, Z is 0, R is —(C ⁇ O)NHR 15 , —CH 2 OH, —CH 2 NH 2 or —CN, and the compound has the structure of Formula (XII), (XIII), (XIV) or (XV), respectively:
  • Z is —S—, —N(R 11 )—, —CH 2 — or —C ⁇ C— and the compound has the structure of Formula (XVI), (XVII), (XVIII) or (IX), respectively:
  • n, x, A, Q 1 , Q 2 , R, R 1 , R 2 , R 3 , R 4 , R 5 and R 11 are as defined above.
  • A is aryl
  • A is phenyl
  • A is phenyl with the following points of attachment:
  • A is heteroaryl
  • A is pyridine or pyrazine.
  • A is pyridine or pyrazine with the following points of attachment, respectively:
  • A is furan, thiophene or isoxazole.
  • A is furan, thiophene or isoxazole with the following points of attachment, respectively:
  • Q 1 and Q 2 are both CH.
  • Q 1 is CH and Q 2 is N.
  • Q 1 is N and Q 2 is CH.
  • R 1 is hydrogen
  • R 1 is alkyl
  • R 1 is methyl
  • the compound has the structure of Formula (XX):
  • the compound has the structure of Formula (XXI):
  • R 3 , R 4 , R 5 and R 12 are as defined above.
  • the compound has the structure of Formula (XXII):
  • R 2 , R 3 , R 4 , R 5 and R 12 are as defined above.
  • the compound has the structure of Formula (XXIII):
  • R 3 , R 4 and R 5 are as defined above.
  • the compound has the structure of Formula (XXIV):
  • R 2 , R 3 , R 4 and R 5 are as defined above.
  • carboxylic acid group (—COOH) of each of Formulas (XXIII) and (XXIV) above is replaced with a carboxylic acid isostere as defined herein.
  • n 0.
  • n 1
  • x is 0.
  • x is 1.
  • x is 2.
  • A is aryl
  • A is heteroaryl
  • Z is —O—.
  • Z is —S—.
  • Z is —N(R 11 )—
  • Z is —CH 2 —.
  • Z is or —C ⁇ C—.
  • R is —(CH 2 ) m C( ⁇ O)OR 12 .
  • R is —(CH 2 ) m NHR 13 .
  • R is —(C ⁇ O)NR 14 R 15 .
  • R is —CH 2 OH.
  • R is —CN
  • R is haloalkyl
  • R is carbocycle
  • R is heterocycle
  • m is 0.
  • m is 1.
  • R 14 is H and R 15 is H, —SO 2 CH 3 , carbocycle, heterocyle, or alkyl substituted with 0, 1, 2 or 3 substituents selected from —OH, —CN, —NR′R′′, C( ⁇ O)OH, C( ⁇ O)NR′R′′, —SO 2 OH, alkoxy, carbocycle, or heterocycle, wherein R′ and R′′ are individually H or alkyl.
  • R 14 and R 15 are taken together with the nitrogen atom to which they are attached to form heterocycle.
  • R 1 is H.
  • R 1 is alkyl
  • R 2 is halo.
  • R 2 is cyano
  • R 2 is amino
  • R 2 is alkyl
  • R 2 is alkoxy
  • R 2 is carbocycle
  • R 2 is heterocycle.
  • R 3 , R 4 and R 5 are the same or different and either absent or, when present, cyano, cyanoalkyl, nitro, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, —(C ⁇ O)alkyl, —(C ⁇ O)NHalkyl, carbocycle, heterocycle, —O-carbocycle or —O-heterocycle.
  • R 3 , R 4 and R 5 are the same or different and either absent or, when present, cyano, nitro, halogen, alkyl, haloalkyl, alkoxy, or haloalkoxy.
  • R 3 , R 4 and R 5 are the same or different and either absent or, when present, —CN, —NO 2 , —F, —Cl, —Br, —CH 3 , —CF 3 , —CHF 2 , —C(CH 3 ) 3 , —OCH 3 , or —OCF 3 .
  • any two of R 3 , R 4 and R 5 taken together with the atoms to which they are attached form carbocycle or heterocycle which is unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halogen, hydroxyl, oxo, halo, alkyl, haloalkyl, alkoxy, haloalkoxy, carbocycle, or heterocycle.
  • R 3 and R 4 taken together with the atoms to which they are attached form heterocycle as depicted below which is unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halogen, hydroxyl, oxo, halo, alkyl, haloalkyl, alkoxy, haloalkoxy, carbocycle, or heterocycle:
  • R 3 and R 4 taken together with the atoms to which they are attached form carbocycle as depicted below which is unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halogen, oxo, halo, alkyl, haloalkyl, alkoxy, haloalkoxy, carbocycle, or heterocycle:
  • Representative compounds of Formula (I), as well as Formulas (II) through (XXIV) as applicable, include any one of the compounds listed in Table A below, as well as a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof. To this end, representative compounds are identified herein by their respective “Compound Number”, which is sometimes abbreviated as “Compound No.” or “Cpd. No.”
  • the compound has the following structure, or a pharmaceutically acceptable isomer, racemate, hydratesolvate, isotope, or salt thereof:
  • the compound has the following structure, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof:
  • the compound has the following structure, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof:
  • the compound has the following structure, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof:
  • the compound has the following structure, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof:
  • the compound has the following structure, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof:
  • the compound has the following structure, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof:
  • the compound has the following structure, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof:
  • the compound has the following structure, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof:
  • the compound has the following structure, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof:
  • the compound has the following structure, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof:
  • the compound has the following structure, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof:
  • the compound has the following structure, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof:
  • the compound has the following structure, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof:
  • the compound has the following structure, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof:
  • the compound has the following structure, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof:
  • the compound has the following structure, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof:
  • the compound has the following structure, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof:
  • certain compounds of Formula (I), as well as Formulas (II) through (XXIV), as applicable can have their carboxylic acid moiety substituted for a carboxylic acid isostere group, as described herein.
  • Representative carboxylic acid isostere compounds derived from the representative compounds listed below are presented in Table B.
  • carboxylic acid isostere groups used for compounds of Table B are as follows:
  • prodrugs and/or metabolites of compounds of Formula (I), as well as Formulas (II) through (XXIV), are provided.
  • prodrugs of a compound of the invention are provided, which upon administration to a subject, undergo chemical conversion by metabolic or other physiological processes to become active pharmacological substances. Conversion by metabolic or other physiological processes includes, without limitation, enzymatic (e.g., specific enzymatically catalyzed) and non-enzymatic (e.g., general or specific acid or base induced) chemical transformation of the prodrug into the active pharmacological substance.
  • enzymatic e.g., specific enzymatically catalyzed
  • non-enzymatic e.g., general or specific acid or base induced
  • a “prodrug” is a substance that, upon administration to a subject, is converted in vivo by the action of biochemicals within the subject's body, such as enzymes, to an active pharmaceutical ingredient.
  • prodrugs include esters of carboxylic acid groups, which can be hydrolyzed by endogenous esterases as are found in the bloodstream of humans and other mammals.
  • substances are provided that can be administered to a subject which are then converted within the subject's body to provide a compound having the structure of Formula (I), or any of Formulas (II) through (XXIV).
  • prodrugs of carboxylic acids are typically esters and amides, which can readily be made from the corresponding carboxylic acid by known techniques.
  • prodrugs may be generated by converting the carboxylic acid moiety of the compounds of Formula (I) through (VII) and (XVI) through (XXIV) to an ester functional group: including, alkyl esters such as methyl, ethyl, isopropyl and n-butyl esters; aryl esters such as phenyl and indanyl esters; double esters such as (acyloxy)alkyl or [(alkoxycarbonyl)oxy]methyl esters; and cyclic carbonates such as (oxodioxolyl)methyl esters.
  • the carboxylic acid moiety may incorporate a carbamoylmethyl, aminoalkyl, or amidoalkyl moiety to provide carbamoylmethyl, aminoalkyl and amidoalkyl esters, respectively.
  • the carboxylic acid moiety can incorporate esters of acylglycerols and bis(acyl-amino)propan-2-ols.
  • the carboxylic acid moiety can incorporate amide groups, including N-hydroxyamide, N-acylsulfonamides and N-acylsulfonylureas.
  • a “metabolite” is a compound that, following administration to a subject, is converted within the body of the subject to yield an active substance. Such conversion often involves hydrolysis, phosphorylation and/or oxidation/reduction processes, and may be mediated by any number of enzymes (e.g., esterases, phosphatases, cytochrome P450, and the like), as well by different environments within the body (e.g., changes in pH).
  • enzymes e.g., esterases, phosphatases, cytochrome P450, and the like
  • compounds of Formula (I), as well as Formulas (II) through (XXII), as applicable are modified to encompass metabolites of the parent compound.
  • compounds of Formula (I), as well as Formulas (II) through (XXII) are modified to have the “A-ring” carboxylic acid of Formula (I) derivatized with carbohydrate or amino acid compounds.
  • the A-ring carboxylic acid moiety is derivatized with glucuronic acid or the amino acid glycine to give compounds of Formulas (XXV) and (XXVI), respectively:
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of any one of Formulas (I) through (XIV) together with at least one pharmaceutically acceptable carrier, diluent, or excipient.
  • the active compound will usually be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier which can be in the form of an ampoule, capsule, sachet, paper, or other container.
  • a carrier or when the carrier serves as a diluent, it can be solid, semi-solid, or liquid material that acts as a vehicle, excipient, or medium for the active compound.
  • the active compound can be adsorbed on a granular solid carrier, for example contained in a sachet.
  • suitable carriers are water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugar, cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid, or lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, polyoxyethylene, hydroxymethylcellulose, and polyvinylpyrrolidone.
  • the carrier or diluent can include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.
  • the term “pharmaceutical composition” refers to a composition containing one or more of the compounds described herein, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof, formulated with a pharmaceutically acceptable carrier, which can also include other additives, and manufactured or sold with the approval of a governmental regulatory agency as part of a therapeutic regimen for the treatment of disease in a mammal.
  • compositions can be formulated, for example, for oral administration in unit dosage form (e.g., a tablet, capsule, caplet, gelcap, or syrup); for topical administration (e.g., as a cream, gel, lotion, or ointment); for intravenous administration (e.g., as a sterile solution free of particulate emboli and in a solvent system suitable for intravenous use); or in any other formulation described herein.
  • unit dosage form e.g., a tablet, capsule, caplet, gelcap, or syrup
  • topical administration e.g., as a cream, gel, lotion, or ointment
  • intravenous administration e.g., as a sterile solution free of particulate emboli and in a solvent system suitable for intravenous use
  • the pharmaceutical composition comprising a compound of any one of Formulas (I) through (XIV) with at least one pharmaceutically acceptable carrier, diluent, or excipient further comprises a second therapeutic agent.
  • the second therapeutic agent is a liver disease therapeutic agent.
  • the liver disease therapeutic agent is ursodeoxycholic acid (UDCA), norUrsodeoxycholic acid, cholestyramine, stanozolol, naltrexone, rifampicin, Alisol B 23-acetate (AB23A), curcumin, dihydroartemisinin, fenofibrate, bezafibrate, metronidazole, methotrexate, colchicine, metformin, betaine, glucagon, naltrexone, a farnesoid X-receptor (FXR) agonist, a peroxisome proliferator-activated receptor (PPAR) agonist, a thyroid hormone receptor beta (TR ⁇ ) agonist, or any combination thereof.
  • UDCA ursodeoxycholic acid
  • norUrsodeoxycholic acid cholestyramine
  • stanozolol cholestyramine
  • stanozolol naltrexone
  • FXR agonists examples include obeticholic acid, Turofexorate isopropyl (WAY-362450), 3-(2,6-dichlorophenyl)-4-(3′-carboxy-2-chlorostilben-4-yl)oxymethyl-5-isopropylisoxazole (GW4064), PX20606 (PX-102), PX-101, INT-767, INT-787, TERN-101, alternativeusin, tropifexor (LJN452), nidufexor, turofexorate isopropyl, fexaramine, silymarin, silybin, hedragonic acid, cafestol, Cilofexor (GS-9674 or Px-104), EDP-305, BAR704, BAR502, EYP-001, RDX-023, AGN-242266, HPG-1860, MET-409, AGN-242256, EP-0242
  • a FXR agonist is a bile acid or analog thereof (e.g., obeticholic acid, INT-767, INT-787, turofexorate isopropyl (WAY-362450), or BAR704) or a non-bile acid agonist (e.g., EDP-305, tropifexor, nidufexor, cilofexor, GW4064, Turofexorate isopropyl, fexaramine, PX20606 (PX-102), TERN-101, alternativeusin, silymarin, silybin, hedragonic acid, BAR502, EYP-001, RDX023-2, AGN-242266, HPG-1860, MET-409, EP-024297, M-480, or cafestol).
  • a non-bile acid agonist e.g., EDP-305, tropifexor, nidufexor, cilofexor, GW4064,
  • a PPAR agonist is a PPAR-alpha agonist, a PPAR-gamma agonist, a PPAR-delta agonist, a PPAR-alpha/gamma dual agonist, a PPAR alpha/delta dual agonist, a PPAR gamma/delta dual agonist, a PPAR alpha/gamma/delta pan agonist, or any combination thereof.
  • Examples of PPAR alpha agonists that may be used in the pharmaceutical compositions described herein include fenofibrate, ciprofibrate, pemafibrate, gemfibrozil, clofibrate, binifibrate, clinofibrate, clofibric acid, nicofibrate, pirifibrate, plafibride, ronifibrate, theofibrate, tocofibrate, and SRI 0171.
  • PPAR gamma agonists examples include rosiglitazone, pioglitazone, deuterium-stabilized R-pioglitazone, efatutazone, ATx08-001, OMS-405, CHS-131, THR-0921, SER-150-DN, KDT-501, GED-0507-34-Levo, CLC-3001, and ALL-4.
  • PPAR delta agonists examples include GW501516 (endurabol or ( ⁇ 4-[( ⁇ 4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl ⁇ methyl)sulfanyl]-2-methylphenoxy ⁇ acetic acid)), MBX8025 (seladelpar or ⁇ 2-methyl-4-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethylsylfanyl]-phenoxy ⁇ -acetic acid), GW0742 ([4-[[[2-[3-fluoro-4-(trifluoromethyl)phenyl]-4-methyl-5-thiazolyl]methyl]thio]-2-methyl phenoxy] acetic acid), L165041, HPP-593, and NCP-1046.
  • GW501516 endurabol or ( ⁇ 4-[( ⁇ 4-methyl-2-[4-(trifluoromethyl)pheny
  • PPAR alpha/gamma agonists examples include saroglitazar, aleglitazar, muraglitazar, tesaglitazar, and DSP-8658.
  • PPAR alpha/delta agonists examples include elafibranor and T913659.
  • PPAR gamma/delta agonists examples include a conjugated linoleic acid (CLA) and T3D-959.
  • Examples of PPAR alpha/gamma/delta agonists that may be used in the pharmaceutical compositions described herein include IVA337 (lanifibranor), TTA (tetradecylthioacetic acid), bavachinin, GW4148, GW9135, bezafibrate, lobeglitazone, 2-(4-(5,6-methylenedioxybenzo[d]thiazol-2-yl)-2-methylphenoxy)-2-methylpropanoic acid (MHY2013), and CS038.
  • IVA337 lanifibranor
  • TTA tetradecylthioacetic acid
  • bavachinin tetradecylthioacetic acid
  • bavachinin tetradecylthioacetic acid
  • GW4148 tetradecylthioacetic acid
  • GW9135 bezafibrate
  • lobeglitazone 2-(4-(5,6-methylenedioxybenzo
  • thyroid hormone receptor beta agonists examples include sobetirome, eprotirome, GC-24, MGL-3196, MGL-3745, VK-2809, KB141 [3,5-dichloro-4-(4-hydroxy-3-isopropylphenoxy) phenylacetic acid], and MB07811 (2R,4S)-4-(3-chlorophenyl)-2-[(3,5-dimethyl-4-(4′-hydroxy-3′-isopropylbenzyl)phenoxy)methyl]-2-oxido-[1,3,2]-dioxaphosphonane).
  • the term “pharmaceutically acceptable carrier” refers to any ingredient other than the disclosed compounds, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof (e.g., a carrier capable of suspending or dissolving the active compound) and having the properties of being nontoxic and non-inflammatory in a patient.
  • Excipients may include, for example: antiadherents, antioxidants, binders, coatings, compression aids, disintegrants, dyes (colors), emollients, emulsifiers, fillers (diluents), film formers or coatings, flavors, fragrances, glidants (flow enhancers), lubricants, preservatives, printing inks, sorbents, suspending or dispersing agents, sweeteners, or waters of hydration.
  • antiadherents antioxidants, binders, coatings, compression aids, disintegrants, dyes (colors), emollients, emulsifiers, fillers (diluents), film formers or coatings, flavors, fragrances, glidants (flow enhancers), lubricants, preservatives, printing inks, sorbents, suspending or dispersing agents, sweeteners, or waters of hydration.
  • excipients include, but are not limited to: butylated hydroxytoluene (BHT), calcium carbonate, calcium phosphate (dibasic), calcium stearate, croscarmellose, crosslinked polyvinyl pyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methyl paraben, microcrystalline cellulose, polyethylene glycol, polyvinyl pyrrolidone, povidone, pregelatinized starch, propyl paraben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethyl cellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (corn), stearic acid, stearic acid, sucrose, talc, titanium dioxide, vitamin A, B
  • the formulations can be mixed with auxiliary agents which do not deleteriously react with the active compounds.
  • auxiliary agents which do not deleteriously react with the active compounds.
  • Such additives can include wetting agents, emulsifying and suspending agents, salt for influencing osmotic pressure, buffers and/or coloring substances, preserving agents, sweetening agents, or flavoring agents.
  • the compositions can also be sterilized if desired.
  • the route of administration can be any route which effectively transports the active compound of the invention to the appropriate or desired site of action, such as oral, nasal, pulmonary, buccal, subdermal, intradermal, transdermal, or parenteral, including intravenous, subcutaneous and/or intramuscular.
  • the route of administration is oral. In another embodiment, the route of administration is topical.
  • Dosage forms can be administered once a day, or more than once a day, such as twice or thrice daily. Alternatively, dosage forms can be administered less frequently than daily, such as every other day, or weekly, if found to be advisable by a prescribing physician or drug's prescribing information.
  • Dosing regimens include, for example, dose titration to the extent necessary or useful for the indication to be treated, thus allowing the patient's body to adapt to the treatment, to minimize or avoid unwanted side effects associated with the treatment, and/or to maximize the therapeutic effect of the present compounds.
  • Other dosage forms include delayed or controlled-release forms. Suitable dosage regimens and/or forms include those set out, for example, in the latest edition of the Physicians' Desk Reference, incorporated herein by reference.
  • the invention provides an oral pharmaceutical composition comprising a compound of any one of Formulas (I) through (XXIV) together with at least one pharmaceutically acceptable oral carrier, diluent, or excipient.
  • the invention provide a topical pharmaceutical composition comprising a compound of any one of Formulas (I) through (XXIV) together with at least one pharmaceutically acceptable topical carrier, diluent, or excipient.
  • the oral pharmaceutical composition is provided to treat cholestatic pruritus, wherein the dosage regimen is, for example, once a day.
  • the topical pharmaceutical composition is provided to treat atopic dermatitis.
  • a composition of a compound described herein including formulating a compound of the invention with a pharmaceutically acceptable carrier or diluent.
  • the pharmaceutically acceptable carrier or diluent is suitable for oral administration.
  • the methods can further include the step of formulating the composition into a tablet or capsule.
  • the pharmaceutically acceptable carrier or diluent is suitable for parenteral administration.
  • the methods further include the step of lyophilizing the composition to form a lyophilized preparation.
  • the invention provides a compound having the structure of any one of Formulas (I) through (XXIV).
  • Such compounds can be synthesized using standard synthetic techniques known to those skilled in the art.
  • compounds of the present invention can be synthesized using appropriately modified synthetic procedures set forth in the following Examples and Reaction Schemes.
  • carboxylic acid isosteres, and their substitution in place of the carboxylic acids disclosed herein may also be accomplished using standard synthetic techniques known to those skilled in the art.
  • reaction may be carried out in any suitable solvent, or other reagents to perform the transformation(s) necessary.
  • suitable solvents are protic or aprotic solvents which are substantially non-reactive with the reactants, the intermediates or products at the temperatures at which the reactions are carried out (i.e., temperatures which may range from the freezing to boiling temperatures).
  • a given reaction may be carried out in one solvent or a mixture of more than one solvent.
  • suitable solvents for a particular work-up following the reaction may be employed.
  • All reagents, for which the synthesis is not described in the experimental part, are either commercially available, or are known compounds or may be formed from known compounds by known methods by a person skilled in the art.
  • the compounds and intermediates produced according to the methods of the invention may require purification. Purification of organic compounds is well known to a person skilled in the art and there may be several ways of purifying the same compound. In some cases, no purification may be necessary. In some cases, the compounds may be purified by crystallization. In some cases, impurities may be stirred out using a suitable solvent.
  • the compounds may be purified by chromatography, particularly flash column chromatography, using purpose-made or prepacked silica gel cartridges and eluents such as gradients of solvents such as heptane, ether, ethyl acetate, acetonitrile, ethanol and the like.
  • the compounds may be purified by preparative HPLC using methods as described.
  • Purification methods as described herein may provide compounds of the present invention which possess a sufficiently basic or acidic functionality in the form of a salt, such as, in the case of a compound of the present invention which is sufficiently basic, a trifluoroacetate or formate salt, or, in the case of a compound of the present invention which is sufficiently acidic, an ammonium salt.
  • a salt of this type can either be transformed into its free base or free acid form, respectively, by various methods known to a person skilled in the art, or be used as salts in subsequent biological assays. It is to be understood that the specific form of a compound of the present invention as isolated and as described herein is not necessarily the only form in which said compound can be applied to a biological assay in order to quantify the specific biological activity.
  • Chemical names were generated using the ChemDraw naming software (Version 17.0.0.206) by PerkinElmer Informatics, Inc. In some cases, generally accepted names of commercially available reagents were used in place of names generated by the naming software.
  • Method 1 Agilent 1260 Infinity II System equipped with an Agilent Poroshell 120 EC-18, 2.7 ⁇ m, 4.6 ⁇ 100 mm column, using H 2 O with 0.1% formic acid as the mobile phase A, and MeCN with 0.1% formic acid as the mobile phase B.
  • An ESI detector in positive mode was used. The gradient was 20-95% mobile phase B over 5 min then held at 95% for 3.8 mins, then return to 20% mobile phase B over 0.2 min. The flow rate was 1 mL/min.
  • Method 2 Agilent 1260 Infinity II System equipped with an Agilent Poroshell 120 EC-18, 2.7 ⁇ m, 4.6 ⁇ 100 mm column, using H 2 O with 0.1% formic acid as the mobile phase A, and MeCN with 0.1% formic acid as the mobile phase B.
  • An ESI detector in negative mode was used. The gradient was 20-95% mobile phase B over 5 min then held at 95% for 3.8 mins, then return to 20% mobile phase B over 0.2 min. The flow rate was 1 mL/min.
  • Method 3 Agilent 1260 Infinity II System equipped with an Agilent Poroshell 120 EC-18, 2.7 ⁇ m, 4.6 ⁇ 100 mm column, using H 2 O with 0.1% formic acid as the mobile phase A, and MeCN with 0.1% formic acid as the mobile phase B.
  • An ESI detector in positive mode was used. The gradient was 20-95% mobile phase B over 5 min then held at 95% for 3.8 mins, then return to 20% mobile phase B over 0.2 min. The flow rate was 1 mL/min.
  • Method 4 Agilent 1260 Infinity II System equipped with an Agilent Poroshell 120 EC-18, 2.7 ⁇ m, 4.6 ⁇ 100 mm column, using H 2 O with 0.1% formic acid as the mobile phase A, and MeCN with 0.1% formic acid as the mobile phase B.
  • An ESI detector in negative mode was used. The gradient was 10-95% mobile phase B over 12 min then held at 95% for 2 min, return to 10% mobile phase B over 1 min. The flow rate was 1 mL/min.
  • Method 5 Shimadzu LCMS-2020 system equipped with a KinetiX EVO C18 2.1 ⁇ 30 mm, 5 ⁇ m column, using H 2 O with 0.025% NH 3 —H 2 O as the mobile phase A, and MeCN as mobile phase B. The flow rate was 1.5 mL/min. An ESI mass detector in negative mode was used. The gradient was 0-60% B over 0.8 min, then hold at 60% B for 0.4 min, then return to 0% B over 0.01 min, and hold at 0% B for 0.34 min.
  • Method 6 Agilent 1200/G6110A System equipped with a Chromolith Flash RP-18e 25 ⁇ 2.0 mm column, using H 2 O with 0.0375% TFA as mobile phase A, and MeCN with 0.01875% TFA as mobile phase B.
  • An ESI mass detector set in positive mode was used. The gradient was 5-95% B over 0.8 min, hold at 95% B for 0.4 min, then return to 5% B over 0.01 min, and hold at 5% B for 0.29 min.
  • Method 7 Shimadzu LCMS-2020 system equipped with a KinetiX EVO C18 2.1 ⁇ 30 mm, 5 ⁇ m column, using H 2 O with 0.025% NH 3 as the mobile phase A, and MeCN as mobile phase B.
  • the flow rate was 1.5 mL/min.
  • An ESI mass detector in negative mode was used. The gradient was 5-95% B over 0.8 min, hold at 95% B for 0.4 min, then return to 5% B over 0.01 min, and hold at 5% B for 0.34 min.
  • Method 8 Agilent 1200/G6110A System equipped with an ACE Excel C18, 2.1 ⁇ 30 mm, 5 ⁇ m column, using H 2 O with 0.025% NH 3 as mobile phase A, and MeCN as mobile phase B. An ESI mass detector set in negative mode was used. The gradient was 10-80% B over 1.2 min, hold at 80% B for 0.4 min, then return to 5% B over 0.01 min, and hold at 5% B for 0.39 min.
  • Method 9 Agilent 1100 System equipped with an Agilent Eclipse XDB-C18, 3.5 ⁇ m, 4.6 ⁇ 150 mm column, using H 2 O with 0.1% trifluoroacetic acid as the mobile phase A, and methanol with 0.1% trifluoroacetic acid as the mobile phase B.
  • the gradient was 5-95% mobile phase B over 12 min then held at 95% mobile phase B for 3 min, then return to 5% mobile phase B for 1 min.
  • the flow rate was 1 mL/min.
  • Method 10 Shimadzu SCL-10A system equipped with Agilent Eclipse XDB-C18, 3.5 ⁇ m, 4.6 ⁇ 150 mm column and PE Sciex API 150 EX, using H 2 O with 0.1% trifluoroacetic acid as the mobile phase A, and methanol with 0.1% trifluoroacetic acid as the mobile phase B.
  • the gradient was 5-95% mobile phase B over 12 min then held at 95% mobile phase B for 3 min, then return to 5% mobile phase B for 1 min.
  • the flow rate was 1 mL/min.
  • Method 11 Shimadzu SCL-10A system equipped with Agilent Eclipse XDB-C18, 3.5 ⁇ m, 4.6 ⁇ 150 mm column and PE Sciex API 150 EX, using H 2 O with 0.1% trifluoroacetic acid as the mobile phase A, and methanol with 0.1% trifluoroacetic acid as the mobile phase B.
  • the gradient was 50-95% mobile phase B over 4 min then held at 95% mobile phase B for 4 min, then return to 50% mobile phase B for 0.1 min.
  • the flow rate was 1 mL/min.
  • Method 12 Waters Acquity system equipped with an Acquity UPLC BEH C18 1.7 ⁇ m, 2.1 ⁇ 50 mm column, using H2O with 0.1% ammonium formate adjusted to pH 3.8 with formic acid as the mobile phase A, and acetonitrile as the mobile phase B. The gradient was 5-100% over 9 minutes then held at 100% mobile phase B for 1 minute. The flow rate was 0.7 mL/min.
  • Method 13 Waters Acquity system equipped with an EVO C18 (5 ⁇ m, 3.0 ⁇ 50 mm) using a low pH buffer gradient of 5% to 100% of MeCN in H 2 O (0.1% HCOOH) over 2.5 min at 2.2 mL/min, and holding at 100% for a total time of 3.5 min.
  • the pyridine, dichloromethane (DCM), tetrahydrofuran (THF), and toluene used in the procedures were from Aldrich Sure-Seal bottles kept under nitrogen (N 2 ). All reactions were stirred magnetically, and temperatures are external reaction temperatures. Chromatographies were typically carried out using a Combiflash Rf flash purification system (Teledyne Isco) equipped with Redisep (Teledyne Isco) Rf Gold Normal-Phase silica gel (SiO 2 ) columns or by using a similar system.
  • Preparative HPLC purifications were typically performed using one of the following systems: 1) Waters System equipped with a Waters 2489 uv/vis detector, an Aquity QDA detector, a Waters xBridge Prep C18 5 ⁇ m OBD, 30 ⁇ 1560 mm column, and eluting with various gradients of H 2 O/MeCN (0.1% formic acid) at a 30 mL/min flow rate, or 2) column: Phenomenex Synergi C18 150 ⁇ 30 mm-4 ⁇ m; mobile phase: [H 2 O (0.225% formic acid)-MeCN]; B %: 55%-85%, 12 min) and were typically concentrated using a Genevac EZ-2.
  • EA ethyl acetate
  • TEA triethylamine
  • DMSO dimethyl sulfoxide
  • Si 2 silica gel
  • AIBN azobisisobutyronitrile
  • DIBAL diisobutylaluminium hydride
  • TFA trifluoroacetic acid
  • DMAP 4-dimethylaminopyridine
  • DPPA diphenylphosphoryl azide
  • BPO benzoyl peroxide
  • 1,1′-bis(diphenylphosphino)ferrocene tetrahydrofuran (THF), 1,4-diazabicyclo[2.2.2]octane bis(sulfur dioxide) adduct (DABSO), hexafluorophosphate azabenzotriazole tetramethyl uronium (HATU), hydroxybenzotriazole (HOBt), N-methyl morpholine (
  • Step 1-1 Synthesis of methyl 3-((4-chloro-2-(trifluoromethyl)phenoxy)methyl)benzoate (Compound 1-0)
  • Step 1-2 Synthesis of 3-((2-methyl-4-(trifluoromethyl)phenox)methyl)benzoic acid (Compound 1-16)
  • Step 2-2 Synthesis of 3-chloro-5-((2,4-dichlorophenoxy)methyl)benzoic acid (Compound 2-1)
  • Step 3-2 Synthesis of 3-((2-chloro-4-methylphenoxy)methyl)benzoic acid (Compound 3-2)
  • Step 4-13 Synthesis of methyl 5-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-2-fluorobenzoate (INT 4-J)
  • Step 5-1 Synthesis of methyl 3-cyano-5-((2,4-dichlorophenoxy)methyl)benzoate (INT 5-B)
  • Step 5-2 Synthesis of 3-cyano-5-((2,4-dichlorophenoxy)methyl)benzoic acid (Compound 5-1)
  • Step 6-2 Synthesis of 3-((2,4-dichlorophenoxy)methyl)-2-methoxybenzoic acid (Compound 6-1)
  • Step 7-1 Synthesis of tert-butyl (3-((2,4-dichlorophenoxy)methyl)benzyl)carbamate (INT 7-A)
  • Step 7-2 Synthesis of (3-((2,4-dichlorophenoxy)methyl)phenyl)methanamine (Compound 7-1)
  • Step 8-1 Synthesis of methyl 5-(bromomethyl)-2-iodobenzoate (INT 8-A)
  • Step 8-2 Synthesis of methyl 5-((2,4-dichlorophenoxy)methyl)-2-iodo-benzoate (INT 8-B)
  • Step 8-3 Synthesis of methyl 5-((2,4-dichlorophenoxy)methyl)-2-methylbenzoate (INT 8-C)
  • Step 8-4 Synthesis of 5-((2,4-dichlorophenoxy)methyl)-2-methylbenzoic acid (Compound 8-1′
  • Step 9-1 Synthesis of methyl 4-bromo-6-(hydroxymethyl)picolinate (INT 9-A)
  • Step 9-2 Synthesis of methyl 4-bromo-6-((2-chloro-4-(trifluoromethyl)phenoxy)-methyl)picolinate (INT 9-B)
  • Step 9-3 Synthesis of 4-bromo-6-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)picolinic acid (Compound 9-1)
  • Step 10-1 Synthesis of methyl 3-(((5-(trifluoromethyl)pyridin-2-yl)oxy)methyl)-benzoate (INT 10-A)
  • Step 11-1 Synthesis of methyl 3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-5-cyclopropylbenzoate (INT 11-B)
  • the reaction vial was capped and heated at 100° C. overnight.
  • the reaction was further degassed and additional tricyclohexyl phosphine (6.62 mg, 23.6 ⁇ mol), cyclopropylboronic acid (52.7 mg, 614 ⁇ mol), and palladium diacetate (5.30 mg, 23.6 ⁇ mol) were added.
  • the reaction mixture was filtered through Celite rinsing with EA and concentrated in vacuo. The residue was taken up in EA, washed with sat.
  • Step 12-1 Synthesis of methyl 3-(((2,4-dichlorophenyl)amino)methyl)benzoate (INT 12-A)
  • Step 15-1 Synthesis of methyl 3-(((2,4-dichlorophenyl)thio)methyl)benzoate (INT 15-A)
  • Step 17-1 3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)benzonitrile (INT-17-1)
  • Step 17-2 5-(3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)phenyl)-1H-1,2,3,4-tetrazole (INT-31)
  • a solution of 3-bromobenzyl alcohol in DMF is treated with NaH and benzylbromide to form 1-((benzyloxy)methyl)-3-bromobenzene that is converted to a Grignard reagent in a separate step by dissolving in dry THE and treating with Mg.
  • the Grignard reagent is reacted with DABSO, sulfuryl chloride and ammonium hydroxide according to Woolven, H. et al. ( Org. Lett. 13:4876, 2011) to provide the O-benzyl protected sulfonamide, Intermediate 19-A.
  • INT 19-A is treated with base, DPPA and acetic acid according to the method of Lockhurst, C. A. et al. ( Tet.
  • a compound of Formula (I) wherein A is phenyl and R is carboxylic acid is dissolved in DMF and cooled to 0° C.
  • Ethyl chloroformate (1.2 eq.) and N-methyl morpholine (1.3 eq.) are added successively and mixture is stirred 10 minutes.
  • Hydroxylamine (2 eq.) in methanol is added and the reaction is allowed to warm to room temperature and stir overnight. Routine workup and purification gives the desired N-hydroxyamide product.
  • 3-Iodobenzyl alcohol is converted to Intermediate 22-A according to the Mitsunobu conditions described in Scheme 2, step 1.
  • the aryl iodide is converted to an alkylphosphinate using a palladium catalyzed cross coupling reaction (Pd(OAc) 2 and PPh 3 as ligand) described by Grady, H. L. (“Preparation of arylphosphinic acid derivatives as building blocks for binding sites”, Retrospective Theses and Dissertations, 10373, 1992) that uses methyl phosphinate in acetonitrile in the presence of NMM as a base.
  • the aryl phosphinic acid product is obtained from hydrolysis of the alkylphosphinate in aqueous HCl.
  • 3-Bromobenzyl alcohol is converted to Intermediate 23-A according to the Mitsunobu conditions described in Scheme 2, step 1.
  • the aryl bromide is converted to a dialkylphosphonate using a palladium catalyzed cross coupling reaction (Pd(OAc) 2 and CM-Phos as ligand) described by Fu, C. W. et al. ( Org. Lett. 17:5906, 2015) that uses diisopropylphosphite in alcohol solvent with DIPEA as a base.
  • the aryl phosphonic acid product is achieved from hydrolysis of the dialkylphosphonate in aqueous HCl.
  • Step 31-3 Synthesis of methyl 6-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)picolinate (Compound 31-C)
  • Step 31-6 Synthesis of methyl 4-ethyl-6-(hydroxymethyl)picolinate (INT 31-E)
  • Step 31-7 Synthesis of methyl 6-(chloromethyl)-4-ethylpicolinate (INT 31-F)
  • Step 31-8 Synthesis of methyl 6-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-4-ethylpicolinate (INT 31-G)
  • Step 32-3 Synthesis of methyl 3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-5-cyanobenzoate (INT 32-C)
  • Step 32-3 Synthesis of 3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-5-cyanobenzoic acid (Compound 32-1)
  • Step 33-1 Synthesis of methyl 3-((2-formylphenoxy)methyl)benzoate (INT 33-A)
  • Step 33-2 Synthesis of methyl 3-((2-(difluoromethyl)phenoxy)methyl)benzoate (INT 33-B)
  • Step 34-1 Synthesis of methyl 3-((2-bromo-4-(trifluoromethyl)phenoxy)methyl)benzoate (INT 34-A)
  • Step 34-2 Synthesis of methyl 3-((2-cyclopropyl-4-(trifluoromethyl)phenoxy)methyl) benzoate (INT 34-B)
  • a 15 mL pressure tube containing a mixture of INT 34-A (300 mg, 771 ⁇ mol) in toluene (4 mL) was charged with potassium phosphate (491 mg, 2.31 mmol), tricyclohexylphosphine (32.4 mg, 116 ⁇ mol), cyclopropylboronic acid (132 mg, 1.54 mmol), and palladium (II) acetate (17.3 mg, 77.1 ⁇ mol).
  • the tube was sealed, and the resulting orange suspension was stirred at 100° C. for 13.5 hours, then cooled to room temperature and partitioned between Et 2 O and H 2 O. The aqueous layer was back-extracted with Et 2 O (2 ⁇ ).
  • Step 35-1 Synthesis of methyl 3-(((3-chloro-5-(trifluoromethyl)pyridin-2-yl)oxy)methyl)benzoate (INT 35-A)
  • Step 35-2 Synthesis of 3-(((3-chloro-5-(trifluoromethyl)pyridin-2-yl)oxy)methyl)benzoic acid (Compound 35-1)
  • Step 36-1 Synthesis of methyl 2-fluoro-3-((2-iodo-4 trifluoromethyl)phenoxy)-methyl)benzoate (INT 36-A)
  • Step 36-2 Synthesis of methyl 2-fluoro-3-((4-(trifluoromethyl)-2-((trimethylsilyl) ethynyl)phenoxy)methyl)benzoate (INT 36-B)
  • Step 36-3 Synthesis of 3-((2-ethynyl-4-(trifluoromethyl)phenoxy)methyl)-2-fluorobenzoic acid (Compound 36-1)
  • Step 37-5 Synthesis of methyl 3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-2-ethylbenzoate (INT 37-E)
  • Step 37-6 Synthesis of 3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-2-ethylbenzoic acid (Compound 37-1)
  • Step 38-1 Synthesis of methyl 3-((tert-butoxycarbonyl)amino)-5-methylbenzoate (INT 38-A)
  • Step 38-2 Synthesis of methyl 3-(bromomethyl)-5-((tert-butoxycarbonyl)amino)benzoate (INT 38-B)
  • Step 38-3 Synthesis of methyl 3-((tert-butoxycarbonyl)amino)-5-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)benzoate (INT 38-C)
  • Step 38-4 Synthesis of methyl 3-amino-5-((2-chloro-4-(trifluoromethyl)phenoxy)methyl) benzoate (INT 38-D)
  • Step 38-5 Synthesis of methyl 3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-5-(dimethylamino)benzoate (INT 38-E)
  • Step 38-6 Synthesis of 3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-5-(dimethylamino) benzoic acid (Compound 38-1)
  • Step 39-4 Synthesis of 6-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-4-propylpicolinic acid (Compound 39-1)
  • Step 40-1 Synthesis of 3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl) benzenesulfonamide (INT 40-A)
  • Step 40-2 Synthesis of 3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)benzenesulfonic acid (Compound 40-1)
  • Step 41-2 Synthesis of 4-methyl-6-((naphthalen-2-yloxy)methyl)picolinic acid (Compound 41-1)
  • Step 42-2 Synthesis of 4-ethyl-6-((naphthalen-2-yloxy)methyl)picolinic acid (Compound 42-1)
  • PBr 3 (1.61 mL, 16.9 mmol) was added to a solution of Br 2 (700 ⁇ L, 13.7 mmol) in hexanes (10.0 mL) at 0° C. The mixture was stirred at 22° C. for 1 h. 4-Hydroxypyridine-2,6-dicarboxylic acid (1.00 g, 5.46 mmol) was added, and the mixture was stirred at 90° C. for 6 h. The mixture was cooled and diluted with CHCl 3 (50 mL). Anhydrous MeOH (50 mL) was added dropwise at 0° C., and the mixture was stirred at 22° C. for 1 h.
  • Step 43-2 Synthesis of methyl 4-bromo-6-(hydroxymethyl)pyridine-2-carboxylate (INT 43-B)
  • Step 43-3 Synthesis of methyl 4-bromo-6-(bromomethyl)pyridine-2-carboxylate (INT 43-C)
  • PBr 3 (450 ⁇ L, 4.74 mmol) was added to a solution of INT 43-B (690 mg, 2.80 mmol) in CHCl 3 (35.0 mL) at 0° C. The mixture was stirred at 22° C. for 5 h, cooled to 0° C., and diluted with sat. aq. K 2 CO 3 (25.0 mL). The aq. phase was extracted with EA (3 ⁇ 30 mL), and the combined organic layers were washed with brine (20 mL), dried (Na 2 SO 4 ), filtered, and concentrated.
  • Step 43-4 Synthesis of methyl 4-bromo-6-((2-chloro-4-(trifluoromethyl)phenoxy)methyl) pyridine-2-carboxylate (INT 43-D)
  • Step 43-5 Synthesis of methyl 4-bromo-6-((2-chloro-4-(trifluoromethyl)phenoxy)methyl) pyridine-2-carboxylate (INT 43-E)
  • Aqueous 2 M NaOH (299 ⁇ L 0.150 mmol) was added to a solution of INT 43-E (74.0 mg, 0.20 mmol) in MeOH (1 mL) and THE (1 mL) at 22° C. The mixture was stirred at 22° C. for 2 h and concentrated. The residue was acidified with aq. 2 M HCl (pH 2) and diluted with H 2 O (10 mL). The aq. phase was extracted with EA (3 ⁇ 10 mL), and the combined organic layers were washed with brine (10 mL), dried (Na 2 SO 4 ), filtered, and concentrated.
  • Step 44-1 Synthesis of methyl 3-bromo-5-((2-chloro-4-(trifluoromethyl)phenoxy)methyl) benzoate (INT 44-A)
  • Step 44-2 Synthesis of methyl 3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-5-(2-methyloxazol-5-yl)benzoate (INT 44-B)
  • Step 44-3 Synthesis of 3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-5-(2-methyloxazol-5-yl)benzoic acid (Compound 44-1)
  • Step 45-2 Synthesis of 3-(3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)phenyl)-1H-1,2,4-triazole (Compound 45-2)
  • Step 46-1 Synthesis of 3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-N-methoxy-N-methyl benzamide (INT 46-A)
  • Step 46-2 Synthesis of 3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)benzaldehyde (INT 46-B)
  • Step 46-3 Synthesis of 2-(3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)phenyl)-1H-imidazole (Compound 46-1)
  • Step 47-1 Synthesis of 1-(3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)phenyl)ethan-1-one (INT 47-A)
  • Step 47-2 Synthesis of 2-bromo-1-(3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl) phenyl)ethan-1-one (INT 47-B)

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