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

Abstract

To provide methods for modulating MRGPR X4.SOLUTION: Methods are provided for modulating MRGPR X4 generally, or more specifically, for treating a MRGPR X4 dependent condition, respectively, by contacting the MRGPR X4 with, or administering to a subject in need thereof, an effective amount of a compound having the structure of Formula (I): (I) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] Related Applications This application is related to U.S. Provisional Application Nos. 62 / 825,741, filed March 28, 2019, 62 / 849,095, filed May 16, 2019, 62 / 864,306, filed June 20, 2019, 62 / 938,277, filed November 20, 2019, 62 / 955,967, filed December 31, 2019, and 62 / 959,799, filed January 10, 2020, each of which is incorporated herein by reference in its entirety. [Background technology]

[0002] background The present invention relates to modulators of the Mas-related G protein-coupled receptor X4, products containing same, and methods of their use and preparation.

[0003] Mas-related G protein receptors (MRGPRs) are a group of orphan receptors with restricted expression in very specific tissues. Little is known about the function of most of these receptors. There are eight related receptors in this class expressed in humans, only four of which have readily identifiable orthologs in other species (i.e., MRGPRs D, E, F, and G). The other four receptors (MRGPRs X1, X2, X3, and X4) have no counterparts in species other than humans based on homology. Summary of the Invention

[0004] The present invention is based, in part, on the identification that functional MRGPR A1 in mice corresponds, at least in part, to human MRGPR X4. These receptors mediate disorders including chronic itch (e.g., pruritus), inflammatory disorders, autoimmunity, skin disorders, cardiovascular disease, pulmonary 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, pulmonary smooth muscle, and dorsal root ganglia. Both MRGPR A1 and MRGPR X4 are now recognized as receptors for (or susceptible to activation by) circulating bilirubin and its metabolites, and are therefore important for itch sensation in conditions of elevated bilirubin, such as cholestatic pruritus. In addition, MRGPR X4 is activated by several additional components of bile, including bile acids and their metabolites, and heme metabolites, including bilirubin and urobilin. Although bile acids and bilirubin are highly elevated in cholestatic pruritus, urobilin, a potent mediator of itch induction in mouse models, may be important for itch sensation in urobilin-elevated states such as uremic pruritus. Therefore, as described in more detail below, modulating MRGPR X4 may enable the treatment of autoimmune diseases such as psoriasis, multiple sclerosis, Steven Johnson's syndrome, and other chronic itch conditions.

[0005] Thus, in one embodiment, MRGPR X4 is administered in combination with an effective amount of a compound having the structure of formula (I): [ka] or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein n, x, A, Q1, Q2, R, R 1 , R 2 , R 3 , R 4 , and R 5 is defined as follows:

[0006] In another embodiment, there is provided a method for treating an MRGPR X4-dependent condition by administering to a subject in need of treatment an effective amount of a compound having the structure of Formula (I), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof.

[0007] In more specific embodiments, the MRGPR X4-dependent condition is one or more of an itch-related condition, a pain-related condition, an inflammation-related condition, or an autoimmune disorder.

[0008] In another embodiment, there is provided a pharmaceutical composition comprising an effective amount of 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.

[0009] In another embodiment, there is provided a compound having one or more of the structures disclosed herein, or pharmaceutically acceptable isomers, racemates, hydrates, solvates, isotopes, or salts thereof.

[0010] In further embodiments, prodrugs and / or metabolites of compounds having the structure of formula (I) are also provided. In the case of prodrugs, the compound (i.e., prodrug) can be administered to a subject, which is then converted in vivo to a compound having the structure of formula (I). In the case of metabolites, following administration of a compound having the structure of formula (I) to a subject, such a compound can be converted in vivo to an active metabolite. [Brief explanation of the drawings]

[0011] [Figure 1] 1 shows in vitro activation of MRGPR X4 by the heme metabolites bilirubin, biliverdin, urobilin, urobilinogen, and stercobilin. [Figure 2A]Induction of itch in wild-type mice by urobilin (FIG. 2A) and urobilin, bilirubin, and deoxycholic acid (FIG. 2B) compared with vehicle (VEH) is shown. [Figure 2B] Induction of itch in wild-type mice by urobilin (FIG. 2A) and urobilin, bilirubin, and deoxycholic acid (FIG. 2B) compared with vehicle (VEH) is shown. [Figure 3A] The bilirubin stability (Figure 3A) and bilirubinergic activity (Figure 3B) of MRGPR X4 after 24 h of storage under various temperature and light storage conditions (time zero (freshly prepared), room temperature in the dark, -20 °C in the dark, room temperature laboratory light, and room temperature 400 nm blue light). [Figure 3B] The bilirubin stability (Figure 3A) and bilirubinergic activity (Figure 3B) of MRGPR X4 after 24 h of storage under various temperature and light storage conditions (time zero (freshly prepared), room temperature in the dark, -20 °C in the dark, room temperature laboratory light, and room temperature 400 nm blue light). [Figure 4A] Urobilin stability (Figure 4A) and urobilinergic activity (Figure 4B) of MRGPR X4 after 24 h of storage under various temperature and light storage conditions: time zero (freshly prepared), room temperature in the dark, -20 °C in the dark, room temperature in laboratory light, and room temperature in blue light. [Figure 4B] Urobilin stability (Figure 4A) and urobilinergic activity (Figure 4B) of MRGPR X4 after 24 h of storage under various temperature and light storage conditions: time zero (freshly prepared), room temperature in the dark, -20 °C in the dark, room temperature in laboratory light, and room temperature in blue light. DETAILED DESCRIPTION OF THE INVENTION

[0012] As described above, the present invention relates to modulators of MRGPR X4, products containing the same, and methods for their use and preparation. The present invention is based, in part, on the identification of MRGPR A1 as a functional counterpart to human MRGPR X4 in mice. These receptors mediate disorders including chronic and intermittent itch (e.g., pruritus), inflammatory disorders, autoimmune disorders, skin disorders, and adverse skin reactions to drugs, as well as infectious diseases. More specifically, both MRGPR A1 and MRGPR X4 are expressed in sensory neurons and dorsal root ganglia. Both MRGPR A1 and MRGPR X4 are receptors for (or are sensitive to activation by) circulating bilirubin and its metabolites, and are therefore now recognized to be important for itch sensation in conditions of elevated bilirubin, such as cholestatic pruritus and end-stage renal failure. Furthermore, MRGPR X4 is also activated by bile acids and their metabolites, which are also elevated in cholestatic pruritus. Furthermore, urobilin, an oxidation product of the heme metabolite urobilinogen, which is excreted exclusively by the kidney, is a potent agonist of MRGPR X4 and pruritogens and may therefore be important for itch sensation in urobilin-elevated conditions such as uremic pruritus, kidney disease, and end-stage renal failure. Therefore, modulation of MRGPR X4 may enable the treatment of autoimmune diseases such as psoriasis, multiple sclerosis, Stevens-Johnson syndrome, atopic disorders such as atopic dermatitis, and other chronic itch conditions, which are discussed in more detail below.

[0013] MRGPRs appear to be sensory receptors that recognize the external environment for exogenous or endogenous signals / chemicals. These receptors may respond to multiple chemical ligands / agonists. For example, MRGPR X4 recognizes bilirubin, bile acids, and urobilin as agonist signals. In certain embodiments, the molecules of the present invention regulate MRGPR X4 by functioning as inverse agonists that can block multiple chemicals and / or as competitive antagonists that can specifically block individual ligands. In one embodiment, such regulation is selective to other MRGPRs, such as MRGPR X1, X2, and / or X3.

[0014] Thus, in one embodiment, MRGPR X4 is administered in combination with an effective amount of a compound having the structure of formula (I): [ka] or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: n is 0 or 1, x is 0, 1, or 2; A is aryl or heteroaryl; Q1 and Q2 are both CR 10 Or, either Q1 or Q2 is CR 10 and the other is N, Z is -O-, -S-, -N(R 11 )-, -CH2-, or -C≡C-; Each R 10 is H or alkyl, R is -(CH2) m C(=O)OR 12 , -(CH2) m NHR 13 , -(C=O)NR 14 R 15 , --CHOH, --CN, haloalkyl, carbocyclic, heterocyclic, or carboxylic acid isostere; m is 0 or 1, R 11 , R 12 , and R 13 are the same or different and are each H or alkyl; R 14 is H and R 15 is H, -SO2CH3, carbocycle, heterocycle, or alkyl substituted with 0, 1, 2, or 3 substituents selected from -OH, -CN, -NR'R'', C(=O)OH, C(=O)NR'R'', -SO2OH, alkoxy, carbocycle, or heterocycle, where R' and R'' are individually H or alkyl; or R 14 and R 15 together with the nitrogen atom to which they are attached form a heterocyclic ring, R 1 is H or alkyl, R 2 is halo, cyano, amino, alkyl, alkoxy, carbocycle, or heterocycle; R 3 , R 4 , and R 5 are the same or different and are absent or, if present, are one of cyano, nitro, halogen, alkyl, haloalkyl, cyanoalkyl, alkoxy, haloalkoxy, -(C=O)alkyl, -(C=O)NHalkyl, carbocycle, heterocycle, -O-carbocycle, or -O-heterocycle; Any two R and R 2 together with the atoms to which they are attached form a heterocyclic ring, Any two R 3 , R 4 , R 5 , and R 10 together with the atoms to which they are attached form a carbocyclic or heterocyclic ring, Each occurrence of a carbocycle or heterocycle is substituted with 0, 1, 2, or 3 substituents individually selected from halogen, hydroxyl, oxo, halo, alkyl, haloalkyl, alkoxy, haloalkoxy, carbocycle, or heterocycle.

[0015] By "modulate" MRGPR X4 is meant that the compound interacts with MRGPR X4 such that it functions as an inverse agonist and / or a competitive antagonist for the receptor. In one embodiment, such modulation is partially or completely selective relative to other MRGPRs, such as MRGPR X1, X2, and / or X3.

[0016] "MRGPR" refers to one or more of the Mas-related G protein-coupled receptors, a group of orphan receptors with restricted expression in highly specialized tissues (e.g., sensory neurons and dorsal root ganglia) and barrier tissues. There are eight related receptors in this class expressed in humans, only four of which have readily identifiable orthologs in other species (i.e., MRGPRs D, E, F, and G). The other four receptors (MRGPRs X1, X2, X3, and X4) have no counterparts in non-human species based on homology.

[0017] "Effective amount" refers to the amount of a particular drug sufficient to achieve a desired effect in a subject being treated with that drug. Ideally, an effective amount of a drug is an amount sufficient to inhibit or treat a disease without causing substantial toxicity to the subject. The effective amount of a drug will depend on the subject being treated, the severity of the affliction, and the method of administration of the pharmaceutical composition. How to determine an effective amount of the disclosed compounds sufficient to achieve a desired effect in a subject will be understood by those skilled in the art in light of this disclosure.

[0018] "Alkyl" refers to saturated or unsaturated, straight- or branched-chain alkyl groups having 1 to 8 carbon atoms, in some embodiments 1 to 6 carbon atoms, in some embodiments 1 to 4 carbon atoms, and in some embodiments 1 to 3 carbon atoms. Examples of 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. Examples of branched-chain alkyl groups include, but are not limited to, isopropyl, isobutyl, sec-butyl, t-butyl, neopentyl, isopentyl, and 2,2-dimethylpropyl groups. Unsaturated alkyl includes alkenyl and alkynyl as defined below.

[0019] "Alkenyl" refers to saturated, straight-chain, or branched-chain alkenyl groups having 2 to 8 carbon atoms, in some embodiments 2 to 6 carbon atoms, in some embodiments 2 to 4 carbon atoms, and in some embodiments 2 to 3 carbon atoms. An alkenyl group is an unsaturated hydrocarbon containing at least one carbon-carbon double bond. Examples of lower alkenyl groups include, but are not limited to, vinyl, propenyl, butenyl, pentenyl, and hexenyl.

[0020] "Alkynyl" refers to straight- or branched-chain alkynyl groups having 2 to 8 carbon atoms, in some embodiments 2 to 6 carbon atoms, in some embodiments 2 to 4 carbon atoms, and in some embodiments 2 to 3 carbon atoms. An alkynyl group is an unsaturated hydrocarbon containing at least one carbon-carbon triple bond. Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, and hexynyl.

[0021] "Halo" or "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0022] "Hydroxy" refers to --OH.

[0023] "Cyano" refers to -CN.

[0024] Amino refers to -NH, -NHalkyl, or N(alkyl), where alkyl is as defined above. Examples of amino include, but are not limited to, -NH, -NHCH, -N(CH), and the like.

[0025] "Haloalkyl" refers to an alkyl as defined above in which one or more hydrogen atoms have been replaced with a halogen. Examples of lower haloalkyl groups include, but are not limited to, -CF3, -CHF2, and the like.

[0026] "Alkoxy" refers to an alkyl, as defined above, attached through an oxygen atom (i.e., -O-alkyl). Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, n-butoxy, isopropoxy, sec-butoxy, tert-butoxy, and the like.

[0027] "Alkoxy" refers to an alkyl as defined above attached through an oxygen atom (i.e., -O-alkyl). Examples of lower haloalkoxy groups include, but are not limited to, -OCF3, and the like.

[0028] "Cycloalkyl" refers to alkyl groups that form a ring structure, which may be substituted or unsubstituted, and the ring may be either fully saturated, partially unsaturated, or fully unsaturated, provided that, where there is unsaturation, conjugation of π electrons within the ring does not result in aromaticity. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. In some embodiments, cycloalkyl groups have 3 to 8 ring members, while in other embodiments, the number of ring carbon atoms ranges 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, as well as fused rings, such as, but not limited to, decalinyl.

[0029] An "aryl" group is a cyclic aromatic hydrocarbon that does 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. In some embodiments, aryl groups contain 6 to 14 carbons in the ring portion of the group. The terms "aryl" and "aryl group" include fused rings in which at least one ring, but not all rings, are aromatic, such as fused aromatic-aliphatic ring systems (e.g., indanyl, tetrahydronaphthyl, etc.). In one embodiment, aryl is phenyl or naphthyl; in another embodiment, aryl is phenyl.

[0030] "Carbocycle" refers to an alkyl group that forms a ring structure that may be substituted or unsubstituted, where the ring is either fully saturated, partially unsaturated, or fully unsaturated, and where there is unsaturation, conjugation of the π electrons within the ring may result in aromaticity. In one embodiment, a carbocycle includes a cycloalkyl, as defined above. In another embodiment, a carbocycle includes an aryl, as defined above.

[0031] "Heterocycle" refers to aromatic and non-aromatic ring moieties containing three or more ring members, one or more of which is a heteroatom, such as, but not limited to, N, O, S, or P. In some embodiments, heterocycles contain 3 to 20 ring members, while other such groups have 3 to 15 ring members. At least one ring contains a heteroatom, but not all rings in a polycyclic system need contain heteroatoms. For example, a dioxolanyl ring and a benzdioxolanyl ring system (a methylenedioxyphenyl ring system) are both heterocyclyl groups within the meaning herein.

[0032] Heterocyclyl groups also include fused ring species, including those in which an aromatic group is fused with a non-aromatic group. Heterocyclyl groups also include polycyclic ring systems containing heteroatoms, such as, but not limited to, quinuclidyl, and include heterocyclyl groups having substituents, including, but not limited to, alkyl, halo, amino, hydroxy, cyano, carboxy, nitro, thio, or alkoxy groups, attached to one of the ring members. Heterocyclyl groups, as defined herein, can be heteroaryl groups or partially or fully saturated cyclic groups containing at least one ring heteroatom. Heterocyclyl groups include, but are not limited to, pyrrolidinyl, furanyl, tetrahydrofuran, 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, adeninyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups.

[0033] "Heteroaryl" refers to an aromatic ring moiety containing five or more ring members, one or more of which is a heteroatom such as, but not limited to, N, O, and S. Heteroaryl groups include, but are not limited to, 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, imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, quinoxalinyl, and quinazolinyl groups. The terms "heteroaryl" and "heteroaryl group" include fused ring compounds in which at least one ring is aromatic, but not all rings are required to be aromatic, including tetrahydroquinolinyl, tetrahydroisoquinolinyl, indolyl, and 2,3-dihydroindolyl.

[0034] "Carboxylic acid isostere" refers to a group that serves as a substitute for a carboxylic acid group (i.e., -COOH). The use of a carboxylic acid isostere may be preferred over a carboxylic acid group for several reasons, including increased selectivity, reduced side effects, reduced toxicity, improved pharmacokinetics, increased stability, and / or simplified synthesis. Carboxylic acid isosteres include hydroxamic acids, acylcyanamides, sulfonamides, phosphonic acids, phosphinic acids, cyanoacetamides, sulfonates, sulfonamides, acylsulfonamides, arylsulfonamides, sulfonylureas, tetrazoles, thiazolidinediones, oxazolidinedione, isoxazoles, isothiazolesquaric 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-dione, 6-hydroxy-1,3-dioxin-4-one, 3-hydroxypyridin-4(1H)-one, and oxadiazolones.

[0035] In one embodiment, the carboxylic acid isostere may be acyclic and may have one of the following structures: a is alkyl, carbocycle, or heterocycle, and each of the carbocycle and heterocycle is R 2 may be singly or multiply substituted): [ka]

[0036] In another embodiment, the carboxylic acid isostere may be cyclic and have one of the following structures: [ka]

[0037] "Isomers" is used herein to encompass all chiral, diastereomeric, or racemic forms of a structure unless a particular stereochemistry or isomeric form is specifically indicated. Such compounds may be optical isomers enriched or resolved at any or all asymmetric atoms, with any degree of enrichment, as is apparent from the depiction. Both racemic and diastereomeric mixtures, as well as individual optical isomers, can be synthesized to be substantially free of their enantiomeric or diastereomeric partners, and all are within the scope of certain embodiments of the present invention. Isomers resulting from the presence of chiral centers include pairs of non-superimposable isomers called "enantiomers." Single enantiomers of a pure compound are optically active (i.e., they can rotate the plane of plane-polarized light and are designated R or S).

[0038] "Isolated optical isomer" means a compound that has been substantially purified from the corresponding optical isomer of the same formula. For example, the isolated isomer can 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 by weight, or at least 98% pure by weight, or at least 99% pure by weight.

[0039] "Substantially enantiomerically or diastereomerically" pure means a level of enantiomeric or diastereomeric enrichment of one enantiomer relative to the other of at least about 80%, and more specifically greater than 80%, 85%, 90%, 95%, 98%, 99%, 99.5% or 99.9%.

[0040] The terms "racemate" and "racemic mixture" refer to an equal mixture of two enantiomers. Racemates are labeled "(±)" because they lack optical activity (i.e., they do not rotate plane-polarized light in either direction because the constituent enantiomers cancel each other out). All compounds bearing an asterisk (*) adjacent to a tertiary or quaternary carbon are optically active isomers and can be purified from their respective racemates and / or synthesized by appropriate chiral syntheses.

[0041] A "hydrate" is a compound that exists in combination with water molecules. The combination can contain a stoichiometric amount of water, such as a monohydrate or dihydrate, or can contain a random amount of water. As used herein, "hydrate" refers to a solid form; i.e., a compound in an aqueous solution may be hydrated, but is not a hydrate as the term is used herein.

[0042] A "solvate" is similar to a hydrate, except that a solvent other than water is present. For example, methanol or ethanol can form an "alcoholate," which can also be stoichiometric or non-stoichiometric. As used herein, the term "solvate" refers to a solid form, i.e., a compound in a solvent solution may be solvated, but is not a solvate as the term is used herein.

[0043] "Isotope" refers to an atom 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 in which one or more atoms are replaced by an isotope of that atom. For example, carbon-12, the most common form of carbon, has six protons and six neutrons, 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). Fluorine has many isotopes, with fluorine-19 being the longest-lived. Thus, isotopes of compounds having the structure of Formula (I) include, but are not limited to, compounds of Formula (I) in which one or more carbon-12 atoms are replaced with carbon-13 and / or carbon-14 atoms, compounds of Formula (I) in which one or more hydrogen atoms are replaced with deuterium and / or tritium, and / or compounds of Formula (I) in which one or more fluorine atoms are replaced with fluorine-19.

[0044] "Salt" generally refers to an organic compound, such as a carboxylic acid or an amine, in its ionic form, combined with a counterion. For example, salts formed between an acid in its anionic form and a cation are called "acid addition salts." Conversely, salts formed between a base in its cationic form and an amine are called "base addition salts."

[0045] The term "pharmaceutically acceptable" refers to a drug that is approved for human consumption and is generally non-toxic. For example, the term "pharmaceutically acceptable salt" refers to a non-toxic inorganic or organic acid and / or base addition salt (see, for example, Lit et al., Salt Selection for Basic Drugs, Int. J. Pharm., 33, 201-217, 1986) (incorporated herein by reference).

[0046] Pharmaceutically acceptable base addition salts of the compounds of the present invention include 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.

[0047] Pharmaceutically acceptable acid addition salts can be prepared from inorganic or organic acids. Examples of inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, sulfuric acid, and phosphoric acid. Suitable organic acids can be selected from the aliphatic, alicyclic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic acid classes of organic acids, including formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, gluconic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, glucuronic acid, maleic acid, fumaric acid, pyruvic acid, aspartic acid, glutamic acid, benzoic acid, anthranilic acid, 4-hydroxybenzoic acid, ... phenylacetic acid, mandelic acid, hippuric acid, malonic acid, oxalic acid, embonic (pamoic) acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, pantothenic acid, trifluoromethanesulfonic acid, 2-hydroxyethanesulfonic acid, p-toluenesulfonic acid, sulfanilic acid, cyclohexylaminosulfonic acid, stearic acid, alginic acid, beta-hydroxybutyric acid, salicylic acid, -galactaric acid, and galacturonic acid.

[0048] Although pharmaceutically unacceptable salts generally are not useful as pharmaceuticals, such 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.

[0049] In another embodiment, a method of treating a subject having an MRGPR X4-dependent condition is provided, the method comprising administering to the subject a pharmaceutically effective amount of a compound having the structure of Formula (I): [ka] or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: n is 0 or 1, x is 0 or 1, A is aryl or heteroaryl; Q1 and Q2 are both CR 10 Or, either Q1 or Q2 is CR 10 and the other is N, Z is -O-, -S-, -N(R 11 )-, -CH2-, or -C≡C-; Each R 10 is H or alkyl, R is -(CH2) m C(=O)OR 12 , -(CH2) m NHR 13 , -(C=O)NR 14 R 15 , --CHOH, --CN, haloalkyl, carbocyclic, heterocyclic, or carboxylic acid isostere; m is 0 or 1, R 11 , R 12 , and R 13 are the same or different and are each H or alkyl; R 14 is H and R 15 is H, -SO2CH3, carbocycle, heterocycle, or -OH, -CN, -NR'R'', C(=O)OH, C(=O)NR'R'', -SO2OH, alkoxy, carbocycle, or heterocycle, where R' and R'' are alkyl substituted with 0, 1, 2, or 3 substituents independently selected from H or alkyl; R 14 and R 15 together with the nitrogen atom to which they are attached form a heterocyclic ring, R 1 is H or alkyl, R 2 is halo, cyano, alkyl, alkoxy, carbocycle, or heterocycle; R 3 , R 4 , and R 5 are the same or different and are absent or, if present, are one of cyano, nitro, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, carbocycle, heterocycle, -O-carbocycle, or -O-heterocycle; Any two R and R 2 together with the atoms to which they are attached form a heterocyclic ring, Any two R 3 , R 4 , R 5 , and R 10 together with the atoms to which they are attached form a carbocyclic or heterocyclic ring, Each occurrence of a carbocycle or heterocycle is substituted with 0, 1, 2, or 3 substituents individually selected from halogen, oxo, halo, alkyl, haloalkyl, alkoxy, haloalkoxy, carbocycle, or heterocycle.

[0050] As used herein, the phrase "MRGPR X4-dependent condition" refers to a condition in which activation, hypersensitization, or desensitization of MRGPR X4 by natural or synthetic ligands initiates, mediates, maintains, or enhances a pathological condition. For example, it is known that some itch or pain is caused by elevated levels of bilirubin and its metabolites or bile acids in patients suffering from pruritus, atopic diseases, or other autoimmune or inflammatory diseases. MRGPR X4 has been found to be sensitive to (or activated by) bilirubin and its metabolites (including urobilin or bile acids). Without being limited by theory, it should be understood that regulating MRGPR X4 can alleviate the sensation of itch or pain.

[0051] In some embodiments, the MRGPR X4-dependent condition is a condition caused by the activation of MRGPR X4 by bile acids. As used herein, the term "bile acid" includes primary bile acids (e.g., bile acids, chenodeoxycholic acid), conjugated bile acids, also known 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. In some embodiments, the bile acid analogs are farnesoid X receptor (FXR) agonists. Thus, the compounds of the present disclosure can be used to treat MRGPR X4-dependent conditions caused by the activation of MRGPR X4 by bile acids and that would benefit from modulating MRGPR X4.

[0052] In some embodiments, the MRGPR X4-dependent condition is an itch-related condition, a pain-related condition, an autoimmune condition, or an autoimmune or inflammatory disorder.

[0053] As used herein, the phrase "itch-associated condition" refers to any condition associated with pruritus (including acute and chronic pruritus). The itch sensation can arise, for example, from the peripheral nervous system (e.g., cutaneous or neuropathic itch) or the central nervous system (e.g., neuropathic, neurogenic, or psychogenic itch). Thus, in one embodiment, the methods of the present invention are directed to treating chronic itch, cholestatic pruritus; contact dermatitis; allergic blepharitis; anemia, atopic dermatitis; bullous pemphigoid; candidiasis; chickenpox, cholestasis, end-stage renal failure; hemodialysis; contact dermatitis; atopic dermatitis; dermatitis herpetiformis; diabetes; drug allergies; dry skin; dyshidrotic dermatitis; ectopic eczema; erythrasma; folliculitis; fungal skin infections; hemorrhoids, herpes; HIV infection; Hodgkin's disease; hyperthyroidism; iron deficiency anemia; kidney disease; leukemia; porphyria; primary biliary cholangitis, primary sclerosing cholangitis, and urticaria. Liver diseases including Laguire syndrome, progressive familial intrahepatic cholestasis, intrahepatic cholestasis of pregnancy, nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), biliary atresia, chronic hepatitis B, chronic viral hepatitis, drug-induced liver injury (DILI), hepatic fibrosis, cholestatic liver disease, and alcoholic liver disease; lymphoma; malignant tumors; multiple myeloma; neurodermatitis; onchocerciasis; Paget's disease; lice infestation; polycythemia vera; lichen planus; lichen sclerosus; pruritus ani; pseudorabies; psoriasis; rectal prolapse; scabies; schistosomiasis; scleroderma, severe stress, stasis dermatitis (stasia) dermatitis); swimmer's itch; thyroid disease; tinea cruris; uremic pruritus; rosacea; cutaneous amyloidosis; scleroderma; acne; wound healing; itchy eyes; and itch-related conditions such as hives.

[0054] As used herein, the phrase "pain-related condition" refers to any pain resulting from a medical condition. Thus, in one embodiment, the methods of the present invention are directed to treating acute pain, advanced prostate cancer, AIDS-related pain, ankylosing spondylitis, arachnoiditis, arthritis, arthrofibrosis, ataxic cerebral palsy, autoimmune atrophic gastritis, avascular necrosis, back pain, Beyset's disease, burning mouth syndrome, bursitis, cancer pain, carpal tunnel syndrome, cauda equina syndrome, central pain syndrome, cerebral palsy, cervical stenosis, Charcot-Marie-Tooth (CMT) disease, and chronic fatigue syndrome. (CFS), chronic functional abdominal pain (CFAP), chronic pain, chronic pancreatitis, lung collapse (pneumothorax), complex regional pain syndrome (RSD), corneal neuropathic pain, Crohn's disease, degenerative disc disease, Dercum's disease, dermatomyositis, diabetic peripheral neuropathy (DPN), dystonia, Ehlers-Danlos syndrome (EDS), endometriosis, eosinophilia-myalgia syndrome (EMS), erythromygia, fibromyalgia, gout, headache, herniated disc, hydrocephalus, intercostal neuralgia , interstitial cystitis, irritable bowel syndrome (IBS), juvenile dermatitis (dermatomyositis), knee injury, lower limb pain, lower back pain and hematuria syndrome, lupus, Lyme disease, sponge kidney disease (MSK), dysesthesias, mesothelioma, migraine, musculoskeletal pain, myofascial pain, myositis, neck pain, neuropathic pain, occipital neuralgia, osteoarthritis, Paget's disease, Parsonage-Turner syndrome, pelvic pain, peripheral neuropathy, phantom limb pain, compressed nerve, polycystic kidney disease, polymyalgia rheumatica, polymyalgia In some embodiments, the present invention provides for the treatment of pain-related conditions such as psoriasis, porphyria, post-herniorrhaphy pain syndrome, post-mastectomy pain syndrome, post-stroke pain, post-thoracotomy pain syndrome, post-herpetic neuralgia (shingles), post-polio syndrome, primary lateral sclerosis, psoriatic arthritis, pudendal neuralgia, radiculopathy, Raynaud's disease, rheumatoid arthritis (RA), sacroiliac joint dysfunction, sarcoidosis, Scheuermann's kyphosis, sciatica, scoliosis, shingles (Herpes Zoster), Sjogren's syndrome, spasmodic torticollis, sphincter of Oddi dysfunction, spinocerebellar ataxia (SCA ataxia), spinal cord injury, lumbar spinal stenosis, syringomyelia, Tarlov's cyst, transverse myelitis, trigeminal neuralgia, neuropathic pain, ulcerative colitis, vascular pain, and vulvodynia.

[0055] As used herein, the term "autoimmune disorder" or "inflammatory disorder" refers to a disease or disorder arising from and / or directed against an individual's own tissues or organs, or their co-isolation or expression, or a condition resulting from them. Typically, various clinical and laboratory markers of autoimmune disease may be present, including, but not limited to, hypergammaglobulinemia, high levels of autoantibodies, antigen-antibody complex deposits in tissues, clinical benefit from corticosteroid or immunosuppressive treatment, and lymphoid cell aggregates in affected tissues. Thus, in one embodiment, methods of the present invention are provided for treating autoimmune disorders such as chronic inflammation, multiple sclerosis, Stevens-Johnson syndrome, appendicitis, bursitis, colitis, cystitis, dermatitis, phlebitis, reflex sympathetic dystrophy / complex regional pain syndrome (RSD / CRPS), rhinitis, tendonitis, tonsillitis, acne vulgaris, reactive airways disease, asthma, respiratory tract infections, autoinflammatory diseases, celiac disease, chronic prostatitis, diverticulitis, glomerulonephritis, hidradenitis suppurativa, hypersensitivity, enteropathy, epithelial bowel 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, psoriasis, pulmonary inflammation, chronic obstructive pulmonary disease, cardiovascular disease, and vasculitis.

[0056] As used herein, the term "administration" refers to providing a compound or a pharmaceutical composition comprising a compound described herein. The compound or composition can be administered to a subject by another person, or it can be self-administered by the subject. Non-limiting examples of routes of administration are oral, parenteral (e.g., intravenous), or topical.

[0057] As used herein, the term "treatment" refers to an intervention that improves the signs or symptoms of a disease or pathological condition. As used herein, the terms "treatment," "treat," and "treating" in relation to a disease, pathological condition, or symptom also refer to any observable beneficial effect of treatment. A beneficial effect can be demonstrated, for example, by delaying the onset of clinical symptoms of a disease in a susceptible subject, reducing the severity of some or all clinical symptoms of a disease, delaying the progression of a disease, reducing the number of disease recurrences, improving the overall health or well-being of the subject, or other parameters well known in the art that are specific to a particular disease. A preventive treatment is a treatment administered to a subject who does not show signs of a disease or who shows only early signs, with the aim of reducing the risk of developing a pathological condition. A therapeutic treatment is a treatment administered to a subject after the onset of signs and symptoms of a disease.

[0058] As used herein, the term "subject" refers to an animal (e.g., a mammal such as a human). A subject treated according to the methods described herein may be a subject diagnosed with an MRGPR X4-dependent condition, such as an itch-related condition, a pain-related condition, or an autoimmune disorder. Diagnosis can be performed by any method or technique known in the art. One skilled in the art will understand that a subject treated according to the present disclosure may have undergone standard testing or may have been identified without testing as an at-risk subject due to the presence of one or more risk factors associated with a disease or condition.

[0059] In another embodiment, the method of treating a subject having an MRGPR X4-dependent condition (e.g., an itch-related condition, a pain-related condition, an autoimmune condition, or an autoimmune disorder) described herein further comprises administering to the subject a pharmaceutically effective amount of a second therapeutic agent. In one embodiment, the itch-related condition is a liver disease. In one embodiment, the second therapeutic agent is a liver disease therapeutic agent. In one embodiment, the agent treating a liver disease is ursodeoxycholic acid (UDCA), norursodeoxycholic acid, cholestyramine, stanozolol, naltrexone, rifampicin, alisol B23-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 (TRβ) agonist, or any combination thereof.

[0060] Examples of FXR agonists that can be used in the methods described herein include obeticholic acid, tulofexolate 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, altenusin, tropifexor (LJN452), nidufexor, tulofexolate isopropyl, fexaramine, silymarin, silybin, and hedragonic acid. 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, IOT-022, M-480, INV-33, RDX023-02, or any combination thereof. In one embodiment, the 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, tulofexolate isopropyl, fexaramine, PX20606 (PX-102), TERN-101, altenusin, silymarin, silybin, EYP-001, RDX023-2, AGN-242266, HPG-1860, MET-409, EP-024297, M-480, or cafestol).

[0061] In one embodiment, the 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 a PPAR alpha / gamma / delta pan agonist.

[0062] Examples of PPAR alpha agonists that can be used in the methods described herein include fenofibrate, ciprofibrate, pemafibrate, gemfibrozil, clofibrate, binifibrate, clinofibrate, clofibric acid, nicofibrate, pirifibrate, plafibride, lonifibrate, theofibrate, tocofibrate, and SRI 0171.

[0063] Examples of PPAR gamma agonists that can be used in the methods described herein 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.

[0064] Examples of PPAR delta agonists that can 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-ylmethylsirphanyl]-phenoxy}-acetic acid), GW0742 ([4-[[[2-[3-fluoro-4-(trifluoromethyl)phenyl]-4-methyl-5-triazolyl]methyl]thio]-2-methylphenoxy]acetic acid), L165041, HPP-593, and NCP-1046.

[0065] Examples of PPAR alpha / gamma agonists that can be used in the methods described herein include saroglitazar, aleglitazar, muraglitazar, tesaglitazar, and DSP-8658.

[0066] Examples of PPAR alpha / delta agonists that can be used in the methods described herein include elafibranor and T913659.

[0067] Examples of PPAR gamma / delta agonists that can be used in the methods described herein include conjugated linoleic acid (CLA) and T3D-959.

[0068] Examples of PPAR alpha / gamma / delta agonists that can be used in the methods described herein include IVA337 (lanifibranor), TTA (tetradecylthioacetic acid), bavaquinin, GW4148, GW9135, bezafibrate, lobeglitazone, 2-(4-(5,6-methylenedioxybenzo[d]thiazol-2-yl)-2-methylphenoxy)-2-methylpropanoic acid (MHY2013), and CS038.

[0069] Examples of thyroid hormone receptor beta agonists that can be used in the methods described herein 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-oxide-[1,3,2]-dioxaphosphonan).

[0070] The second therapeutic agent can be administered simultaneously, separately, or sequentially with the compound of the present disclosure. If administered simultaneously, the second therapeutic agent and the compound of the present disclosure can be administered in separate dosage forms or in the same dosage form.

[0071] In another embodiment, a method of treating a subject having an itch-associated condition is provided, comprising administering to the subject a therapeutically effective amount of a compound having the structure (I) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or pharmaceutically acceptable salt thereof. In one embodiment, the itch-associated condition is cholestatic pruritus, uremic pruritus, atopic dermatitis, dry skin, psoriasis, contact dermatitis, or eczema.

[0072] In one embodiment of Formula (I), n is 1 and R 1 is H, Z is O, and R is -C(=O)OR 12 and the compound has the structure of formula (II): [ka] or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein x, A, Q1, Q2, R 2 , R 3 , R 4 , R 5 , and R 12 is as defined above.

[0073] In one embodiment of Formula (I), n is 0, Z is O, and the compound has the structure of Formula (III): [ka] or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein x, A, Q1, Q2, R 2 , R 3 , R 4 , R 5 , and R 12 is as defined above.

[0074] In one embodiment of Formula (II), x is 0 and the compound has the structure of Formula (IV): [ka] or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein A, Q1, Q2, R 3 , R 4 , R 5 , and R 12 is as defined above.

[0075] In one embodiment of Formula (II), x is 1 and the compound has the structure of Formula (V): [ka] or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein A, Q1, Q2, R 2 , R 3 , R 4 , R 5 , and R 12 is as defined above.

[0076] In one embodiment of Formula (III), x is 0 and the compound has the structure of Formula (VI): [ka] or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein x, A, Q1, Q2, R 3 , R 4 , R 5 , and R 12 is as defined above.

[0077] In one embodiment of Formula (III), x is 1 and the compound has the structure of Formula (VII): [ka] or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein x, A, Q1, Q2, R 2 , R 3 , R 4 , R 5 , and R 12is as defined above.

[0078] In another embodiment, R 12 When is hydrogen in each of formulas (II)-(VII), the resulting carboxylic acid group (—COOH) is replaced with a carboxylic acid isostere as defined herein.

[0079] In one embodiment of Formula (I), n is 1 and R 1 is H, Z is O, and R is —(C═O)NHR 15 , —CHOH, —CHNH, or —CN, and the compound has the structure of formula (VIII), (IX), (X), or (XI), respectively: [ka] or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein x, A, Q1, Q2, R 2 , R 3 , R 4 , R 5 , and R 15 is as defined above.

[0080] In one embodiment of Formula (I), n is 0, Z is O, and R is —(C═O)NHR 15 , —CHOH, —CHNH, or —CN, and the compound has the structure of formula (XII), (XIII), (XIV), or (XV), respectively: [ka] or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein x, A, Q1, Q2, R 2 , R 3 , R 4 , R 5 , and R 15 is as defined above.

[0081] In one embodiment of formula (I), Z is -S-, -N(R 11)-, -CH2-, or -C≡C-, and the compound has the structure of formula (XVI), (XVII), (XVIII), or (IX), respectively; [ka] or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein n, x, A, Q1, Q2, R 2 , R 1 , R 2 , R 3 , R 4 , R 5 , and R 11 is as defined above.

[0082] In one embodiment of any one of formulas (I) through (XIX), A is aryl.

[0083] In one embodiment of any one of formulas (I) through (XIX), A is phenyl.

[0084] In one embodiment of any one of formulas (I) through (XIX), A is phenyl with the following points of attachment: [ka]

[0085] In one embodiment of any one of formulas (I) through (XIX), A is heteroaryl.

[0086] In one embodiment of any one of formulas (I) through (XIX), A is pyridine or pyrazine.

[0087] In one embodiment of any one of formulas (I) through (XIX), A is pyridine or pyrazine, each having the following points of attachment: [ka]

[0088] In one embodiment of any one of formulas (I) through (XIX), A is furan, thiophene, or isoxazole.

[0089] In one embodiment of any one of formulas (I) through (XIX), A is furan, thiophene, or isoxazole, each having the following points of attachment: [ka]

[0090] In one embodiment of any one of formulas (I) through (XIX), Q1 and Q2 are both CH.

[0091] In one embodiment of any one of formulas (I) through (XIX), Q 1 is CH and Q 2 is N.

[0092] In one embodiment of any one of formulas (I) through (XIX), Q1 is N and Q2 is CH.

[0093] In one embodiment of any one of formulas (I)-(XIX), R 1 is hydrogen.

[0094] In one embodiment of any one of formulas (I)-(XIX), R 1 is alkyl.

[0095] In one embodiment of any one of formulas (I)-(XIX), R 1 is methyl.

[0096] In one embodiment of Formula (I), the compound has the structure of Formula (XX): [ka] or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein x, R 2 , R 3 , R 4 , R5, R 5 , and R12 is as defined above.

[0097] In one embodiment of Formula (I), the compound has the structure of Formula (XXI): [ka] or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 3 , R 4 , R 5 , and R 12 is as defined above.

[0098] In one embodiment of Formula (I), the compound has the structure of Formula (XXII): [ka] or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 2 , R 3 , R 4 , R 5 , and R 12 is as defined above.

[0099] In another embodiment, R 12 When is hydrogen in each of the above formulas (XX)-(XXII), the resulting carboxylic acid group (—COOH) is replaced with a carboxylic acid isostere as defined herein.

[0100] In one embodiment of Formula (I), the compound has the structure of Formula (XXIII): [ka] or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 3 , R 4 , and R 5 is as defined above.

[0101] In one embodiment of Formula (I), the compound has the structure of Formula (XXIV): [ka] or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 2 , R 3 , R 4 , and R 5 is as defined above.

[0102] In another embodiment, the carboxylic acid group (—COOH) in each of formulas (XXIII) and (XXIV) above is replaced with a carboxylic acid isostere, as defined herein.

[0103] In one embodiment of any one of formulas (I) through (XXIV), n is 0.

[0104] In one embodiment of any one of formulas (I) through (XXIV), n is 1.

[0105] In one embodiment of any one of formulas (I) through (XXIV), x is 0.

[0106] In one embodiment of any one of formulas (I) through (XXIV), x is 1.

[0107] In one embodiment of any one of formulas (I) through (XXIV), x is 2.

[0108] In one embodiment of any one of formulas (I) through (XXIV), A is aryl.

[0109] In one embodiment of any one of formulas (I) through (XXIV), A is heteroaryl.

[0110] In one embodiment of any one of formulas (I) through (XXIV), Z is —O—.

[0111] In one embodiment of any one of formulas (I) through (XXIV), Z is -S-.

[0112] In one embodiment of any one of formulas (I)-(XXIV), Z is —N(R 11 )-.

[0113] In one embodiment of any one of formulas (I) through (XXIV), Z is -CH2-.

[0114] In one embodiment of any one of formulas (I) through (XXIV), Z is or -C≡C-.

[0115] In one embodiment of any one of formulas (I)-(XXIV), R is —(CH) m C(=O)OR 12 is.

[0116] In one embodiment of any one of formulas (I)-(XXIV), R is —(CH) m NHR 13 is.

[0117] In one embodiment of any one of formulas (I)-(XXIV), R is —(C═O)NR 14 R 15 is.

[0118] In one embodiment of any one of formulas (I)-(XXIV), R is —CH 2 OH.

[0119] In one embodiment of any one of formulas (I) through (XXIV), R is —CN.

[0120] In one embodiment of any one of formulas (I) through (XXIV), R is haloalkyl.

[0121] In one embodiment of any one of formulas (I) through (XXIV), R is a carbocycle.

[0122] In one embodiment of any one of formulas (I) through (XXIV), R is a heterocycle.

[0123] In one embodiment of any one of formulas (I) through (XXIV), m is 0.

[0124] In one embodiment of any one of formulas (I) through (XXIV), m is 1.

[0125] In one embodiment of any one of formulas (I)-(XXIV), R 14 is H and R 15 is H, —SO2CH3, carbocycle, heterocycle, or alkyl substituted with 0, 1, 2, or 3 substituents selected from —OH, —CN, —NR′R″, C(═O)OH, C(═O)NR′R″, —SO2OH, alkoxy, carbocycle, or heterocycle, and R′ and R″ are individually H or alkyl.

[0126] In one embodiment of any one of formulas (I)-(XXIV), R 14 and R 15 together with the nitrogen atom to which they are attached form a heterocyclic ring.

[0127] In one embodiment of any one of formulas (I)-(XXIV), R 1 is H.

[0128] In one embodiment of any one of formulas (I)-(XXIV), R 1 is alkyl.

[0129] In one embodiment of any one of formulas (I)-(XXIV), R 2 is a halo.

[0130] In one embodiment of any one of formulas (I)-(XXIV), R 2 is cyano.

[0131] In one embodiment of any one of formulas (I)-(XXIV), R 2 is an amino.

[0132] In one embodiment of any one of formulas (I)-(XXIV), R 2 is alkyl.

[0133] In one embodiment of any one of formulas (I)-(XXIV), R 2 is an alkoxy.

[0134] In one embodiment of any one of formulas (I)-(XXIV), R 2 is a carbocyclic ring.

[0135] In one embodiment of any one of formulas (I)-(XXIV), R 2 is a heterocycle.

[0136] In one embodiment of any one of formulas (I)-(XXIV), R 3 , R 4 , and R 5 are the same or different and are absent or, if present, are either cyano, cyanoalkyl, nitro, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, —(C═O)alkyl, —(C═O)NHalkyl, carbocycle, heterocycle, —O-carbocycle, or —O-heterocycle.

[0137] In one embodiment of any one of formulas (I)(XXIV), R 3 , R 4 , and R 5 are the same or different and are absent or, if present, are either cyano, nitro, halogen, alkyl, haloalkyl, alkoxy, or haloalkoxy.

[0138] In one embodiment of any one of formulas (I)-(XXIV), R 3 , R 4 , and R 5 are the same or different and are absent, or, if present, are either -CN, -NO2, -F, -Cl, -Br, -CH3, -CF3, -CHF2, -C(CH3)3, -OCH3, or -OCF3.

[0139] In one embodiment of any one of formulas (I)-(XXIV), R 3 , R 4 , and R 5 any two of, taken together with the atoms to which they are attached, form a carbocycle or heterocycle that is unsubstituted or substituted with 1, 2, or 3 substituents independently selected from halogen, hydroxyl, oxo, halo, alkyl, haloalkyl, alkoxy, haloalkoxy, carbocycle, or heterocycle.

[0140] In one embodiment of any one of formulas (I)-(XXIV), R 3 and R 4 taken together with the atoms to which they are attached form a heterocycle that is unsubstituted or substituted with 1, 2, or 3 substituents independently selected from halogen, hydroxyl, oxo, halo, alkyl, haloalkyl, alkoxy, haloalkoxy, carbocycle, or heterocycle, as shown below. [ka]

[0141] In one embodiment of any one of formulas (I)-(XXIV), R 3 and R 4 taken together with the atoms to which they are attached form a carbocycle that is unsubstituted or substituted with 1, 2, or 3 substituents independently selected from halogen, oxo, halo, alkyl, haloalkyl, alkoxy, haloalkoxy, carbocycle, or heterocycle, as shown below. [ka]

[0142] Representative compounds of formula (I), and, where applicable, formulas (II) through (XXIV), include any one of the compounds set forth in Table A below, as well as pharmaceutically acceptable isomers, racemates, hydrates, solvates, isotopes, or salts thereof. For this purpose, representative compounds are identified herein by their respective "Compound Numbers," which may also be abbreviated as "Compound No." or "Cpd. No."

[0143] [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12] [Table 1-13] [Table 1-14] [Table 1-15] [Table 1-16] [Table 1-17] [Table 1-18] [Table 1-19] [Table 1-20] [Table 1-21] [Table 1-22] [Table 1-23]

[0144] In more specific embodiments, the compound has the following structure: or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof: [ka]

[0145] In more specific embodiments, the compound has the following structure: or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof: [ka]

[0146] In more specific embodiments, the compound has the following structure: or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof: [ka]

[0147] In more specific embodiments, the compound has the following structure: or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof: [ka]

[0148] In more specific embodiments, the compound has the following structure: or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof: [ka]

[0149] In more specific embodiments, the compound has the following structure: or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof: [ka]

[0150] In more specific embodiments, the compound has the following structure: or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof: [ka]

[0151] In more specific embodiments, the compound has the following structure: or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof: [ka]

[0152] In more specific embodiments, the compound has the following structure: or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof: [ka]

[0153] In more specific embodiments, the compound has the following structure: or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof: [ka]

[0154] In more specific embodiments, the compound has the following structure: or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof: [ka]

[0155] In more specific embodiments, the compound has the following structure: or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof: [ka]

[0156] In more specific embodiments, the compound has the following structure: or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof: [ka]

[0157] In more specific embodiments, the compound has the following structure: or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof: [ka]

[0158] In more specific embodiments, the compound has the following structure: or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof: [ka]

[0159] In more specific embodiments, the compound has the following structure: or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof: [ka]

[0160] In more specific embodiments, the compound has the following structure: or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof: [ka]

[0161] In more specific embodiments, the compound has the following structure: or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof: [ka]

[0162] In another embodiment, certain compounds of Formula (I), as well as compounds of Formulas (II) through (XXIV), where applicable, can have their carboxylic acid moieties substituted with carboxylic acid isostere groups, as described herein. Representative carboxylic acid isostere compounds derived from the representative compounds listed below are shown in Table B. [ka]

[0163] For this purpose, the carboxylic acid isostere groups used in the compounds of Table B are as follows: [ka]

[0164] [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4]

[0165] In other embodiments, prodrugs and / or metabolites of compounds of Formula (I), and Formulas (II)-(XXIV), are provided.

[0166] Thus, in one embodiment, prodrugs of the compounds of the present 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, but is not limited to, enzymatic (e.g., specific enzyme-catalyzed) and non-enzymatic (e.g., general or specific acid- or base-induced) chemical conversion of the prodrug to the active pharmacological substance.In general, such prodrugs are functional derivatives of the compounds of the present invention that can be easily converted into the compounds of the present invention in vivo.Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in Design of Prodrugs, ed. H. Bundgaard, Elsevier, 1985.

[0167] Thus, a "prodrug" is a substance that, when administered to a subject, is converted in vivo into an active pharmaceutical ingredient by the action of biochemicals in the subject's body, such as enzymes. Examples of prodrugs include esters of carboxylic acid groups, which can be hydrolyzed by endogenous esterases, such as those found in the bloodstream of humans and other mammals. In one embodiment, a substance is provided that can be administered to a subject, which is then converted in the subject's body to provide a compound having the structure of Formula (I), or the structure of any of Formulas (II)-(XXIV).

[0168] In this regard, prodrugs of carboxylic acids are typically esters and amides, which can be readily prepared from the corresponding carboxylic acids by known techniques. For example, in one embodiment, prodrugs can be generated by converting the carboxylic acid moiety of compounds of Formulae (I)-(VII) and (XVI)-(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. In another embodiment, the carboxylic acid moiety can incorporate a carbamoylmethyl, aminoalkyl, or amidoalkyl moiety to provide carbamoylmethyl, aminoalkyl, and amidoalkyl esters, respectively. In yet another embodiment, the carboxylic acid moiety can incorporate an ester of acylglycerol and bis(acyl-amino)propan-2-ol. In a further embodiment, the carboxylic acid moiety can incorporate an amide group, including N-hydroxyamide, N-acylsulfonamide, and N-acylsulfonylurea.

[0169] As used herein, a "metabolite" is a compound that, after administration to a subject, is converted within the subject's body to yield an active substance. Such conversion often involves hydrolysis, phosphorylation, and / or oxidation / reduction processes and can be mediated by any number of enzymes (e.g., esterases, phosphatases, cytochrome P450, etc.), as well as by different environments within the body (e.g., changes in pH).

[0170] In one embodiment, compounds of formula (I), and, where applicable, compounds of formulae (II)-(XXII), are modified to include metabolites of the parent compound. In another embodiment, compounds of formula (I), and compounds of formulae (II)-(XXII), are modified to have the "A-ring" carboxylic acid of formula (I) derivatized with a carbohydrate or amino acid compound. In a further embodiment, the A-ring carboxylic acid moiety is derivatized with glucuronic acid or the amino acid glycine to provide compounds of formulae (XXV) and (XXVI), respectively. [ka]

[0171] In certain embodiments, the present invention provides pharmaceutical compositions comprising any one of compounds of Formulas (I) to (XIV) together with at least one pharmaceutically acceptable carrier, diluent, or excipient. For example, the active compound is typically mixed with a carrier, diluted by a carrier, or enclosed within a carrier, which may be in the form of an ampoule, capsule, sachet, paper, or other container. When the active compound is mixed with a carrier, or when the carrier functions as a diluent, it may be a solid, semi-solid, or liquid material that acts as a vehicle, excipient, or medium for the active compound. The active compound may be adsorbed onto a granular solid carrier, for example, contained in a sachet. Some examples of suitable carriers are water, salt solution, alcohol, polyethylene glycol, 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 ether of cellulose, silicic acid, fatty acid, fatty acid amine, fatty acid monoglyceride and diglyceride, pentaerythritol fatty acid ester, polyoxyethylene, hydroxymethylcellulose, and polyvinylpyrrolidone.Similarly, carriers or diluents can comprise any sustained-release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with wax.

[0172] As used herein, the term "pharmaceutical composition" refers to a composition containing one or more of the compounds described herein, or pharmaceutically acceptable isomers, racemates, hydrates, solvates, isotopes, or salts thereof, formulated in a pharmaceutically acceptable carrier, which may also include other additives, and which is manufactured or sold with the approval of a government regulatory agency as part of a therapeutic regimen for the treatment of a mammalian disease. Pharmaceutical compositions can be formulated, for example, for oral administration in a unit dosage form (e.g., 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 matter and in a solvent system suitable for intravenous use), or in any other formulation described herein. Conventional procedures and ingredients for the selection and preparation of appropriate formulations can be found, for example, in The Science and Practice of Pharmacy, 21 st Ed., Lippencott Williams & Wilkins (2005), and in The National Formulary of the United States (USP 36 NF31), published in 2013.

[0173] In some embodiments, a pharmaceutical composition comprising a compound of any one of Formulas (I)-(XIV) together with at least one pharmaceutically acceptable carrier, diluent, or excipient further comprises a second therapeutic agent. In one embodiment, the second therapeutic agent is a drug for treating liver disease. In one embodiment, the drug for treating liver disease is ursodeoxycholic acid (UDCA), norursodeoxycholic acid, cholestyramine, stanozolol, naltrexone, rifampicin, alisol B23-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 (TRβ) agonist, or any combination thereof.

[0174] Examples of FXR agonists that can be used in the pharmaceutical compositions described herein include obeticholic acid, tulofexolate 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, altenusin, tropifexor (LJN452), and nifedipine. dufexor, tulofexolate 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, IOT-022, M-480, INV-33, RDX023-02, or any combination thereof. In one embodiment, the FXR agonist is a bile acid or analog thereof (e.g., obeticholic acid, INT-767, INT-787, tulofexolate isopropyl (WAY-362450), or BAR704) or a non-bile acid agonist (e.g., EDP-305, tropifexor, nidufexor, cilofexor, GW4064, tulofexolate isopropyl, fexaramine, PX20606 (PX-102), TERN-101, altenusin, silymarin, silybin, hedragonic acid, BAR502, EYP-001, RDX023-2, AGN-242266, HPG-1860, MET-409, EP024297, M-480, or cafestol).

[0175] In one embodiment, the 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 a combination thereof.

[0176] Examples of PPAR alpha agonists that can be used in the pharmaceutical compositions described herein include fenofibrate, ciprofibrate, pemafibrate, gemfibrozil, clofibrate, binifibrate, clinofibrate, clofibric acid, nicofibrate, pirifibrate, plafibride, lonifibrate, theofibrate, tocofibrate, and SRI 0171.

[0177] Examples of PPAR gamma agonists that can be used in the pharmaceutical compositions described herein 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.

[0178] Examples of PPAR delta agonists that can be used in the pharmaceutical compositions 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-ylmethylsirphanyl]-phenoxy}-acetic acid), GW0742 ([4-[[[2-[3-fluoro-4-(trifluoromethyl)phenyl]-4-methyl-5-triazolyl]methyl]thio]-2-methylphenoxy]acetic acid), L165041, HPP-593, and NCP-1046.

[0179] Examples of PPAR alpha / gamma agonists that can be used in the pharmaceutical compositions described herein include saroglitazar, aleglitazar, muraglitazar, tesaglitazar, and DSP-8658.

[0180] Examples of PPAR alpha / delta agonists that can be used in the pharmaceutical compositions described herein include elafibranor and T913659.

[0181] Examples of PPAR gamma / delta agonists that can be used in the pharmaceutical compositions described herein include conjugated linoleic acid (CLA) and T3D-959.

[0182] Examples of PPAR alpha / gamma / delta agonists that can be used in the pharmaceutical compositions described herein include IVA337 (lanifibranor), TTA (tetradecylthioacetic acid), bavaquinin, GW4148, GW9135, bezafibrate, lobeglitazone, 2-(4-(5,6-methylenedioxybenzo[d]thiazol-2-yl)-2-methylphenoxy)-2-methylpropanoic acid (MHY2013), and CS038.

[0183] Examples of thyroid hormone receptor beta agonists that can be used in the pharmaceutical compositions described herein include 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-oxide-[1,3,2]-dioxaphosphonane).

[0184] As used herein, the term "pharmaceutically acceptable carrier" refers to any component (e.g., a carrier capable of suspending or dissolving an active compound) other than the disclosed compounds or their pharmaceutically acceptable isomers, racemates, hydrates, solvates, isotopes, or salts, which has the properties of being non-toxic and non-inflammatory to patients. Excipients can include, for example, anti-adherents, antioxidants, binders, coatings, compression aids, disintegrants, dyes (colors), emollients, emulsifiers, fillers (diluents), film-forming agents or coatings, flavors, fragrances, flow agents (glidants), lubricants, preservatives, printing inks, adsorbents, suspending or dispersing agents, sweeteners, or hydrating water. Exemplary excipients include, but are not limited to, butylated hydroxytoluene (BHT), calcium carbonate, calcium phosphate (dibasic), calcium stearate, croscarmellose, cross-linked polyvinylpyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, hydroxypropyl cellulose, hydroxypropylmethylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methylparaben, microcrystalline cellulose, polyethylene glycol, polyvinylpyrrolidone, povidone, pregelatinized starch, propylparaben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethylcellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (corn), stearic acid, stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, and xylitol.

[0185] Preparation can be mixed with auxiliary agent that does not react adversely with active compound.Such additives can include wetting agent, emulsifying agent and suspending agent, salt for affecting osmotic pressure, buffer and / or coloring agent, preservative, sweetener or flavoring agent.Composition can also be sterilized if necessary.

[0186] The route of administration can be any route that effectively delivers the active compounds of the present invention to the appropriate or desired site of action, such as oral, nasal, pulmonary, buccal, subcutaneous, intradermal, transdermal, or parenteral, including intravenous, subcutaneous, and / or intramuscular. In one embodiment, the route of administration is oral. In another embodiment, the route of administration is topical.

[0187] The dosage form can be administered once a day, or more than twice a day, such as twice or three times a day. Alternatively, the dosage form can be administered less frequently than daily, such as every other day or every week, if found to be recommended by the prescribing physician or the drug's prescription information. The dosing regimen includes, for example, dose escalation as necessary or useful for the indication being treated, thus allowing the patient's body to adapt to the treatment, minimize or avoid undesirable side effects associated with the treatment, and / or maximize the therapeutic effect of the compound. Other dosage forms include delayed or controlled release dosage forms. Suitable dosing regimens and / or dosage forms include, for example, those described in the latest edition of the U.S. Physicians' Desk Reference, which is incorporated herein by reference.

[0188] In one embodiment, the present invention provides an oral pharmaceutical composition comprising a compound of any one of Formulas (I)-(XXIV) and at least one pharmaceutically acceptable oral carrier, diluent, or excipient. In certain embodiments, the present invention provides a topical pharmaceutical composition comprising a compound of any one of Formulas (I)-(XXIV) together with at least one pharmaceutically acceptable carrier, diluent, or excipient. For example, an oral pharmaceutical composition is provided for treating cholestatic pruritus, with a dosing regimen of, for example, once daily. In one embodiment, a topical pharmaceutical composition is provided for treating atopic dermatitis.

[0189] In another embodiment, a method for making a composition of a compound described herein is provided, comprising formulating a compound of the present invention with a pharmaceutically acceptable carrier or diluent. In some embodiments, the pharmaceutically acceptable carrier or diluent is suitable for oral administration. In some such embodiments, the method can further comprise formulating the composition into a tablet or capsule. In other embodiments, the pharmaceutically acceptable carrier or diluent is suitable for parenteral administration. In some such embodiments, the method further comprises lyophilizing the composition to form a lyophilized preparation.

[0190] In certain embodiments, the present invention provides compounds having the structure of any one of Formulas (I) to (XXIV). Such compounds can be synthesized using standard synthetic techniques known to those skilled in the art. For example, compounds of the present invention can be synthesized using appropriately modified synthetic procedures described in the following examples and reaction schemes. To this end, carboxylic acid isosteres and their substitution for the carboxylic acids disclosed herein can also be achieved using standard synthetic techniques known to those skilled in the art.

[0191] To this end, the reactions, processes, and synthetic methods described herein are not limited to the specific conditions described in the following experimental section, but rather are intended as a guide to those of appropriate skill in the art. For example, the reactions can be carried out in any suitable solvent or other reagent to effect the desired transformation. Generally, suitable solvents are protic or aprotic solvents that are substantially unreactive with the reactants, intermediates, or products at the temperatures at which the reactions are carried out (i.e., temperatures ranging from freezing to boiling). A given reaction can be carried out in one solvent or a mixture of two or more solvents. Depending on the particular reaction, solvents appropriate for the particular post-reaction workup can be used.

[0192] All reagents whose synthesis is not described in the experimental section are commercially available, known compounds, or can be prepared from known compounds by known methods by those skilled in the art. The compounds and intermediates produced according to the methods of the present invention may require purification. Purification of organic compounds is well known to those skilled in the art, and there may be several methods for purifying the same compound. In some cases, purification may not be necessary. In some cases, compounds may be purified by crystallization. In some cases, impurities may be removed using an appropriate solvent. In some cases, compounds may be purified by chromatography, particularly flash column chromatography, using dedicated or pre-packed silica gel cartridges and eluents such as gradients of solvents such as heptane, ether, ethyl acetate, acetonitrile, ethanol, etc. In some cases, compounds may be purified by preparative HPLC using the methods described.

[0193] The purification method described herein can provide compounds of the present invention having sufficiently basic or acidic functional groups in the form of salts, such as trifluoroacetate or formate salts for sufficiently basic compounds of the present invention, or ammonium salts for sufficiently acidic compounds of the present invention. This type of salt can be converted to its free base or free acid form, respectively, by various methods known to those skilled in the art, or can be used as a salt in subsequent biological assays. It should be understood that the specific form of the compound of the present invention isolated and described herein is not necessarily the only form in which the compound can be applied to biological assays to quantify specific biological activity.

[0194] Chemical names were generated using ChemDraw naming software (version 17.0.0.206) from PerkinElmer Informatics, Inc. In some cases, generally accepted names of commercially available reagents were used in place of names generated by the naming software. [Example]

[0195] General method 1 H NMR (400 MHz) spectra were obtained in deuterated chloroform (CDCl), deuterated methanol (CD3OD), or dimethyl sulfoxide-D6 (DMSO) solutions. HPLC retention times, purity, and mass spectra (LCMS) were obtained using one of the following methods:

[0196] Method 1: Agilent 1260 Infinity II System equipped with an Agilent Poroshell 120 EC-18, 2.7 μm, 4.6 x 100 mm column using HO with 0.1% formic acid as mobile phase A and MeCN with 0.1% formic acid as mobile phase B. An ESI detector in positive mode was used. The gradient was 20 to 95% mobile phase B over 5 minutes, followed by a hold at 95% for 3.8 minutes, then a return to 20% mobile phase B over 0.2 minutes. The flow rate was 1 mL / min.

[0197] Method 2: Agilent 1260 Infinity II System equipped with an Agilent Poroshell 120 EC-18, 2.7 μm, 4.6 x 100 mm column using 0.1% formic acid in HO as mobile phase A and 0.1% formic acid in MeCN as mobile phase B. An ESI detector in negative mode was used. The gradient was 20 to 95% mobile phase B over 5 minutes, followed by a hold at 95% for 3.8 minutes, then a return to 20% mobile phase B over 0.2 minutes. The flow rate was 1 mL / min.

[0198] Method 3: Agilent 1260 Infinity II System equipped with an Agilent Poroshell 120 EC-18, 2.7 μm, 4.6 x 100 mm column using 0.1% formic acid in HO as mobile phase A and 0.1% formic acid in MeCN as mobile phase B. An ESI detector in positive mode was used. The gradient was 20 to 95% mobile phase B over 5 minutes, followed by a hold at 95% for 3.8 minutes, then a return to 20% mobile phase B over 0.2 minutes. The flow rate was 1 mL / min.

[0199] Method 4: Agilent 1260 Infinity II System equipped with an Agilent Poroshell 120 EC-18, 2.7 μm, 4.6 x 100 mm column using HO with 0.1% formic acid as mobile phase A and MeCN with 0.1% formic acid as mobile phase B. An ESI detector in negative mode was used. The gradient was 10 to 95% mobile phase B over 12 minutes, followed by a 2-minute hold at 95%, then a 10% return to mobile phase B over 1 minute. The flow rate was 1 mL / min.

[0200] Method 5: Shimadzu LCMS-2020 system equipped with a KinetiX EVO C18 2.1 x 30 mm, 5 μm column using H2 with 0.025% NH3-H2O as 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 to 60% B over 0.8 min, then held at 60% B for 0.4 min, then returned to 0% B over 0.01 min, and held at 0% B for 0.34 min.

[0201] Method 6: Agilent 1200 / G6110A System equipped with a Chromolith Flash RP-18e 25 x 2.0 mm column using 0.0375% TFA in H2O as mobile phase A and 0.01875% TFA in MeCN as mobile phase B. The ESI mass detector was set in positive mode. The gradient was 5 to 95% B over 0.8 min, then held at 95% B for 0.4 min, then returned to 5% B over 0.01 min, and held at 5% B for 0.29 min.

[0202] Method 7: Shimadzu LCMS-2020 system equipped with a KinetiX EVO C18 2.1 x 30 mm, 5 μm column using HO containing 0.025% NH3 as 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 to 95% B over 0.8 min, then held at 95% B for 0.4 min, then returned to 5% B over 0.01 min, and held at 5% B for 0.34 min.

[0203] Method 8: Agilent 1200 / G6110A System equipped with an ACE Excel C18 2.1 x 30 mm, 5 μm column using HO containing 0.025% NH3 as mobile phase A and MeCN as mobile phase B. The ESI mass detector was set in negative mode. The gradient was 10 to 80% B over 1.2 minutes, held at 80% B for 0.4 minutes, then returned to 5% B over 0.01 minutes and held at 5% B for 0.39 minutes.

[0204] Method 9: Agilent 1100 System equipped with an Agilent Eclipse XDB-C18, 3.5 μm, 4.6 × 150 mm column using HO containing 0.1% trifluoroacetic acid as mobile phase A and methanol containing 0.1% trifluoroacetic acid as mobile phase B. The gradient was 5 to 95% B over 12 minutes, then held at 95% mobile phase B for 3 minutes, then returned to 5% mobile phase B for 1 minute. The flow rate was 1 mL / min.

[0205] Method 10: Shimadzu SCL-10A system equipped with an Agilent Eclipse XDB-C18, 3.5 μm, 4.6 × 150 mm column and a PE Sciex API 150 EX, using HO containing 0.1% trifluoroacetic acid as mobile phase A and methanol containing 0.1% trifluoroacetic acid as mobile phase B. The gradient was 5 to 95% B over 12 min, then held at 95% mobile phase B for 3 min, then returned to 5% mobile phase B for 1 min. The flow rate was 1 mL / min.

[0206] Method 11: Shimadzu SCL-10A system equipped with an Agilent Eclipse XDB-C18, 3.5 μm, 4.6 x 150 mm column and a PE Sciex API 150 EX, using HO containing 0.1% trifluoroacetic acid as mobile phase A and methanol containing 0.1% trifluoroacetic acid as mobile phase B. The gradient was 50 to 95% B over 4 min, then held at 95% mobile phase B for 4 min, then returned to 50% mobile phase B for 0.1 min. The flow rate was 1 mL / min.

[0207] Method 12: Waters Acquity system equipped with an Acquity UPLC BEH C18 1.7 μm, 2.1 × 50 mm column using HO containing 0.1% aluminum formate adjusted to pH 3.8 with formic acid as mobile phase A and acetonitrile as mobile phase B. The gradient was 5 to 100% over 9 minutes, followed by a 1 minute hold at 100% mobile phase B. The flow rate was 0.7 mL / min.

[0208] Method 13: Waters Acquity system equipped with an EVO C18 (5 μm, 3.0 × 50 mm) using a low pH buffer gradient of MeCN in HO (0.1% HCOOH) from 5% to 100% at 2.2 mL / min over 2.5 min, held at 100% for a total time of 3.5 min.

[0209] Pyridine, dichloromethane (DCM), tetrahydrofuran (THF), and toluene used in the procedures were from Aldrich Sure-Seal bottles kept under nitrogen (N). All reactions were magnetically stirred and at the external reaction temperature. Chromatography was typically performed using a Combiflash RF flash purification system (Teledyne Isco) equipped with a Redisep (Teledyne Isco) RF Gold normal-phase silica gel (SiO) column or similar system.

[0210] Preparative HPLC purification was typically performed using one of the following systems: 1) a Waters System equipped with a Waters 2489 uv / vis detector, Aquity QDA detector, and a Waters xBridge Prep C18 5 μm OBD, 30 × 1560 mm column, eluting with various gradients of HO / MeCN (0.1% formic acid) at a flow rate of 30 mL / min; or 2) a Phenomenex Synergi C18 150 × 30 mm, 4 μm column; mobile phase: [HO (0.225% formic acid)-MeCN]; B%: 55%–85%, 12 min), typically concentrated using a Genevac EZ-2.

[0211] The following additional abbreviations are used: ethyl acetate (EA), triethylamine (TEA), dimethyl sulfoxide (DMSO), silica gel (SiO2), azobisisobutyronitrile (AIBN), diisobutylaluminum hydride (DIBAL), trifluoroacetic acid (TFA), 4-dimethylaminopyridine (DMAP), diphenylphosphoryl azide (DPPA), benzoyl peroxide (BPO), 1,1'-bis(diphenylphosphino)ferrocene (dppf or DPPF), tetrahydrofuran (THF), 1,4-diazabicyclo[2.2.2]octane bis(sulfur dioxide) adduct (DABSO), azabenzotriazole tetramethyluronium hexafluorophosphate (HATU), hydroxybenzotriazole. Azole (HOBt), N-methylmorpholine (NMM), N-bromosuccinimide (NBS), diisopropylethylamine (DIPEA), diethyl azodicarboxylate (DEAD), 2-[2-(dicyclohexylphosphino)phenyl]-N-methylindole (CM-Phos), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC), isopropanol (IPA), dimethylformamide (DMF), dimethylacetamide (DMA), acetonitrile (MeCN or ACN), 1,1'-thiocarbonyldiimidazole (TCDI), petroleum ether (PE), not determined (ND), retention time (RT), molecular weight (MW), room temperature (rt), time (h), and not applicable (N / A).

[0212] Example 1 Synthesis of Compound 1-0, Compound 1-16, and other representative compounds [ka] [ka] Reagents: (i) bases (Na2CO3, K2CO3, KO t Bu), solvent (THF or DMF), ii. NaOH, solvent (THF, MeOH or DMF)

[0213] Step 1-1. Synthesis of methyl 3-((4-chloro-2-(trifluoromethyl)phenoxy)methyl)benzoate (Compound 1-0) [ka] To a stirred solution of methyl 3-(bromomethyl)benzoate (150 mg, 655 μmol) in MeCN (3 mL) was added 2-methyl-4-(trifluoromethyl)phenol (115 mg, 655 μmol) and K2CO3 (118 mg, 0.85 mmol). The reaction mixture was heated at 60 °C for 3 h, then cooled to room temperature and diluted with HO (3 mL). The aqueous layer was extracted with Et2O (2 × 6 mL) and EA (1 × 6 mL), and the combined organic layers were dried (Na2SO4), filtered, concentrated, and purified by SiO2 chromatography (EA / hexanes) to give 203 mg (77.4%) of methyl 3-((2-methyl-4-(trifluoromethyl)phenoxy)methyl)benzoate (compound 1-0) as a white solid. C 17 H 15 LCMS-ESI calculated for F3O3 (m / z): 324.3, found 346.1 [M+Na] + , t R =6.68 minutes (method 1).

[0214] The compounds listed in Table 1A were made using the procedure in Scheme 1.

[0215] [Table 3-1] [Table 3-2]

[0216] Step 1-2. Synthesis of 3-((2-methyl-4-(trifluoromethyl)phenoxy)methyl)benzoic acid (Compound 1-16) [ka] To a stirred solution of methyl 3-((2-methyl-4-(trifluoromethyl)-phenoxy)methyl)benzoate (Compound 1-0) (206 mg, 0.635 mmol) in THF (3 mL) was added 1 M NaOH (3 mL, 3.18 mmol). The reaction mixture was heated at 60 °C overnight, the volatiles were removed in vacuo, and the resulting aqueous layer was acidified with 3 M HCl. The resulting solution was filtered, extracted with EA and EtO, dried (Na SO ), filtered, and concentrated to give a crude solid, which was purified by reverse-phase SiO chromatography to give 155 mg (79%) of 3-((2-methyl-4-(trifluoromethyl)phenoxy)methyl)benzoic acid (Compound 1-16) as a white solid. 16 H 13 LCMS-ESI calculated for F3O3 (m / z): 310.2, found 333.1 [M+Na] + , t R =10.4 minutes. (Method 3).

[0217] The compounds listed in Table 1B were made using the procedure in Scheme 1.

[0218] [Table 4-1] [Table 4-2] [Table 4-3] [Table 4-4] [Table 4-5] [Table 4-6] [Table 4-7] [Table 4-8] [Table 4-9] [Table 4-10] [Table 4-11] [Table 4-12] [Table 4-13] [Table 4-14]

[0219] Example 2 Synthesis of Compound 2-1 and Other representative compounds [ka] [ka] Reagents: (i) PPh3, DIAD, THF, (ii) NaOH, solvent (THF, MeOH, or DMF)

[0220] Step 2-1. Synthesis of methyl 3-chloro-5-((2,4-dichlorophenoxy)methyl)benzoate (INT 2-A) [ka] To a stirred solution of methyl 3-chloro-5-hydroxybenzoate (100 mg, 0.50 mmol) in DCM (5 mL) was added triphenylphosphine (131 mg, 0.50 mmol) and DEAD (108.7 μL, 0.60 mmol). The reaction mixture was purged with N (3×) and stirred at 10 °C for 16 h (under an atmosphere of N), then concentrated and purified by flash SiO chromatography (EA / petroleum ether) to afford 150 mg (87.0%) of methyl 3-chloro-5-((2,4-dichlorophenoxy)methyl)benzoate (INT 2-A) as a pink solid. TLC (10% EA / petroleum ether): R f =0.50. 1 H NMR(400MHz, CDCl3-d)-d)δ7.99(d, J=1.8Hz, 2H), 7.70-7.66(m, 1H), 7.42(d, J=2 .6Hz, 1H), 7.34(d, J=2.4Hz, 1H), 6.87(d, J=8.8Hz, 1H), 5.14(s, 2H), 3.95(s, 3H).

[0221] Step 2-2. Synthesis of 3-chloro-5-((2,4-dichlorophenoxy)methyl)benzoic acid (compound 2-1) [ka] To a stirred solution of methyl 3-chloro-5-((2,4-dichlorophenoxy)methyl)benzoate (INT 2-A) (100 mg, 0.29 mmol) in MeOH (1 mL) and THF (1 mL) was added 2 M NaOH (0.43 mL, 0.87 mmol). The reaction mixture was heated at 30° C. for 1 h and then concentrated in vacuo. The resulting residue was purified by reverse-phase HPLC to afford 12.6 mg (13%) of 3-chloro-5-((2,4-dichlorophenoxy)methyl)benzoic acid (compound 2-1) as a white solid. 14 LCMS-ESI calculated for H9Cl3O3 (m / z): 331.5, found 328.8 [M−H] + , t R =0.72 minutes. 1H NMR (400MHz, DMSO-d6) δ7.99(s, 1H), 7.86(s, 1H), 7.77(s, 1H), 7.62(d, J=2.6Hz, 1H), 7.40(dd, J=2.6, 8.8Hz, 1H), 7.25(d, J=8.9Hz, 1H), 5.31(s, 2H).

[0222] The compounds listed in Table 2 were made using the procedure in Scheme 2.

[0223] [Table 5]

[0224] Example 3 Synthesis of Compound 3-1, Compound 3-2, and Other representative compounds [ka] [ka] Reagents: (i) bases (Na2CO3, K2CO3, KO t Bu), DMF, (ii) NaOH, solvent (THF, MeOH, or DMF).

[0225] Step 3-1. Synthesis of 3-((2-chloro-4-methylphenoxy)methyl)benzonitrile (INT3-A) [ka] To a stirred solution of 3-(bromomethyl)benzonitrile (500 mg, 2.55 mmol) in DMF (8 mL) was added 2-chloro-4-methylphenol (360 mg, 2.5 mmol) and Na2CO3 (0.81 g, 7.65 mmol). The reaction mixture was stirred overnight at room temperature and then quenched with 150 mL of HO. The resulting precipitate was collected, washed with HO (2 x 20 mL), and dried to give 600 mg (91.3%) of 3-((2-chloro-4-methylphenoxy)methyl)benzonitrile (INT 3-A). C 15 H12 LCMS-ESI calculated for CNO (m / z): 257.7, found 258.0 [M+H] + , t R =5.43 minutes. (Method 11).

[0226] The compounds listed in Table 3A were made using the procedure in Scheme 3, step 3-1, using 3-(bromomethyl)benzonitrile and 2,4-dichlorophenol.

[0227] [Table 6]

[0228] Step 3-2. Synthesis of 3-((2-chloro-4-methylphenoxy)methyl)benzoic acid (Compound 3-2) [ka] To a stirred solution of 3-((2-chloro-4-methylphenoxy)methyl)benzonitrile (INT3-A) (300 mg, 0.12 mmol) in MeOH (5 mL) was added a solution of NaOH (375 mg, 9.4 mmol) in HO (8 mL). The reaction vessel was sealed and stirred at 90 °C overnight, then cooled to room temperature and concentrated to remove MeOH. The aqueous layer was washed with EA and acidified with 4 N HCl. The resulting precipitate was collected to give 210 mg (65%) of 3-((2-chloro-4-methylphenoxy)methyl)benzoic acid (compound 3-2). C 15 H 13 LCMS-ESI calculated for C11O3 (m / z): 276.7, found 277.3 [M+H] + , t R =14.01 minutes. 1 H NMR (400MHz, CDCl3): 8.19(s, 1H), 8.06(d, J=8Hz, 1H), 7.77(d, J=8Hz, 1H), 7.53(t, J=8 Hz, 1H), 7.22(s, 1H), 6.99(d, J=8Hz, 1H), 6.86(d, J=8Hz, 1H), 5.18(s, 2H), 2.27(s, 3H).

[0229] The compounds listed in Table 3B were made using the procedure in Scheme 3, step 3-2.

[0230] [Table 7]

[0231] Example 4 Compound 4-1 and Synthesis of other representative compounds [ka] [ka] Reagents: (i) NBS, AIBN, CCl4, 100°C. (ii) See Scheme 1.

[0232] Step 4-1. Synthesis of methyl 3-(bromomethyl)-2-fluorobenzoate (INT-4A) [ka] To a stirred solution of methyl 2-fluoro-3-methylbenzoate (1.0 g, 5.95 mmol) in CCl4 (5 mL) was added NBS (1.06 g, 5.95 mmol) and AIBN (19.6 mg, 119 mmol). After stirring at 100 °C for 2 h, the reaction mixture was concentrated and the resulting residue was purified by SiO2 chromatography to give 858 mg (58%) of methyl 3-(bromomethyl)-2-fluorobenzoate (INT-4A) as a white solid. TLC (10% EA / petroleum ether): R f =0.50. LCMS-ESI (m / z) calculated for C9H8BrFO2: 245.97, found 247.0 [M+H] + , t R =0.86 minutes (method 6).

[0233] Step 4-2. Synthesis of methyl 3-((2,4-dichlorophenoxy)methyl)-2-fluorobenzoate (INT4-B) [ka] To a stirred solution of methyl 3-(bromomethyl)-2-fluorobenzoate (INT-4A) (500 mg, 2.02 mmol) in MeCN (2 mL) was added KCO (559.4 mg, 4.05 mmol) and 2,4-dichlorophenol (329.9 mg, 2.02 mmol). After stirring at 50 °C for 16 h, the reaction mixture was concentrated and the resulting residue was purified by SiO chromatography to give 537 mg (81%) of methyl 3-((2,4-dichlorophenoxy)methyl)-2-fluorobenzoate (INT4-B) as a white solid. TLC (10% EA / petroleum ether): R f =0.45. C 15 H 11 LCMS-ESI calculated for Cl2BrFO3 (m / z): 328.01, found 329.1 [M+H] + , t R =1.03 minutes (method 6).

[0234] Step 4-3. Synthesis of 3-((2,4-dichlorophenoxy)methyl)-2-fluorobenzoic acid (compound 4-1) [ka] To a stirred solution of methyl 3-((2,4-dichlorophenoxy)methyl)-2-benzoate (INT 4-B) (100 mg, 0.303 mmol) in MeOH (1 mL) and THF (1 mL) was added 2 M NaOH (455.7 μL, 0.9 mmol). After stirring at 10° C. for 16 h, the reaction mixture was concentrated and the resulting residue was purified by preparative HPLC to give 6.4 mg (7%) of 3-((2,4-dichlorophenoxy)methyl)-2-fluorobenzoic acid (compound 4-1) as a white solid. 14 LCMS-ESI calculated for H9Cl2FO3 (m / z): 313.99, found 312.9 [MH] + , t R =0.663 minutes (method 7). 1H NMR (400MHz, DMSO-d6) δ7.84(t, J=6.7Hz, 1H), 7.75(brt, J=7.0Hz, 1H), 7.60(d, J=2.4Hz, 1H), 7.42-7.30(m, 3H), 5.28(s, 2H).

[0235] Synthesis of Compounds 1-55 [ka] Step 4-4. Synthesis of methyl 3-(bromomethyl)-2-fluorobenzoate (INT 4-C) [ka] To a stirred solution of methyl 2-fluoro-3-methylbenzoate (1.0 g, 5.9 mmol) in CCl4 (20 mL) was added NBS (1.2 g, 6.5 mmol) and AIBN (98 mg, 0.59 mmol). The reaction mixture was heated to reflux for 3 h, then cooled to rt and concentrated in vacuo to give the crude product. The crude product was purified by SiO2 chromatography (EA / hexanes) to give 399 mg (27%) of methyl 3-(bromomethyl)-2-fluorobenzoate (INT4-C) as a white solid. LCMS-ESI (m / z) was not observed, t R = 5.05 minutes (method 7 minutes).

[0236] Step 4-5. Synthesis of methyl 3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-2-fluorobenzoate (INT4-D) [ka] To a stirred solution of INT4-C (449 mg, 1.82 mmol) in MeCN (4 mL) was added 2-chloro-4-(trifluoromethyl)phenol (357 mg, 1.82 mmol) and K2CO3 (327 mg, 2.36 mmol). After heating at 60 °C for 18 h, the reaction mixture was cooled to rt and diluted with HO (3 mL). The aqueous layer was extracted with Et2O (2 × 6 mL) and EA (6 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo to give a crude white solid, which was purified by SiO2 chromatography (EA / hexanes) to give 551.6 mg (83.7%) of methyl 3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-2-fluorobenzoate (INT 4-D) as a white solid. C 16 H 11 LCMS-ESI calculated for ClF4O3 (m / z): 362.7, found 363.1 [M+H] + , (Method 7 minutes).

[0237] Step 4-6. Synthesis of 3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-2-fluorobenzoic acid (1-55) [ka] To a stirred solution of INT 4-D (551 mg, 1.52 mmol) in THF (8 mL) was added 1 M NaOH (7.6 mL, 7.60 mmol). The reaction mixture was heated at 60 °C overnight, then concentrated in vacuo, diluted with 3 M HCl, extracted with EA and Et O, dried (Na SO ), filtered, and concentrated in vacuo. The resulting white solid was dissolved in MeCN (5 mL) and HO (5 mL) and lyophilized to give 460.5 mg (86.9%) of 3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-2-fluorobenzoic acid (compound 1-55) as a white solid. C 15 LCMS-ESI calculated for H9ClF4O3 (m / z): 348.68, found 349.1 [M+H] + , t R =10.28 min. (15 min purity). 1H NMR (500MHz, DMSO-d6) δ13.36(br s, 1H), 7.92-7.87(m, 2H), 7.83-7.80(m, 1H), 7.73(dd, J=8.5, 2.0Hz, 1H), 7.51(d, J=8.5Hz, 1H), 7.36(app t, J=7.5Hz, 1H), 5.40(s, 2H).

[0238] Synthesis of Compound 1-65 [ka] Step 4-7. Synthesis of methyl 3-fluoro-5-methylbenzoate (INT 4-E) [ka] A solution of 3-fluoro-5-methyl-benzoic acid (5 g, 32.4 mmol) and HSO (15.91 g, 162.2 mmol, 8.65 mL) in MeOH (30 mL) was stirred at 70 °C for 12 h. The reaction mixture was poured into HO (100 mL) and extracted with EA. The combined organic phases were dried and concentrated to give a residue that was purified by SiO chromatography (PE / EA) to give 4.5 g (82.5%) of methyl 3-fluoro-5-methyl-benzoate (INT 4-E) as a yellow oil. 1 H NMR (400MHz, CDCl3) δppm2.40(s, 3H) 3.92(s, 3H) 7.08(br d, J=9.26Hz, 1H) 7.51(br d, J=9.13Hz, 1H) 7.65(s, 1H).

[0239] Step 4-8. Synthesis of methyl 3-(bromomethyl)-5-fluorobenzoate (INT 4-F) [ka] A solution of methyl INT 4-E (4.5 g, 26.76 mmol), NBS (5.24 g, 29.44 mmol), and AIBN (219.71 mg, 1.34 mmol) in CCl (50 mL) was stirred at 70 °C for 12 h. The reaction was concentrated and purified by SiO chromatography (PE / EA) to give 4.9 g (74%) of crude methyl 3-(bromomethyl)-5-fluorobenzoate (INT 4-F) as a yellow oil. TLC (10:1 petroleum ether:EA):R f =0.70. 1H NMR (400MHz, CDCl3) δppm7.86(t, J=1.41Hz, 1H)7.64-7.67(m, 1H)7.31(dt, J=8.71, 2.06Hz, 1H), 4.48(s, 2H)3.94(s, 3H).

[0240] Step 4-9. Synthesis of methyl 3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-5-fluorobenzoate (INT 4-G) [ka] A mixture of INT 4-F (3 g, 12.1 mmol), 2-chloro-4-(trifluoromethyl)phenol (3.58 g, 18.2 mmol), and KCO (5.03 g, 36.4 mmol) in MeCN (50 mL) was stirred at 30 °C for 12 h. The reaction mixture was filtered and concentrated to give a residue that was purified by SiO chromatography (PE / EA) to give 2.4 g (55%) of methyl 3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-5-fluorobenzoate (INT 4-G) as a white solid. TLC (5:1 petroleum ether:EA):R f =0.60.

[0241] Step 4-10. Synthesis of 3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-5-fluorobenzoic acid (1-65) [ka] A mixture of INT 4G (2.4 g, 6.6 mmol) and NaOH (794 mg, 19.9 mmol) in THF (1 mL) and HO (0.5 mL) was stirred at 30° C. for 2 hours. The reaction mixture was acidified with 1N HCl and extracted with EA. The combined organic layers were dried (NaSO) and concentrated to provide a residue, which was dissolved in PE / EA and filtered. The filter cake was diluted with MeCN / HO and lyophilized to give 1.91 g (82%) of 3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-5-fluorobenzoic acid (compound 1-56) as a white solid. 15 LCMS-ESI calculated for H9ClF4O3 (m / z): 348.6, found 347.0 [M−H] + , t R =0.958 minutes. (Method 8). 1 H NMR (400MHz, CDCl3-d) δppm7.99(s, 1H) 7.77(br d, J=8.19Hz, 1H) 7.70(d, J=1.96Hz, 1H) 7.51(br d, J=8.68Hz, 2H) 7.03(d, J=8.56Hz, 1H) 5.26(s, 2H).

[0242] Synthesis of Compound 1-85 [ka]

[0243] Step 4-11. Synthesis of methyl 2-fluoro-5-methylbenzoate (INT 4-H) [ka] To a solution of 2-fluoro-5-methyl-benzoic acid (10 g, 64.9 mmol) in MeOH (200 mL) was added thionyl chloride (23.53 mL, 324.4 mmol) dropwise at 25 °C. After 0.5 h at 25 °C, the mixture was concentrated and purified by SiO chromatography (PE / EA) to give 10.6 g (97%) of methyl 2-fluoro-5-methylbenzoate (INT 4-H) as a colorless oil. TLC (1:1 petroleum ether:EA):R f =0.90.

[0244] Step 4-12. Synthesis of methyl 5-(bromomethyl)-2-fluorobenzoate (INT 4-I) [ka] To a solution of INT 4-H (8 g, 47.6 mmol) in CHCl (200 mL) was added NBS (10.16 g, 57.1 mmol) and AIBN (781.2 mg, 4.76 mmol). After 12 h at 70 °C, the reaction was diluted with HO (200 mL) and extracted into EA (3 × 100 mL). The combined organic layers were dried (NaSO), concentrated, and purified by SiO chromatography (PE / EA) to afford 10.6 g (97%) of methyl 5-(bromomethyl)-2-fluorobenzoate (INT 4-I) as a white solid contaminated with a second, unidentified product. TLC (10:1 petroleum ether:EA):R f = 0.4, 0.35. LCMS-ESI (m / z) calculated for C9H8BrFO2: 247.06, found 248.8 [M−H] + , t R =0.702 minutes. 1 H NMR (400MHz, CDCl3-d) δ8.01-7.94(m, 1H), 7.62-7.52(m, 1H), 7.17-7.10(m, 1H), 4.49(s, 2H), 3.95(s, 3H).

[0245] Step 4-13. Synthesis of methyl 5-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-2-fluorobenzoate (INT 4-J) [ka] To a solution of INT 4-I (4 g, 16.19 mmol) and 2-chloro-4-(trifluoromethyl)phenol (3.18 g, 16.19 mmol) in MeCN (30 mL) was added KCO (6.71 g, 48.57 mmol). After 2 h at 50 °C, the reaction mixture was filtered, concentrated, and purified by SiO2 chromatography (PE) to provide 1.7 g (29%) of methyl 5-((2-chloro-4-(trifluoromethyl)phenoxy(methyl)-2-fluorobenzoate) (INT 4-J) as a white solid. TLC (10:1 petroleum ether:EA):R f =0.40. C 16 H 11 LCMS-ESI calculated for ClF4O3 (m / z): 362.7, found 363.0 [MH] + , t R =1.07 minutes (method 6). 1 H NMR (400MHz, CDCl3-d) δ8.05 (dd, J=2.3, 6.7Hz, 1H), 7.72~7.63 (m, 2H), 7.55~7 .45(m, 1H), 7.26~7.15(m, 1H), 7.04(d, J=8.6Hz, 1H), 5.20(s, 2H), 3.97(s, 3H).

[0246] Step 4-14. Synthesis of 5-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-2-fluorobenzoic acid (1-85) [ka] To a solution of INT 4-J (1.7 g, 4.63 mmol) in HO (10 mL), THF (10 mL), and MeOH (5 mL) was added LiOH HO (582.33 mg, 13.88 mmol). After 2 h at 25 °C, HO (30 μL) was added to the reaction mixture, and the organic solvent was removed under reduced pressure to provide 1.57 g (97%) of 5-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-2-fluorobenzoic acid (compound 1-85) as a white solid. 15 LCMS-ESI calculated for H9ClF4O3 (m / z): 348.68, found 349.0 [MH] +, t R =0.925 minutes. (Method 6). 1 H NMR (400MHz, DMSO-d6) δ7.96-7.90(m, 1H), 7.87(d, J=2.0Hz, 1H), 7.72(dd, J=1.7, 8.7Hz , 1H), 7.66(dt, J=2.3, 5.3Hz, 1H), 7.44(d, J=8.6Hz, 1H), 7.36~7.28(m, 1H), 5.34(s, 2H).

[0247] Synthesis of Compound 1-101 [ka] Step 4-15. Synthesis of 4,4,5,5-tetramethyl-2-(2-methyl-4-(trifluoromethyl)phenyl)-1,3,2-dioxaborolane (INT 4-K) [ka] To a solution of 1-bromo-2-methyl-4-(trifluoromethyl)benzene (7.3 g, 30.5 mmol) in dioxane (100 mL) was added AcOK (11.99 g, 122.16 mmol, 4 equiv.), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (15.51 g, 61.1 mmol), and Pd(dppf)Cl.CHCl (2.49 g, 3.05 mmol). After stirring at 100 °C under N for 12 h, the mixture was filtered and the filtrate was concentrated to give the crude product, which was purified by SiO chromatography (PE) to provide 6.3 g (72%) of 4,4,5,5-tetramethyl-2-(2-methyl-4-(trifluoromethyl)phenyl)-1,3,2-dioxaborolane (INT 4-K) as a yellow oil. TLC (PE): R f =0.90. 1 H NMR (400MHz, CDCl3-d) δ7.93-7.84 (m, 1H), 7.46-7.39 (m, 2H), 2.61 (s, 3H), 1.38 (s, 13H).

[0248] Step 4-16. Synthesis of 2-methyl-4-(trifluoromethyl)phenol (INT 4-L) [ka] To a solution of INT 4-K (5.8 g, 20.27 mmol) in EtOH (40 mL) and HO (20 mL) was added m-CPBA (6.17 g, 30.41 mmol, 85% purity). After stirring at 25 °C for 12 h, the mixture was poured into saturated NaSO (100 mL) and concentrated to remove volatiles. The resulting solution was diluted with HO (50 mL) and extracted with EA (3 × 80 mL). The combined organic layers were washed with saturated NaHCO solution (2 × 50 mL) and brine (100 mL × 2), then dried (NaSO), concentrated, and purified by SiO chromatography to provide 2.5 g (70%) of 2-methyl-4-(trifluoromethyl)phenol (INT4-L) as a colorless oil. TLC (5:1 PE:EA):R f =0.50. 1 H NMR (400MHz, CDCl3-d) δ7.45-7.39(m, 1H), 7.38-7.32(m, 1H), 6.90-6.79(m, 1H), 5.87-5.77(m, 1H), 2.31(s, 3H).

[0249] Step 4-17. Synthesis of methyl 2-fluoro-3-((2-methyl-4-(trifluoromethyl)phenoxy)-methyl)benzoate (INT 4-M) [ka] To a solution of INT 4-C (2.8 g, 11.33 mmol) and INT 4-L (2.4 g, 13.6 mmol) in MeCN (30 mL) was added KCO (2.04 g, 14.7 mmol). After 12 h at 60 °C, the reaction mixture was filtered, concentrated, and purified by SiO chromatography (EA / PE) to provide 3.0 g (77%) of methyl 2-fluoro-3-((2-methyl-4-(trifluoromethyl)phenoxy)benzoate (INT4-M) as a colorless oil. 17 H 14LCMS-ESI calculated for F4O3 (m / z): 342.29, found 343.0 [M+H] + , t R =1.04 minutes (method 6). 1 H NMR (400MHz, CDCl3-d) δ7.98-7.91(m, 1H), 7.77-7.69(m, 1H), 7.49-7.41(m, 2H), 7 .31-7.22(m, 1H), 7.03-6.92(m, 1H), 5.40-5.15(m, 2H), 3.98(s, 3H), 2.34(s, 3H).

[0250] Step 4-18. Synthesis of 5-((2-methyl-4-(trifluoromethyl)phenoxy)methyl)-2-fluorobenzoic acid (1-101) [ka] To a solution of INT 4-M (3.0 g, 8.76 mmol) in THF (30 mL) and MeOH (30 mL) was added 2 M NaOH (30 mL, 60 mmol). After 12 h at 40 °C, the pH was adjusted to pH 5 with HCl (1 M), forming a solid precipitate that was collected by filtration. The resulting product was dissolved in EA (500 mL), dried (NaSO), filtered, and concentrated to give 2.35 g (81%) of 5-((2-methyl-4-(trifluoromethyl)phenoxy)methyl)-2-fluorobenzoic acid (1-101) as a pale yellow solid. 16 H 12 LCMS-ESI calculated for F4O3 (m / z): 328.2, found 326.9 [MH] + , t R =0.73 minutes. (Method 7). 1 H NMR (400MHz, CD4OD) δ7.90~7.82(m, 1H), 7.74~7.66(m, 1H), 7.52~7.42(m, 2H), 7.32~7.24(m, 1H), 7.20~ 7.13(m, 1H), 5.44-5.15(m, 2H), 2.30(s, 3H).

[0251] Synthesis of Compounds 4-10 [ka] Step 4-19. Synthesis of methyl 3-(bromomethyl)-5-methylbenzoate (INT 4-N) [ka] To a solution of methyl 3,5-dimethylbenzoate (5 g, 30.5 mmol) in CCl4 (200 mL) was added NBS (5.96 g, 33.5 mmol) and AIBN (1.00 g, 6.1 mmol). After stirring at 80 °C for 12 h, the reaction mixture was concentrated and purified by SiO2 chromatography (PE / EA) to give 8.4 g (79%) of crude methyl 3-(bromomethyl)-5-methylbenzoate (INT4-N) as a colorless oil with 70% purity. 10 H 11 LCMS-ESI calculated for BrO2 (m / z): 243.1, found 245 [M+H] + , t R =0.873 minutes. 1 H NMR (400MHz, CDCl3-d) δ7.87(s, 1H), 7.80(s, 1H), 7.48~7.37(m, 1H), 4.49(s, 2H), 3.96~3.89(m, 4H), 2.41(s, 5H).

[0252] Step 4-20. Synthesis of methyl 3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-5-methylbenzoate (INT 4-O) [ka] A mixture of INT 4-N (3 g, 8.64 mmol), 2-chloro-4-(trifluoromethyl)phenol (1.7 g, 8.64 mmol), and KCO (5.03 g, 36.4 mmol) in MeCN (30 mL) was stirred at 60 °C for 12 h. The reaction mixture was filtered and concentrated to give a residue that was purified by SiO chromatography (PE / EA) to give 2.8 g (90%) of methyl 3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-5-methylbenzoate (INT4-O) as a white solid. TLC (5:1 petroleum ether:EA):R f =0.60. C 17 H 14 LCMS-ESI calculated for ClF3O3 (m / z): 358.7, found 359 [M+H] + t R =1.06 minutes.

[0253] Step 4-21. Synthesis of 3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-5-methylbenzoic acid (4-10) [ka] A mixture of INT 4-O (2.8 g, 7.81 mmol) and 2 M NaOH (30 mL, 30 mmol) in THF (30 mL) and MeOH (30 mL) was stirred at 30 °C for 12 h. The volatile solvents were removed in vacuo, and the resulting solution was acidified to pH 5 with 1 N HCl. The resulting precipitate was collected by filtration, and the crude product was triturated with 10:1 PE:EA to give 2.1 g (72%) of 3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-5-methylbenzoic acid (compound 4-10) as a white solid. C 16 H 12 LCMS-ESI calculated for ClF3O3 (m / z): 344.71, found 342.9 [M+H] + , t R =0.761 minutes. (Method 7). 1H NMR (400MHz, CD4OD) δ8.02-7.95(m, 1H), 7.86-7.81(m, 1H), 7.75-7.68(m, 1H), 7.62-7.52(m, 2H), 7.36-7.27(m, 1H), 5.29(s, 2H), 2.44(s, 3H).

[0254] The compounds listed in Table 4 were made using the procedure in Scheme 4.

[0255] [Table 8-1] [Table 8-2] [Table 8-3] [Table 8-4]

[0256] Example 5 Compound 5-1 and Synthesis of other representative compounds [ka] [ka] Reagents: (i) Zn(CN)2, Zn, Pd2(dba)3, dppf, DMF, 120 °C, (ii) NaOH, solvent (THF, MeOH, or DMF).

[0257] Step 5-1. Synthesis of methyl 3-cyano-5-((2,4-dichlorophenoxy)methyl)benzoate (INT 5-B). [ka] To a stirred solution of methyl 3-bromo-5-((2,4-dichlorophenoxy)methyl)benzoate INT 5-A (100 mg, 256.37 μmol, prepared via Scheme 1 from methyl 3-bromo-5-(bromomethyl)benzoate and 2,4-dichlorophenol) in DMF (2 mL) was added Zn (33.53 mg, 512.75 μmol), Pd(dba) (23.48 mg, 25.64 μmol), DPPF (28.43 mg, 51.27 μmol), and Zn(CN) (60.21 mg, 512.75 μmol, 32.55 μL). The mixture was stirred at 120° C. for 2 hours, filtered, concentrated, and purified by preparative thin-layer chromatography to give 60 mg (69.2%) of methyl 3-cyano-5-((2,4-dichlorophenoxy)methyl)benzoate (INT 5-B) as a white solid. 16 H 11 C 12 LCMS-ESI calculated for NO3 (m / z): 336.2, m / z not observed, t R =1.1 minutes (method 6). 1 H NMR (400MHz, CDCl3) δ8.34(s, 1H), 8.31(s, 1H), 7.99(s, 1H), 7.44(d, J=2.4 Hz, 1H), 7.24~7.17(m, 1H), 6.89(d, J=8.8Hz, 1H), 5.19(s, 2H), 3.99(s, 3H).

[0258] Step 5-2. Synthesis of 3-cyano-5-((2,4-dichlorophenoxy)methyl)benzoic acid (compound 5-1) [ka] To a stirred solution of methyl 3-cyano-5-[(2,4-dichlorophenoxy)methyl]benzoate (INT 5-B) (60 mg, 178.48 μmol) in MeOH (1 mL) and THF (1 mL) was added NaOH (2 M, 267.72 μL). The mixture was stirred at 10° C. for 16 hours and then concentrated. The resulting residue was dissolved in HO (20 mL) and acidified (1 M HCl) to pH 5. The resulting precipitate was collected and purified by preparative HPLC to give 3.2 mg (5.6%) of 3-cyano-5-((2,4-dichlorophenoxy)methyl)benzoic acid (compound 5-1) as a white solid. 15 LCMS-ESI calculated for H9C12NO3 (m / z): 322.14, found 319.9 [M+H] + , t R =0.727 minutes. (Method 6) 1 H NMR (400MHz, DMSO-d6) δ8.32(s, 1H), 8.25(s, 1H), 8.11(s, 1H), 7.62(s, 1H), 7.41(br d, J=8.8Hz, 1H), 7.27(d, J=8.9Hz, 1H), 5.34~5.32(m, 1H), 5.35(s, 1H).

[0259] The compounds listed in Table 5 were made using the procedure in Scheme 5.

[0260] [Table 9]

[0261] Example 6 Synthesis of compound 6-1 [ka] [ka] Reagents: (i) CH3I, DMF, K2CO3, 10°C, (ii) See Scheme 4, (iii) See Scheme 1.

[0262] Step 6-1. Synthesis of methyl 2-methoxy-3-methylbenzoate (INT 6-A) [ka] To a solution of 2-hydroxy-3-methyl-benzoic acid (1 g, 6.6 mmol) in DMF (15 mL) was added KCO (2.73 g, 19.7 mmol) and CHCl (4.66 g, 32.86 mmol, 2.1 mL). The mixture was stirred at 10 °C for 2 h. Additional CHCl (2.33 g, 16.43 mmol, 1.0 mL) was added, and the mixture was stirred for an additional 16 h. The reaction mixture was quenched by the addition of HO (50 mL) and then extracted with EA (100 mL × 3). The combined organic layers were dried (NaSO), filtered, and concentrated under vacuum to give a residue that was purified by SiO chromatography to provide 1.0 g (85%) of methyl 2-methoxy-3-methylbenzoate (INT 6-A) as a colorless oil. TLC (33% EA / petroleum ether): R f =0.45. 1 H NMR (400MHz, CDCl3) δppm 2.33 (s, 3H) 3.84 (s, 3H) 3.92 (s, 3H) 7.06 (t, J = 7.64Hz, 1H) 7.35 (d, J = 7.46Hz, 1H) 7.64 (d, J = 7.70Hz, 1H).

[0263] Step 6-2. Synthesis of 3-((2,4-dichlorophenoxy)methyl)-2-methoxybenzoic acid (compound 6-1) [ka] Compound 6-1 was prepared from INT 6-A according to the procedures in Scheme 4 followed by Scheme 1 to provide 1.0 g (85%) of 3-((2,4-dichlorophenoxy)methyl)-2-methoxybenzoic acid (6-1) as a colorless oil. 10 H 12 LCMS-ESI calculated for O3 (m / z): 180.2, m / z not observed, t R =0.70 minutes (method 7). 1H NMR (400MHz, DMSO-d6) δppm3.82 (s, 3H) 5.22 (s, 2H) 7.25 (t, J=7.64Hz, 1H) 7.30~7.35 (m, 1H) 7.37-7. 43(m, 1H)7.60(d, J=2.57Hz, 1H)7.68(dd, J=7.52, 1.65Hz, 1H)7.73(dd, J=7.76, 1.77Hz, 1H)13.03(br s, 1H).

[0264] The compounds listed in Table 6 were made using the procedures in Scheme 6.

[0265] [Table 10]

[0266] Example 7 Synthesis of compound 7-1 [ka] [ka] Reagents: (i) base (Na2CO3K2CO3, KO t Bu), MeCN, 60°C, (ii) 4M HCl / dioxane.

[0267] Step 7-1. Synthesis of tert-butyl (3-((2,4-dichlorophenoxy)methyl)benzyl)carbamate (INT 7-A) [ka] To a stirred solution of 2,4-dichlorophenol (271 mg, 1.67 mmol) in MeCN (7 mL) was added tert-butyl (3-(bromomethyl)benzyl)carbamate (500 mg, 1.67 mmol) and K2CO3 (299 mg, 2.17 mmol). The flask was sealed, and the resulting white suspension was heated at 60 °C for 3 h. The reaction mixture was cooled to room temperature, diluted with HO (10 mL), extracted with Et2O (2 x 10 mL), dried (Na2SO4), filtered through Celite, and concentrated in vacuo to afford 627 mg (96%) of tert-butyl (3-((2,4-dichlorophenoxy)methyl)benzyl)carbamate (INT7-A). C 19 H 21 LCMS-ESI calculated for Cl2NO3 (m / z): 381, found 404.1 [M+Na] + , t R =12.2 minutes. (Method 3). 1 H NMR (500Hz, CDCl3) 7.37(d, J=2.5, 1H), 7.34-7.33(m, 3H), 7.25-7.22(m, 1H), 7.134(d d, J=9.0, 2.5, 1H), 6.858(d, J=9.0, 1H), 5.10(s, 2H), 4.33(d, J=5.5, 2H), 1.45(s, 9H).

[0268] Step 7-2. Synthesis of (3-((2,4-dichlorophenoxy)methyl)phenyl)methanamine (Compound 7-1) [ka] To a stirred solution of tert-butyl (3-((2,4-dichlorophenoxy)methyl)-benzyl)carbamate (INT7-A) (200 mg, 523 μmol) in dioxane (5 mL) was added 4 M hydrogen chloride in dioxane (5 mL, 20.9 mmol). After 3 h, the reaction mixture became a suspension and was filtered. The filtrate was concentrated to give 101 mg of a crude white solid, which was recrystallized from EtOH (0.7 mL) to give 15.5 mg (10.5%) of (3-((2,4-dichlorophenoxy)methyl)phenyl)methanamine (compound 7-1) as a white solid.14 H 13 LCMS-ESI calculated for ClNO (m / z): 281, found 282.1 [M+H] + , t R =6.345 minutes. (Method 3). 1 H NMR (500Hz, DMSO-d6)8.26(br s, 3H), 7.61(d, J=3.0, 1H), 7.55(s, 1H), 7.49-7.47(m, 3H), 7.39(dd, J=9.0, 2.5, 1H), 7.28(d, J=9.0, 1H), 5.22(s, 2H), 4.05(s, 2H).

[0269] The compounds listed in Table 7 were made using the procedures in Scheme 7.

[0270] [Table 11]

[0271] Compounds described in Example 8 Compound 8-1 and Synthesis of other representative compounds [ka] [ka] Reagents (I) NBs, AIBN, CCl4, 100°C, (ii) base (K2CO3, KO t Bu), solvent (MeCN, DMF, DCM), (iii) Pd(dppf)Cl2, boronic acid, K2CO3, dioxane; (iv) NaOH, solvent (THF, MeOH, or DMF).

[0272] Step 8-1. Synthesis of methyl 5-(bromomethyl)-2-iodobenzoate (INT 8-A) [ka] To a solution of methyl 2-iodo-5-methylbenzoate (1 g, 3.62 mmol) in CCl4 (10 mL) was added NBS (644.7 mg, 3.62 mmol) and AIBN (11.9 mg, 72.5 μmol). The mixture was stirred at 100 °C for 2 h and concentrated under reduced pressure to give a residue that was purified by flash SiO2 chromatography (EA / petroleum ether) to give 733 mg (57.0%) of methyl 5-(bromomethyl)-2-iodobenzoate (INT8-A) as a brown solid. TLC: (10% EA / petroleum ether) R f :0.5. 1 H NMR (400MHz, CDCl3) δ7.98(d, J=8.1Hz, 1H), 7.84(d, J=2.3Hz, 1H), 7.20(dd, J=2.3, 8.1Hz, 1H), 4.46-4.43(m, 2H), 3.95(s, 3H).

[0273] Step 8-2. Synthesis of methyl 5-((2,4-dichlorophenoxy)methyl)-2-iodobenzoate (INT 8-B) [ka] To a solution of methyl 5-(bromomethyl)-2-iodobenzoate (INT 8-A) (733 mg, 2.06 mmol) in MeCN (5 mL) was added KCO (571 mg, 4.13 mmol) and 2,4-dichlorophenol (337 mg, 2.06 mmol). After stirring at 50 °C for 16 h, the reaction mixture was concentrated in vacuo and purified by flash SiO chromatography to give methyl 5-((2,4-dichlorophenoxy)methyl)-2-iodobenzoate (INT8-B) in 780 mg (86.4%) yield as a white solid. TLC: (10% EA / petroleum ether) Rf: 0.3. 1 H NMR (400MHz, CDCl3) δ8.02(d, J=8.2Hz, 1H), 7.88(d, J=2.1Hz, 1H), 7.41(d, J=2.4Hz, 1H), 7.3 0~7.28(m, 1H), 7.17(dd, J=2.4, 8.8Hz, 1H), 6.86(d, J=8.8Hz, 1H), 5.10(s, 2H), 3.96(s, 3H).

[0274] Step 8-3. Synthesis of methyl 5-((2,4-dichlorophenoxy)methyl)-2-methylbenzoate (INT 8-C) [ka] To a solution of methyl 5-((2,4-dichlorophenoxy)methyl)-2-iodobenzoate (INT 8-B) (200 mg, 457.6 μmol) in dioxane (1 mL) and HO (1 mL) was added Pd(dppf)Cl (16.7 mg, 22.9 μmol), KCO (189.7 mg, 1.4 mmol), and MeB(OH) (54.8 mg, 915 μmol). The mixture was stirred at 100 °C for 2 h, concentrated, and purified by flash SiO chromatography (EA / petroleum ether) to provide 100 mg (67.2%) of methyl 5-((2,4-dichlorophenoxy)methyl)-2-methylbenzoate (INT 8-C) as a white solid. TLC: (10% EA / petroleum ether) R f =0.4. 1 H NMR (400MHz, CDCl3) δ7.98(d, J=1.6Hz, 1H), 7.51(dd, J=1.7, 7.8Hz, 1H), 7.40(d, J=2.6Hz, 1H), 7.31-7.2 8(m, 1H), 7.16(dd, J=2.4, 8.8Hz, 1H), 6.88(d, J=8.8Hz, 1H), 5.12(s, 2H), 3.96-3.90(m, 3H), 2.61(s, 3H).

[0275] Step 8-4. Synthesis of 5-((2,4-dichlorophenoxy)methyl)-2-methylbenzoic acid (compound 8-1) [ka] To a solution of methyl 5-[(2,4-dichlorophenoxy)methyl]-2-methylbenzoate (INT 8-C) (100 mg, 307.52 μmol) in MeOH (1 mL) and THF (1 mL) was added NaOH (2 m, 461.27 μL). After stirring at 10° C. for 16 hours, the mixture was concentrated in vacuo and purified by preparative HPLC to provide 29 mg (30.3%) of 5-((2,4-dichlorophenoxy)methyl)-2-methylbenzoic acid (compound 8-1) as a white solid. 15 H 12 LCMS-ESI calculated for Cl2O3 (m / z): 310.02, found 308.9 [MH] + , t R =0.718 minutes. (Method 7). 1 H NMR (400MHz, CDCl3) δ8.12(s, 1H), 7.57(br d, J=7.9Hz, 1H), 7.40(d, J=2.4Hz, 1H), 7.32(d, J=7.5Hz, 1H), 7.17(dd, J=2.4, 8.8Hz, 1H), 6.89(d, J=8.8Hz, 1H), 5.14(s, 2H), 2.67(s, 3H).

[0276] The compounds listed in Table 8 were made using the procedure in Scheme 8.

[0277] [Table 12]

[0278] Example 9 Synthesis of compound 9-1 [ka] [ka] Reagents: (i) NaBH4, DCM, MeOH, (ii) PPh3, NEt3, DEAD, THF, (iii) NaOH, solvent (THF, MeOH, or DMF).

[0279] Step 9-1. Synthesis of methyl 4-bromo-6-(hydroxymethyl)picolinate (INT 9-A) [ka] To a stirred solution of dimethyl 4-bromopyridine-2,6-dicarboxylate (1.0 g, 3.6 mmol) in MeOH (12 mL) and DCM (6 mL) at 0 °C, sodium borohydride (0.17 g, 4.4 mmol) was added in three portions. The reaction mixture was warmed to room temperature and stirred overnight. Additional sodium borohydride (0.17 g, 4.4 mmol) was added. After 2 h, the reaction mixture was diluted with NH4Cl(aq) (10 mL) and DCM (10 mL). The aqueous layer was extracted with DCM (2 × 10 mL) and EA (10 mL), dried (Na2SO4), filtered through Celite, and concentrated in vacuo to give a crude white solid, which was purified by SiO2 chromatography (10% MeOH in EA / hexanes) to give 514 mg (57%) of methyl 4-bromo-6-(hydroxymethyl)picolinate (INT9-A) as a white solid. CH 10 LCMS-ESI calculated for BrNO3 (m / z): 258.98, m / z not observed, t R =3.21 minutes. (Method 1).

[0280] Step 9-2. Synthesis of 4-bromo-6-((2-chloro-4-(trifluoromethyl)phenoxy)-methyl)picolinate methyl (INT 9-B) [ka] To a stirred solution of 2-chloro-4-(trifluoromethyl)phenol (87.9 mg, 0.447 mmol) in THF (10 mL) was added methyl 4-bromo-6-(hydroxymethyl)picolinate (INT 9-A) (100 mg, 0.406 mmol), triphenylphosphine (107 mg, 0.406 mmol), and TEA (56.7 μL, 406 μmol). The reaction mixture was cooled to 0 °C, and diisopropyl azodicarboxylate (82.2 mg, 80.0 μL, 0.406 mmol) was added dropwise. The reaction mixture was stirred at 0 °C for 30 min, warmed to room temperature, and stirred overnight. The reaction mixture was concentrated in vacuo to give the crude product, which was purified by SiO chromatography (EA / hexanes) to afford 94 mg (55%) of methyl 4-bromo-6-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)picolinate (INT9-B) as an off-white solid. 15 H 10 LCMS-ESI (m / z) calculated for BrClF3NO3: 422.95; m / z not observed, t R =6.73 minutes. (Method 1).

[0281] Step 9-3. Synthesis of 4-bromo-6-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)picolinic acid (Compound 9-1) [ka] To a stirred solution of methyl 4-bromo-6-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)picolinate (INT 9-B) (94.5 mg, 223 μmol) in 2 mL of THF was added 1 M NaOH (1 mL, 1.11 mmol). The reaction mixture was heated at 60° C. overnight, cooled, and acidified with 3 M HCl. The mixture was extracted with EA and EtO, and the combined organics were dried (NaSO), filtered, and concentrated in vacuo to afford 77.6 mg (85%) of 4-bromo-6-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)picolinate (compound 9-1) as a white solid. 14 H 18LCMS-ESI calculated for BrClF3NO3 (m / z): 408.93; found 410.0 [M+H] + , t R =10.7 minutes. (Method 3).

[0282] The compounds listed in Table 9 were made using the procedures in Scheme 9.

[0283] [Table 13]

[0284] Example 10 Synthesis of compound 10-1 [ka] [ka] Reagent (i)KO t Bu, dioxane, (ii) NaOH, solvent (THF, MeOH, or DMF).

[0285] Step 10-1. Synthesis of methyl 3-(((5-(trifluoromethyl)pyridin-2-yl)oxy)methyl)-benzoate (INT 10-A) [ka] To a pressure vessel containing a solution of methyl 3-(hydroxymethyl)benzoate (499 mg, 3.00 mmol) in 1,4-dioxane (9 mL) was added 2-chloro-5-(trifluoromethyl)pyridine (363 mg, 2.00 mmol) and potassium tert-butoxide (337 mg, 3.00 mmol). The vessel was sealed, and the reaction mixture was heated and stirred at 90 °C overnight, then cooled to room temperature. The reaction mixture was partitioned between EtO and HO. The phases were separated, and the aqueous layer was further extracted with diethyl ether (2x). The organic phases were combined, washed with brine, dried (NaSO), filtered, and concentrated under reduced pressure. The resulting colorless oil was purified by flash SiO2 chromatography (EA / hexanes) to afford 177 mg (28.4%) of methyl 3-(((5-(trifluoromethyl)pyridin-2-yl)oxy)methyl)benzoate (INT 10-A) as a colorless oil. 15 H 12 LCMS-ESI calculated for F3NO3 (m / z): 311.1, found 312.1 [M+H] + , t R =6.25 minutes. (Method 1). 1 H NMR (500MHz, DMSO-d6) δ8.608(s, 1H), 8.114(dd, J=8.5, 2.5Hz, 1H), 8.050(s, 1H), 7.934(d, J=7.5Hz, 1 H), 7.753(d, J=8.0Hz, 1H), 7.551(t, J=7.5Hz, 1H), 7.129(d, J=9.0Hz, 1H), 5.512(s, 2H), 3.858(s, 3H). 19 F NMR (470MHz, DMSO-d6) δ60.140(s).

[0286] Step 10-2. Synthesis of 3-(((5-(trifluoromethyl)pyridin-2-yl)oxy)methyl)benzoic acid (compound 10-1) [ka] To a 20 mL vial containing a stirred solution of methyl 3-(((5-(trifluoromethyl)pyridin-2-yl)oxy)methyl)benzoate (INT 10-A) (177 mg, 0.569 mmol) in THF (6 mL) was placed 1 M NaOH (2.27 mL, 2.27 mmol). After stirring at 50 °C for 12 h, the reaction mixture was concentrated in vacuo, and the residue was dissolved in HO and acidified to pH 4-5 using 3 M HCl. The resulting white precipitate was extracted with EtO (3x). The combined organic layers were washed with brine, dried (NaSO), and concentrated in vacuo to afford 151 mg (89.3%) of 3-(((5-(trifluoromethyl)pyridin-2-yl)oxy)methyl)benzoic acid (compound 10-1) as a white solid. 14 H 11 LCMS-ESI calculated for F3NO3 (m / z): 297.2, found 298.1 [M+H] + , t R =9.33 minutes. (Method 3). 1 H NMR (500MHz, DMSO-d6)δ13.006(br s, 1H), 8.595(s, 1H), 8.100(dd, J=9.0, 2.5Hz, 1H), 8.015(s, 1H), 7.900(d, J=8.0Hz, 1 H), 7.702(d, 8.0Hz, 1H), 7.522(t, J=7.5Hz, 1H), 7.115(d, J=8.5Hz, 1H), 5.493(s, 2H). 19 F NMR (470MHz, DMSO-d6) δ60.126(s).

[0287] The compounds listed in Table 10 were made using the procedure in Scheme 10.

[0288] [Table 14]

[0289] Example 11 Synthesis of compound 11-1 [ka] [ka] Reagents (i) tricyclohexylphosphine, Pd(OAc)2, cyclopropylboronic acid, potassium phosphate, toluene, (ii) NaOH, solvent (THF, MeOH, or DMF).

[0290] Step 11-1. Synthesis of methyl 3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-5-cyclopropylbenzoate (INT 11-B) [ka] To a degassed solution of methyl 3-bromo-5-((2-chloro-4-(trifluoromethyl)phenoxy)m)methyl)benzoate (INT 11-A) (200 mg, 472 μmol, prepared in Scheme 2 from methyl 3-bromo-5-(hydroxymethyl)benzoate and 2-chloro-4(trifluoromethyl)phenol), tricyclohexylphosphine (6.62 mg, 23.6 μmol), potassium phosphate (230 mg, 1.09 mmol), and cyclopropylboronic acid (52.7 mg, 614 μmol) in toluene (4 mL) was added palladium diacetate (5.30 mg, 23.6 μmol). The reaction vial was capped and heated at 100 °C overnight. The reaction was further degassed, and additional tricyclohexylphosphine (6.62 mg, 23.6 μmol), cyclopropylboronic acid (52.7 mg, 614 μmol), and palladium diacetate (5.30 mg, 23.6 μmol) were added. After heating at 100° C. for 4 h, the reaction mixture was filtered through Celite, rinsed with EA, and concentrated in vacuo. The residue was taken up in EA, washed with saturated sodium bicarbonate and brine, dried (NaSO), filtered, and concentrated in vacuo to give the crude material, which was purified by SiO chromatography (EA / hexanes) to give 132 mg (72%) of methyl 3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-5-cyclopropylbenzoate (INT11-B). 19 H 16 LCMS-ESI calculated for ClF3O3 (m / z): 384.1, m / z not observed, t R=7.02 minutes. (Method 1). 1 H NMR (500Hz, DMSO-d6) δ7.86(d, J=2.5, 1H), 7.85(s, 1H), 7.71(dd, J=8.8, 2.5, 1H), 7.64(s, 1H), 7.46, (s, 1 H), 7.41(d, J=9.0, 1H), 5.35(s, 2H), 3.85(s, 3H), 2.07-2.02(m, 1H), 1.03-1.00(m, 2H), 0.73-0.70(m, 2H).

[0291] Step 11-2. Synthesis of 3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-5-cyclopropylbenzoic acid (compound 11-1) [ka] To a stirred solution of methyl 3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-5-cyclopropylbenzoate (INT 11-B, 132 mg, 0.343 mmol) in THF (2 mL) was added 1 M NaOH (2 mL, 1.72 mmol). After heating at 60 °C overnight, the reaction mixture was cooled and acidified with 3 M HCl. The mixture was extracted with EA and EtO, dried (NaSO), filtered, and concentrated in vacuo. The crude solid was purified by reverse-phase HPLC to give 71.2 mg (56%) of 3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-5-cyclopropylbenzoic acid (compound 11-1) as a white solid. C 18 H 14 LCMS-ESI calculated for ClF3O3 (m / z): 370.7; found 393.1 [M+Na] + , t R =11.25 minutes. (Method 3). 1 H NMR (500Hz, DMSO-d6) δ13.00(s, 1H), 7.87(s, 1H), 7.82(s, 1H), 7.71(d, J=8.0, 1H), 7.62(s , 1H), 7.43-7.41(m, 2H), 5.34(s, 2H), 2.04(m, 1H), 1.01(d, J=7.0, 2H), 0.72-0.71(m, 2H).

[0292] The compounds listed in Table 11 were made using the procedure in Scheme 11.

[0293] [Table 15]

[0294] Example 12 Synthesis of compound 12-1 [ka] [ka] Reagents: (i) NaH, DMF, (ii) NaOH, solvent (THF, MeOH, or DMF).

[0295] Step 12-1. Synthesis of methyl 3-(((2,4-dichlorophenyl)amino)methyl)benzoate (INT 12-A) [ka] To a stirred solution of methyl 3-(bromomethyl)benzoate (300 mg, 1.31 mmol) and 2,4-dichloroaniline (0.23 g, 1.44 mmol) in DMF (2 mL) at 0 °C was added NaH (60% in mineral oil, 38 mg, 0.95 mmol). After 1 at 0 °C, the mixture was diluted with HO (20 mL) and extracted with EA (2 × 50 mL). The organic layers were combined, washed with brine, dried (NaSO), filtered, and concentrated to provide the crude product, which was purified by SiO chromatography to afford 230 mg (56%) of methyl 3-(((2,4-dichlorophenyl)amino)methyl)benzoate (INT 12-A), which was 30% pure and therefore used without further purification. 15 H 13 LCMS-ESI calculated for C12NO2 (m / z): 310.2, found 311.2 [M+H] + , t R =5.7 minutes (method 11).

[0296] Step 12-2. Synthesis of 3-(((2,4-dichlorophenyl)amino)methyl)benzoic acid (compound 12-1) [ka] To a stirred solution of crude methyl 3-(((2,4-dichlorophenyl)amino)methyl)benzoate (INT 12-A) (230 mg, 0.74 mmol) in MeOH (3 mL) was added a solution of NaOH (290 mg, 7.4 mmol) in HO (1 mL). The reaction was heated to reflux for 2 min, cooled to room temperature, and concentrated in vacuo to remove MeOH. The aqueous layer was acidified to pH 2 with 4 N HCl (aq) and extracted with EA (2 × 50 mL). The combined organic layers were washed with HO, brine, dried (MgSO), filtered, and concentrated in vacuo to provide the crude material, which was purified by SiO chromatography to provide 5 mg (2.3%) of 3-(((2,4-dichlorophenyl)amino)methyl)benzoic acid) (compound 12-1). C 14 H 11 C 11 LCMS-ESI calculated for NO2 (m / z): 296.2, found 296.5 [M+H] + , t R =13.88 minutes. (Method 9). 1 H NMR (400MHz, DMSO-d6) δ7.88(s, 1H), 7.76(d, J=8Hz, 1H), 7.42(d, J=8Hz, 1H), 7.35(m, 2H), 7.06(d, J=8Hz, 1H), 6.51(d, J=8Hz, 1H), 6.39(t, J=8Hz, 1H), 4.43(d, J=4Hz, 2H).

[0297] The compounds listed in Table 12 were made using the procedure in Scheme 12.

[0298] [Table 16]

[0299] Example 13 Synthesis of compound 13-1 [ka] [ka] Reagents (i) NaOH, MeOH, heat.

[0300] Step 13-1. Synthesis of 3-((2,3-dichlorophenoxy)methyl)benzamide (Compound 13-1) [ka] To a stirred solution of INT 13-1 (0.3 g, 1.1 mmol, prepared from 3-(bromomethyl)benzonitrile and 2,3-dichlorophenol via Scheme 3) in MeOH (5 mL) was added a solution of NaOH (0.34 g, 8.6 mmol) in HO (5 mL). After heating at 90 °C for 4 h, the reaction mixture was cooled to room temperature and the resulting solid was collected and washed with HO (10 mL). This material was dried under high vacuum to provide 68.8 mg (21%) of 3-((2,3-dichlorophenoxy)methyl)benzamide (compound 13-1). 14 H 11 LCMS-ESI calculated for Cl2NO2 (m / z): 296.2, found 297.2 [M+H] + , t R =11.8 minutes. (Method 10). 1 H NMR (400MHz, CDCl3) δ7.92(s, 1H), 7.78(d, J=8Hz, 1H), 7.65(d, J=8Hz, 1H), 7.50(t, J =8Hz, 1H), 7.10(m, 2H), 6.86(d, J=8Hz, 1H), 6.22(bs, 1H), 5.59(bs, 1H), 5.21(s, 2H).

[0301] The compounds listed in Table 13 were made using the procedure in Scheme 13.

[0302] [Table 17]

[0303] Example 14 Synthesis of compound 14-1 [ka] [ka] Reagents: (i) PPh3, NEt3, DIAD, THF.

[0304] Step 14-1. Synthesis of (3-((2,4-dichlorophenoxy)methyl)phenyl)methanol (Compound 14-1) [ka] To a stirred solution of 2,4-dichlorophenol (324 mg, 1.99 mmol) in THF (15 mL) was added 1,3-phenylenedimethanol (250 mg, 1.81 mmol), triphenylphosphine (475 mg, 1.81 mmol), and TEA (183 mg, 252 μL, 1.81 mmol). The reaction mixture was cooled to 0°C, and diisopropyl azodicarboxylate (356 μL, 1.81 mmol) was added dropwise. The reaction mixture was stirred at 0°C for 30 minutes, warmed to room temperature, and stirred overnight. The reaction mixture was concentrated in vacuo to give the crude product, which was purified by SiO2 chromatography (EA / hexanes) to give 90.9 mg (17.7%) of (3-((2,4-dichlorophenoxy)methyl)phenyl)methanol (compound 14-1) as an off-white solid. 14 H 12 LCMS-ESI calculated for Cl2O2 (m / z): 282.0, found 282.21 [M+H] + , t R =10.08 minutes. (Method 3).

[0305] The compounds listed in Table 14 were made using the procedure in Scheme 14.

[0306] [Table 18]

[0307] Example 15 Synthesis of compound 15-1 [ka] [ka] Reagents: (i) Base (Na2CO3K2CO3KO t Bu), solvent (THF or DMF), ii. NaOH, solvent (THF, MeOH or DMF).

[0308] Step 15-1. Synthesis of methyl 3-(((2,4-dichlorophenyl)thio)methyl)benzoate (INT 15-A) [ka] To a stirred solution of 2,4-dichlorobenzenethiol (750 mg, 4.19 mmol) in MeCN (20 mL) was added methyl 3-(bromomethyl)benzoate (959 mg, 4.19 mmol) and potassium carbonate (753 mg, 5.45 mmol). The reaction mixture was heated at 60 °C for 3 h, cooled to room temperature, diluted with HO (20 mL), and extracted with EtO (2 × 20 mL). The combined organic layers were dried (NaSO), filtered, and concentrated to afford 1.3 g (94%) of methyl 3-(((2,4-dichlorophenyl)thio)methyl)benzoate (INT 15-A) as a yellow oil that solidified upon standing. 15 H 12 LCMS-ESI calculated for Cl2O2S (m / z): 325.9, found 327.1 [M+H] + , t R =12.5 minutes. (Method 3).

[0309] Step 15-2. Synthesis of 3-(((2,4-dichlorophenyl)thio)methyl)benzoic acid (15-1) [ka] To a stirred solution of methyl 3-(((2,4-dichlorophenyl)thio)methyl)benzoate (INT 15-A) (250 mg, 0.764 mmol) in THF (3 mL) was added 1 M NaOH (4 mL, 3.82 mmol). The reaction mixture was heated at 60 °C for 3 h, and the aqueous layer was extracted with EA (2 × 5 mL), dried (NaSO), filtered, and concentrated to give a crude solid, which was purified by reverse-phase HPLC to give 240.3 mg (99%) of 3-(((2,4-dichlorophenyl)thio)methyl)benzoic acid (compound 15-1) as an off-white solid. 14 H 10 LCMS-ESI calculated for Cl2O2S (m / z): 311.97, found 313.1 [M+Na] + , tR=10.59 minutes. (Method 3).

[0310] The compounds listed in Table 15 were made using the procedures in Scheme 15.

[0311] [Table 19]

[0312] Example 16 Compound 16-1 and Synthesis of other representative compounds [ka] [ka] Reagents: (i) base, Cu(OAc)2, DCM, ii) NaOH, solvent (THF, MeOH or DMF).

[0313] Step 16-1. Synthesis of methyl 3-(2,4-dichlorophenoxy)benzoate (INT 16-A). [ka] To a stirred solution of (3-(methoxycarbonyl)phenyl)boronic acid (221 mg, 1.2 mmol) and 2,4-dichlorophenol (100 mg, 0.61 mmol) in anhydrous DCM (5 mL) was added Cu(OAc) (111 mg, 0.61 mmol) and TEA (0.86 mL, 0.61 mmol). After stirring overnight, the reaction mixture was filtered, concentrated, and purified by SiO chromatography (EA / hexanes) to afford 182 mg (27%) of methyl 3-(2,4-dichlorophenoxy)benzoate (INT 16-A). 14 H 10 LCMS-ESI calculated for Cl2O3 (m / z): 296, found 297.5 [M+H] + , t R =5.96 minutes. (Method 11).

[0314] Step 16-2. Synthesis of 3-(2,4-dichlorophenoxy)benzoic acid (16-1) [ka] To a stirred solution of methyl 3-(2,4-dichlorophenoxy)benzoate (INT 16-A) (50 mg, 0.17 mmol) in MeOH (3 mL) was added 1 M NaOH (67 mg, 1.68 mmol). The reaction mixture was heated to reflux for 2 h. The pH was adjusted to 2 by the addition of 4 N HCl (aq) and then extracted with EA. The organic layer was washed with brine, dried (mg SO), filtered, and concentrated in vacuo to give a crude solid, which was purified by SiO chromatography (EA / hexanes) to give 10 mg (21%) of 3-(2,4-dichlorophenoxy)benzoic acid (compound 16-1) as a white solid. 13 LCMS-ESI calculated for H8Cl2O3 (m / z): 281.99, found 283.6 [M+H] + , t R =14.15 minutes. (Method 10).

[0315] The compounds listed in Table 16 were made using the procedure in Scheme 16.

[0316] [Table 20]

[0317] Example 17 Compound 17-1, Compound I-31, and Other representative tetrazole isosteres [ka] [ka] Reagents: (i) base (NaCO 3、 K2CO3, KO t Bu), solvents (acetone, MeCN, DMF), (ii) NaN3, NH4Cl, DMF.

[0318] Step 17-1: 3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)benzonitrile (INT-17-1) [ka] A mixture of 3-(bromomethyl)benzonitrile (500 mg, 2.55 mmol), 2-chloro-4-(trifluoromethyl)phenol (0.551 g, 2.81 mmol), and K2CO3 (1.06 g, 7.65 mmol) in acetone (10.0 mL) was heated at 80 °C for 1 h. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (40 g cartridge) eluting with a mixture of hexane and EA to give 750 mg (94%) of 3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)benzonitrile (compound 17-1) as a solid. 1 HNMR (400MHz, DMSO) δ7.96-7.92(m, 1H), 7.90-7.87(m, 1H), 7.87-7.80(m, 2H), 7.72(ddd, J=8.7, 2.3, 0.7Hz, 1H), 7.66(t, J=7.7Hz, 1H), 7.43(d, J=8.5Hz, 1H), 5.38(s, 2H), LCMS:m / z(ES-), [MH]- :310.15, HPLC t R =5.78 minutes. (Method 12).

[0319] Step 17-2: 5-(3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)phenyl)-1H-1,2,3,4-tetrazole (INT-31) [ka] A mixture of compound 17-1 (100 mg, 0.321 mmol), NaN (31.3 mg, 0.481 mmol), and NHCl (27.5 mg, 0.513 mmol) in DMF (1.00 mL) was heated at 130 °C for 12 h. The mixture was cooled to room temperature and poured into 2 M HCl at 0 °C. The mixture was filtered, and the solid was dried to provide 5-(3-((2-chloro-4-(trifluoromethyl)-phenoxy)methyl)phenyl)-1H-1,2,3,4-tetrazole (INT-31) as a solid (102 mg, 90%). 1 HNMR (400MHz, CD3OD) δ8.17(s, 1H), 8.00(d, J=7.8Hz, 1H), 7.72(dd, J=8.1, 5.0Hz, 2H), 7.67, -7.53(m, 2H), 7.33(d, J=8.7Hz, 1H), 5.37(s, 2H), LCMS:C 15 H 10 Calculated for ClF3N4O: 354, found 355.06, [MH] + , t R =4.35 minutes. (Method 12).

[0320] The compounds listed in Table 17 were made using the procedure in Scheme 17.

[0321] [Table 21-1] [Table 21-2]

[0322] Example 18 General synthesis of representative arylsulfonamide isosteres [ka] Reagents: (i) NaH, DMF, BnBr, (ii) ArSO2Cl, pyr, CHCl2, (iii) H2, Pd / C, MeOH, (iv) See Scheme 2, Step 1.

[0323] A solution of 3-aminobenzyl alcohol in DMF is treated with NaH and benzyl bromide to form 3-((benzyloxy)methyl)aniline. After isolation, 3-((benzyloxy)methyl)aniline is dissolved in CHCl and treated with pyridine and arylsulfonyl chloride (ArSOCl) to give the O-benzyl-protected arylsulfonamide, which is deprotected by catalytic hydrogenation to give the alcohol intermediate 18-A. Preparation of the final compound is accomplished according to the Mitsunobu reaction described in Scheme 2, Step 1.

[0324] Example 19 General synthesis of representative sulfonylurea isosteres [ka] Reagents: (i) NaH, DMF, BnBr, (ii) Mg, THF, DABSO, SO2Cl2, NH4OH, (iii) base (K2CO3, Et3N, i-Pr2EtN), DPPA, HOAc, (iv) H2, Pd / C, MeOH, (v) See Scheme 2, Step 1.

[0325] A solution of 3-bromobenzyl alcohol in DMF is treated with NaH and benzyl bromide to form 1-((benzyloxy)methyl)-3-bromobenzene, which is converted to the Grignard reagent in a separate step by dissolving it in dry THF and treating with Mg. The Grignard reagent is treated with DABSO, sulfonyl 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, CA et al. (Tet. Lett. 48:8878, 2007) to provide the O-benzyl-protected sulfonylurea, intermediate 19-B. INT 19-B is deprotected by catalytic hydrogenation to give the free alcohol intermediate, which is converted to the final compound according to the Mitsunobu reaction described in Scheme 2, Step 1.

[0326] Example 20 General synthesis of representative N-acylsulfonamide isosteres [ka] Reagents: (i) ZnCl2, Ac2O, (ii) H2Pd / C, MeOH, (iii) See Scheme 2, Step 1.

[0327] Intermediate 19-A (see Example 19) is reacted with ZnCl and acetic anhydride (ACO) according to Pham, MV et al. (Angew. Chem IE 51:10610, 2012) to provide an O-benzyl-protected N-acylsulfonamide intermediate, which is deprotected by catalytic hydrogenation to give the free alcohol, intermediate 20-A. The alcohol is converted to the final compound according to the Mitsunobu reaction described in Scheme 2, Step 1.

[0328] Example 21 General synthesis of representative N-hydroxyamide isosteres [ka] Reagents: (i) EtCO2Cl, NMm, DMF, (ii) NH2OH MeOH.

[0329] A compound of formula (I) where A is phenyl and R is a carboxylic acid is dissolved in DMF and cooled to 0°C. Ethyl chloroformate (1.2 equivalents) and N-methylmorpholine (1.3 equivalents) are added sequentially, and the mixture is stirred for 10 minutes. Hydroxylamine (2 equivalents) in methanol is added, and the reaction is allowed to warm to room temperature and stirred overnight. Regular workup and purification afford the desired N-hydroxyamide product.

[0330] Example 22 General synthesis of representative phosphinic acid isosteres [ka] Reagents: (i) See Scheme 2, Step 1. (ii) Methyl phosphinate, Pd(OAc)2, PPh3, NMM, MeCN, (iii) HCl, H2O.

[0331] 3-Iodobenzyl alcohol is converted to intermediate 22-A according to the Mitsunobu reaction described in Scheme 2, Step 1. The aryl iodide is converted to an alkyl phosphinate using a palladium-catalyzed cross-coupling reaction (Pd(OAc)2 and PPh3 as the ligand) described by Grady, HL ("Preparation of arylphosphinic acid derivatives as building blocks for binding sites", Retrospective Theses and Dissertations, 10373, 1992) using methyl phosphinate in acetonitrile in the presence of NMM as a base. The aryl phosphinic acid product is obtained from hydrolysis of the alkyl phosphinate in aqueous HCl.

[0332] Example 23 General synthesis of representative phosphonate isosteres [ka] Reagents: (i) See Scheme 2, Step 1. (ii) HPO(Oi-Pr) 2、 Pd(OAc)2, CM-Phos, t-BuOH / i-PrOH, DIPEA, (iii) HCl, H2O.

[0333] 3-Bromobenzyl alcohol is converted to intermediate 23-A according to the Mitsunobu reaction 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 the ligand), as described by Fu, CW et al. (Org. Lett. 17:5906, 2015), which uses diisopropyl phosphite in an alcohol solvent and DIPEA as the base. The arylphosphonate product is obtained by hydrolysis of the dialkylphosphonate in aqueous HCl.

[0334] Example 24 General synthesis of representative pyrrolidine-2,4-dione isosteres [ka] Reagents: (i) ethylmalonyl chloride, CH2Cl2Et3N, (ii) KHMDS, toluene, (iii) HBr, water, (iv) H2, Pd / C, MeOH, (v) See Scheme 2, Step 1.

[0335] Conversion of the starting phenylglycine amino acid derivative to pyrrolidine-2,4-dione is achieved via a three-step addition / cyclization / decarboxylation sequence as described in WO 2007 / 063010 to give intermediate 24-A. This intermediate is deprotected by catalytic hydrogenation to give the free alcohol, which is converted to the final compound according to the Mitsunobu reaction described in Scheme 2, Step 1. The starting amino acid methyl ester can be prepared by a variety of methods known to those skilled in the art, for example, by the Strecker amino acid synthesis of 3-((benzyloxy)methyl)benzaldehyde (described below) and esterification.

[0336] Example 25 General synthesis of representative furan-2,4-dione isosteres [ka] Reagents: (i) NaH, DMF, BnBr, (ii) LDA, THF, [ka] (iii) HBr, water; (iv) H2, Pd / C, MeOH; (v) See Scheme 2, Step 1.

[0337] Commercially available 3-hydroxymethylbenzaldehyde is reacted with NaH and benzyl bromide to form 3-((benzyloxy)methyl)benzaldehyde. This intermediate is converted to cyclopentane-1,3-dione in a two-step sequence described in WO 2007 / 063010 to give intermediate 25-A. This intermediate is deprotected by catalytic hydrogenation to give the free alcohol, which is converted to the final compound according to the Mitsunobu reaction described in Scheme 2, Step 1.

[0338] Example 26 General synthesis of representative cyclopentane-1,3-dione isosteres [ka] Reagents: (i) NaH, DMF, BnBr; (ii) t -BuLi, Et2O, CuI, [ka] (iii) HF / pyridine, CH3CN, (iv) Jones reagent, acetone, (v) H2, Pd / C, MeOH, (vi) See Scheme 2, Step 1.

[0339] A solution of 3-bromobenzyl alcohol in DMF is treated with NaH and benzyl bromide to form 1-((benzyloxy)methyl)-3-bromobenzene. This intermediate is converted to cyclopentane-1,3-dione via a three-step conjugate addition / deprotection / oxidation sequence as described by Lassalas, P. et al. (ACS Med. Chem. Lett. 8:864, 2017) to give intermediate 26-A. This intermediate is deprotected by catalytic hydrogenation to give the free alcohol, which is converted to the final compound according to the Mitsunobu reaction described in Scheme 2, Step 1.

[0340] Example 27 General synthesis of representative difluorophenol isosteres [ka] Reagents: (i) See Scheme 11, Step 1. (ii) See Scheme 2, Step 1.

[0341] 3-Bromobenzyl alcohol and commercially available 4-hydroxy-3,5-difluorophenylboronic acid are coupled according to the Suzuki coupling method described in Example 11 to give intermediate 27-A, which is converted to the final compound according to the Mitsunobu reaction described in Scheme 2, Step 1.

[0342] Example 28 General synthesis of representative 3-substituted 5-oxo-thiadiazole isosteres [ka] Reagents: (i) NaH, DMF, BnBr, (ii) NH2OH.HCl, Et3N, EtOH, (iii) TCDI, THF, BF3-OEt2 / THF, (iv) H2, Pd / C, MeOH, (v) See Scheme 2, Step 1.

[0343] A solution of 3-cyanobenzyl alcohol in DMF is treated with NaH and benzyl bromide to form 3-((benzyloxy)methyl)benzonitrile. The aryl cyanide is then converted to a 3-substituted 5-oxo-thiadiazole in two steps according to Kohara, Y. et al. (J. Hetercyclic Chem. 37:1419, 2000) to give intermediate 28-A. This intermediate is deprotected by catalytic hydrogenation to give the free alcohol, which is converted to the final compound according to the Mitsunobu reaction described in Scheme 2, Step 1.

[0344] Example 29 General synthesis of representative 3-substituted oxadiazolone isosteres [ka] Reagents: (i) NaH, DMF, BnBr, (ii) NHOH.HCl, EtN, EtOH, (iii) CDI, DBU, 1,4-dioxane, (iv) H, Pd / C, MeOH, (v) See Scheme 2, Step 1.

[0345] A solution of 3-cyanobenzyl alcohol in DMF is treated with NaH and benzyl bromide to form 3-((benzyloxy)methyl)benzonitrile. The aryl cyanide is then converted to a 3-substituted oxadiazolone in two steps according to Yu, X. et al. (Org. Lett. 18:5412, 2-016) to give intermediate 29-A. This intermediate is deprotected by catalytic hydrogenation to give the free alcohol, which is converted to the final compound according to the Mitsunobu reaction described in Scheme 2, Step 1.

[0346] Example 30 General synthesis of representative thiazolidine 2,4-dione isosteres [ka] Reagents: (i) NaH, DMF, BnBr; (ii) ZnI, TMSCN, HCl (conc.), iii) MeOH, catalyst. Salicylaldehyde; (iv) SOCl, pyridine, thiourea, NaOAc, EtOH, HCl (aq.), EtOH; (v) H, Pd / C, MeOH; (vi) See Scheme 2, Step 1.

[0347] Commercially available 3-hydroxymethylbenzaldehyde is reacted with NaH and benzyl bromide to form 3-((benzyloxy)methyl)benzaldehyde. The resulting ether aldehyde is converted to a mandelate salt according to Sirimanne and Patterson (J. Label. Cmpd. Radiopharm. 33:725, 1993) to obtain an esterified mandelic acid derivative, intermediate 30-A. Intermediate 30-A is converted to thiazolidine-2,4-dione according to Koyama et al. (Biorg. Med. Chem. Lett. 13:1801, 2003), and catalytic hydrogenation allows deprotection of the alcohol to obtain intermediate 30-B. Alcohol 30-B is converted to the final compound according to the Mitsunobu reaction described in Step 1 of Scheme 2.

[0348] Example 31 Alternative synthesis of compounds 1-56 and synthesis of 31-2 [ka] [ka] Reagents (i) NaBH4, DCM, MeOH, (ii) SOCl2, DCM, (iii) K2CO3, CH3CN (iv) NaOH, solvent (THF, MeOH, or DMF).

[0349] Step 31-1. Synthesis of methyl 6-(hydroxymethyl)picolinate (INT 31-A) [ka] To a stirred solution of dimethylpyridine-2,6-dicarboxylate (20 g, 102.5 mmol) in MeOH (20 mL) at 0 °C, sodium borohydride (5.81 g, 153.7 mmol) was added in three portions. The reaction mixture was warmed to room temperature and stirred for 1 h. The reaction mixture was diluted with NH4Cl(aq) (10 mL) and extracted with EA (3 x 500 mL) and EA (10 mL). The combined organic layers were dried (Na2SO4), concentrated in vacuo, and purified by SiO2 chromatography (EA / 10% MeOH in hexanes) to afford 12 g (70%) of methyl 6-(hydroxymethyl)pyridine-2-carboxylate (INT 31-A) as a white solid. TLC (EA): R f =0.60.

[0350] Step 31-2. Synthesis of methyl 6-(chloromethyl)picolinate (INT 31-B) [ka] To a flask containing a stirred solution of INT 31-A (5.00 g, 29.9 mmol) in DCM (62.5 mL) was added thionyl chloride (4.36 mL, 59.8 mmol) at room temperature. After stirring for 14 h, the reaction mixture was adjusted to pH 10-11 by dropwise addition of saturated aqueous KCO solution. The organic layer was collected, and the aqueous layer was back-extracted twice with DCM. The organic layers were combined, washed with brine, dried (NaSO), and purified by SiO2 chromatography (EA / hexanes) to afford 3.9 g (69.7%) of methyl 6-(chloromethyl)picolinate (INT 31-B) as a colorless oil that solidified upon standing to give a white crystalline powder. LCMS-ESI (m / z) calculated for C8H8ClNO2: 185.61, m / z 186.1 (M+H). + , t R =3.64 minutes. (Method 1). 1 H NMR (500MHz, DMSO-d6) δ8.09-7.99(m, 2H), 7.81(dd, J=7.5, 1.3Hz, 1H), 4.86(s, 2H), 3.89(s, 3H).

[0351] Step 31-3. Synthesis of methyl 6-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)picolinate (Compound 31-C) [ka] A solution of 2-chloro-4-(trifluoromethyl)phenol (4.497 g, 22.9 mmol) in MeCN (70 mL) was added to a flask containing INT 31-C (3.861 g, 20.8 mmol), followed by KCO (4.312 g, 31.2 mmol) and potassium iodide (345.3 mg, 2.08 mmol). The resulting suspension was heated to 60 °C. After stirring for 16 h, the reaction mixture was cooled to room temperature, diluted with HO, and extracted three times with EtO. The combined organic layers were washed with brine, dried (NaSO), and purified by SiO chromatography (EA / hexanes) to afford 6.64 g (92.4%) of methyl 6-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)picolinate (INT 31-C) as a white solid. 15 H 11 LCMS-ESI calculated for ClF3NO3 (m / z): 345.70, found 346.1 [M+H] + , t R =5.99 minutes. (Method 1).

[0352] Step 31-4. Synthesis of 6-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)picolinic acid (Compound 1-56) [ka] To a flask containing a stirred solution of INT 31-C (500 mg, 1.45 mmol) in THF (7.23 mL) was added 1 M NaOH (7.23 mL, 7.23 mmol). After stirring at 50 °C for 17 h, the mixture was diluted with THF and HO, but no distinct layers were observed. EtO was added to effect separation of the organic and aqueous layers. The aqueous layer was collected and acidified to pH 3-4 using 3 M HCl. The resulting white precipitate was extracted three times with EtO, and the combined organic extracts were washed with brine, dried (NaSO), and concentrated under reduced pressure to give 310 mg (64.6%) of 6-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)picolinic acid (compound 1-56) as a white solid. 14 LCMS-ESI calculated for H9ClF3NO3 (m / z): 331.68, found 332.1 [M+H] + , t R =5.34 minutes. (Method 1).

[0353] Synthesis of compound 31-2 [ka]

[0354] Step 31-5. Synthesis of dimethyl 4-ethylpyridine-2,6-dicarboxylate (INT 31-D) [ka] To a solution of dimethylpyridine-2,6-dicarboxylate (10 g, 51.2 mmol) and propanal (18.7 mL, 256.2 mmol) in HSO (100 mL) was added FeSO (5.70 g, 20.49 mmol) and 30% H0 (9.9 mL, 102.5 mmol) dropwise over 15 min. After stirring at 0 °C for 15 min, the mixture was diluted with saturated KCO (aq) and extracted with EA. The organic layer was dried (NaSO), concentrated in vacuo, and purified by SiO chromatography (petroleum ether / EA) to give 4.5 g (39%) of dimethyl 4-ethylpyridine-2,6-dicarboxylate (INT 31-D) as a yellow solid. TLC (3:1 petroleum ether:EA):R f =0.6. 1 H NMR (400MHz, CDCl3) δ 8.13-8.20 (m, 2H) 4.00-4.03 (m, 6H) 2.78-2.87 (m, 2H) 1.29-1.37 (m, 3H).

[0355] Step 31-6. Synthesis of methyl 4-ethyl-6-(hydroxymethyl)picolinate (INT 31-E) [ka] To a solution of INT-31-D (4.5 g, 20.2 mmol) in MeOH (80 mL) and DCM (20 mL) was added NaBH (1.14 g, 30.24 mmol) at 0 °C. After stirring at 20 °C for 12 h, the mixture was diluted with saturated aqueous solution. NH Cl was extracted with EA. The organic layer was dried (Na SO ), concentrated in vacuo, and purified by SiO chromatography (petroleum ether / EA) to give 2.8 g (71%) of methyl 4-ethyl-6-(hydroxymethyl)picolinate (INT 31-E) as a yellow solid. TLC (1:1 petroleum ether:EA):R f =0.4. 1 H NMR (400MHz, CDCl3) δ7.84-7.93 (m, 1H) 7.34-7.43 (m, 1H) 4.79-4.86 (m, 2H) 3.93-4.00 (m, 3H) 2.68-2.77 (m, 2H) 1.27 (t, J=7.64Hz, 3H).

[0356] Step 31-7. Synthesis of methyl 6-(chloromethyl)-4-ethylpicolinate (INT 31-F) [ka] To a solution of INT-31-E (2.8 g, 14.34 mmol) in DCM (100 mL) at 0 °C was added SOCl (14.01 mL, 193 mmol). After 1.5 h, the reaction mixture was concentrated to give 2.5 g (82%) of methyl 6-(chloromethyl)-4-ethylpicolinate (INT-31F) as a yellow oil, which was used in the next step without further purification. 10 H 12 LCMS-ESI calculated for ClNO2 (m / z): 213.66; found 214.0 [M+H] + , t R =0.842 minutes. (Method 6).

[0357] Step 31-8. Synthesis of methyl 6-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-4-ethylpicolinate (INT 31-G) [ka] To a solution of INT-31-F (2.5 g, 11.70 mmol) and 2-chloro-4-(trifluoromethyl)phenol (2.0 g, 10.18 mmol) in MeCN (160 mL) was added KCO (4.85 g, 35.10 mmol). The suspension was stirred at 80 °C for 12 h, cooled, filtered, and the residue collected and purified by SiO chromatography (PE:EA) to give 4 g (82%) of methyl 6-((2-chloro-4-)trifluoromethyl)phenoxy)methyl)-4-ethylpicolinate (INT-31-G) as a pale yellow solid. TLC (3:1 petroleum ether:EA):R f =0.55. 1H NMR (400MHz, CDCl3) δppm1.32(t, J=7.58Hz, 3H)2.79(q, J=7.62Hz, 2H)4.03~4.05(m, 3H)5.4 0(s, 2H) 7.06(d, J=8.56Hz, 1H) 7.50(dd, J=8.68, 1.59Hz, 1H) 7.67~7.74(m, 2H) 7.97(s, 1H).

[0358] Step 31-9. Synthesis of 6-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-4-ethylpicolinic acid (compound 31-2) [ka] A solution of INT-31-G (3.4 g, 9.1 mmol) and LiOH-HO (1.15 g, 27.3 mmol) in THF (5 mL) and HO (1 mL) was stirred at 30 °C for 12 h. The reaction mixture was acidified to pH 6 with 1 N HCl and then extracted with EA. The combined organic extracts were dried (NaSO), concentrated, and dissolved in MeCN. HO was added to produce a white precipitate, which was collected by filtration and washed with HO. The resulting filter cake was lyophilized to provide 1.93 g (58%) of 6-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-4-ethylpicolinic acid (compound 31-2) as a white solid. 16 H 13 LCMS-ESI calculated for ClF3NO3 (m / z): 359.7, found 360.0 [M+H] + , t R =0.95 minutes. (Method 5-95AB_R_220&254.lcm). 1 H NMR (400MHz, CDCl3) δppm8.07(s, 1H) 7.76(s, 1H) 7.72(d, J=1.88Hz, 1H) 7.53(dd, J=8.63, 1 .63Hz, 1H)7.06(d, J=8.63Hz, 1H)5.34(s, 2H)2.84(q, J=7.63Hz, 2H)1.33(t, J=7.57Hz, 3H).

[0359] Example 32 Synthesis of compound 32-1 [ka] [ka] Reagents (i) thionyl-Cl, POCl3, MeOH, (ii) SOCl2, DCM, (iii) K2CO3, CH3CN (iv) NaOH, solvent (THF, MeOH, or DMF).

[0360] Step 32-1. Synthesis of methyl 3-cyano-5-methylbenzoate (INT 32-A) [ka] Thionyl chloride (7 mL) was added to 3-(methoxycarbonyl)-5-methylbenzoic acid (1.5 g, 7.7 mmol). After stirring at reflux for 1 h, the reaction mixture was dissolved and concentrated with toluene three times. The residue was dissolved in DCM (5 mL) and added to NHOH (5 mL) at 0 °C, giving a white precipitate. The reaction mixture was stirred at 0 °C for 5 min. H2O and EA were added, and the mixture was filtered to give 1.40 g of a white solid. POCl3 (4.7 mL) was added to the filtered solid, and the reaction mixture was heated at 100 °C for 1 h. The reaction mixture was cooled, concentrated in vacuo, dissolved in DCM, and treated with saturated NaHCO3. The mixture was extracted with EA (2 × 20 mL), dried (Na2SO4), filtered, and concentrated in vacuo to give 1.15 g of crude material. The crude material was purified by SiO chromatography (EA / hexanes) to afford 952 mg (70%) of methyl 3-cyano-5-methylbenzoate (INT 32-A) as a white solid. 10 LCMS-ESI calculated for H9NO2 (m / z): 175.19, found 176.2 [M+H] + , t R =4.87 minutes. (Method 1). 1 H NMR (500MHz, CDCl3) δ 8.12 (br s, 1H), 8.07 (br s, 1H), 7.63 (br s, 1H), 3.94 (s, 3H), 2.45 (s, 3H).

[0361] Step 32-2. Synthesis of methyl 3-(bromomethyl)-5-cyanobenzoate (INT 32-B) [ka] To a stirred solution of INT 32-A (0.50 g, 2.9 mmol) in CCl (10 mL) was added NBS (0.56 g, 3.1 mmol) and AIBN (94 mg, 0.57 mmol). The reaction mixture was heated to 77 °C (reflux) for 4 h, then concentrated in vacuo and purified by SiO chromatography (EA / hexanes) to afford 247 mg (34%) of methyl 3-(bromomethyl)-5-cyanobenzoate (INT 32-B) as a white solid. 10 LCMS-ESI (m / z) calculated for HBrNO: 254.08, m / z 255.2 (M+H) + , t R =5.05 minutes. (Method 1).

[0362] Step 32-3. Synthesis of methyl 3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-5-cyanobenzoate (INT 32-C) [ka] To a stirred solution of INT 32-B (124 mg, 488 μmol) in MeCN (3 mL) were added 2-chloro-4-(trifluoromethyl)phenol (95.9 mg, 488 μmol) and KCO (87.7 mg, 634 μmol). After heating at 60° C. for 12 h, the reaction mixture was cooled to RT and diluted with HO (6 mL). The aqueous layer was extracted with EtO (2×6 mL) and EA (6 mL), dried (NaSO), filtered through Celite, and concentrated in vacuo to give 146.1 mg (81%) of methyl 3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-5-cyanobenzoate (INT 32-C) as a beige solid. 17 H 11 LCMS-ESI calculated for ClF3NO3 (m / z): 369.72, found 370.0 [M+H] + , t R=6.39 minutes. (Method 1).

[0363] Step 32-3. Synthesis of 3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-5-cyanobenzoic acid (compound 32-1) [ka] Solid NaOH (79 mg, 1.98 mmol) was placed in a vial containing a stirred solution of INT 32-C (146.1 mg, 395.2 μmol) in MeOH (2 mL) and THF (2 mL). After stirring at 50 °C for 12 h, the reaction mixture was diluted with HO and acidified to pH 4-5 using 3 M HCl. The resulting white precipitate was extracted with EtO (3 × 10 mL) and EA (2 × 10 mL). The organic layers were combined, washed with brine, dried (NaSO), and concentrated under reduced pressure to give a crude solid, which was purified by reverse-phase HPLC (HO / CHCN). Lyophilization of the combined pure fractions afforded 82.6 mg (59%) of 3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-5-cyanobenzoic acid (compound 32-1) as a white solid. 16 LCMS-ESI calculated for H9ClF3NO3 (m / z): 355.0, found 354.0 [M−H] + , t R =10.07 minutes. (Method 4). 1 H NMR (500MHz, DMSO-d6) δ13.60(br s, 1H), 8.36(s, 1H), 8.29(s, 1H), 8.18(s, 1H), 7.89(s, 1H), 7.74(dd, J=8.5, 2.0Hz, 1H), 7.43(d, J=9.0Hz, 1H), 5.46(s, 2H).

[0364] The compounds listed in Table 32 were made using the procedures in Scheme 32.

[0365] [Table 22]

[0366] Example 33 Synthesis of compound 33-1 [ka] [ka] Reagents: (i) bases (Na2CO3, K2CO3, KO t Bu), solvent (THF or DMF), ii. diethylaminosulfur trifluoride, DCM, iii. NaOH, solvent (THF, MeOH or DMF).

[0367] Step 33-1. Synthesis of methyl 3-((2-formylphenoxy)methyl)benzoate (INT 33-A) [ka] To a stirred solution of methyl 3-(bromomethyl)benzoate (300 mg, 1.31 mmol) in MeCN (6 mL) was added 2-hydroxybenzaldehyde (160 mg, 1.31 mmol) and K2CO3 (235 mg, 1.70 mmol). After heating at 60 °C for 18 h, the mixture was cooled to RT, diluted with HO (6 mL), and the aqueous layer was extracted with Et2O (2 x 6 mL) and EA (6 mL). The combined organic layers were dried (Na2SO4), filtered through Celite, and purified by SiO2 chromatography (EA / hexanes) to afford 315 mg (89%) of methyl 3-((2-formylphenoxy)methyl)benzoate (INT 33-A) as a white solid. C 16 H 14 LCMS-ESI calculated for O4 (m / z): 270.1, found 271.5 (M+H) + , t R =5.4 minutes. (Method 1).

[0368] Step 33-2. Synthesis of methyl 3-((2-(difluoromethyl)phenoxy)methyl)benzoate (INT 33-B) [ka] To a stirred solution of INT 33-A (50 mg, 0.18 mmol) in DCM (2 mL) was added diethylaminosulfur trifluoride (0.12 mL, 0.92 mmol). After heating at 40° C. overnight, additional diethylaminosulfur trifluoride (0.12 mL, 0.92 mmol) was added, and the reaction mixture was stirred at 40° C. overnight. The reaction mixture was cooled to RT, diluted with HO, and extracted with DCM (3×5 mL). The combined organic extracts were dried (NaSO), filtered, concentrated in vacuo, and purified by SiO chromatography (EA / hexanes) to provide 28.7 mg (53%) of methyl 3-((2-(difluoromethyl)phenoxy)methyl)benzoate (INT 33-B). 16 H 14 LCMS-ESI calculated for F2O3 (m / z): 292.28, found 273.2 (M+H) + , t R =5.94 minutes. (Method 1). 1 H NMR (500MHz, CDCl3) δ8.09(s, 1H), 8.03-8.01(m, 1H), 7.65-7.63(m, 1H), 7.60(d, J=10Hz, 1H), 7.48(d, J=10.0Hz, 1H), 7.41-7.39(m, 1H), 7.06(t, J=10.0Hz, 1H), 7.02(t, J=55Hz, 1H), 6.99-6.97(m, 1H), 5.17(s, 2H), 3.94(s, 3H).

[0369] Step 33-3. Synthesis of 3-((2-(difluoromethyl)phenoxy)methyl)benzoic acid (compound 33-1) [ka] To a stirred solution of INT 33-B (28.7 mg, 98.2 μmol) in THF (2 mL) was added 1 M NaOH (0.5 mL, 491 μmol). The reaction mixture was heated at 60° C. overnight, concentrated in vacuo, diluted with 3 M HCl, and extracted (EA and EtO). The combined organic layers were dried (NaSO), filtered, and concentrated in vacuo to give 20.0 mg (73%) of 3-((2-(difluoromethyl)phenoxy)methyl)benzoic acid (compound 33-1) as a white solid. C 15 H 12 LCMS-ESI calculated for F2O3 (m / z): 278.3, observed 277.2 [MH] + , t R =8.02 minutes. (Method 4). 1 H NMR (500MHz, DMSO-d6) δ12.99(br s, 1H), 8.05(s, 1H), 7.91(d, J=7.5Hz, 1H), 7.73(d, J=7.0Hz, 1H), 7.54-7.45(m, 3H), 7.26-7.04(m, 3H), 5.30(s, 2H).

[0370] The compounds listed in Table 33 were made using the procedures in Scheme 33.

[0371] [Table 23]

[0372] Example 34 Synthesis of compound 34-1 [ka] [ka] Reagents: (i) bases (Na2CO3, K2CO3, KO t Bu), solvent (THF or DMF), ii. tricyclohexylphosphine, potassium phosphate, Pd(OAc)2, boronic acid, toluene, iii. NaOH, solvent (THF, MeOH or DMF).

[0373] Step 34-1. Synthesis of methyl 3-((2-bromo-4-(trifluoromethyl)phenoxy)methyl)benzoate (INT 34-A) [ka] Methyl 3-(bromomethyl)benzoate (300 mg, 1.31 mmol) and K2CO3 (235 mg, 1.70 mmol) were placed in a vial containing a stirred solution of 2-bromo-4-(trifluoromethyl)phenol (316 mg, 1.31 mmol) in MeCN (5 mL). The resulting yellow suspension was stirred at 60 °C for 16 h, cooled to room temperature, diluted with HO, and extracted three times with Et2O. The organic layers were combined, washed with brine, concentrated under reduced pressure, and purified by SiO2 chromatography (EA / hexanes) to afford 451 mg (88.5%) of methyl 3-((2-bromo-4-(trifluoromethyl)phenoxy)benzoate (INT 34-A) as a white solid. C 16 H 12 LCMS-ESI calculated for BrF3O3 (m / z): 389.2, found 391.0 (M+H) + , t R =6.7 minutes. (Method 1).

[0374] Step 34-2. Synthesis of methyl 3-((2-cyclopropyl-4-(trifluoromethyl)phenoxy)methyl)benzoate (INT 34-B) [ka] A 15 mL pressure tube containing a mixture of INT 34-A (300 mg, 771 μmol) in toluene (4 mL) was charged with potassium phosphate (491 mg, 2.31 mmol), tricyclohexylphosphine (32.4 mg, 116 μmol), cyclopropylboronic acid (132 mg, 1.54 mmol), and palladium(II) acetate (17.3 mg, 77.1 μmol). The tube was sealed, and the resulting orange suspension was stirred at 100 °C for 13.5 h, then cooled to room temperature and partitioned between EtO and HO. The aqueous layer was back-extracted with EtO (2×). The organic layers were combined, washed with brine, dried (NaSO), concentrated under reduced pressure, and purified by SiO chromatography (EA / hexanes) to provide 201 mg (74%) of methyl 3-((2-cyclopropyl)-4-(trifluoromethyl)phenoxy)methyl)benzoate (INT 34-B). 19 H 17 LCMS-ESI calculated for F3O3 (m / z): 350.34, found 373.2 (M+Na) + , t R =6.8 minutes. (Method 1). 1 H NMR (500MHz, DMSO-d6) δ8.11(s, 1H), 7.93(d, J=7.7Hz, 1H), 7.78(d, J=7.4Hz, 1H), 7.58(t, J=7.7Hz, 1H), 7.49(dd, J=8.2, 2.0Hz, 1H), 7. 21 (d.

[0375] Step 34-3. Synthesis of 3-((2-cyclopropyl-4-(trifluoromethyl)phenoxy)methyl)benzoic acid (compound 34-1) [ka] To a stirred solution of INT 34-B (195 mg, 557 μmol) in THF (5 mL) was added 1 M NaOH (2.23 mL, 2.23 mmol). The solution was stirred at 50 °C for 12.5 h overnight, concentrated under reduced pressure, dissolved in HO, and acidified to pH 4-5 using 3 M HCl. The resulting white precipitate was extracted three times into EtO. The organic layers were combined, washed with brine, dried (NaSO), and concentrated under reduced pressure to give the crude product, which was purified by preparative HPLC (CHCN / HO containing 0.1% formic acid) to give 66 mg (35%) of 3-((2-cyclopropyl-4-(trifluoromethyl)phenoxy)methyl)benzoic acid (compound 34-1) as a white solid. 18 H 15 LCMS-ESI calculated for F3O3 (m / z): 336.3, found 335.2 [MH] + , t R =10.83 minutes. (Method 4). 1 H NMR (499MHz, DMSO-d6) δ13.03(s, 1H), 8.09(s, 1H), 7.91(d, J=7.8Hz, 1H), 7.74(d, J=7.7Hz, 1H), 7.55(t, J=7.7Hz, 1H), 7.50(dd, J=8.7, 2.3Hz, 1H), 7.21(d, J=8.6Hz, 1H), 7.15(d, J=2.3Hz, 1H), 5.33(s, 2H), 2.18(tt, J=8.5, 5.3Hz, 1H), 0.99~0.91(m, 2H), 0.76~0.69(m, 2H). 19 F NMR (376MHz, DMSO-d6) δ-59.98.

[0376] Example 35 Synthesis of compound 35-1 [ka] [ka] Reagents: (i) bases (Na2CO3, K2CO3, KO t Bu), solvent (THF, dioxane, or DMF), iii. NaOH, solvent (THF, MeOH, or DMF).

[0377] Step 35-1. Synthesis of methyl 3-(((3-chloro-5-(trifluoromethyl)pyridin-2-yl)oxy)methyl)benzoate (INT 35-A) [ka] To a 48 mL pressure vessel containing a solution of 2,3-dichloro-5-(trifluoromethyl)pyridine (433 mg, 2.01 mmol) in 1,4-dioxane (9 mL) was added methyl 3-(hydroxymethyl)benzoate (500 mg, 3.01 mmol) and potassium tert-butoxide (338 mg, 3.01 mmol). The vessel was sealed and the reaction mixture was heated at 90° C. for 15.5 h and then cooled to room temperature. The reaction mixture was partitioned between EtO and HO. The phases were separated and the aqueous layer was extracted with EtO (2×). The organic phases were combined, washed with brine, dried (Na2SO4), concentrated, and purified by SiO2 chromatography (EA / hexanes) to afford 198 mg (28.6%) of methyl 3-(((3-chloro-5-(trifluoromethyl)pyridin-2-yl)oxy)methyl)benzoate (INT 35-A) as a white solid. 15 H 11 LCMS-ESI calculated for ClF3NO3 (m / z): 345.7, found 346.1 (M+H) + , t R =6.6 minutes. (Method 1). 1 H NMR (500MHz, DMSO-d6) δ8.59(dd, J=2.2, 1.1Hz, 1H), 8.44(d, J=1.9Hz, 1H), 8.09(t, J=1.8Hz, 1H), 7.9 4(dt, J=7.7, 1.5Hz, 1H), 7.76(dt, J=7.6, 1.5Hz, 1H), 7.57(t, J=7.7Hz, 1H), 5.60(s, 2H), 3.86(s, 3H).

[0378] Step 35-2. Synthesis of 3-(((3-chloro-5-(trifluoromethyl)pyridin-2-yl)oxy)methyl)benzoic acid (compound 35-1) [ka] To a 20 mL vial containing a stirred solution of INT 35-A (190 mg, 550 μmol) in THF (5 mL) was placed 1 M NaOH (2.20 mL, 2.20 mmol). After stirring at 50 °C for 22.5 h, the reaction mixture was concentrated under reduced pressure, and the resulting residue was dissolved in HO and acidified to pH 4-5 using 3 M HCl. The resulting white precipitate was extracted with EtO (3×). The organic layers were combined, washed with brine, dried (NaSO), and concentrated under reduced pressure to give 150 mg (82.3%) of 3-(((3-chloro-5-(trifluoromethyl)pyridin-2-yl))oxy)methyl)benzoic acid (compound 35-1) as a white powder. 14 LCMS-ESI calculated for H9ClF3NO3 (m / z): 331.7, found 333.2 (M+Na) + , t R =10.1 minutes. (Method 3). 1 H NMR (500MHz, DMSO-d6) δ13.05(s, 1H), 8.60(d, J=1.1Hz, 1H), 8.44(d, J=2.2Hz, 1H), 8.06 (s, 1H), 7.92(d, J=7.8Hz, 1H), 7.73(d, J=7.7Hz, 1H), 7.54(t, J=7.7Hz, 1H), 5.59(s, 2H). 19 F NMR (376MHz, DMSO-d6) δ-60.02.

[0379] Example 36 Synthesis of compound 36-1 [ka] [ka] Reagents: (i) bases (Na2CO3, K2CO3, KO t Bu), solvent (THF, dioxane, or DMF), (ii). ethynyl(trimethyl)silane, dichloropalladium, triphenylphosphine, CuI, TEA, THF, (iii). NaOH, solvent (THF, MeOH, or DMF).

[0380] Step 36-1. Synthesis of methyl 2-fluoro-3-((2-iodo-4-(trifluoromethyl)phenoxy)-methyl)benzoate (INT 36-A) [ka] To a solution of INT 4-A (300 mg, 1.21 mmol) and 2-iodo-4-(trifluoromethyl)phenol (349.72 mg, 1.21 mmol) in CHCN (10 mL) was added KCO (218.17 mg, 1.58 mmol). After stirring at 60 °C for 12 hours, the reaction mixture was filtered and the filtrate was concentrated to provide 500 mg (91%) of methyl 2-fluoro-3-((2-iodo-4-(trifluoromethyl)phenoxy)methyl)benzoate (INT 36-A), which was used without further purification. 16 H 11 LCMS-ESI calculated for F4IO3 (m / z): 454.16, found 454.9 (M+H) + , t R =1.04 minutes. (Method 6).

[0381] Step 36-2. Synthesis of methyl 2-fluoro-3-((4-(trifluoromethyl)-2-((trimethylsilyl)ethynyl)phenoxy)methyl)benzoate (INT 36-B) [ka] To a solution of INT 36-A (500 mg, 1.10 mmol) in THF (10 mL) was added ethynyl(trimethyl)silane (167.7 μL, 1.21 mmol), dichloropalladium triphenylphosphine (77.28 mg, 110.09 μmol), CuI (20.97 mg, 110.09 μmol), and TEA (459.72 μL, 3.30 mmol). After stirring at 40 °C for 12 h, the mixture was poured into HO (20 mL) and extracted with EA (3 × 20 mL). The organic layer was dried (NaSO), concentrated, and purified by SiO chromatography (PE, EA) to provide 200 mg (42%) of methyl 2-fluoro-3-((4-(trifluoromethyl)-2-((trimethylsilyl)ethynyl)phenoxy)methyl)benzoate (INT 36-B) as a white solid. TLC (5:1 PE:EA, R f =0.7) 1 H NMR (400MHz, CDCl3) δ7.95-7.90(m, 2H), 7.74(s, 1H), 7.57-7.53(m, 1H), 7.33 ~7.27(m, 1H), 7.05~7.01(m, 1H), 5.29(s, 2H), 3.96(s, 3H), 0.31~0.27(m, 9H).

[0382] Step 36-3. Synthesis of 3-((2-ethynyl-4-(trifluoromethyl)phenoxy)methyl)-2-fluorobenzoic acid (compound 36-1) [ka] To a suspension of INT 36-B (185 mg, 0.44 mmol) in MeOH (5 mL), HO (5 mL), and THF (5 mL) was added NaOH (52.3 mg, 1.4 mmol). After stirring at 30 °C for 1.5 h, the reaction mixture was concentrated, dissolved in MeOH (5 mL), filtered, and purified by preparative HPLC (HO / CHCN with formic acid) to provide 59 mg (48%) of 3-((2-ethynyl-4-(trifluoromethyl)phenoxy)methyl)-2-fluorobenzoic acid (compound 36-1) as a white solid. 17 H 10LCMS-ESI calculated for F4O3 (m / z): 338.3, found 339.1 (M+Na) + , t R =0.786 minutes. (Method 6). 1 H NMR (400MHz, DMSO-d6) δppm 4.44 (s, 1H) 5.38 (s, 2H) 7.36 (t, J = 7.69Hz, 1H) 7.43 (d, J = 8.50Hz, 1H) 7.75-7.84 (m, 3H) 7.88 (td, J = 7.38, 1.75Hz, 1H).

[0383] Example 37 Synthesis of compound 37-1 [ka] [ka] Reagents: (i) dioxaborolane or boronic acid, Pd(dppf)Cl-CHCl, dioxane, (ii) H, Pd / C, MeOH, (iii) NaBH, MeOH, (iv) SOCl, DCM, (v) base (NaCO, KCO, KO t Bu), solvent (THF, dioxane, or DMF), (iv). NaOH, solvent (THF, MeOH, or DMF).

[0384] Step 37-1. Synthesis of methyl 3-(hydroxymethyl)-2-vinylbenzoate (INT 37-A) [ka] To a suspension of dimethyl 2-bromobenzene-1,3-dicarboxylate (1 g, 3.66 mmol) and Na2CO3 (776.25 mg, 7.32 mmol) in 1,4-dioxane (20 mL) and HO (4 mL) was added 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaneborolane (683.25 μL, 4.03 mmol). The reaction mixture was treated with Pd(dppf)Cl2-CHCl2 (149.5 mg, 183.1 μmol) and stirred at 100 °C for 12 h. The mixture was filtered. The filtrate was partitioned between EA (30 mL) and HO (30 mL). The aqueous layer was back-extracted with EA (30 mL). The combined organic extracts were dried (NaSO), filtered, and concentrated in vacuo to give a residue that was purified by SiO chromatography to provide 680 mg (84.3%) of methyl 3-(hydroxymethyl)-2-vinylbenzoate (INT 37-A) as a colorless oil. TLC (5:1 PE:EA): Rf=0.7.

[0385] Step 37-2. Synthesis of methyl 2-ethyl-3-(hydroxymethyl)benzoate (INT 37-B) [ka] H2 (15 psi) was bubbled through a solution of INT 37-A (680 mg, 3.09 mmol), Pd / C (70 mg, 308.8 umol, 10% purity) in MeOH (10 mL) at 30 °C for 12 min. The reaction mixture was filtered, and the filtrate was concentrated to give the crude product, which was purified by SiO2 chromatography (EA / PE) to provide 560 mg (81.6%) of methyl 2-ethyl-3-(hydroxymethyl)benzoate (INT 37-B) as a colorless oil. TLC (5:1 PE:EA):R f =0.4. 1 H NMR (400MHz, CDCl3) δppm 1.25 (t, J = 7.40Hz, 3H) 3.15 (q, J = 7.46Hz, 2H) 3.92 (s, 6H) 7.30 (t, J = 7.76Hz, 1H) 7.85 (d, J = 7.70Hz, 2H).

[0386] Step 37-3. Synthesis of methyl 2-ethyl-3-(hydroxymethyl)benzoate (INT 37-C) [ka] To a solution of INT 37-B (0.4 g, 1.80 mmol) in THF (10 mL) at 0 °C was added NaBH (102.13 mg, 2.70 mmol) and MeOH (2 mL). After stirring at 70 °C for 12 h, the mixture was poured into saturated NH Cl (aq. 20 mL) and extracted with EA (3 × 20 mL). The combined organic layers were dried (Na SO ), concentrated, and purified by preparative TLC to provide 170 mg (48.6%) of methyl 2-ethyl-3-(hydroxymethyl)benzoate (INT 37-C) as a yellow oil. TLC (5:1 PE:EA):R f =0.5.

[0387] Step 37-4. Synthesis of methyl 3-(chloromethyl)-2-ethylbenzoate (INT 37-D) [ka] To a solution of INT 37-C (70 mg, 360.4 μmol) in DCM (2 mL) was added SOCl (130.7 μL, 1.80 mmol) at 0° C. After stirring at 30° C. for 1 h, the reaction mixture was concentrated in vacuo to provide 72 mg (94%) of methyl 3-(chloromethyl)-2-ethyl-benzoate (INT 37-D) as a brown gum, which was used in the next step without further purification. TLC (5:1 PE:EA):R f =0.7.

[0388] Step 37-5. Synthesis of methyl 3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-2-ethylbenzoate (INT 37-E) [ka] To a suspension of INT 37-D (70 mg, 329.15 μmol) and KCO (136.47 mg, 987.44 μmol) in CHCN (2 mL) was added 2-chloro-4-(trifluoromethyl)phenol (71.16 mg, 362.06 μmol, 1.1 equiv.). After stirring at 80 °C for 12 h, the reaction mixture was filtered, and the filtrate was concentrated in vacuo to provide a residue that was purified by SiO chromatography (EA / PE) to provide 59 mg (48%) of methyl 3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-2-ethyl-benzoate (INT 37-E) as a pale yellow gum. TLC (10:1 PE:EA):R f =0.75. C 18 H 16 LCMS-ESI calculated for ClF3O3 (m / z): 372.7, found 373.4 (M+H) + , t R =1.14 minutes. (Method 6). 1 H NMR (400MHz, CDCl3) δ7.78(dd, J=1.3, 7.8Hz, 1H), 7.66~7.63(m, 1H), 7.62(s, 1H), 7.46(dd, J=1.6, 8.7Hz, 1H), 7 .30~7.22(m, 1H), 7.03(d, J=8.6Hz, 1H), 5.22(s, 2H), 3.89(s, 3H), 2.97(q, J=7.5Hz, 2H), 1.23(t, J=7.5Hz, 3H).

[0389] Step 37-6. Synthesis of 3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-2-ethylbenzoic acid (compound 37-1) [ka] To a solution of INT 37-E (156 mg, 418.5 μmol) in THF (3 mL), MeOH (1 mL), and HO (1 mL) was added NaOH (42.92 mg, 1.07 mmol). After stirring at 50° C. for 12 hours, the mixture was acidified with 3M hydrochloric acid and then partitioned between EA (10 mL) and HO (10 mL). The organic layer was dried (NaSO), filtered, and concentrated in vacuo. The resulting residue was purified by preparative HPLC (HO (0.225% FA)—CHCN) to provide 144 mg (77%) of 3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-2-ethylbenzoic acid (compound 37-1). 17 H 14 LCMS-ESI calculated for ClF3O3 (m / z): 358.7, found 357.0 (M−H) + , t R =0.95 minutes. (Method 8). 1 H NMR (400MHz, CDCl3) δ8.02(dd, J=1.1, 7.8Hz, 1H), 7.74(d, J=7.0Hz, 1H), 7.69(d, J=2.1Hz, 1H), 7.52(dd, J=1.7, 8.7Hz, 1H), 7.36(t, J=7.8Hz, 1H), 7.09(d, J=8.6Hz, 1H), 5.28(s, 2H), 3.12(q, J=7.5Hz, 2H), 1.31(t, J=7.5Hz, 3H)

[0390] Example 38 Synthesis of compound 38-1 [ka] [ka] Reagents: (i) BocO, DMAP, CHCN, (ii) NBs, AIBN or BPO, CCl, (iii) base (NaCO, KCO, KO t Bu), solvent (THF, dioxane, or DMF), (iv) acid (HCl, TFA), solvent (dioxane, THF), (v) MeI, K2CO3, CH3CN, (vi) NaOH, solvent (THF, MeOH, or DMF).

[0391] Step 38-1 Synthesis of methyl 3-((tert-butoxycarbonyl)amino)-5-methylbenzoate (INT 38-A) [ka] To a solution of methyl 3-amino-5-methylbenzoate (1 g, 6.05 mmol, 1), di-tert-butyl dicarbonate (2.64 g, 12.11 mmol), and TEA (1.69 mL, 12.11 mmol) in CHCN (15 mL) was added 4-dimethylaminopyridine (73.96 mg, 605.37 μmol). The reaction mixture was stirred at 50 °C for 12 h and then filtered. The filtrate was concentrated, and the residue was purified by SiO chromatography (EA / PE) to provide 850 mg (53%) of methyl 3-((tert-butoxycarbonyl)amino)-5-methylbenzoate (INT 38-A) as a yellow gum. TLC (5:1 PE:EA):R f =0.7. 1 H NMR (400MHz, CDCl3) δppm 1.46 (s, 9H) 2.40 (s, 3H) 3.91 (s, 3H) 7.28 (s, 1H) 7.75 (s, 1H) 7.82 (s, 1H).

[0392] Step 38-2 Synthesis of methyl 3-(bromomethyl)-5-((tert-butoxycarbonyl)amino)benzoate (INT 38-B) [ka] To a solution of INT 38-A (750 mg, 2.83 mmol) and NBS (604 mg, 3.39 mmol) in CCl (10 mL) was added AIBN (46 mg, 282 μmol). After stirring at 80 °C for 12 h, the reaction mixture was filtered and purified by SiO chromatography (EA / PE) to provide 800 mg (82%) of methyl 3-(bromomethyl)-5-((tert-butoxycarbonyl)amino)benzoate (INT 38-B) as a brown gum. TLC (10:1 PE:EA):R f =0.45.

[0393] Step 38-3 Synthesis of methyl 3-((tert-butoxycarbonyl)amino)-5-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)benzoate (INT 38-C) [ka] To a suspension of INT 38-B (560 mg, 1.63 mmol) and KCO (674.57 mg, 4.88 mmol) in CHCN (10 mL) was added 2-chloro-4-(trifluoromethyl)phenol (351.76 mg, 1.79 mmol). After stirring at 80 °C for 12 h, the reaction mixture was filtered, concentrated, and purified by SiO chromatography to provide 140 mg (18%) of methyl 3-((tert-butoxycarbonyl)amino)-5-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)benzoate (INT 38-C) as a pale yellow gum. TLC (10:1 PE:EA):R f =0.60.C 21 H 21 LCMS-ESI calculated for ClF3NO5 (m / z): 459.85, found 458 [MH] + , t R =1.12 minutes (method 6). 1 H NMR (400MHz, DMSO-d6) δ9.72(s, 1H), 8.15(s, 1H), 7.87(d, J=1.9Hz, 1H), 7.78(s, 1H) ), 7.72~7.68(m, 2H), 7.39(d, J=8.9Hz, 1H), 5.35(s, 2H), 3.85(s, 3H), 1.48(s, 9H).

[0394] Step 38-4 Synthesis of methyl 3-amino-5-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)benzoate (INT 38-D) [ka] A solution of INT 38-C (60 mg, 130.48 μmol) in HCl / dioxane (4 M, 1 mL) was stirred at 30° C. for 1 h. The reaction mixture was concentrated in vacuo to give 55 mg of crude methyl 3-amino-5-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)benzoate (INT 38-D) as a gray solid, which was used in the next step without further purification. TLC (10:1 PE:EA):R f =0.65.

[0395] Step 38-5 Synthesis of methyl 3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-5-(dimethylamino)benzoate (INT 38-E) [ka] To a suspension of INT 38-D (50 mg, 138.99 μmol) and KCO (38.42 mg, 278 μmol) in MECN (3 mL) was added MeI (17.31 μL, 277.99 μmol). The reaction mixture was stirred at 30 °C for 12 h, filtered, and purified by SiO chromatography to provide 12 mg (22%) of methyl 3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-5-(dimethylamino)benzoate (INT 38-E) as a pale yellow gum. TLC (5:1 PE:EA):R f =0.8.C 18 H 17 LCMS-ESI calculated for ClF3NO3 (m / z): 387.8, found 388 [MH] + , t R =0.99 minutes (method 6). 1 H NMR (400MHz, CDCl3) δppm7.66 (d, J=1.88Hz, 1H) 7.46 (dd, J=8.63, 1.63Hz, 1H) 7.42 (s, 1H) 7.36 (s, 1H) 7.00~7.06 (m, 2H) 5.21 (s, 2H) 3.92 (s, 3H) 3.02 (s, 6H).

[0396] Step 38-6 Synthesis of 3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-5-(dimethylamino)benzoic acid (compound 38-1) [ka] To a solution of INT 38-E (12 mg, 30.95 μmol) in THF (1 mL), MeOH (0.5 mL), and HO (0.5 mL) was added NaOH (4.95 mg, 123.78 μmol). After stirring at 50° C. for 4 hours, the mixture was acidified with 3M hydrochloric acid. The mixture was partitioned between EA (10 mL) and HO (10 mL), and the resulting organic layer was dried (NaSO), filtered, and purified by preparative HPLC (HO (0.225% FA)—CHCN) to provide 3.6 mg (31%) of 3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-5-(dimethylamino)benzoic acid (compound 38-1) as a white solid. 17 H 15 LCMS-ESI calculated for ClF3NO3 (m / z): 373.76, found 374.1 [M+H] + , t R =0.93 minutes (method 6). 1 H NMR (400MHz, CDCl3) δ7.67(d, J=1.8Hz, 1H), 7.50~7.44(m, 2H), 7.41(s, 1H), 7.09~7.02(m, 2H), 5.23(s, 2H), 3.03(s, 6H).

[0397] Example 39 Synthesis of compound 39-1 [ka] [ka] Reagents: (i) i PrMgCl-LiCl, 3-bromoprop-1-ene, CuCN, THF, (ii) Pd(dppf)Cl2, CO(gas), TEA, MeOH, DCM, (iii) Pd / C, H2(gas), MeOH, (ii) See Scheme 31.

[0398] Step 39-1. Synthesis of 4-allyl-2,6-dichloropyridine (INT 39-A) [ka] i To a mixture of PrMgCl-LiCl (1M, 12.78 mL) in THF (100 mL) at −60° C. was added 2,6-dichloro-4-iodopyridine (2.8 g, 10.22 mmol). The mixture was stirred at −60° C. for 0.5 h, then 3-bromoprop-1-ene (1.55 g, 12.78 mmol) and CuCN (1.14 g, 12.78 mmol) were added, and the mixture was stirred at 25° C. for 16 h. The reaction mixture was quenched by the addition of HO (100 mL) and extracted with EA (3×50 mL). The combined organic layers were dried and concentrated to give a residue that was purified by preparative TLC (PE) to give 1.4 g (73%) of 4-allyl-2,6-dichloropyridine (INT 39-A) as a yellow oil. TLC (PE):R f =0.50.

[0399] Step 39-2. Synthesis of dimethyl 4-allylpyridine-2,6-dicarboxylate (INT 39-B) [ka] CO gas (20.85 g, 744.47 mmol) was bubbled into a solution of INT 39-A (1.4 g, 7.44 mmol), Pd(dppf)Cl2CH2Cl2 (3.04 g, 3.72 mmol), and TEA (6.22 mL, 44.67 mmol) in MeOH (10 mL). The mixture was stirred at 70 °C for 12 h and then filtered. The resulting residue was purified by SiO2 chromatography (EA / PE) to provide 1.75 g (60%) of dimethyl 4-allylpyridine-2,6-dicarboxylate (INT 39-B) as a black solid. TLC (1:1 EA:PE):R f =0.50.

[0400] Step 39-3. Synthesis of dimethyl 4-propylpyridine-2,6-dicarboxylate (INT 39-C) [ka] A solution of INT 39-B (2.9 g, 12.33 mmol) and Pd / C (0.3 g, 1.23 mmol, 10% purity) in MeOH (80 mL) was stirred under H (50 psi) at 25 °C for 12 h. The reaction mixture was filtered and concentrated to give a residue that was purified by SiO chromatography (EA) to give 2.5 g (85%) of dimethyl 4-propylpyridine-2,6-dicarboxylate (INT 39-C) as a yellow solid. TLC (1:1 EA:PE):R f =0.80. 1 H NMR (400MHz, CDCl3) δppm 8.14 (s, 2 H) 4.02 (s, 6H) 2.76 (t, J=7.64Hz, 2H) 1.75 (sxt, J=7.46Hz, 2H) 0.98 (t, J=7.34Hz, 3H).

[0401] Step 39-4. Synthesis of 6-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-4-propylpicolinic acid (compound 39-1) [ka] The synthesis of compound 39-1 was completed from INT 39-C as shown in Scheme 31. 17 H 15 LCMS-ESI calculated for ClF3NO3 (m / z): 373.76, found 373.8 (M+H) + , t R =0.786 minutes. (Method 6). 1 H NMR (400MHz, DMSO-d6) δ7.85-7.91(m, 2H) 7.71(dd, J=8.76, 1.63Hz, 1H) 7.61(s, 1H) 7.45(d, J= 8.63Hz, 1H), 5.42(s, 2H) 2.70(t, J=7.50Hz, 2H) 1.62(m, J=7.40Hz, 2H) 0.87(t, J=7.32Hz, 3H).

[0402] Example 40 Synthesis of compound 40-1 [ka] [ka] Reagents: (i) bases (Na2CO3, K2CO3, KO t (Bu), solvent (THF, dioxane, or DMF); (ii) NaOH, solvent (THF, MeOH, or DMF).

[0403] Step 40-1. Synthesis of 3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)benzenesulfonamide (INT 40-A) [ka] To a solution of 3-(bromomethyl)benzenesulfonamide (100 mg, 400 μmol) in CHCN (3 mL) was added 2-chloro-4-(trifluoromethyl)phenol (78.6 mg, 400 μmol) and KCO (111 mg, 800 μmol). After stirring at 30 °C for 12 h, the mixture was concentrated to give the crude product, which was purified by preparative HPLC (HO (0.225% FA) / CHCN) to provide 70 mg (48%) of 3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)benzenesulfonamide (INT 40-A) as a white solid. 14 H 11 LCMS-ESI calculated for ClF3NO3S (m / z): 365.8, found 364.0 (M−H) + , t R =0.967 minutes. (Method 7).

[0404] Step 40-2. Synthesis of 3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)benzenesulfonic acid (compound 40-1) [ka] To a solution of INT 40-A (30 mg, 82 μmol) in THF (3 mL) was added HCl (2 M, 41.01 μL) and NaNO (9.6 mg, 139 μmol). After stirring at 40 °C for 12 hours, the mixture was concentrated to give the crude product, which was purified by preparative HPLC (HO (0.1% TFA) / CHCN) to provide 2.6 mg (8.5%) of 3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)benzenesulfonic acid (compound 40-1) as a brown gum. 14 H 10 LCMS-ESI calculated for ClF3O4S (m / z): 366.7, found 365.0 (M−H) + , t R =0.708 minutes. (Method 7).

[0405] Example 41 Synthesis of compound 41-1 [ka] [ka] Reagents: (i) Pd(dppf)Cl2-CH2Cl2, CO(gas), TEA, (ii) See Scheme 31.

[0406] Step 41-1. Synthesis of dimethyl 4-methylpyridine-2,6-dicarboxylate (INT41-A) [ka] To a solution of 2,6-dichloro-4-methyl-pyridine (1 g, 6.17 mmol) in DMF (20 mL) and MeOH (10 mL) was added Pd(dppf)Cl-CHCl (504.05 mg, 617.22 μmol) and TEA (3.44 mL, 24.69 mmol). After stirring at 80 °C under CO (50 PSI) for 16 h, the reaction mixture was filtered, concentrated, diluted with HO, and extracted with EA (2 × 50 mL). The combined organic layers were dried (NaSO), filtered, concentrated, and purified by SiO chromatography (EA / PE) to afford 900 mg (68%) of dimethyl 4-methylpyridine-2,6-dicarboxylate (INT41-A) as a yellow solid. TLC (2:1 EA:PE):R f =0.20. C 10 H 11 LCMS-ESI calculated for NO4 (m / z): 209.2, found 210.6 (M+H) + , t R =0.756 minutes. (Method 7). 1 H NMR (400MHz, DMSO-d6) δ8.12 (d, J=0.7Hz, 2H), 3.91 (s, 6H), 2.49-2.48 (s, 3H).

[0407] Step 41-2. Synthesis of 4-methyl-6-((naphthalen-2-yloxy)methyl)picolinic acid (compound 41-1) [ka] 4-Methyl-6-((naphthalen-2-yloxy)methyl)picolinic acid (compound 41-1) was synthesized from INT 41-A and naphthalen-2-ol according to Scheme 31 (steps i-iv) and obtained as a white solid. 18 H 15 LCMS-ESI calculated for NO3 (m / z): 293.3, found 294.2 (M+H) + , t R =0.789 minutes. (Method 7). 1H NMR (400MHz, DMSO-d6) δ12.93-13.50 (m, 1H) 7.77-7.90 (m, 4H) 7.64 (s, 1H) 7.42-7.50 (m, 2H)7.33-7.40(m, 1H)7.30(dd, J=8.94, 2.44Hz, 1H)5.22-5.41(m, 2H)2.38-2.45(m, 3H).

[0408] The compounds listed in Table 41 were made using the procedures in Scheme 41.

[0409] [Table 24]

[0410] Example 42 Synthesis of compound 42-1 [ka] [ka] Reagents: (i) aldehyde, aqueous H2SO4, FeSO4, 30% H2O2, (ii). See Scheme 31.

[0411] Step 42-1. Synthesis of dimethyl 4-ethylpyridine-2,6-dicarboxylate (INT 42-A) [ka] To a solution of dimethylpyridine-2,6-dicarboxylate (10 g, 51.2 mmol) and propanal (18.65 mL, 256.2 mmol) in HSO (100 mL) was added FeSO (5.70 g, 20.49 mmol) and 30% H0 (9.85 mL, 102.47 mmol) dropwise over 15 min. After stirring at 0 °C for 15 min, the mixture was diluted with saturated KCO (aq) and extracted with EA (3 × 200 mL). The combined organic layers were dried (NaSO), filtered, concentrated, and purified by SiO chromatography (EA / PE) to give 4.5 g (39%) of dimethyl 4-ethylpyridine-2,6-dicarboxylate (INT 42-A) as a yellow solid. TLC (3:1 EA:PE):R f =0.60. 1 H NMR (400MHz, CDCl3) δ 8.13-8.20 (m, 2H) 4.00-4.03 (m, 6H) 2.78-2.87 (m, 2H) 1.29-1.37 (m, 3H).

[0412] Step 42-2. Synthesis of 4-ethyl-6-((naphthalen-2-yloxy)methyl)picolinic acid (compound 42-1) [ka] 4-Ethyl-6-((naphthalen-2-yloxy)methyl)picolinic acid (compound 42-1) was synthesized from INT 42-A and naphthalen-2-ol according to Scheme 31 (steps i-iv) and obtained as a white solid. 19 H 17 LCMS-ESI calculated for NO3 (m / z): 307.4, found 307.9 (M+H) + , t R =0.743 minutes. (Method 6). 1 H NMR (400MHz, DMSO-d6) δ12.82-13.61 (m, 1H) 7.78-7.91 (m, 4H) 7.68 (s, 1H) 7.43-7.50 (m, 2H) 7.33-7 .39(m, 1H)7.31(dd, J=8.88, 2.50Hz, 1H)5.26~5.41(m, 2H)2.74(q, J=7.63Hz, 2H)1.13~1.30(m, 3H)

[0413] The compounds listed in Table 42 were made using the procedures in Scheme 42.

[0414] [Table 25]

[0415] Example 43 Synthesis of compound 43-1 [ka] [ka] Reagents: (i) PBr3, Br2, hexane, (ii) NaBH4, MeOH, DCM, (iii) PBr3, CHCl3, (iv) base (Na2CO3, K2CO3, KO t Bu), solvent (THF, dioxane, or DMF), (iv). Zn(CN), Pd(PPh), DMF, (v) NaOH, solvent (THF, MeOH, or DMF).

[0416] Step 43-1. Synthesis of dimethyl 4-bromopyridine-2,6-dicarboxylate (INT 43-A) [ka] PBr3 (1.61 mL, 16.9 mmol) was added to a solution of Br2 (700 μL, 13.7 mmol) in hexane (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 CHCl3 (50 mL). Anhydrous MeOH (50 mL) was added dropwise at 0 °C, and the mixture was stirred at 22 °C for 1 h. The mixture was concentrated, and the residue was dissolved in DCM (50 mL) and diluted with saturated aqueous NaHCO3 (50 mL). The aqueous phase was extracted with DCM (4 × 50 mL), and the combined organic layers were dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by SiO chromatography (EA / hexane) to provide 924 mg (62%) of dimethyl 4-bromopyridine-2,6-dicarboxylate (INT 43-A) as a solid. LCMS-ESI (m / z) calculated for CHBrNO: 274.07, found 276.1 (M+H). + , t R =2.04 minutes. (Method 13).

[0417] Step 43-2. ​​Synthesis of methyl 4-bromo-6-(hydroxymethyl)pyridine-2-carboxylate (INT 43-B) [ka] NaBH4 (191 mg, 5.06 mmol) was added to a solution of INT 43-A (924 mg, 3.37 mmol) in MeOH and DCM (4:1 v / v, 50 mL) at 0 °C. The mixture was stirred at 0 °C for 30 min. Saturated aqueous NaHCO3 (50 mL) was added, and the aqueous phase was extracted with DCM (4 × 30 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated to provide 690 mg (83%) of methyl 4-bromo-6-(hydroxymethyl)pyridine-2-carboxylate (INT 43-B) as a solid. LCMS-ESI (m / z) calculated for CHBrNO3: 246.06, found 246.1 (M+H). + , t R =1.78 minutes. (Method 13).

[0418] Step 43-3. Synthesis of methyl 4-bromo-6-(bromomethyl)pyridine-2-carboxylate (INT 43-C) [ka] PBr3 (450 μL, 4.74 mmol) was added to a solution of INT 43-B (690 mg, 2.80 mmol) in CHCl3 (35.0 mL) at 0 °C. The mixture was stirred at 22 °C for 5 h, cooled to 0 °C, and diluted with saturated aqueous K2CO3 (25.0 mL). The aqueous phase was extracted with EA (3 × 30 mL), and the combined organic layers were washed with brine (20 mL), dried (Na2SO4), filtered, and concentrated. The residue was purified by SiO2 chromatography (EA / hexanes) to provide 700 mg (81%) of methyl 4-bromo-6-(bromomethyl)pyridine-2-carboxylate (INT 43-C) as a solid. LCMS-ESI (m / z) calculated for CHBr2NO2: 308.96, found 246.1 (M+H). + , t R =2.22 minutes. (Method 13).

[0419] Step 43-4. Synthesis of methyl 4-bromo-6-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)pyridine-2-carboxylate (INT 43-D) [ka] 2-Chloro-4-(trifluoromethyl)phenol (490 mg, 2.49 mmol) and CsCO (1.48 g, 4.53 mmol) were added to a solution of INT 43-C (700 mg, 2.27 mmol) in anhydrous DMF (5 mL) at 22 °C. The mixture was stirred at 50 °C for 18 h, cooled to rt, and diluted with HO (25 mL). The aqueous phase was extracted with EA (3 × 30 mL), and the combined organic layers were washed with brine (20 mL), dried (NaSO), filtered, and concentrated. The residue was purified by SiO chromatography (EA / hexanes) to provide 750 mg (78%) of methyl 4-bromo-6-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)pyridine-2-carboxylate (INT 43-D) as a solid. C 15 H 10 LCMS-ESI calculated for BrClF3NO3 (m / z): 422.95; found 424.4 (M+H) + , t R =2.78 minutes. (Method 13).

[0420] Step 43-5. Synthesis of methyl 4-bromo-6-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)pyridine-2-carboxylate (INT 43-E) [ka] Zn(CN) (59.7 mg, 0.509 mmol) and Pd(PPh) (44.1 mg, 0.038 mmol) were added to a solution of INT 43-D (108 mg, 0.254 mmol) in degassed DMF (2.00 mL) at 22 °C. The mixture was purged with N for 5 minutes and stirred at 150 °C for 6 hours. The mixture was concentrated, and the residue was purified by SiO chromatography (EA / hexanes) to provide 74 mg (79%) of methyl 4-bromo-6-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)pyridine-2-carboxylate (INT 43-E) as a solid. 16 H 10 LCMS-ESI calculated for ClF3N2O3 (m / z): 370.03, m / z not observed) + , tR =2.78 minutes. (Method 13).

[0421] Step 43-6. Synthesis of 6-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-4-cyano-pyridine-2-carboxylic acid (compound 43-1) [ka] An aqueous solution of 2M NaOH (299 μL, 0.150 mmol) was added to a solution of INT 43-E (74.0 mg, 0.20 mmol) in MeOH (1 mL) and THF (1 mL) at 22 °C. The mixture was stirred at 22 °C for 2 hours and concentrated. The residue was acidified with 2M aqueous HCl (pH ∼2) and diluted with H2O (10 mL). The aqueous phase was extracted with EA (3 × 10 mL), and the combined organic layers were washed with brine (10 mL), dried (Na2SO4), filtered, and concentrated. The residue was purified by reverse-phase chromatography (H2O (+0.1% formic acid) / CH3CN) to provide 63 mg (89%) of 6-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-4-cyano-pyridine-2-carboxylic acid (compound 43-1) as a solid. C 15 LCMS-ESI calculated for H8ClF3N2O3 (m / z): 356.7, found 357.1 (M+H) + , t R =3.91 minutes. (Method 12). 1 H NMR (500MHz, DMSO-d6) δ13.84 (br s, 1H), 8.39(d, J=1.4Hz, 1H), 8.17(d, J=1.4Hz, 1H), 7.92(d, J=2.2Hz, 1H), 7.73(dd, J=2.3, 8.7Hz, 1H), 7.48(d, J=8.7Hz, 1H), 5.51(s, 2H).

[0422] Example 44 Synthesis of compound 44-1 [ka] [ka] Reagents: (i) bases (Na2CO3, K2CO3, KO t Bu), solvent (THF, dioxane, or DMF), (ii) 2-methyloxazole, Pd(PPh3)4, KOAc, DMF, (v) NaOH, solvent (THF, MeOH, or DMF).

[0423] Step 44-1. Synthesis of methyl 3-bromo-5-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)benzoate (INT 44-A) [ka] A mixture of methyl 3-bromo-5-(bromomethyl)benzoate (3.60 g, 11.7 mmol), 2-chloro-4-(trifluoromethyl)phenol (1.48 mL, 11.1 mmol), and K2CO3 (4.85 g, 35.1 mmol) in acetone (30 mL) was stirred at 90 °C for 1 hour. The mixture was filtered, and the filtrate was concentrated. The residue was purified by SiO2 chromatography (EA / hexane) to provide 2.36 g (48%) of methyl 3-bromo-5-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)benzoate (INT 44-A) as a solid. C 16 H 11 LCMS-ESI calculated for BrClF3O3 (m / z): 423.61, found 442.2 (M+H2O) + , t R =3.29 minutes (method 13). 1 H NMR (400MHz, CDCl3) δ8.18-8.13(m, 1H), 8.05(tt, J=1.5, 0.7Hz, 1H), 7.84(td, J=1.7, 0.8Hz, 1H) ), 7.68 (dt, J=2.3, 0.7Hz, 1H), 7.52~7.45 (m, 1H), 7.06~6.94 (m, 1H), 5.20 (s, 2H), 3.94 (s, 3H).

[0424] Step 44-2. Synthesis of methyl 3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-5-(2-methyloxazol-5-yl)benzoate (INT 44-B) [ka] A mixture of INT 44-A (150 mg, 0.354 mmol), 2-methyloxazole (58.0 μL, 0.708 mmol), Pd(PPh3)4 (41.0 mg, 0.035 mmol), and KOAc (70.0 mg, 0.708 mmol) in DMF (4.00 mL) was stirred at 110 °C for 16 h. The mixture was cooled and diluted with HO (20 mL). The aqueous phase was extracted with EA (3 × 20.0 mL), and the combined organic layers were washed with brine (20 mL), dried (MgSO4), filtered, and concentrated. The residue was purified by SiO2 chromatography (EA / hexanes) to provide 98 mg (65%) of methyl 3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-5-(2-methyloxazol-5-yl)benzoate (INT 44-B) as a solid. C 20 H 15 LCMS-ESI calculated for ClF3NO4 (m / z): 425.06, found 426.25 [M+H] + , t R =2.79 minutes (method 13). 1 H NMR (500MHz, CDCl3) δ8.25(t, J=1.6Hz, 1H), 8.07~8.03(m, 1H), 7.95~7.89(m, 1H), 7.71~7.65(m, 1H), 7. 49(ddd, J=8.7, 2.3, 0.8Hz, 1H), 7.33(s, 1H), 7.08~7.00(m, 1H), 5.26(s, 2H), 3.97(s, 3H), 2.56(s, 3H).

[0425] Step 44-3. Synthesis of 3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-5-(2-methyloxazol-5-yl)benzoic acid (compound 44-1) [ka] A solution of NaOH (1 M in HO, 676 μL, 0.676 mmol) was added to a mixture of INT 44-B (96.0 mg, 0.225 mmol) in THF and HO (3:1 v / v, 4.00 mL). The mixture was stirred at 22 °C for 4 hours. The mixture was acidified with 1 M aqueous HCl (pH 2) and diluted with EA (20 mL). The aqueous phase was extracted with EA (2 × 30.0 mL), and the combined organic layers were washed with brine (20 mL), dried (MgSO), filtered, and concentrated. The residue was purified by SiO chromatography (MeOH / DCM) to provide 77.5 mg (83%) of 3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-5-(2-methyloxazol-5-yl)benzoic acid (compound 44-1) as a solid. C 19 H 13 LCMS-ESI calculated for ClF3NO4 (m / z): 411.05, found 412.2 [M+H] + , t R =4.59 minutes (method 12). 1 H NMR (500MHz, DMSO-d6) δ13.35(s, 1H), 8.17(dd, J=1.7Hz, 1H), 8.04~7.98(m, 2H), 7.88(d, J=2.3H) z, 1H), 7.73(dd, J=8.9, 2.3Hz, 1H), 7.66(s, 1H), 7.45(d, J=8.7Hz, 1H), 5.43(s, 2H), 2.50(s, 3H).

[0426] Example 45 Synthesis of compounds 45-1 and 45-2 [ka] [ka] Reagents: (i) bases (NaH, Na2CO3, K2CO3, KO t Bu), solvent (THF, dioxane, or DMF), (ii). dimethylformamide dimethyl acetal, N2H4-H2O, AcOH.

[0427] Step 45-1. Synthesis of 3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)benzamide (Compound 45-1) [ka] To a solution of 3-(bromomethyl)benzamide (254 mg, 1.29 mmol) in DMF (5 mL) at 0 °C was added NaH. The reaction mixture was stirred and warmed to rt over 30 minutes, after which 2-chloro-4-(trifluoromethyl)phenol (250 mg, 1.17 mmol) was added. After 4 hours, the reaction mixture was diluted with EA, washed with HO, 1M HCl, 1M NaOH, HO, brine, dried (NaSO), filtered, and concentrated. The resulting crude residue was purified by reverse-phase SiO chromatography to provide material that was triturated with (MeOH / HO), filtered, and dried in vacuo to provide 260 mg (67%) of 3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)benzamide (compound 45-1). C 15 H 11 LCMS-ESI calculated for ClF3NO2 (m / z): 329.04, found 330.1 [M+H] + , t R =12.14 minutes (method 10). 1 H NMR (300MHz, CDCl3) δ7.96(s, 1H), 7.80(d, J=7.7Hz, 1H), 7.69(s, 1H), 7.68(d, J=8.3Hz, 1H), 7.54(d, J=7.7Hz, 1H), 7.51(d, J=6.6Hz, 1H), 7.05(d, J=8.7Hz, 1H), 6.11(bs, 1H), 5.69(bs, 1H), 5.28(s, 2H).

[0428] Step 45-2. Synthesis of 3-(3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)phenyl)-1H-1,2,4-triazole (compound 45-2) [ka] A solution of compound 45-1 (260 mg, 0.079 mmol) in dimethylformamide dimethyl acetal (4 mL) was heated at 120 °C for 2 h. The reaction mixture was cooled to rt and concentrated in vacuo. The resulting residue was dissolved in AcOH (4 mL), and N2H4-H2O (47 mg, 0.946 mmol) was added dropwise. After stirring at 90 °C for 2 h, the mixture was concentrated, diluted with Et2O, and cooled to 0 °C. The resulting precipitate was collected by filtration and purified by SiO2 chromatography (EA / hexanes) to provide 125 mg (45%) of 3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)benzamide (compound 45-2). C 16 H 11 LCMS-ESI calculated for ClF3N3O (m / z): 353.05, found 354.5 (M+H) + , t R =13.56 minutes (method 10). 1 H NMR (300MHz, CDCl3) δ8.30(s, 1H), 8.16(s, 1H), 8.04(d, J=7.5Hz, 1H), 7.76(d, J=2.9Hz, 1H), 7.56-7.44(m, 3H), 7.03(d, J=8.6Hz, 1H), 5.24(s, 2H).

[0429] The compounds listed in Table 45 were made using the procedures in Scheme 45.

[0430] [Table 26]

[0431] Example 46 Synthesis of compound 46-1 [ka] [ka] Reagents: (i) N,O-dimethylhydroxylamine hydrochloride, HATU, DIPEA, DMF, (ii) DIBAL, THF, -78°C, (iii) oxalaldehyde, NH4OH, EtOH.

[0432] Step 46-1. Synthesis of 3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-N-methoxy-N-methylbenzamide (INT 46-A) [ka] To a solution of compound 1-29 (500 mg, 1.51 mmol) in DMF (10 mL) was added N,O-dimethylhydroxylamine hydrochloride (161 mg, 1.66 mmol), HATU (632 mg, 1.66 mmol), and DIPEA (585 mg, 4.5 mmol). After stirring for 18 hours, the reaction mixture was acidified with TFA and purified by reverse-phase SiO chromatography (MeOH / HO, 0 / 1% TFA) to provide 530 mg (94%) of 3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-N-methoxy-N-methylbenzamide (INT 46-A). 17 H 15 LCMS-ESI calculated for ClF3NO3 (m / z): 373.07, m / z not observed, t R =6.2 minutes (method 11).

[0433] Step 46-2. Synthesis of 3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)benzaldehyde (INT 46-B) [ka] To a solution of INT46-A (1000 mg, 2.68 mmol) in THF (10 mL) at −78° C. was added DIBAL (3.21 mL of a 1 M / THF solution, 3.21 mmol). After stirring the reaction mixture for 30 min, HO was added and the solution was extracted with EA, dried (NaSO), and purified by SiO chromatography (EA / hexanes) to provide 600 mg (71.1%) of 3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)benzaldehyde (INT 46-B). 15 H 10LCMS-ESI calculated for ClF3O2 (m / z): 314.03, m / z not observed, t R =6.3 minutes (method 11).

[0434] Step 46-3. Synthesis of 2-(3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)phenyl)-1H-imidazole (Compound 46-1) [ka] To a solution of INT 46-B (100 mg, 0.32 mmol) in EtOH (5 mL) at 0 °C, oxalaldehyde (0.04 mL of an 8.8 M / HO solution, 0.35 mmol) and NHOH (0.053 mL of a 29% solution in EtOH, 0.44 mmol) were added. After stirring for 48 h, the mixture was concentrated and purified by SiO chromatography (EA / hexanes) to provide 40 mg (35%) of 2-(3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)phenyl)-1H-imidazole (compound 46-1) as a white solid. 17 H 12 LCMS-ESI calculated for ClF3N2O (m / z): 352.74, found 353.2 (M+H) + , t R =11.97 minutes (method 10). 1 H NMR (400MHz, DMSO-d6) δ12.6(s, 1H), 8.08(s, 1H), 8.00-7.75(m, 2H), 7.72(d, J=6Hz, 1H), 7.60-7.35(m, 3H), 7.26(bs, 1H), 7.04(bs, 1H), 5.38(s, 2H).

[0435] Example 47 Synthesis of compound 47-1 [ka] [ka] Reagents: (i) MeMgBr, Et2O, (ii) Br2, DCM, (iii) formamide.

[0436] Step 47-1. Synthesis of 1-(3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)phenyl)ethan-1-one (INT 47-A) [ka] To a solution of INT 46-A (480 mg, 1.28 mmol) in EtO (20 mL) was added MeMgBr (0.557 mL of a 3 M solution in EtO, 1.67 mmol). After stirring the reaction mixture for 6 h, the reaction mixture was quenched with 0.1 m HCl (50 mL) and extracted into EA. The resulting organic layer was washed with brine, dried (NaSO), filtered, concentrated, and purified by SiO chromatography (EA / hexanes) to provide 224 mg (53%) of 1-(3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)phenyl)ethan-1-one (INT 47-A). 17 H 15 LCMS-ESI calculated for ClF3NO3 (m / z): 373.07, m / z not observed, t R =6.2 minutes (method 11).

[0437] Step 47-2. Synthesis of 2-bromo-1-(3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)phenyl)ethan-1-one (INT 47-B) [ka] To a solution of INT 47-A (224 mg, 0.68 mmol) in DCM (15 mL) was added Br (0.035 mL, 0.68 mmol). The reaction mixture was stirred for 30 minutes, then quenched with NH Cl (aq) and extracted into DCM. The resulting organic layer was washed with NaHCO (sat. aq), water, and brine, dried (Na SO ), concentrated, and purified by SiO chromatography (EA / hexanes) to provide 140 mg (50%) of 2-bromo-1-(3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)phenyl)ethan-1-one (INT 47-B). 16 H 11 LCMS-ESI calculated for BrClF3O2 (m / z): 405.96, found 407.2 [M+H] + , t R =5.529 minutes (method 11).

[0438] Step 47-3. Synthesis of 5-(3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)phenyl)-1H-imidazole (Compound 47-1) [ka] A solution of INT 47-B (100 mg, 0.3 mmol) in formamide (5 mL) was stirred at 170° C. for 4 hours, and the reaction mixture was concentrated and purified by reverse-phase C18 chromatography (HO / MeOH) to provide 6 mg (5%) of 5-(3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)phenyl)-1H-imidazole (compound 47-1). 17 H 12 LCMS-ESI calculated for ClF3N3 (m / z): 352.06, found 353.4 (M+H) + , t R =12.14 minutes (method 10).

[0439] Example 48 Synthesis of compound 48-1 [ka] [ka] Reagents: (i) ethynyltrimethylsilane, Pd(OAc)2, PPh3, (ii) DEAD, PPh3, THF, (iii) CuI, TMSN3, DMF, EtOH.

[0440] Step 48-1. Synthesis of (3-ethynylphenyl)methanol (INT 48-A) [ka] To a solution of (3-ethynylphenyl)methanol (1.5 g, 8.02 mmol) in TEA (8 mL) was added ethynyltrimethylsilane (1.58 g, 16 mmol), palladium acetate (180 mg, 0.8 mmol), and PPh (422 mg, 1.6 mmol). After stirring at 95 °C for 1 h, the reaction mixture was filtered through Celite and washed with EA. The resulting organic layer was dried, washed with HO (3x) and brine, dried (NaSO), filtered, concentrated, and purified by SiO chromatography (EA / hexanes) to provide 800 mg (76%) of (3-ethynylphenyl)methanol (INT 48-A). LCMS-ESI (m / z) calculated for CHO: 132.06, found 133.3 [M+H]. + , t R =3.1 minutes (method 11).

[0441] Step 48-2. Synthesis of 2-chloro-1-((3-ethynylbenzyl)oxy)-4-(trifluoromethyl)benzene (INT 48-B) [ka] To a solution of DEAD (55 mg of a 40% solution, 2.7 mmol) in THF (3 mL) at 0° C. was added PPh (71.2 mg, 2.7 mmol) and INT 48-A (30 mg, 8.02 mmol). After stirring the reaction mixture for 1 h, the reaction mixture was concentrated and purified by SiO chromatography (EA / hexanes) to provide 65 mg (93%) of crude 2-chloro-1-((3-ethynylbenzyl)oxy)-4-(trifluoromethyl)benzene (INT 48-B), which was carried on to the next step without further purification.

[0442] Step 48-3. Synthesis of 4-(3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)phenyl)-2H-1,2,3-triazole (compound 48-1) [ka] To a solution of INT 48-B (65 mg, 2 mmol) in DMF (8 mL) and EtOH (1 mL) was added CuI (122 mg, 0.64 mmol). The mixture was purged with N2, and TMSN3 (741 mg, 6.4 mmol) was added. After stirring at 120 °C for 18 h, the reaction mixture was filtered over Celite, concentrated, and purified by SiO2 chromatography (EA / hexane) and reverse-phase chromatography (MeOH / HO with 0.1% TFA) to provide 65 mg (93%) of 4-(3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)phenyl)-2H-1,2,3-triazole (compound 48-1). C 16 H 11 LCMS-ESI calculated for ClF3N3O (m / z): 353.05, found 354.4 (M+H) + , t R =5.39 minutes (method 11).

[0443] Example 49 Synthesis of compound 49-1 [ka] [ka] Reagents: (i) DEAD, PPh3, THF.

[0444] Step 49-1. Synthesis of 5-(3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)phenyl)-3-methyl-1,2,4-oxadiazole (compound 49-1) [ka] To a stirred solution of (3-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl)methanol (500 mg, 2.6 mmol) in THF (5 mL) was added triphenylphosphine (830 mg, 3.1 mmol) and DEAD (911 μL of a 70% solution, 3.2 mmol). After stirring for 2 h, the reaction mixture was diluted with EA, washed with saturated NaHCO, HO, and brine, dried (NaSO), concentrated, and purified by SiO chromatography (EA / hexanes) to a residue which was triturated with MeOH / HO to afford 670 mg (69.1%) of 5-(3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)phenyl)-3-methyl-1,2,4-oxadiazole (compound 49-1). 17 H 12 LCMS-ESI calculated for ClF3N2O2 (m / z): 368.05, found 369.1 (M+H) + , t R =14.59 minutes (50 - 95 - 4 minutes). 1 H NMR (300MHz, DMSO-d6) δ8.23(s, 1H), 8.08(d, J=7.8Hz, 1H), 7.89(bs, 1H), 7.80(d, J=6.5Hz, 1H), 7.50-7.30(m, 2H), 7.46(d, J=8.5Hz, 1H), 5.46(s, 2H), 2.43(s, 3H).

[0445] Example 50 Synthesis of compound 50-1 [ka] [ka] Reagents: (i) Na2CO3, DMF.

[0446] Step 50-1. Synthesis of 2-chloro-1-((3-(difluoromethyl)benzyl)oxy)-4-(trifluoromethyl)benzene (Compound 50-1) [ka] To a stirred solution of (3-(difluoromethyl)phenyl)methanol (500 mg, 2.26 mmol) in DMF (8 mL) were added 2-chloro-4-(trifluoromethyl)phenol (450 mg, 2.26 mmol) and Na2CO3 (720 mg, 6.79 mmol). After stirring at 50 °C for 18 h, the reaction mixture was diluted with HO, extracted into EA, and washed with HO and brine. The organic layer was concentrated and chromatographed on SiO2 (EA / hexanes) to afford 165 mg (22%) of 2-chloro-1-((3-(difluoromethyl)benzyl)oxy)-4-(trifluoromethyl)benzene (compound 50-1). C 15 H 10 LCMS-ESI calculated for ClF5O (m / z): 336.03, found 359.2 [M+Na] + , t R =5.68 minutes (method 11). 1 H NMR (300MHz, CDCl3) 7.70(s, 1H), 7.63(s, 1H), 7.625-7.45(m, 4H), 7.04(d, J=8.6Hz, 1H), 6.70(t, J H-F =56Hz, 1H), 5.27(s, 2H).

[0447] Example 52 Synthesis of compound 52-1 [ka] [ka] Reagents: (I) HATU, DIPEA, DMF.

[0448] Step 52-1. Synthesis of N-benzyl-3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)benzamide (Compound 52-1) [ka] To a stirred solution of compound 1-55 (113 mg, 0.34 mmol) in DMF (5 mL) were added HATU (137 mg, 0.36 mmol), DIPEA (126 mg, 0.98 mmol), and phenylmethanamine (35 mg, 0.33 mmol). After stirring at rt for 16 h, the reaction mixture was diluted with EA and washed with 30 mL each of HO, 1 M HCl, 1 M NaOH, NaHCO, and brine. The organic layer was dried (NaSO), concentrated, and purified by SiO chromatography (EA / hexanes) to give 62 mg (54%) of N-benzyl-3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)benzamide (compound 52-1). 22 H 17 LCMS-ESI calculated for ClF3NO2 (m / z): 419.1, found 420.3 [M+H] + , t R =12.98 minutes (method 10). 1 H NMR (400MHz, DMSO-d6) δ9.11(s, 1H), 8.02(s, 1H), 7.90-7.88(m, 2H), 7.72(d, J=8, 1H), 7.65(d, J=8, 1H) , 7.54(t, J=8, 1H), 7.45(d, J=8, 1H), 7.33(t, J=4, 4H), 7.26(d, J=4, 1H), 5.38(s, 2H), 4.49(d, J=4, 2H).

[0449] The compounds listed in Table 52 were made using the procedures in Scheme 52.

[0450] [Table 27-1] [Table 27-2] [Table 27-3] [Table 27-4]

[0451] Example 53 Synthesis of compound 53-1 [ka] [ka] Reagents: (i) TFA, DCM.

[0452] Step 53-1. Synthesis of 3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-N-(2-(methylamino)ethyl)benzamide (Compound 53-1) [ka] A solution of tert-butyl (2-(3-((2-chloro-4-(trifluoromethyl)phenoxy)m)methyl)benzamido)ethyl)(methyl)carbamate (50 mg, 0.099 mmol) (prepared from compounds 1-55 and tert-butyl (2-aminoethyl)(methyl)carbamate via Scheme 52) in 1:1 DCM:TFA (5 mL) was stirred at rt for 16 h. The reaction mixture was concentrated, dissolved in HO / CHCN, and lyophilized to afford 30 mg (60%) of 3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-N-(2-(methylamino)ethyl)benzamide (compound 53-1). 18 H 18 LCMS-ESI calculated for ClF3N2O2 (m / z): 386.1, found 387.4 (M+H) + , t R =12.98 minutes (method 10).

[0453] The compounds listed in Table 53 were made using the procedures in Scheme 53.

[0454] [Table 28]

[0455] Example 54 Synthesis of compound 54-1 [ka] [ka] Reagents: (i) NaOH, EtOH.

[0456] Step 54-1. Synthesis of (3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)benzoyl)-L-valine (Compound 54-1) [ka] To a solution of methyl (3-((2-chloro-4-(trifluoromethyl)phenoxy)-methyl)benzoyl)-L-valinate (250 mg, 0.56 mmol) (prepared from compounds 1-55 and methyl L-valinate via Scheme 52) in EtOH (5 mL) was added 2 M NaOH (1.12 g, 1.1 mmol). After stirring at rt for 16 h, the reaction mixture was diluted with EA and acidified with 1 M HCl. The organic layer was collected, washed with brine, dried (NaSO), concentrated, and purified by reverse-phase SiO chromatography (MeOH / HO with 0.1% formic acid) to afford 36 mg (15%) of (3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)benzoyl)-L-valine (compound 54-1). 20 H 19 LCMS-ESI calculated for ClF3NO4 (m / z): 429.1, found 430.6 [M+H] + , t R =5.31 minutes (method 11).

[0457] The compounds listed in Table 54 were made using the procedures in Scheme 54.

[0458] [Table 29-1] [Table 29-2]

[0459] Example 55 Synthesis of compound 55-1 [ka] [ka] Reagents: (i) TFA, DCM.

[0460] Step 55-1. Synthesis of (3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)benzoyl)-L-asparagine (Compound 55-1) [ka] A solution of tert-butyl (3-((2-chloro-4-(trifluoromethyl)phenoxy)-methyl)benzoyl)-L-aspartate (200 mg, 0.4 mmol) (prepared from compounds 1-55 and tert-butyl L-aspartate via Scheme 52) in 1:1 TFA:DCM (5 mL) was stirred at rt for 16 h. The mixture was concentrated and purified using reverse-phase SiO chromatography (MeOH / HO with 0.1% formic acid) to afford 107 mg (60%) of (3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)benzoyl)-L-asparagine (compound 55-1). 19 H 16 LCMS-ESI calculated for ClF3N2O5 (m / z): 444.1, found 445.4 (M+H) + , t R =4.70 minutes (method 11).

[0461] The compounds listed in Table 55 were made using the procedures in Scheme 55.

[0462] [Table 30]

[0463] Example 56 Synthesis of compound 56-1 [ka] [ka] Reagents: (i) Thionyl-Cl, EtOH, DCM.

[0464] Step 56-1. Synthesis of ethyl 3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-2-fluorobenzoate (compound 56-1) [ka] To a solution of compound 1-55 (30 mg, 0.086 mmol) in DCM (3 mL) was added thionyl chloride (19 μL, 0.26 mmol). After stirring for 2 h, the reaction mixture was concentrated and dissolved in EtOH (1 mL). After 1 h, the mixture was concentrated and purified by RP-HPLC chromatography to provide 32 mg (31%) of ethyl 3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-2-fluorobenzoate (compound 56-1). 17 H 13 LCMS-ESI calculated for ClF4O3 (m / z): 376.7, found 378.1 (M+H) + , t R =12.5 minutes (chemical purity).

[0465] The compounds listed in Table 56 were made using the procedures in Scheme 56.

[0466] [Table 31]

[0467] Example 57 Synthesis of compound 57-1 [ka] [ka] Reagents: (i) Pd(dppf)Cl2-CH2Cl2, TEA, DMF, MeOH, CO, (ii) NaBH4, MeOH, DCM, (iii) SOCl2, DCM; (iv) NaOH, DMF.

[0468] Step 57-1. Synthesis of dimethyl 4-methylpyridine-2,6-dicarboxylate (INT 57-1) [ka] To a solution of 2,6-dichloro-4-methyl-pyridine (6.8 g, 41.97 mmol) in DMF (100 mL) and MeOH (50 mL) was added Pd(dppf)Cl-CHCl (3.43 g, 4.20 mmol), TEA (23.37 mL, 167.9 mmol). The reaction was stirred at 80 °C under CO (1.18 g, 41.97 mmol, 50 Psi) for 16 h. The reaction mixture was filtered, concentrated, diluted with HO (100 mL), and extracted with EA (2 × 100 mL). The organic layer was collected, dried, filtered, concentrated, and purified by SiO chromatography (EA / petroleum ether) to provide 6.7 g (76%) of dimethyl 4-methylpyridine-2,6-dicarboxylate (INT 57-1) as a yellow solid. 10 H 11 LCMS-ESI calculated for NO4 (m / z): 209.07, found 210.1 [M+H] + , t R =0.742 minutes (method 6).

[0469] Step 57-2. Synthesis of methyl 6-(hydroxymethyl)-4-methylpicolinate (INT 57-2) [ka] To a solution of INT 57-1 (6.7 g, 31.39 mmol) in MeOH (400 mL) and DCM (100 mL) at 0 °C, NaBH (1.78 g, 47.08 mmol) was added portionwise. After stirring at 0 °C for 12 h, the reaction mixture was quenched by the addition of aqueous NH Cl (200 mL) and extracted into EA (3 × 200 mL). The combined organic layers were dried (Na SO ), filtered, concentrated, and purified by SiO chromatography to provide 3.7 g (64%) of methyl 6-(hydroxymethyl)-4-methylpicolinate (INT 57-2). CH 11 LCMS-ESI calculated for NO3 (m / z): 181.2, found 182.7 [M+H] + , t R =0.323 minutes (method 6). 1 H NMR (400MHz, CDCl3) δ7.85(s, 1H), 7.35(s, 1H), 4.81(s, 2H), 3.97(s, 3H), 3.81-3.26(m, 1H), 2.49-2.38(s, 3H).

[0470] Step 57-3. Synthesis of methyl 6-(chloromethyl)-4-methylpicolinate (INT 57-3) [ka] To a solution of INT 57-2 (200 mg, 1.1 mmol) in DCM (7 mL) at 0 °C was added SOCl (1 mL, 13.8 mmol). After stirring at rt for 1.5 h, the reaction mixture was concentrated to provide 32 mg (31%) of methyl 6-(chloromethyl)-4-methylpicolinate (INT 57-3) as a white solid, which was used without further purification. CH 10 LCMS-ESI calculated for ClNO2 (m / z): 199.04, found 200.0 [M+H] + , t R =0.755 minutes (method 6).

[0471] Step 57-4. Synthesis of 6-(((2-chloro-4-(trifluoromethyl)phenyl)amino)methyl)-4-methylpicolinic acid (compound 57-1) [ka] To a solution of INT 57-3 (200 mg, 1.0 mmol) and 2-chloro-4-(trifluoromethyl)aniline (195.9 mg, 1.00 mmol) in DMF (3 mL) was added NaOH (400.7 mg, 10.02 mmol). The reaction mixture was stirred at 25 °C for 0.5 h. The mixture was diluted with HO (10 mL) and adjusted to pH = 7 with HCl (36%), then filtered and concentrated to give a residue, which was purified by reverse-phase preparative HPLC (HO / CHCN containing 0.225% FA) to provide 2.2 mg (0.67%) of 6-(((2-chloro-4-(trifluoromethyl)phenyl)amino)methyl)-4-methylpicolinic acid (compound 57-1) as a white solid. 15 H 12 LCMS-ESI calculated for ClF3N2O2 (m / z): 344.05, found 345.0 (M+H) + , t R =0.873 minutes (method 6). 1 H NMR (400MHz, MeOD4) δppm2.35~2.51(s, 3H)4.58~4.70(s, 2H)6.60~6.81(m, 1H)7.26~7.35(m, 1H)7.39~7.46(m, 1H)7.50~7.60(s, 1H)7.80~8.05(s, 1H)

[0472] Example 58 Synthesis of compounds 58-1 and 58-2 [ka] [ka] Reagents: (i) Pd(dppf)Cl2·DCM, TEA, DMF, CO, (ii) LiBH4, THF, (iii) DIAD, PPh3, THF, (iv) NaH, THF, MeI.

[0473] Step 58-1. Synthesis of methyl 1-oxo-1,2,3,4-tetrahydroisoquinoline-5-carboxylate (INT 58-1) [ka] Pd(dppf)Cl2·DCM (285 mg, 0.35 mmol) was added to a solution of 5-bromo-3,4-dihydro-2H-isoquinolin-1-one (395 mg, 1.75 mmol) and TEA (1.22 mL, 8.74 mmol) in DMF (6.00 mL) at 22 °C. The mixture was evacuated and refilled with CO for three cycles. MeOH (3.08 mL) was added, and the mixture was heated to 85 °C under a CO atmosphere (1 atm) for 16 h. The mixture was diluted with EA (25 mL) and filtered through a pad of Celite. The filtrate was concentrated under reduced pressure. The residue was diluted with EA (100 mL) and HO (100 mL). The aqueous phase was extracted with EA (3 × 25.0 mL). The combined organic layers were washed with brine (50 mL), dried (Na2SO4), filtered, and concentrated. The residue was purified by SiO chromatography (hexane and EA) to provide 285 mg (80%) of methyl 1-oxo-1,2,3,4-tetrahydroisoquinoline-5-carboxylate (INT 58-1). 11 H 11 LCMS-ESI calculated for NO3 (m / z): 205.07, found 205.74 [M+H] + , t R =1.82 minutes (method 13). 1 H NMR (400MHz, CDCl3) δ8.30 (dd, J=7.7, 1.5Hz, 1H), 8.09 (dd, J=7.8, 1.5Hz, 1H), 7.42 (dd, J=7.8Hz, 1H), 5.95(s, 1H), 3.92(s, 3H), 3.58~3.52(m, 2H), 3.49~3.40(m, 2H).

[0474] Step 58-2. Synthesis of 5-(hydroxymethyl)-3,4-dihydroisoquinolin-1(2H)-one (INT 58-2) [ka] LiBH4 (2M in THF, 2.66 mL, 5.32 mmol) was added to a solution of INT 58-1 (182 mg, 0.887 mmol) in THF (5.00 mL) at 22 °C under N2. The mixture was stirred at 22 °C for 20 h. The mixture was diluted with saturated aqueous NH4Cl (10 mL). The aqueous phase was extracted with EA (3 × 20 mL), and the combined organic phases were washed with brine (50 mL), dried (Na2SO4), filtered, and concentrated to provide 88 mg (56%) of 5-(hydroxymethyl)-3,4-dihydroisoquinolin-1(2H)-one (INT 58-2) as an oil. C 10 H 11 LCMS-ESI calculated for NO2 (m / z): 177.08, found 178.13 [M+H] + , t R =1.39 minutes (method 13). 1 H NMR (500MHz, CDCl3) δ8.07 (dd, J=7.8, 1.4Hz, 1H), 7.52 (dd, J=7.6, 1.4Hz, 1H), 7.36 (t, J=7.7Hz) , 1H), 5.95(s, 1H), 4.75(s, 2H), 3.57(td, J=6.7, 2.9Hz, 2H), 3.07(t, J=6.6Hz, 2H), 1.72(s, 1H).

[0475] Step 58-3. Synthesis of 5-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-3,4-dihydroisoquinolin-1(2H)-one (compound 58-1) [ka] DIAD (108 μL, 0.55 mmol) was added to a mixture of INT 58-2 (88.0 mg, 0.497 mmol), 2-chloro-4-(trifluoromethyl)phenol (69.7 μL, 0.521 mmol), and PPh (143 mg, 0.546 mmol) in THF (5.00 mL) at 0° C. under N. The mixture was stirred at 22° C. for 18 h. The mixture was concentrated, and the residue was purified by reverse-phase chromatography (HO (+0.1% formic acid) and MeCN) to provide 32.7 mg (19%) of 5-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-3,4-dihydroisoquinolin-1(2H)-one (compound 58-1) as a solid. 17 H 13 LCMS-ESI calculated for ClF3NO2 (m / z): 355.06, found 356.07 [M+H] + , t R =4.69 minutes (method 12). 1 H NMR (500MHz, CDCl3) δ8.00(s, 1H), 7.90(dd, J=7.8, 1.4Hz, 1H), 7.88~7.85(m, 1H), 7.73(ddd, J=8.7, 2.3, 0.9Hz, 1H), 7.68(dd, J =7.6, 1.4Hz, 1H), 7.52(d, J=8.6Hz, 1H), 7.40(dd, J=7.6Hz, 1H), 5.38(s, 2H), 3.38(td, J=6.6, 2.8Hz, 2H), 2.96(t, J=6.6Hz, 2H).

[0476] Step 58-4. Synthesis of 5-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-2-methyl-3,4-dihydroisoquinolin-1(2H)-one (compound 58-2) [ka] NaH (24.9 mg, 1.08 mmol) was added to a solution of compound 58-1 (154 mg, 50% purity, 0.216 mmol) in THF (5.00 mL) at 0 °C under N. The mixture was stirred at 22 °C for 30 min. Iodomethane (67.4 μL, 1.08 mmol) was added, and the mixture was stirred at 70 °C for 1 h. The mixture was diluted with MeOH (10.0 mL) and concentrated. The product was purified by reverse-phase chromatography (HO (+0.1% formic acid) and MeCN) to provide 60 mg (76%) of 5-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-2-methyl-3,4-dihydroisoquinolin-1(2H)-one (compound 58-2) as a solid. 18 H 15 LCMS-ESI calculated for ClF3NO2 (m / z): 369.77, found 370.08 [M+H] + , t R =5.08 minutes (method 12). 1 H NMR (500MHz, CDCl3) δ8.00(s, 1H), 7.92(dd, J=7.8, 1.4Hz, 1H), 7.86(dd, J=2.3, 0.7Hz, 1H), 7.73(ddd, J=8.7, 2.3, 0.8Hz, 1H), 7 .66(dd, J=7.6, 1.4Hz, 1H), 7.52(d, J=8.7Hz, 1H), 7.39(dd, J=7.7Hz, 1H), 5.38(s, 2H), 3.56(t, J=6.7Hz, 2H), 3.07~2.99(m, 4H).

[0477] Example 59 Synthesis of compound 59-1 [ka] [ka] Reagents: (i) NaBH4, MeOH, (ii) DIAD, PPh3, THF, (iii) N-chlorosulfonyl isocyanate, THF.

[0478] Step 59-1. Synthesis of (3-vinylphenyl)methanol (INT 59-1) [ka] NaBH4 (327 mg, 8.66 mmol) was slowly added to a solution of 3-vinylbenzaldehyde (1.00 mL, 7.87 mmol) in MeOH (20 mL) under N2 at 22 °C. The mixture was stirred at 22 °C for 1 h and concentrated under reduced pressure. The residue was purified by SiO2 chromatography (EA / hexanes) to provide 1.05 g (99%) of (3-vinylphenyl)methanol (INT 59-1). LCMS-ESI (m / z) mass was not observed, t R =2.00 minutes (method 13). 1 H NMR (400MHz, CDCl3) δ7.42(s, 1H), 7.37~7.30(m, 2H), 7.26(d, J=3.1Hz, 1H), 6.73(dd, J=17.6, 10 .9Hz, 1H), 5.78(dd, J=17.6, 0.9Hz, 1H), 5.27(dd, J=10.9, 0.9Hz, 1H), 4.70(s, 2H), 1.67(s, 1H).

[0479] Step 59-2. Synthesis of 2-chloro-4-(trifluoromethyl)-1-((3-vinylbenzyl)oxy)benzene (INT 59-2) [ka] DIAD (1.29 mL, 6.56 mmol) was added dropwise to a mixture of INT 59-1 (800 mg, 5.96 mmol), 2-chloro-4-(trifluoromethyl)phenol (793 mL, 5.93 mmol), and PPh3 (2.35 g, 8.94 mmol) in THF (15.0 mL) under N2 at 22 °C. The mixture was stirred at 22 °C for 6 h and concentrated. The residue was purified by SiO2 chromatography (EA / hexanes) to provide 1.73 g (93%) of 2-chloro-4-(trifluoromethyl)-1-((3-vinylbenzyl)oxy)benzene (INT 59-2) as an oil. LCMS-ESI (m / z) mass spectrometry (MS / MS) showed no observed cleavage, and t R =2.95 minutes (method 13). 1H NMR (500MHz, CDCl3) δ7.66(dd, J=2.3, 0.7Hz, 1H), 7.49(s, 1H), 7.48~7.43(m, 1H), 7.41~7.35(m, 3H), 7.06-6.99 (m, 1H), 6.74(dd, J=17.6, 10.9Hz, 1H), 5.78(dd, J=17.6, 0.9Hz, 1H), 5.29(dd, J=10.9, 0.8Hz, 1H), 5.21(s, 2H).

[0480] Step 59-3. Synthesis of 4-(3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)phenyl)azetidin-2-one (compound 59-1) [ka] N-Chlorosulfonyl isocyanate (578 μL, 6.64 mmol) was added to a solution of INT 59-2 (1.73 g, 5.53 mmol) in THF (5.00 mL) under N at 22 °C over 10 min. The mixture was stirred at 22 °C for 16 h. The mixture was added to a vigorously stirred mixture of HO (10.0 mL), sodium carbonate (1.93 g, 18.3 mmol), and sodium sulfite (1.05 g, 8.30 mmol) over 20 min at 0 °C. The mixture was stirred at 22 °C for 2 h. The mixture was acidified with 1 M aqueous HCl (pH ∼5) and diluted with EA (100 mL). The aqueous phase was extracted with EA (3 × 50.0 mL), and the combined organic layers were dried (MgSO), filtered, and concentrated. The residue was purified by reverse-phase chromatography (HO (+0.1% formic acid) and MeCN (50-100%) to provide 189 mg (10%) of 4-(3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)phenyl)azetidin-2-one (compound 59-1) as a solid. 17 H 13 LCMS-ESI calculated for ClF3NO2 (m / z): 355.06, found 356.07 [M+H] + , t R =4.93 minutes (method 12). 1H NMR (500MHz, CDCl3) δ8.41(s, 1H), 7.86(dd, J=2.3, 0.7Hz, 1H), 7.75~7.67(m, 1H), 7.50(d, J=1.9Hz, 1H), 7.48~7.38(m, 3H), 7.36(dt , J=6.8, 2.1Hz, 1H), 5.33(s, 2H), 4.67(dd, J=5.3, 2.5Hz, 1H), 3.36(ddd, J=14.6, 5.3, 2.2Hz, 1H), 2.67(ddd, J=14.6, 2.5, 1.0Hz, 1H).

[0481] Example 60 Synthesis of compound 60-1 [ka] [ka] Reagents: (i) H2SO4, MeOH, (ii) Zn(CN)2, Pd(Ph3)4, DMF, (iii) PdCl2(PPh3)2, CuI, Et3N, 1,4-dioxane, (iv) NaOH, THF.

[0482] Step 60-1. Synthesis of methyl 3-bromo-5-iodobenzoate (INT 60-1) [ka] H2SO4 (600 μL, 11.3 mmol) was added to a solution of 3-bromo-5-iodobenzoic acid (10.0 g, 30.6 mmol) in MeOH (65 mL). The mixture was stirred at 75 °C for 18 h. The mixture was cooled to 22 °C and concentrated. The residue was diluted with EA (100 mL), washed with saturated aqueous NaHCO3 (100 mL), dried (Na2SO4), filtered, and concentrated to provide 9.90 g (95%) of methyl 3-bromo-5-iodobenzoate (INT 60-1) as a solid. LCMS-ESI (m / z) calculated for CHBrIO2: 339.86, found 339.6 [M+H] + , t R =2.72 minutes (method 13).

[0483] Step 60-2. Synthesis of methyl 3-bromo-5-cyanobenzoate (INT 60-2) [ka] Zinc cyanide (1.76 g, 15.0 mmol) and Pd(PPh3)4 (2.88 g, 2.49 mmol) were added to a solution of INT 60-1 (8.50 g, 2.49 mmol) in DMF (60 mL). The mixture was stirred at 80 °C for 2 h. The mixture was cooled to 22 °C and concentrated. The residue was diluted with EA (100 mL). The organic layer was washed with HO (3 × 50.0 mL) and brine (150 mL), dried (Na2SO4), filtered, and concentrated. The residue was purified by SiO2 chromatography (EA / hexanes) to provide 3.00 g (50%) of methyl 3-bromo-5-cyanobenzoate (INT 60-2) as a solid. LCMS-ESI (m / z): no mass observed, t R =2.38 minutes (method 13).

[0484] Step 60-3. Synthesis of methyl 3-((2-chloro-4-(trifluoromethyl)phenyl)ethynyl)-5-cyanobenzoate (INT 60-3) [ka] 2-Chloro-1-ethynyl-4-(trifluoromethyl)benzene (551 μL, 1.87 mmol), PdCl(PPh) (132 mg, 0.19 mmol), and CuI (17.9 mg, 0.094 mmol) were added to a solution of INT 60-2 (225 mg, 0.94 mmol) in 1,4-dioxane (2 mL) and EtN (2.0 mL). The mixture was stirred at 80 °C for 24 h. The mixture was cooled to 22 °C and diluted with saturated aqueous NH Cl (20 mL). The aqueous phase was extracted with EA (3 × 50 mL), and the combined organic layers were concentrated. The residue was purified by SiO chromatography (EA / hexane) to provide 250 mg (73%) of methyl 3-((2-chloro-4-(trifluoromethyl)phenyl)ethynyl)-5-cyanobenzoate (INT 60-3) as a solid.18 LCMS-ESI calculated for H9ClF3NO2 (m / z): 363.03, found 365.5 [M+H] + , t R =2.92 minutes (method 13). 1 H NMR (400MHz, CDCl3) δ8.42(t, J=1.5Hz, 1H), 8.30(t, J=1.4Hz, 1H), 8.00(t, J=1. 4Hz, 1H), 7.72(s, 1H), 7.68(d, J=8.1Hz, 1H), 7.54(d, J=7.6Hz, 1H), 3.99(s, 3H).

[0485] Step 60-4. Synthesis of 3-((2-chloro-4-(trifluoromethyl)phenyl)ethynyl)-5-cyanobenzoic acid (compound 60-1) [ka] A 2M aqueous solution of NaOH (165 μL, 0.330 mmol) was added to a solution of INT 60-3 (60.0 mg, 0.165 mmol) in THF (2 mL) at 22 °C. The mixture was stirred at 22 °C for 12 h and concentrated. The residue was diluted with HO (10.0 mL) and acidified with 2M HCl (pH ∼2). The aqueous phase was extracted with EA (3 × 20.0 mL), and the combined organic layers were dried (NaSO), filtered, and concentrated. The residue was purified by SiO chromatography (MeOH / DCM) to provide 55.0 mg (95%) of 3-((2-chloro-4-(trifluoromethyl)phenyl)ethynyl)-5-cyanobenzoic acid (compound 60-1) as a solid. 17 LCMS-ESI calculated for H7ClF3NO2 (m / z): 349.01, found 348.49 [MH] + , t R =4.55 minutes (method 12). 1 H NMR (400MHz, DMSO-d6) δ8.37-8.32(m, 2H), 8.30(s, 1H), 8.08(s, 1H), 7.97(d, J=8.0Hz, 1H), 7.82(dd, J=8.1, 1.1Hz, 1H).

[0486] Example 61 Synthesis of compound 61-1 [ka] [ka] Reagents: (i) Pd / C, H2, EA.

[0487] Step 61-1. Synthesis of methyl 3-(2-(2-chloro-4-(trifluoromethyl)phenyl)ethyl)-5-cyanobenzoate (INT 61-1) [ka] INT 60-3 (100 mg, 0.275 mmol) and Pd / C (100 mg, 0.0940 mmol) in EA (10.0 mL) were stirred under hydrogen (1 atm) at 22 °C for 4 hours. The mixture was filtered through Celite, washed with EA (100 mL), and the filtrate was concentrated. The residue was purified by SiO chromatography (EA / hexane) to provide 101 mg (100%) of methyl 3-(2-(2-chloro-4-(trifluoromethyl)phenyl)ethyl)-5-cyanobenzoate (INT 61-1) as a solid. C 18 H 13 LCMS-ESI calculated for ClF3NO2 (m / z): 367.06, found 367.3 [MH] + , t R =2.85 minutes (method 13).

[0488] Step 61-2. Synthesis of 3-(2-chloro-4-(trifluoromethyl)phenethyl)-5-cyanobenzoic acid (compound 61-2) [ka] A 2M NaOH solution (197 μL, 0.156 mmol) was added to a solution of INT 61-1 (60.0 mg, 0.156 mmol) in THF (2 mL). The mixture was stirred at 22 °C for 12 hours and concentrated. The residue was acidified with 2M HCl (pH ∼2) and diluted with H2O (10 mL). The aqueous phase was extracted with EA (3 × 20 mL), and the combined organic layers were dried (Na2SO4), filtered, and concentrated. The residue was purified by reverse-phase chromatography (H2O (+0.1% formic acid) and ACN) to provide 47.0 mg (85%) of 3-(2-chloro-4-(trifluoromethyl)phenethyl)-5-cyanobenzoic acid (compound 61-2) as a solid. C 17 H 11 LCMS-ESI calculated for ClF3NO2 (m / z): 353.04, found 352.1 [MH] + , t R =4.73 minutes (method 12). 1 H NMR (500MHz, DMSO-d6) δ13.54(s, 1H), 8.13(t, J=1.5Hz, 1H), 8.05(t, J=1.6Hz, 1H), 7.98(t, J=1.6Hz, 1H ), 7.83 (d, J=1.2Hz, 1H), 7.66 (dd, J=8.0, 1.3Hz, 1H), 7.58 (d, J=8.0Hz, 1H), 3.07 (dq, J=9.8, 6.3Hz, 4H).

[0489] Example 62 Synthesis of compound 62-1 [ka] [ka] Reagents: (I) NaBH4, EtOH, (ii) DIAD, PPh3, THF, (iii) NaOH, MeOH, THF.

[0490] Step 62-1. Synthesis of methyl 3-(1-hydroxyethyl)benzoate (INT 62-1) [ka] NaBH4 (752 mg, 19.9 mmol) was added to a mixture of methyl 3-acetylbenzoate (1.18 g, 6.62 mmol) in EtOH (15.0 mL) at 22 °C. The mixture was stirred at 0 °C for 30 min and at 22 °C for 1 h. The mixture was diluted with saturated aqueous NH4Cl (30.0 mL). The aqueous phase was extracted with EA (3 × 30.0 mL) and the combined organic layers were dried (Na2SO4), filtered, and concentrated. The residue was purified by SiO2 chromatography (EA / hexane) to provide 830 mg (70%) of methyl 3-(1-hydroxyethyl)benzoate (INT 62-1) as a solid. LCMS-ESI (m / z) mass was not observed, t R =1.93 minutes (method 12). 1 H NMR (400MHz, CDCl3) δ8.05(tt, J=1.8, 0.6Hz, 1H), 7.98~7.92(m, 1H), 7.59(dddd, J=7.7, 1.8, 1.2, 0.6Hz, 1H), 7.43(tt, J=7.7, 0.4Hz, 1H), 4.97(q, J=6.5Hz, 1H), 3.92(s, 3H), 1.84(s, 1H), 1.52(d, J=6.5Hz, 3H).

[0491] Step 62-2. Synthesis of methyl 3-(1-(2-chloro-4-(trifluoromethyl)phenoxy)ethyl)benzoate (INT 62-2) [ka] DIAD (981 μL, 4.98 mmol) was added to a mixture of INT 62-1 (816 mg, 4.53 mmol), 2-chloro-4-(trifluoromethyl)phenol (886 mg, 4.51 mmol), and PPh (1.78 g, 6.79 mmol) in THF (25.0 mL) at 22 °C. The mixture was stirred at 22 °C for 3 h. The mixture was concentrated, and the residue was purified by SiO chromatography (EA / hexane) to provide 1.40 g (86%) of methyl 3-(1-(2-chloro-4-(trifluoromethyl)phenoxy)ethyl)benzoate (INT 62-2) as a solid. 17 H 14LCMS-ESI calculated for ClF3O3 (m / z): 358.06, found 357.06 [MH] + , t R =2.87 minutes (method 13).

[0492] Step 62-3. Synthesis of 3-(1-(2-chloro-4-(trifluoromethyl)phenoxy)ethyl)benzoic acid (compound 62-1) [ka] An aqueous solution of 2M NaOH (4.68 mmol, 2.34 mL) was added to a solution of INT 62-2 (14.0 g, 3.90 mmol) in MeOH (12 mL) and THF (12 mL) at 22 °C. After 12 h, the mixture was concentrated, and the residue was diluted with HO (10.0 mL) and 2M HCl (pH ∼4). The aqueous phase was extracted with EA (3 × 25.0 mL). The combined organic layers were dried (NaSO), filtered, and concentrated, and the residue was purified by SiO chromatography (MeOH / DCM) to provide 1.34 g (99%) of 3-(1-(2-chloro-4-(trifluoromethyl)phenoxy)ethyl)benzoic acid (compound 62-1) as a solid. C 16 H 12 LCMS-ESI calculated for ClF3O3 (m / z): 344.04, found 343.04 [MH] + , t R =5.17 minutes (method 12). 1 H NMR (400MHz, DMSO-d6) δ13.04(s, 1H), 8.03(t, J=1.6Hz, 1H), 7.90~7.84(m, 1H), 7.82(d, J=2.0Hz, 1H), 7.71~7.64(m , 1H), 7.60~7.54(m, 1H), 7.50(t, J=7.7Hz, 1H), 7.24(d, J=8.7Hz, 1H), 5.89(q, J=6.3Hz, 1H), 1.62(d, J=6.3Hz, 3H).

[0493] Example 63 Synthesis of compound 63-1 [ka] [ka] Reagents: (i) K2CO3, DMF, (ii) NaH, MeI, DMF, (iii) TFA, DCM.

[0494] Step 63-1. Synthesis of tert-butyl N-((3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)phenyl)methyl)carbamate (INT 63-1) [ka] tert-Butyl N-((3-(bromomethyl)phenyl)methyl)carbamate (100 mg, 0.333 mmol) was added to a mixture of 2-chloro-4-(trifluoromethyl)phenol (50.0 μL, 0.366 mmol) and K2CO3 (51.0 mg, 0.366 mmol) in DMF (1 mL) under N2 at 22 °C. The mixture was stirred at 40 °C for 16 h. The mixture was diluted with HO (20 mL), and the aqueous layer was extracted with DCM (3 × 20 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated. The residue was purified by SiO2 chromatography (EA / hexanes) to provide 122 mg (88%) of tert-butyl N-((3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)phenyl)methyl)carbamate (INT 63-1). C 20 H 21 LCMS-ESI calculated for ClF3NO3 (m / z): 415.12, found 414.17 [M+H] + , t R =2.86 minutes (method 13). 1 H NMR (400MHz, CDCl3) δ7.66(d, J=2.3Hz, 1H), 7.45(ddd, J=8.6, 2.2, 0.9Hz, 1H), 7.40-7.33(m, 3H), 7. 28-7.27(m, 1H), 7.01(d, J=8.6Hz, 1H), 5.20(s, 2H), 4.86(s, 1H), 4.34(d, J=6.0Hz, 2H), 1.46(s, 9H).

[0495] Step 63-2. Synthesis of tert-butyl N-((3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)phenyl)methyl)-N-methyl-carbamate (INT 63-2) [ka] NaH (60 wt%, 12.2 mg, 0.317 mmol) was added to a solution of INT 63-1 (120 mg, 0.289 mmol) in THF (2 mL) under N at 22 °C. The mixture was stirred at 22 °C for 15 min. Iodomethane (21.6 μL, 0.346 mmol) was added, and the mixture was stirred at 50 °C for 24 h. The mixture was concentrated, and the residue was purified by SiO chromatography (EA / hexanes) to provide 71.2 mg (57%) of tert-butyl N-((3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)phenyl)methyl)-N-methyl-carbamate (INT 63-2). C 21 H 23 LCMS-ESI calculated for ClF3NO3 (m / z): 429.13, found 428.17 [MH] + , t R =3.29 minutes (method 13). 1 H NMR (500MHz, CDCl3) δ7.66(d, J=2.2Hz, 1H), 7.48~7.43(m, 1H), 7.38~7.33(m, 2H), 7.30(s, 1H), 7.21(s , 1H), 7.01(d, J=8.6Hz, 1H), 5.20(s, 2H), 4.45(s, 2H), 2.82(d, J=26.0Hz, 3H), 1.47(d, J=15.5Hz, 9H).

[0496] Step 63-3. Synthesis of 1-(3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)phenyl)-N-methylmethanamine (Compound 63-1) [ka] A solution of TFA (500 μL) was added dropwise to a solution of INT 63-2 (70.0 mg, 0.745 mmol) in DCM (1.5 mL). The mixture was stirred at 22 °C for 5 h. The mixture was basified with 1 M NaOH (10 mL) and stirred at 22 °C for 15 min. The aqueous phase was extracted with DCM (3 × 20 mL), and the combined organic layers were washed with brine (20 mL), dried (MgSO), filtered, and concentrated. The residue was purified by reverse-phase chromatography (HO (+0.03% ammonium carbonate) / MeCN) to provide the free form as an oil. HCl (2 M in EtO, 121 μL, 0.121 mmol) was added to a solution of the free form (40.0 mg, 0.121 mmol) in EtO (2 mL) at 22 °C. After 10 min, the mixture was concentrated to provide 42.2 mg (70%) of 1-(3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)phenyl)-N-methylmethanamine (compound 63-1). 16 H 15 LCMS-ESI calculated for ClF3NO (m / z): 329.08, found 330.09 (M+H) + , t R =3.87 minutes (method 12). 1 H NMR (500MHz, CDCl3) δ8.98(s, 2H), 7.88(d, J=2.5Hz, 1H), 7.71(dd, J=8.7, 2.3Hz, 1H), 7.59(d, J=1.5Hz, 1H), 7. 54(qd, J=4.0, 3.5, 1.6Hz, 1H), 7.53~7.50(m, 2H), 7.45(d, J=8.7Hz, 1H), 5.34(s, 2H), 4.15(s, 2H), 2.56(s, 3H).

[0497] Example 64 Synthesis of compound 64-1 [ka] [ka] Reagents: (i) NaBH4, DMF, (ii) DIAD, PPh3, THF, (iii) NaOH, heating.

[0498] Step 64-1. Synthesis of 2-(3-(hydroxymethyl)phenyl)acetonitrile (INT 64-1) [ka] To a solution of methyl 3-(cyanomethyl)benzoate (3 g, 17.1 mmol) in THF (150 ml) was added NaBH (1.3 g, 34 mmol) in five portions. The mixture was heated to 80 °C and stirred for 30 min. After cooling to rt, MeOH was added dropwise, and the mixture was stirred at 80 °C for 30 min and at rt for 16 h. The solution was quenched with HO (30 mL) and concentrated. The resulting residue was diluted with HO and extracted with EA. The organic layer was washed with HO, then brine, dried (NaSO), filtered, and concentrated. The crude residue was purified by SiO chromatography (EA / hexanes) to provide 1.0 g (40%) of 2-(3-(hydroxymethyl)phenyl)acetonitrile (INT 64-1). LCMS-ESI (m / z) calculated for CHNO: 147.07, found 170.3 (M+HO) + , t R =2 minutes (method 11).

[0499] Step 64-2. Synthesis of 2-(3-((2,4-dichlorophenoxy)methyl)phenyl)acetonitrile (INT 64-2) [ka] To a solution of DIAD (495 mg, 2.4 mmol) in THF (10 mL) was added PPh (641 mg, 2.4 mmol) and stirred for 10 min. Then, a solution of INT 64-1 (300 mg, 0.2 mmol) in THF (5 mL) was added, followed by a solution of 2,4-dichlorophenol (332 mg, 2 mmol) in THF (5 mL). The reaction was stirred at rt for 16 h, diluted with EA, washed successively with saturated NaHCO (aq) and brine, then dried over (NaSO), filtered, and concentrated. The resulting crude residue was purified twice by SiO chromatography (EA / hex) to provide 0.21 g (35%) of 2-(3-((2,4-dichlorophenoxy)methyl)phenyl)acetonitrile (INT 64-2). 1 H NMR (400MHz, CDCl3) δ7.27-7.5(m, 5H), 7.16(d, J=8Hz, 1H), 6.87(d, J=8Hz, 1H), 5.13(s, 2H), 3.77(s, 2H).

[0500] Step 64-3. Synthesis of 2-(3-((2,4-dichlorophenoxy)methyl)phenyl)acetic acid (compound 64-1) [ka] INT 64-2 (100 mg, 0.34 mmol) was dissolved in a solution of NaOH (aqueous, 2 M, 5 mL) and heated to 130° C. in a sealed tube for 24 h. The reaction mixture was acidified with 1 M HCl and extracted with EA. The organic layer was dried, washed with brine, dried (NaSO), filtered, and concentrated. The resulting residue was further dried under high vacuum to provide 20 mg (19%) of 2-(3-((2,4-dichlorophenoxy)methyl)phenyl)acetic acid (compound 64-1). LCMS-ESI (m / z) mass spectrometry (MS / MS) was not observed, t R =13.8 minutes (method 10). 1 H NMR (400MHz, DMSO-d6) δ7.60(s, 1H), 7.40~7.30(m, 4H), 7.30~7.20(m, 2H), 5.20(s, 2H), 3.59(s, 2H).

[0501] Example 65 Synthesis of compound 65-1 [ka] [ka] Reagents: (I) Na2CO3, DMF, (ii) Fe, HCl, MeOH

[0502] Step 65-1. Synthesis of 2-chloro-1-((3-nitrobenzyl)oxy)-4-(trifluoromethyl)benzene (INT 65-1) [ka] To a 250 mL flask was added 1-(bromomethyl)-3-nitrobenzene (1.0 g, 4.37 mmol), 2-chloro-4-(trifluoromethyl)phenol (858 mg, 4.37 mmol), Na2CO3 (1.39 g, 13 mmol), and DMF (50 mL). After stirring at 50 °C for 18 h, the reaction was quenched with HO and extracted into EA. The organic layer was dried (Na2SO4), concentrated, and purified by SiO2 chromatography (EA / hexanes) to provide 1.0 g (69%) of 2-chloro-1-((3-nitrobenzyl)oxy)-4-(trifluoromethyl)benzene (INT 65-1). LCMS-ESI mass spectrometry (MSMS) showed no observed cleavage, indicating a cleavage of 1.0 g (69%) of 2-chloro-1-((3-nitrobenzyl)oxy)-4-(trifluoromethyl)benzene. R =5.66 minutes (method 11).

[0503] Step 65-2. Synthesis of 3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)aniline (Compound 65-1) [ka] INT 65-1 (1.0 g, 3.02 mmol) was dissolved in MeOH (10 mL), and excess 2N HCl and Fe powder (210 mg, 3.77 mmol) were added. The reaction mixture was heated to 80 °C for 18 hours, filtered through Celite, concentrated, and purified on SiO (EA / hexanes). The resulting material was further purified by reverse-phase chromatography (MeOH / HO with 0.1% formic acid) to provide 800 mg (60%) of 3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)aniline (compound 65-1). 14 H 11 LCMS-ESI calculated for ClF3NO (m / z): 301.05, found 302.1 (M+H) + , t R =2 minutes (method 11).

[0504] Example 66 MRGPRX4 activity HEK cells stably transfected to express human MRGPRX4 were maintained in a 37°C incubator with 5% CO2 and grown in DMEM medium with 10% fetal bovine serum (FBS) and 1% each of sodium pyruvate, Glutamax, penicillin / streptomycin, and geneticin. HEK cells stably transfected to express mouse MRGPRA1 were maintained in the same incubator and grown in DMEM medium with 10% FBS, 1% each of sodium pyruvate, Glutamax, penicillin / streptomycin, geneticin, and 2.2 mg / mL hygromycin.

[0505] Cells were plated in 12 μL of Opti-MEM at 20,000 cells per well in a 384-well assay plate and stored overnight in an incubator. On the day of the assay, compounds solubilized at 10 mM in DMSO were added as a 10-point curve (1:3 serial dilutions to a final highest concentration of 10 μM) using a Tecan D300E digital dispenser. Agonists were diluted in assay buffer (final concentrations of 5.7 mM Tris-HCl, 43 mM NaCl, 50 mM LiCl, pH = 8), and 2 μL of the appropriate agonist was added to each well. Final agonist concentrations were 10 μM bilirubin, 20 μM deoxycholate, or 100 μM conjugated bilirubin (obtained from Lee Biosolutions, catalog number 910-12). The final concentration of DMSO was kept constant across the plate. The plate was incubated in the dark at 37°C for 1 hour, then at room temperature for 30 minutes. IP-1 standard and HTRF detection reagents were added according to the IP-One-Gq kit (part number 62IPAPEJ) purchased from Cisbio, and incubated in the dark at room temperature for 1 hour. The plate was read on a Molecular Devices SpectraMax iD5 plate reader. HTRF ratios were calculated from the raw data and graphed using GraphPad Prism to determine the IC for each compound. 50 The value was calculated.

[0506] Activity data (vs. 10 μM bilirubin agonist) for selected MRGPRX4 antagonists are shown in Table 66A. Activity ranges are indicated as follows: "+++++" indicates antagonist activity below 100 nM, "++++" indicates antagonist activity between 100-500 nM, "+++" indicates activity between 500-1000 nM, "++" indicates activity between 1000-2500 nM, and "+" indicates activity greater than 2500 nM.

[0507] [Table 32-1] [Table 32-2] [Table 32-3] [Table 32-4]

[0508] Activity data for selected MRGPRX4 antagonists (against 10 μM bilirubin agonist, 20 μM deoxycholic acid, 100 μM conjugated bilirubin, 50 μM urobilin, or 20 μM obeticholic acid) are shown in Table 66B.

[0509] [Table 33]

[0510] Example 67 Pharmacokinetic studies in mice Compounds were formulated at 5 mg / mL in 5% DMSO, 5% Solutol, and 90% phosphate-buffered saline at a concentration of 5 mg / mL and typically appeared as a fine, homogenous suspension. Male C57BL / 6 mice (n = 3 / compound) were administered a 50 mg / kg dose of each compound by oral gavage under non-fasting conditions. Blood samples were collected into K2-EDTA via the saphenous vein at 0.25, 0.5, 1, 2, 4, 8, and 24 hours post-dose. Plasma was prepared and stored at ≤60°C until analysis. Plasma sample preparation for analysis was performed by protein precipitation using acetonitrile (containing celecoxib as an internal standard) followed by centrifugation. Compound concentrations were measured in extracted plasma using LC-MS / MS against an eight-point calibration curve covering a range of 1–3000 ng / mL. Pharmacokinetic parameters, such as area under the curve, clearance, and half-life, were estimated using non-compartmental analysis using Phoenix WinNonlin. The dose was confirmed by analysis of the residual dose by UPLC-UV compared to a single point calibration sample. The results of these studies are shown in Table 67.

[0511] [Table 34]

[0512] Example 68 Urobilin is a potent MRGPRX4 agonist and pruritogen. Plasma urobilin is the oxidation product of the heme metabolite urobilinogen. Urobilinogen is a by-product of bilirubin reduction in the intestine. Some urobilinogen remains in the large intestine, where it is converted to stercobilin. Some urobilinogen is reabsorbed into the bloodstream and transported to the kidneys, where it is oxidized to urobilin when exposed to air.

[0513] Heme metabolites (bilirubin, biliverdin, urobilin, urobilinogen, and stercobilin) ​​were analyzed for in vitro activation of MRGPRX4. Cells were plated in 12 μL of Opti-MEM at 20,000 cells per well in a 384-well assay plate and stored overnight in an incubator. On the day of the assay, various agonists solubilized at 10 mM in 0.1% NaOH were added as a 10-point curve (1:3 serial dilutions to a final top concentration of 10 mM) using a Tecan D300E digital dispenser. Agonists were diluted in assay buffer (final concentration 5.7 mM Tris-HCl, 43 mM NaCl, 50 mM LiCl, pH = 8), and 2 μL of the appropriate agonist was added to each well. Plates were incubated in the dark at 37°C for 1 h, then at room temperature for 30 min. IP-1 standard and HTRF detection reagents were added according to the IP-One-Gq kit (part number 62IPAPEJ) purchased from Cisbio, and incubated in the dark at room temperature for 1 hour. Plates were read on a Molecular Devices SpectraMax iD5 plate reader. HTRF ratios were calculated from the raw data and graphed using GraphPad Prism, and IC50 values ​​for each compound were calculated.

[0514] The results of this study are shown in Figure 1. Urobilin was shown to be at least 10 times more effective than bilirubin at activating MRGPRX4.

[0515] The ability of urobilin to induce itch in wild-type mice was also tested. A typical mouse itch study was performed as follows: C57B6J male mice were housed in multiples under temperature- and humidity-controlled conditions with a normal light cycle (6 AM on, 6 PM off). Mice were handled and habituated to the testing room before testing and then placed in individual SCLABA testing chambers. After 20 minutes, mice were administered vehicle (saline, pH 7-8) PO. Thirty minutes later, the study pruritogen (100 mL in saline) or saline was administered subcutaneously (SC) in the midline of the neck behind the ear. Using the SCLABA system, video recording was performed for 30 minutes after the first pruritogen injection. Scratching bouts were scored from the SCLABA thumbnail using the 12 / 45 / 85 / 100 waveform criteria. Group sizes were typically 9-10 mice per group.

[0516] As shown in Figure 2A, urobilin induced a scratching response in mice in a dose-dependent manner. The itch-inducing effect of urobilin was also compared with that of deoxycholate and bilirubin agonists. As shown in Figure 2B, urobilin was a potent inducer of the scratching response in mice.

[0517] Example 69 Bilirubin and urobilin can be degraded by light, Reduces agonist activity at MRGPRX4. Bilirubin and urobilin are agonists of MRGPRX4, which have been demonstrated to be active pruritogens. Phototherapy has been shown to reduce itch in patients with cholestatic pruritus, which is due to light-induced degradation or chemical modification of bilirubin. To further investigate the contribution of photodegradation to the reduction of MRGPRX4 agonism, bilirubin and urobilin were pretreated with different illuminations and their activity was measured.

[0518] Stock solutions of both bilirubin and urobilirubin were made at 210 μM in 0.1 N NaOH (aqueous). Samples were stored either at room temperature in the dark, in a -20 °C freezer in the dark, at room temperature on a countertop under normal laboratory lighting conditions, or at room temperature under a 400 nM blue light lamp (similar to a medical lamp used to treat jaundice). Samples were evaluated after 24 hours, and the percent remaining urobilin and bilirubin was determined by measuring the degradation of the analytes contained in the sample compared to a time-zero standard, as determined by tandem mass spectrometry (LC-MS / MS). Samples (24 hours) were also evaluated for their ability to stimulate MRGPRX4.

[0519] After 24 hours, the freezer stock showed the highest amount of bilirubin remaining (44% of time zero), while all other conditions (room temperature dark, room temperature lab light, and room temperature blue light) had no detectable bilirubin remaining (Figure 3A). All samples stored at room temperature (dark, room light, and blue light) showed a significant decrease in agonist activity compared to the frozen samples (Figure 3B).

[0520] Although urobilin was more stable than bilirubin, degradation was still observed in all conditions. After 24 hours, samples stored in the dark had the highest amount of urobilin remaining (40%) compared to the time-zero measurement, while only 21% remained in the frozen samples stored in the dark. While 34% remained in the room-temperature samples stored in ambient light, no detectable urobilin remained in the room-temperature samples stored in blue light, indicating a higher vulnerability to light at that wavelength (Figure 4A). The blue light samples had little agonist activity compared to the other three groups investigated (room-temperature dark, frozen dark, and room-temperature light), corresponding to the remaining urobilin measured in these samples (Figure 4B).

[0521] Example 70 The agonistic effect of MRGPRX4 by FXR agonists is This may be blocked by typical MRGPRX4 agonists. BAR502, a dual agonist of FXR and GPBAR1, also has agonist activity (5700 nM) against MRGPRX4. Activity data for selected MRGPRX4 antagonists against 10 μM BAR502 in Table 70 shows antagonists in the range of 11-48 nM.

[0522] [Table 35]

[0523] All U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications, and non-patent publications mentioned herein and / or listed in the Application Data Sheet are incorporated herein by reference in their entirety. In general, the terms used in the following claims should not be construed to limit the claims to the specific embodiments disclosed in the specification and the claims, but should be construed to include all possible embodiments and the full scope of equivalents to which such claims are entitled.

Claims

1. MRGPRX4 in an effective amount of a compound having the structure of formula (I): 【Chemical 1】 or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: n is 0 or 1; x is 0, 1, or 2; A is aryl or heteroaryl; Q 1 and Q 2 But both are CR 10 or Q 1 Or Q 2 One of them is CR 10 and the other is N, Z is -O-, -S-, -N(R 11 ) -, -CH 2 - or -C≡C-, Each R 10 is H or alkyl, R is -(CH 2 ) m C(=O)OR 12 , -(CH 2 ) m NHR 13 , —(C═O)NR 14 R 15 , --CH 2 OH, —CN, haloalkyl, carbocyclic, heterocyclic, or carboxylic acid isostere; m is 0 or 1; R 11 , R 12 , and R 13 are the same or different and are each H or alkyl; R 14 is H and R 15 But H, -SO 2 CH 3 , a carbocycle, a heterocycle, or —OH, —CN, —NR′R″, C(═O)OH, C(═O)NR′R″, —SO 2 alkyl substituted with 0, 1, 2, or 3 substituents selected from OH, alkoxy, carbocycle, or heterocycle, where R′ and R″ are individually H or alkyl; or R 14 and R 15 form a heterocyclic ring together with the nitrogen atom to which they are attached, R 1 is H or alkyl, R 2 is halo, cyano, amino, alkyl, alkoxy, carbocycle, or heterocycle; R 3 , R 4 , and R 5 are the same or different and are absent, or if present, are either cyano, nitro, halogen, alkyl, haloalkyl, cyanoalkyl, alkoxy, haloalkoxy, -(C=O)alkyl, -(C=O)NHalkyl, carbocycle, heterocycle, -O-carbocycle, or -O-heterocycle; Any two R and R 2 form a heterocyclic ring together with the atoms to which they are attached, Any two R 3 , R 4 , R 5 , and R 10 together with the atoms to which they are attached form a carbocyclic or heterocyclic ring, A method wherein each occurrence of carbocycle or heterocycle is substituted with 0, 1, 2, or 3 substituents individually selected from halogen, hydroxyl, oxo, halo, alkyl, haloalkyl, alkoxy, haloalkoxy, carbocycle, or heterocycle.

2. an effective amount of a compound having the structure of formula (I), 【Chemistry 2】 or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, to a subject in need thereof, wherein: n is 0 or 1; x is 0, 1, or 2; A is aryl or heteroaryl; Q 1 and Q 2 But both are CR 10 or Q 1 Or Q 2 One of them is CR 10 and the other is N, Z is -O-, -S-, -N(R 11 ) -, -CH 2 - or -C≡C-, Each R 10 is H or alkyl, R is -(CH 2 ) m C(=O)OR 12 , -(CH 2 ) m NHR 13 , —(C═O)NR 14 R 15 , --CH 2 OH, —CN, haloalkyl, carbocyclic, heterocyclic, or carboxylic acid isostere; m is 0 or 1; R 11 , R 12 , and R 13 are the same or different and are each H or alkyl; R 14 is H and R 15 But H, -SO 2 CH 3 , a carbocycle, a heterocycle, or —OH, —CN, —NR′R″, C(═O)OH, C(═O)NR′R″, —SO 2 alkyl substituted with 0, 1, 2, or 3 substituents selected from OH, alkoxy, carbocycle, or heterocycle, where R′ and R″ are individually H or alkyl; or R 14 and R 15 form a heterocyclic ring together with the nitrogen atom to which they are attached, R 1 is H or alkyl, R 2 is halo, cyano, amino, alkyl, alkoxy, carbocycle, or heterocycle; R 3 , R 4 , and R 5 are the same or different and are absent, or if present, are either cyano, nitro, halogen, alkyl, haloalkyl, cyanoalkyl, alkoxy, haloalkoxy, -(C=O)alkyl, -(C=O)NHalkyl, carbocycle, heterocycle, -O-carbocycle, or -O-heterocycle; Any two R and R 2 form a heterocyclic ring together with the atoms to which they are attached, Any two R 3 , R 4 , R 5 , and R 10 together with the atoms to which they are attached form a carbocyclic or heterocyclic ring, A method wherein each occurrence of carbocycle or heterocycle is substituted with 0, 1, 2, or 3 substituents individually selected from halogen, hydroxyl, oxo, halo, alkyl, haloalkyl, alkoxy, haloalkoxy, carbocycle, or heterocycle.

3. The method of claim 2, wherein the MRGPR X4-dependent condition is a condition caused by activation of MRGPR X4 by a bile acid or an analog thereof.

4. 3. The method of claim 2, wherein the MRGPR X4-dependent condition is an itch-associated condition, a pain-associated condition, or an autoimmune disorder.

5. The itch-related condition is selected from the group consisting of chronic itch, cholestatic pruritus, contact dermatitis, allergic blepharitis, anemia, atopic dermatitis, bullous pemphigoid, candidiasis, chickenpox, cholestasis, end-stage renal failure, hemodialysis, contact dermatitis, dermatitis herpetiformis, diabetes, drug allergy, dry skin, dyshidrotic dermatitis, ectopic eczema, eczema, erythrasma, folliculitis, and fungal infections.

5. The method of claim 4, wherein the condition is a sexually transmitted disease, hemorrhoids, herpes, HIV infection, Hodgkin's disease, hyperthyroidism, iron deficiency anemia, kidney disease, leukemia, liver disease, lymphoma, malignant tumor, multiple myeloma, neurodermatitis, onchocerciasis, Paget's disease, lice infestation, polycythemia vera, pruritus ani, pseudorabies, psoriasis, rectal prolapse, scabies, schistosomiasis, scleroderma, severe stress, stasis dermatitis, swimmer's itch, thyroid disease, tinea cruris, uremic pruritus, or urticaria.

6. 6. The method of claim 5, wherein the itch-related condition is cholestatic pruritus, uremic pruritus, atopic dermatitis, dry skin, psoriasis, contact dermatitis, or eczema.

7. 6. The method of claim 5, wherein the itch-associated condition is a liver disease, and the liver disease is primary biliary cholangitis, primary sclerosing cholangitis, Alagille syndrome, progressive familial intrahepatic cholestasis, intrahepatic cholestasis of pregnancy, nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), biliary atresia, chronic hepatitis B, chronic viral hepatitis, drug-induced liver injury (DILI), hepatic fibrosis, cholestatic liver disease, or alcoholic liver disease.

8. 3. The method of claim 2, further comprising administering to the subject a pharmaceutically effective amount of a second therapeutic agent.

9. 9. The method of claim 8, wherein the MRGPR X4-dependent condition is a liver disease and the second therapeutic agent is ursodeoxycholic acid (UDCA), norursodeoxycholic acid, cholestyramine, stanozolol, naltrexone, rifampicin, alisol B23-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 (TRβ) agonist, or any combination thereof.

10. The FXR agonist may be obeticholic acid, tulofexolate 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, altenusin, tropifexor (LJN452), nidufexor, tulofexolate isopropyl, fexaramine, silymarin, silybin, hedragonic acid 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, IOT-022, M-480, INV-33, RDX023-02, or any combination thereof.

11. the 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 a PPAR alpha / gamma / delta pan agonist, and optionally the PPAR alpha agonist is fenofibrate, ciprofibrate, pemafibrate, gemfibrozil, clofibrate, binifibrate, clinofibrate, clofibric acid, nicofibrate, pirifibrate, plafibride, lonifibrate, theofibrate, tocofibrate, or SRI 0171; the PPAR gamma agonist is 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, or ALL-4; the PPAR delta agonist is 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-ylmethylsirphanyl]-phenoxy}-acetic acid), GW0742 ([4-[[[2-[3-fluoro-4-(trifluoromethyl)phenyl]-4-methyl-5-triazolyl]methyl]thio]-2-methylphenoxy]acetic acid), L165041, HPP-593, or NCP-1046; the PPAR alpha / gamma agonist is saroglitazar, aleglitazar, muraglitazar, tesaglitazar, or DSP-8658; the PPAR alpha / delta agonist is elafibranor or T913659; the PPAR gamma / delta agonist is conjugated linoleic acid (CLA) or T3D-959; 10. The method of claim 9, wherein the PPAR alpha / gamma / delta agonist is IVA337 (lanifibranol), TTA (tetradecylthioacetic acid), bavaquinin, GW4148, GW9135, bezafibrate, lobeglitazone, 2-(4-(5,6-methylenedioxybenzo[d]thiazol-2-yl)-2-methylphenoxy)-2-methylpropanoic acid (MHY2013), or CS038.

12. 10. The method of claim 9, wherein the TRβ agonist is sobetirome, eprotirome, GC-24, MGL-3196, MGL-3745, VK-2809, KB141 [3,5-dichloro-4-(4-hydroxy-3-isopropylphenoxy)phenylacetic acid], MB07811 (2R,4S)-4-(3-chlorophenyl)-2-[(3,5-dimethyl-4-(4'-hydroxy-3'-isopropylbenzyl)phenoxy)methyl]-2-oxide-[1,3,2]-dioxaphosphonane), or any combination thereof.

13. The pain-related condition may be acute pain, advanced prostate cancer, AIDS-related pain, ankylosing spondylitis, arachnoiditis, arthritis, arthrofibrosis, ataxic cerebral palsy, autoimmune atrophic gastritis, avascular necrosis, back pain, Beyset's disease (syndrome), burning mouth syndrome, bursitis, cancer pain, carpal tunnel syndrome, cauda equina syndrome, central pain syndrome, cerebral palsy, cervical stenosis, Charcot-Marie-Tooth (CMT) disease, chronic fatigue syndrome (CFS), chronic inflammatory bowel disease (CKD), or chronic muscular atrophy (CFS). Clinically significant abdominal pain (CFAP), chronic pain, chronic pancreatitis, collapsed lung (pneumothorax), complex regional pain syndrome (RSD), corneal neuropathic pain, Crohn's disease, degenerative disc disease, Dercum's disease, dermatomyositis, diabetic peripheral neuropathy (DPN), dystonia, Ehlers-Danlos syndrome (EDS), endometriosis, eosinophilia-myalgia syndrome (EMS), erythromygia, fibromyalgia, gout, headache, herniated disc, hydrocephalus, intercostal neuralgia, interstitial bladder inflammation, irritable bowel syndrome (IBS), juvenile dermatitis (dermatomyositis), knee injury, leg pain, lower back pain and hematuria syndrome, lupus, Lyme disease, sponge kidney disease (MSK), dysesthesias, mesothelioma, migraine, musculoskeletal pain, myofascial pain, myositis, neck pain, neuropathic pain, occipital neuralgia, osteoarthritis, Paget's disease, Parsonage-Turner syndrome, pelvic pain, peripheral neuropathy, phantom limb pain, compressed nerve, polycystic kidney disease, polymyalgia rheumatica, polymyositis, pontine steroids, steroids, steroid drugs ...

5. The method of claim 4, wherein the condition is leucoderma, post-herniorrhaphy pain syndrome, post-mastectomy pain syndrome, post-stroke pain, post-thoracotomy pain syndrome, post-herpetic neuralgia (shingles), post-polio syndrome, primary lateral sclerosis, psoriatic arthritis, pudendal neuralgia, radiculopathy, Raynaud's disease, rheumatoid arthritis (RA), sacroiliac joint dysfunction, sarcoidosis, Scheuermann's kyphosis, sciatica, scoliosis, shingles (Herpes Zoster), Sjogren's syndrome, spasmodic torticollis, sphincter of Oddi dysfunction, spinocerebellar ataxia (SCA ataxia), spinal cord injury, lumbar spinal stenosis, syringomyelia, Tarlov's cyst, transverse myelitis, trigeminal neuralgia, neuropathic pain, ulcerative colitis, vascular pain, or vulvodynia.

14. 5. The method of claim 4, wherein the autoimmune disorder is chronic inflammation, multiple sclerosis, Stevens-Johnson syndrome, appendicitis, bursitis, colitis, cystitis, dermatitis, phlebitis, reflex sympathetic dystrophy / complex regional pain syndrome (rsd / crps), rhinitis, tendonitis, tonsillitis, acne vulgaris, reactive airways disease, asthma, respiratory tract infection, autoinflammatory disease, celiac disease, chronic prostatitis, diverticulitis, glomerulonephritis, hidradenitis suppurativa, hypersensitivity, enteropathy, epithelial bowel 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, or vasculitis.

15. 15. The method of any one of claims 1-14, wherein the compound has the structure of a compound listed in Table A or B, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof.

16. A compound having the structure of formula (I) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, and a pharmaceutically acceptable excipient; 【Chemistry 3】 or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: n is 0 or 1; x is 0, 1, or 2; A is aryl or heteroaryl; Q 1 and Q 2 But both are CR 10 or Q 1 Or Q 2 One of them is CR 10 and the other is N, Z is -O-, -S-, -N(R 11 ) -, -CH 2 - or -C≡C-, Each R 10 is H or alkyl, R is -(CH 2 ) m C(=O)OR 12 , -(CH 2 ) m NHR 13 , —(C═O)NR 14 R 15 , --CH 2 OH, —CN, haloalkyl, carbocyclic, heterocyclic, or carboxylic acid isostere; m is 0 or 1; R 11 , R 12 , and R 13 are the same or different and are each H or alkyl; R 14 is H and R 15 But H, -SO 2 CH 3 , a carbocycle, a heterocycle, or —OH, —CN, —NR′R″, C(═O)OH, C(═O)NR′R″, —SO 2 alkyl substituted with 0, 1, 2, or 3 substituents selected from OH, alkoxy, carbocycle, or heterocycle, where R′ and R″ are individually H or alkyl; or R 14 and R 15 form a heterocyclic ring together with the nitrogen atom to which they are attached, R 1 is H or alkyl, R 2 is halo, cyano, amino, alkyl, alkoxy, carbocycle, or heterocycle; R 3 , R 4 , and R 5 are the same or different and are absent, or if present, are either cyano, nitro, halogen, alkyl, haloalkyl, cyanoalkyl, alkoxy, haloalkoxy, -(C=O)alkyl, -(C=O)NHalkyl, carbocycle, heterocycle, -O-carbocycle, or -O-heterocycle; Any two R and R 2 form a heterocyclic ring together with the atoms to which they are attached, Any two R 3 , R 4 , R 5 , and R 10 together with the atoms to which they are attached form a carbocyclic or heterocyclic ring, A pharmaceutical composition wherein each occurrence of a carbocycle or heterocycle is substituted with 0, 1, 2, or 3 substituents individually selected from halogen, hydroxyl, oxo, halo, alkyl, haloalkyl, alkoxy, haloalkoxy, carbocycle, or heterocycle.

17. 17. The pharmaceutical composition of claim 16, further comprising a second therapeutic agent.

18. 18. The pharmaceutical composition of claim 17, wherein the second therapeutic agent is ursodeoxycholic acid (UDCA), norursodeoxycholic acid, cholestyramine, stanozolol, naltrexone, rifampicin, alisol B23-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 (TRβ) agonist, or any combination thereof.

19. (a) The FXR agonist is selected from the group consisting of obeticholic acid, tulofexolate 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, altenusin, tropifexor (LJN452), nidufexor, and turofexol. fexolate 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, IOT-022, M-480, INV-33, RDX023-02, or any combination thereof; (b) the 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 a PPAR alpha / gamma / delta pan agonist; and optionally the PPAR alpha agonist is fenofibrate, ciprofibrate, pemafibrate, gemfibrozil, clofibrate, binifibrate, clinofibrate, clofibric acid, nicofibrate, pirifibrate, plafibride, lonifibrate, theofibrate, tocofibrate, or SRI 0171; the PPAR gamma agonist is 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, or ALL-4; the PPAR delta agonist is 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-ylmethylsirphanyl]-phenoxy}-acetic acid), GW0742 ([4-[[[2-[3-fluoro-4-(trifluoromethyl)phenyl]-4-methyl-5-triazolyl]methyl]thio]-2-methylphenoxy]acetic acid), L165041, HPP-593, or NCP-1046; the PPAR alpha / gamma agonist is saroglitazar, aleglitazar, muraglitazar, tesaglitazar, or DSP-8658; the PRAR alpha / delta agonist is elafibranor or T913659; the PPAR gamma / delta agonist is conjugated linoleic acid (CLA) or T3D-959; the PPAR alpha / gamma / delta agonist is IVA337 (lanifibranol), TTA (tetradecylthioacetic acid), bavaquinin, GW4148, GW9135, bezafibrate, lobeglitazone, 2-(4-(5,6-methylenedioxybenzo[d]thiazol-2-yl)-2-methylphenoxy)-2-methylpropanoic acid (MHY2013), or CS038; or (c) The pharmaceutical composition of claim 18, wherein the TRβ agonist is sobetirome, eprotirome, GC-24, MGL-3196, MGL-3745, VK-2809, KB141 [3,5-dichloro-4-(4-hydroxy-3-isopropylphenoxy)phenylacetic acid], MB07811 (2R,4S)-4-(3-chlorophenyl)-2-[(3,5-dimethyl-4-(4'-hydroxy-3'-isopropylbenzyl)phenoxy)methyl]-2-oxide-[1,3,2]-dioxaphosphonane), or any combination thereof.

20. A compound having one of the following structures: or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof: 【Table 1-1】 【Table 1-2】 【Table 1-3】

21. A compound having one of the above structures listed in Table A, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof.

22. A compound having one of the above structures listed in Table B, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof.

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