Modulators of MAS-related G protein receptor X4 and related products and methods

Abstract

Provided are methods for modulating MRGPR X4 in general by contacting the MRGPR X4 with an effective amount of a compound or more specifically for treating a MRGPR X4-dependent condition by administering the compound to a subject in need thereof, wherein the compound has the structure of formula (I): (I) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof, wherein n, x, A, Q1, Q2, Z, R, R 1 , R 2 , R 3 , R 4 and R 5 As defined herein. Also provided are pharmaceutical compositions containing such compounds as well as the compounds themselves. #imgabs0#

Description

[0001] Related Applications

[0002] This application is related to U.S. Provisional Application No. 62 / 825,741 filed on March 28, 2019; U.S. Provisional Application No. 62 / 849,095 filed on May 16, 2019; U.S. Provisional Application No. 62 / 864,306 filed on June 20, 2019; U.S. Provisional Application No. 62 / 938,277 filed on November 20, 2019; U.S. Provisional Application No. 62 / 955,967 filed on December 31, 2019; and U.S. Provisional Application No. 62 / 959,799 filed on January 10, 2020; each of which is incorporated herein by reference in its entirety. Technical Field

[0003] The present invention relates to a regulator of Mas-related G protein coupled receptor X4, a product containing the regulator, and a use and preparation method thereof. Background Art

[0004] Mas-related G protein receptors (MRGPRs) are a group of orphan receptors with limited expression in very specialized tissues. The functions of most of these receptors are poorly understood. There are eight related receptors in this class that are expressed in humans, of which only four have readily identifiable orthologs in other species (i.e., MRGPR D, E, F, and G). Based on homology, the other four receptors (MRGPR X1, X2, X3, and X4) have no counterparts in species other than humans. Summary of the invention

[0005] The present invention is based in part on the identification that mouse MRGPR A1 corresponds functionally, at least in part, to human MRGPR X4. Conditions mediated by these receptors include chronic itch (e.g., pruritus), inflammatory conditions, autoimmunity, skin conditions, cardiovascular disease, lung inflammation / COPD, and adverse skin reactions to drugs. More specifically, both MRGPR A1 and MRGPR X4 are expressed in sensory neurons, skin melanocytes, dendritic cells, polymorphonuclear cells, macrophages, bronchial epithelial cells, lung smooth muscle, and dorsal root ganglia. It has now been identified that both MRGPR A1 and MRGPR X4 are receptors for (or are sensitive to activation of) circulating bilirubin and its metabolites, and are therefore important for itch sensation in conditions where bilirubin is elevated, such as cholestatic pruritus. In addition, MRGPR X4 is activated by a variety of additional components of bile, including bile acids and their metabolites and heme metabolites, including bilirubin and urobilin. Bile acids and bilirubin are highly elevated in cholestatic pruritus, while urobilin is a potent mediator of itch induction in mouse models and may therefore be important for itch sensation in conditions where urobilin is elevated, such as uremic pruritus. Thus, modulation of MRGPR X4 allows for the treatment of autoimmune diseases such as psoriasis, multiple sclerosis, Steven Johnson's Syndrome, and other chronic itches, as explained in more detail below.

[0006] Thus, in one embodiment, a method is provided for modulating MRGPR X4 by contacting the MRGPR X4 with an effective amount of a compound having the structure of Formula (I):

[0007]

[0008] or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof, wherein n, x, A, Q 1 , Q 2 , Z, R, R 1 , R 2 , R 3 , R 4 and R 5 As defined below.

[0009] In another embodiment, a method for treating a MRGPR X4-dependent disorder by administering to a subject in need thereof an effective amount of a compound having the structure of Formula (I), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof is provided.

[0010] In more specific embodiments, the MRGPR X4-dependent disorder is one or more of an itch-related condition, a pain-related condition, an inflammation-related condition, or an autoimmune disorder.

[0011] In another embodiment, a pharmaceutical composition is provided, comprising a combination of a compound having a structure of formula (I), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof, and a pharmaceutically acceptable excipient.

[0012] In another embodiment, a compound is provided having one or more of the structures disclosed herein or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof.

[0013] In another embodiment, a prodrug and / or metabolite of a compound having a structure of formula (I) is also provided. In the case of a prodrug, the compound (i.e., prodrug) can be administered to a subject and then converted into a compound having a structure of formula (I) in vivo. In the case of a metabolite, after administering a compound having a structure of formula (I) to a subject, such compound can be converted into an active metabolite in vivo. BRIEF DESCRIPTION OF THE DRAWINGS

[0014] Figure 1 In vitro activation of MRGPRX4 by the heme metabolites bilirubin, biliverdin, urobilin, urobilinogen, and stercobilin was shown.

[0015] Figure 2A-2B The results are shown for the comparison with vehicle (VEH) ( Figure 2A ) and urobilin, bilirubin, and deoxycholic acid ( Figure 2B ) compared with the induction of itch by urobilin in wild-type mice.

[0016] Figure 3A-3B The bilirubin stability of MRGPRX4 after 24 h storage under different temperature and light storage conditions is shown ( Figure 3A ) and bilirubin agonism ( Figure 3B ) (time zero (freshly prepared), room temperature dark, -20°C dark, room temperature lab light, and room temperature 400 nm blue light).

[0017] Figure 4A-4B The urobilin stability of MRGPRX4 after 24 h storage under different temperature and light storage conditions is shown ( Figure 4A ) and urobilinogenetic effects ( Figure 4B ) (time zero (freshly prepared), room temperature dark, -20 °C dark, room temperature lab light, and room temperature blue light). DETAILED DESCRIPTION

[0018] As noted above, the present invention relates to modulators of MRGPR X4, products containing said modulators, and methods of use and preparation thereof. The present invention is based, in part, on the identification that MRGPR A1 in mice corresponds functionally to human MRGPR X4. Conditions mediated by these receptors include chronic and intermittent itching (e.g., pruritus), inflammatory conditions, autoimmunity, skin conditions, and adverse skin reactions to drugs and infectious diseases. More specifically, both MRGPR A1 and MRGPR X4 are expressed in sensory neurons and dorsal root ganglia. It has now been identified that both MRGPR A1 and MRGPR X4 are receptors for (or are sensitive to activation by) circulating bilirubin and its metabolites, and are therefore important for the sensation of itch in conditions where bilirubin is elevated, such as cholestatic pruritus and end-stage renal failure. In addition, 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 that is excreted exclusively by the kidney, is a potent agonist of MRGPRX4 and pruritogen, and thus may be important for itch sensation in conditions where urobilin is elevated, such as uremic pruritus, nephropathy, and end-stage renal failure. Thus, modulation of MRGPR X4 allows for the treatment of autoimmune diseases, such as psoriasis, multiple sclerosis, Stevens Johnson syndrome, atopic diseases, such as atopic dermatitis, and other chronic pruritic conditions, as explained in more detail below.

[0019] MRGPRs appear to be sensory receptors that recognize their external environment for exogenous or endogenous signals / chemicals. These receptors may respond to a variety of chemical ligands / agonists. For example, MRGPR X4 recognizes bilirubin, bile acids, and urobilin as agonist signals. In certain embodiments, the molecules of the invention modulate MRGPR X4 by acting as inverse agonists capable of blocking a variety of chemical entities and / or as competitive antagonists capable of specifically blocking a single ligand. In one embodiment, such modulation is selective for other MRGPRs, such as MRGPR X1, X2, and / or X3.

[0020] Thus, in one embodiment, a method for modulating MRGPR X4 is provided, the method comprising contacting MRGPRX4 with an effective amount of a compound having the structure of formula (I):

[0021]

[0022] or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof, wherein:

[0023] n is 0 or 1;

[0024] x is 0, 1, or 2;

[0025] A is aryl or heteroaryl;

[0026] Q 1 and Q 2 All CR 10 , or Q 1 or Q 2 One of them is CR 10 and the other is N;

[0027] Z is -O-, -S-, -N(R 11 )-、-CH 2 -or-C≡C-;

[0028] Each R 10 is H or alkyl;

[0029] 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 ring, heterocyclic ring or carboxylic acid isostere;

[0030] m is 0 or 1;

[0031] R 11 , R 12 and R 13 are the same or different and individually are H or alkyl;

[0032] R 14 is H, and R 15 It is H, -SO 2 CH 3 , carbocyclic, heterocyclic or alkyl substituted by 0, 1, 2 or 3 substituents selected from the following: -OH, -CN, -NR'R", C(=O)OH, C(=O)NR'R", -SO 2 OH, alkoxy, carbocyclic or heterocyclic, wherein R' and R" are independently H or alkyl, or

[0033] R 14 and R 15 Together with the nitrogen atom to which it is attached, it forms a heterocyclic ring;

[0034] R 1 is H or alkyl;

[0035] R 2 is halo, cyano, amino, alkyl, alkoxy, carbocyclic or heterocyclic;

[0036] R 3 , R 4 and R 5 are the same or different and are absent, or when present, are cyano, nitro, halogen, alkyl, haloalkyl, cyanoalkyl, alkoxy, haloalkoxy, -(C=O)alkyl, -(C=O)NHalkyl, carbocycle, heterocycle, -O-carbocycle or -O-heterocycle, or

[0037] Any two R and R 2 Together with the atoms to which they are attached, they form a heterocyclic ring;

[0038] Any two R 3 , R 4 , R 5 and R 10 Together with the atoms to which they are attached, they form a carbocyclic or heterocyclic ring;

[0039] and wherein each occurrence of carbocycle or heterocycle is substituted with 0, 1, 2 or 3 substituents individually selected from the group consisting of halogen, hydroxy, oxo, halo, alkyl, haloalkyl, alkoxy, haloalkoxy, carbocycle or heterocycle.

[0040] "Modulating" MRGPR X4 means that a compound interacts with MRGPR X4 in a manner such that it acts as an inverse agonist and / or as a competitive antagonist of the receptor. In one embodiment, such modulation is partially or completely selective for other MRGPRs, such as MRGPR X1, X2 and / or X3.

[0041] "MRGPR" refers to one or more Mas-related G protein-coupled receptors, a group of orphan receptors with limited expression in very specialized tissues (e.g., sensory neurons and dorsal root ganglia) and barrier tissues. There are eight related receptors in this class that are expressed in humans, of which only four have readily identifiable orthologs in other species (i.e., MRGPR D, E, F, and G). Based on homology, the other four receptors (MRGPR X1, X2, X3, and X4) have no counterparts in non-human species.

[0042] "Effective amount" refers to the amount of a given agent sufficient to achieve a desired effect in a subject treated with the agent. Ideally, an effective amount of an agent is an amount sufficient to inhibit or treat a disease without causing significant toxicity in a subject. The effective amount of an agent will depend on the subject being treated, the severity of the ailment, and the mode of administration of the pharmaceutical composition. In light of the present disclosure, one skilled in the art will appreciate methods of determining an effective amount of a disclosed compound sufficient to achieve a desired effect in a subject.

[0043] "Alkyl" means a saturated or unsaturated straight or branched chain alkyl group 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. Examples of branched chain alkyl groups include, but are not limited to, isopropyl, isobutyl, sec-butyl, tert-butyl, neopentyl, isopentyl, and 2,2-dimethylpropyl. Unsaturated alkyl groups include alkenyl and alkynyl groups as defined below.

[0044] "Alkenyl" means a straight or branched alkenyl group 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, ethenyl, propenyl, butenyl, pentenyl, and hexenyl.

[0045] "Alkynyl" means a straight or branched chain alkynyl group 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. Alkynyl is an unsaturated hydrocarbon containing at least one carbon-carbon triple bond. Examples of alkynyl include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, and hexynyl.

[0046] "Halo" or "halogen" refers to fluorine, chlorine, bromine and iodine.

[0047] "Hydroxyl" refers to -OH.

[0048] "Cyano" refers to -CN.

[0049] Amino refers to -NH 2 , -NH alkyl or N(alkyl) 2 , wherein alkyl is as defined above. Examples of amino groups include but are not limited to -NH 2 、-NHCH 3 、-N(CH 3 ) 2 wait.

[0050] "Haloalkyl" refers to an alkyl group as defined above in which one or more hydrogen atoms are replaced by a halogen. Examples of lower haloalkyl groups include, but are not limited to, -CF 3 , -CHF 2 wait.

[0051] "Alkoxy" refers to an alkyl group as defined above attached through an oxygen atom (ie, -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.

[0052] "Haloalkoxy" refers to a haloalkyl group as defined above attached through an oxygen atom (ie, -O-haloalkyl). Examples of lower haloalkoxy groups include, but are not limited to, -OCF 3 wait.

[0053] "Cycloalkyl" refers to an alkyl group forming a ring structure, which may be substituted or unsubstituted, wherein the ring is fully saturated, partially unsaturated or fully unsaturated, wherein if unsaturated, the conjugation of the π electrons in the ring does not produce aromaticity. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. In some embodiments, the cycloalkyl group has 3 to 8 ring members, while in other embodiments, the number of ring carbon atoms is in the range of 3 to 5, 3 to 6 or 3 to 7. Cycloalkyl further includes, but is not limited to, polycyclic cycloalkyl groups such as norbornyl, adamantyl, bornyl, camphenyl, isocamphenyl and carenyl and fused rings such as, but not limited to, decahydronaphthyl.

[0054] Aryl is a cyclic aromatic hydrocarbon that does not contain heteroatoms. Representative aryl includes but is not limited to phenyl, azulenyl, heptyl, biphenyl, indenyl, fluorenyl, phenanthrenyl, triphenylene, pyrenyl, naphthyl, pyrenyl, biphenylene, anthracenyl and naphthyl. In certain embodiments, aryl contains 6 to 14 carbons in the ring portion of the group. The terms "aryl" and "aryl groups" include condensed rings, wherein at least one ring but not necessarily all rings are aromatic, such as condensed aromatic-aliphatic ring systems (e.g., indanyl, tetrahydronaphthyl, etc.). In one embodiment, aryl is phenyl or naphthyl, and in another embodiment, aryl is phenyl.

[0055] "Carbocycle" refers to an alkyl group forming a ring structure, which may be substituted or unsubstituted, wherein the ring is fully saturated, partially unsaturated, or fully unsaturated, wherein if unsaturation is present, conjugation of the π electrons in the ring may produce aromaticity. In one embodiment, the carbocycle comprises a cycloalkyl group as defined above. In another embodiment, the carbocycle comprises an aryl group as defined above.

[0056] "Heterocycle" refers to aromatic and non-aromatic ring moieties containing 3 or more ring members, one or more of which are heteroatoms, such as, but not limited to, N, O, S, or P. In some embodiments, heterocyclyl groups contain from 3 to 20 ring members, while other such groups have from 3 to 15 ring members. At least one ring contains heteroatoms, but each ring in a polycyclic system need not contain heteroatoms. For example, dioxolanyl and benzodioxolanyl ring systems (methylenedioxyphenyl ring systems) are both heterocyclyl groups within the meaning of this article.

[0057] Heterocyclyl also includes fused ring materials, including those with fused aromatic and non-aromatic groups. Heterocyclyl also includes polycyclic systems containing heteroatoms such as, but not limited to, quinuclidine, and also includes heterocyclyls with substituents, including, but not limited to, alkyl, halide, amino, hydroxyl, cyano, carboxyl, nitro, thio or alkoxy, bonded to one of the ring members. Heterocyclyl as defined herein can be heteroaryl or a partially or fully saturated cyclic group containing at least one ring heteroatom. Heterocyclyl groups include, but are not limited to, pyrrolidinyl, furanyl, tetrahydrofuranyl, dioxolanyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, thienyl, benzothienyl, benzofuranyl, dihydrobenzofuranyl, indolyl, dihydroindolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl.

[0058] "Heteroaryl" refers to an aromatic ring moiety containing 5 or more ring members, one or more of which is a heteroatom such as, but not limited to, N, O, and S. Heteroaryl includes, but is not limited to, groups such as pyrrolyl, pyrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazyl, pyrazinyl, pyrimidinyl, thienyl, triazolyl, tetrazolyl, triazinyl, thiazolyl, thienyl, oxazolyl, isoxazolyl, benzothienyl, benzofuranyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolyl, isoquinolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, quinoxalinyl, and quinazolinyl. The terms "heteroaryl" and "heteroaryl groups" include fused ring compounds, such as those in which at least one ring, but not necessarily all rings, are aromatic, including tetrahydroquinolinyl, tetrahydroisoquinolinyl, indolyl and 2,3-dihydroindolinyl.

[0059] "Carboxylic acid isosteres" refers to groups that serve as substitutes for carboxylic acid groups (i.e., -COOH). The use of carboxylic acid isosteres may be preferred over carboxylic acid groups for a variety of reasons, including greater selectivity, reduced side effects, reduced toxicity, improved pharmacokinetics, increased stability, and / or simplified synthesis. Carboxylic acid isosteres include hydroxamic acid, acyl cyanamide, sulfonamide, phosphonic acid, phosphinic acid, cyanoacetamide, sulfonate, sulfonamide, acylsulfonamide, arylsulfonamide, sulfonylurea, tetrazole, thiazolidinedione, oxazolidinedione, isoxazole, isothiazole, squaric acid, 3-hydroxyquinolin-2-one, 4-hydroxyquinolin-2-one, 5-oxo-1,2,4-oxadiazole, 5-oxo-1,2,4-thiadiazole, 5-thioxo-1,2,4-oxadiazole, hydroxyisoxazole, phenol, tetrameric acid, tetronic acid, cyclopentane-1,3-dione, 6-hydroxy-1,3-dioxin-4-one, 3-hydroxypyridin-4(1H)-one and oxadiazolone.

[0060] In one embodiment, the carboxylic acid isostere may be acyclic and have one of the following structures (wherein R a is an alkyl group, a carbocyclic ring or a heterocyclic ring, wherein each of the carbocyclic ring and the heterocyclic ring may be replaced by R 2 Single or multiple substitution):

[0061]

[0062] In another embodiment, the carboxylic acid isostere can be cyclic and have one of the following structures:

[0063]

[0064] "Isomer" is used herein to encompass all chiral forms, diastereomeric forms, or racemic forms of a structure, unless a specific stereochemistry or isomeric form is specifically indicated. Such compounds can be enriched or resolved optical isomers at any or all asymmetric atoms to any degree of enrichment, as can be apparent from the diagrams. Both racemic and diastereomeric mixtures, as well as individual optical isomers, can be synthesized to be substantially free of their enantiomers or diastereomeric partners, and these are within the scope of certain embodiments of the present invention. Isomers produced due to the presence of chiral centers include a pair of non-superimposable isomers referred to as "enantiomers". A single enantiomer of a pure compound is optically active (i.e., it is capable of rotating the plane of plane polarized light and is designated as R or S).

[0065] "Isolated optical isomers" means compounds that have been substantially purified from the corresponding optical isomers of the same formula. For example, the purity of the isolated isomers can be at least about 80%, at least 80%, or at least 85% by weight. In other embodiments, the purity of the isolated isomers is at least 90%, or at least 98%, or at least 99% by weight.

[0066] "Substantially enantiomeric or diastereomeric" purity refers to the level of enantiomeric or diastereomeric enrichment of one enantiomer relative to the other enantiomer or diastereomer of at least about 80%, and more specifically greater than 80%, 85%, 90%, 95%, 98%, 99%, 99.5% or 99.9%.

[0067] The terms "racemate" and "racemic mixture" refer to a mixture of equal amounts of two enantiomers. A racemate is labeled "(±)" because it is optically inactive (i.e., does not rotate plane-polarized light in either direction because its constituent enantiomers cancel each other out). All enantiomers adjacent to a tertiary or quaternary carbon are labeled with an asterisk ( * ) are all optically active isomers, which can be purified from the corresponding racemates and / or synthesized by appropriate chiral synthesis.

[0068] A "hydrate" is a compound that exists in association with water molecules. The association may contain a stoichiometric amount of water, such as a monohydrate or a dihydrate, or may contain a random amount of water. As used herein, "hydrate" refers to a solid form; in other words, a compound in aqueous solution may be hydrated but is not a hydrate as the term is used herein.

[0069] "Solvates" are similar to hydrates, except that a solvent other than water is present. For example, methanol or ethanol can form "alcoholates," which likewise can be stoichiometric or non-stoichiometric. As used herein, "solvate" refers to a solid form; in other words, a compound in a solvent solution, while solvated, is not a solvate as the term is used herein.

[0070] "Isotopes" refer to atoms having the same number of protons but different numbers of neutrons, and isotopes of compounds of formula (I) include any such compounds in which one or more atoms are replaced by isotopes of the atom. For example, carbon 12 is the most common form of carbon, having six protons and six neutrons, while 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). Although fluorine has multiple isotopes, fluorine 19 has the longest lifetime. Therefore, isotopes of compounds having a structure of formula (I) include, but are not limited to, compounds of formula (I) below: wherein one or more carbon 12 atoms are replaced by carbon 13 and / or carbon 14 atoms, wherein one or more hydrogen atoms are replaced by deuterium and / or tritium, and / or wherein one or more fluorine atoms are replaced by fluorine 19.

[0071] "Salt" generally refers to an organic compound in ionic form, such as a carboxylic acid or an amine, combined with a counterion. For example, a salt formed between an acid in anionic form and a cation is called an "acid addition salt." Conversely, a salt formed between a base in cationic form and an anion is called a "base addition salt."

[0072] The term "pharmaceutically acceptable" refers to pharmaceutical agents that have been approved for human consumption and are generally non-toxic. For example, the term "pharmaceutically acceptable salt" refers to non-toxic inorganic or organic acid and / or base addition salts (see, e.g., Lit et al., Salt Selection for Basic Drugs, Int. J. Pharm., 33, 201-217, 1986) (incorporated herein by reference).

[0073] Pharmaceutically acceptable base addition salts of the compounds of the present invention include, for example, metal salts, including alkali metal salts, alkaline earth metal salts and transition metal salts, such as calcium salts, magnesium salts, potassium salts, sodium salts, and zinc salts. Pharmaceutically acceptable base addition salts also include organic salts formed from basic amines, such as N, N'dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine.

[0074] 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 may be selected from aliphatic, cycloaliphatic, aromatic, aromatic aliphatic, heterocyclic, carboxylic, and sulfonic acid classes of organic acids, examples of which include formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, 4-hydroxybenzoic, phenylacetic, mandelic, hippuric, malonic, oxalic, pamoic (pamoic) acid, methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, trifluoromethanesulfonic, 2-hydroxyethanesulfonic, p-toluenesulfonic, sulfanilic, cyclohexylaminosulfonic, stearic, alginic, β-hydroxybutyric, salicylic, -galactaric, and galacturonic acid.

[0075] Although pharmaceutically unacceptable salts are generally not useful as medicaments, such salts may be useful, for example, as intermediates in the synthesis of compounds having the structure of Formula I, for example, by purification by recrystallization.

[0076] In another embodiment, a method of treating a subject suffering from a MRGPR X4-dependent disorder is provided, the method comprising administering to the subject a pharmaceutically effective amount of a compound having the structure of Formula (I):

[0077]

[0078] or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof, wherein:

[0079] n is 0 or 1;

[0080] x is 0 or 1;

[0081] A is aryl or heteroaryl;

[0082] Q 1 and Q 2 All CR 10 , or Q 1 or Q 2 One of them is CR 10 and the other is N;

[0083] Z is -O-, -S-, -N(R 11 )-、-CH 2 -or-C≡C-;

[0084] Each R 10 is H or alkyl;

[0085] 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 ring, heterocyclic ring or carboxylic acid isostere;

[0086] m is 0 or 1;

[0087] R 11 , R 12 and R 13 are the same or different and individually are H or alkyl;

[0088] R 14 is H, and R 15 It is H, -SO 2 CH 3 , carbocyclic, heterocyclic or alkyl substituted by 0, 1, 2 or 3 substituents selected from the following: -OH, -CN, -NR'R", C(=O)OH, C(=O)NR'R", -SO 2 OH, alkoxy, carbocyclic or heterocyclic, wherein R' and R" are independently H or alkyl, or

[0089] R14 and R 15 Together with the nitrogen atom to which it is attached, it forms a heterocyclic ring;

[0090] R 1 is H or alkyl;

[0091] R 2 is a halide, a cyano group, an alkyl group, an alkoxy group, a carbocyclic ring or a heterocyclic ring;

[0092] R 3 , R 4 and R 5 are the same or different and are absent, or when present, are cyano, nitro, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, carbocycle, heterocycle, -O-carbocycle or -O-heterocycle, or

[0093] Any two R and R 2 Together with the atoms to which they are attached, they form a heterocyclic ring;

[0094] Any two R 3 , R 4 , R 5 and R 10 Together with the atoms to which they are attached, they form a carbocyclic or heterocyclic ring;

[0095] and wherein each occurrence of carbocycle or heterocycle is substituted with 0, 1, 2 or 3 substituents individually selected from the group consisting of halogen, oxy, halo, alkyl, haloalkyl, alkoxy, haloalkoxy, carbocycle or heterocycle.

[0096] As used herein, the phrase "MRGPR X4-dependent condition" means a condition in which the pathological condition is initiated, mediated, maintained or enhanced by activation, hypersensitization or desensitization of MRGPR X4 by a natural or synthetic ligand. For example, some itch or pain sensations are known to be caused by elevated bilirubin and its metabolites or bile acids in patients with pruritus, atopy 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 is understood that by modulating MRGPR X4, itch or pain sensations may be alleviated.

[0097] 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., cholic acid, 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 analog is a farnesoid X-receptor (FXR) agonist. Therefore, 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 which would benefit from modulation of MRGPR X4.

[0098] In some embodiments, the MRGPR X4-dependent disorder is an itch-related condition, a pain-related condition, an autoimmune condition or disorder, or an inflammatory disorder.

[0099] As used herein, the phrase "itch-related disorder" means pruritus associated with any condition (including acute pruritus and chronic pruritus). The itch sensation can originate, for example, from the peripheral nervous system (e.g., cutaneous or neuropathic pruritus) or from the central nervous system (e.g., neuropathic, neurogenic or psychogenic pruritus). Thus, in one embodiment, the methods of the invention are provided for treating pruritus-related conditions such as chronic pruritus; cholestatic pruritus; contact dermatitis; allergic blepharitis; anemia; atopic dermatitis; bullous pemphigoid; candidiasis; varicella; cholestasis; end-stage renal failure; hemodialysis; contact dermatitis; atopic dermatitis; dermatitis herpetiformis; diabetes; drug allergy; dry skin; dyshidrotic dermatitis; atopic eczema; erythrasma; folliculitis; fungal skin infections; hemorrhoids; herpes; HIV infection; Hodgkin's disease; hyperthyroidism; iron deficiency anemia; kidney disease; leukemia; porphyria; liver disease, including primary biliary cholangitis, primary sclerosing cholangitis, Alagille syndrome, syndrome, progressive familial intrahepatic cholestasis, intrahepatic cholestasis of pregnancy, nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), biliary atresia, chronic hepatitis B, drug-induced chronic viral hepatitis, DILI, liver fibrosis, cholestatic liver disease, and alcoholic liver disease; lymphoma; malignancies; multiple myeloma; neurodermatitis; onchocerciasis; Paget's disease; pediculosis; polycythemia vera; lichen planus; lichen sclerosus; pruritus ani; pseudorabies; psoriasis; rectal prolapse; scabies; schistosomiasis; scleroderma; severe stress; stasis dermatitis; swimmer's itch; thyroid disease; tinea cruris; uremic pruritus; rosacea; amyloidosis cutanea; scleroderma; acne; wound healing; ocular pruritus; and urticaria.

[0100] As used herein, the phrase "pain-related condition" means any pain due to a medical condition. Thus, in one embodiment, the methods of the invention are provided for treating pain-related conditions such as acute pain, advanced prostate cancer, AIDS-related pain, ankylosing spondylitis, arachnoiditis, arthritis, arthrofibrosis, ataxic cerebral palsy, autoimmune atrophic gastritis, avascular necrosis, back pain, Behcet's disease, burning mouth syndrome, bursitis, cancer pain, carpal tunnel, cauda equina syndrome, central pain syndrome, cerebral palsy, cervical spinal stenosis, Charcot-Marie-Tooth (CMT) disease, chronic fatigue syndrome (CFS), chronic functional abdominal pain (CFAP), chronic pain, chronic pancreatitis, collapsed lung (pneumothorax), complex regional pain syndrome (RSD), corneal neuropathic pain, Crohn's disease, degenerative disc disease, Dercum's disease, dermatomyositis, diabetic peripheral neuropathy (DPN), dystonia, Ehlers-Danlos syndrome (Ehlers-Danlos syndrome). Syndrome, EDS, endometriosis, eosinophilia-myalgia syndrome (EMS), erythromelalgia, fibromyalgia, gout, headache, herniated disc, hydrocephalus, intercostal neuralgia, interstitial cystitis, irritable bowel syndrome (IBS), juvenile dermatositis, knee injury, leg pain, low back pain and hematuria syndrome, lupus, Lyme disease, medullary sponge kidney (MSK), meralgia paresthesia, mesothelioma, migraine, musculoskeletal pain, myofascial pain, myositis, neck pain, neuropathic pain, occipital neuralgia, osteoarthritis, Paget's disease, Parsonage-Turner syndrome syndrome), pelvic pain, peripheral neuropathy, phantom limb pain, nerve compression, polycystic kidney disease, polymyalgia rheumatica, polymyositis, porphyria, post-herniorrhagic 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, Scheuemann's kyphosis disease, sciatica, scoliosis, shingles,Herpes Zoster, Sjogren's syndrome, spasmodic torticollis, sphincter of Oddidysfunction, spinocerebellar ataxia (SCA ataxia), spinal cord injury, spinal stenosis, syringomyelia, Tarlov cysts, transverse myelitis, trigeminal neuralgia, neuropathic pain, ulcerative colitis, vascular pain, or vulvar pain.

[0101] As used herein, the term "autoimmune disorder" or "inflammatory disorder" means a disease or disorder caused by and / or directed against an individual's own tissues or organs, or a co-segregation or manifestation thereof, or a condition resulting therefrom. Typically, various clinical and laboratory markers of autoimmune diseases 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 therapy, and lymphocyte aggregates in affected tissues. Thus, in one embodiment, the methods of the invention are provided for treating autoimmune disorders such as chronic inflammation, multiple sclerosis, Steven Johnson's syndrome, appendicitis, bursitis, colitis, cystitis, dermatitis, phlebitis, reflex sympathetic dystrophy / complex regional pain syndrome (rsd / crps), rhinitis, tendinitis, tonsillitis, acne vulgaris, reactive airway disorders, asthma, airway infections, autoinflammatory diseases, celiac disease, chronic prostatitis, diverticulitis, glomerulonephritis, hidradenitis suppurativa, allergies, intestinal disorders, epithelial intestinal disorders, 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, lung inflammation, chronic obstructive pulmonary disease, cardiovascular disease, and vasculitis.

[0102] As used herein, the term "administering" refers to providing a compound as described herein or a pharmaceutical composition comprising the compound. The compound or composition can be administered to a subject by another person, or the device can be administered by the subject himself. Non-limiting examples of routes of administration are oral, parenteral (e.g., intravenous), or topical.

[0103] As used herein, the term "treatment" refers to the intervention of signs or symptoms that improve a disease or pathological condition. As used herein, the terms "treatment", "treat" and "treating" with respect to a disease, pathological condition or symptom also refer to any observable beneficial effect of treatment. Beneficial effects can be demonstrated, for example, by delayed onset of clinical symptoms of a disease in susceptible subjects, reduced severity of some or all clinical symptoms of the disease, a slowed progression of the disease, a reduced number of recurrences of the disease, an improvement in the overall health or well-being of the subject, or by other parameters that are well known in the art and specific to a particular disease. Preventive treatment is the treatment administered to a subject who does not show signs of disease or only shows early signs, with the aim of reducing the risk of pathology. Therapeutic treatment is the treatment given to a subject after the signs and symptoms of the disease appear.

[0104] As used herein, the term "subject" refers to an animal (e.g., a mammal, such as a human). A subject to be treated according to the methods described herein can be a subject that has been diagnosed with a 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 appreciate that a subject to be treated according to the present disclosure may have undergone standard testing, or may have been identified without examination as being at risk due to the presence of one or more risk factors associated with a disease or condition.

[0105] In another embodiment, the methods described herein for treating a subject having a MRGPR X4-dependent condition (e.g., an itch-related condition, a pain-related condition, an autoimmune condition, or an autoimmune disorder) further comprise 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 liver disease therapeutic agent is ursodeoxycholic acid (UDCA), norursodeoxycholic acid, cholestyramine, stanozolol, naltrexone, rifampicin, alismatol B 23-acetate (AB23A), curcumin, dihydroartemisinin, fenofibrate, bezafibrate, metronidazole, methotrexate, colchicine, metformin, betaine, glucagon, naltrexone, farnesoid X-receptor (FXR) agonist, peroxisome proliferator-activated receptor (PPAR) agonist, thyroid hormone receptor β (TRβ) agonist or any combination thereof.

[0106] Examples of FXR agonists that can be used in the methods described herein include obeticholic acid, turofexorate isopropyl (WAY-362450), 3-(2,6-dichlorophenyl)-4-(3'-carboxy-2-chlorostilbene-4-yl)oxymethyl-5-isopropylisoxazole (GW4064), PX20606 (PX-102), PX-101, INT-767, INT-787, TERN-101, altenusin, tropifexor (LJN452), nidufexor, turofexorate 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. In one embodiment, the FXR agonist is a bile acid or an analog thereof (e.g., obeticholic acid, INT-767, INT-787, BAR502, herzognic acid, or BAR704) or a non-bile acid agonist (e.g., EDP-305, tropifil, nidofil, zrofil, GW4064, tropilide isopropyl, fexamine, PX20606 (PX-102), TERN-101, silymarin, silybin, EYP-001, RDX023-2, AGN-242266, HPG-1860, MET-409, EP-024297, M-480, or cafestol).

[0107] In one embodiment, the PPAR agonist is a PPAR-α agonist, a PPAR-γ agonist, a PPAR-δ agonist, a PPAR-α / γ dual agonist, a PPARα / δ dual agonist, a PPARγ / δ dual agonist, or a PPARα / γ / δ pan agonist.

[0108] Examples of PPARα agonists that can be used in the methods described herein include fenofibrate, ciprofibrate, pemafibrate, gemfibrozil, clofibrate, binifibrate, clinofibrate, clofibric acid, nicofibrate, pirifibrate, plafibride, ronifibrate, theofibrate, tocofibrate, or SRI 0171.

[0109] Examples of PPARγ 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-levorotatory, CLC-3001, or ALL-4.

[0110] Examples of PPARδ 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-ylmethylsulfanyl]-phenoxy}-acetic acid), GW0742 ([4-[[[2-[3-fluoro-4-(trifluoromethyl)phenyl]-4-methyl-5-thiazolyl]methyl]thio]-2-methylphenoxy]acetic acid), L165041, HPP-593, and NCP-1046.

[0111] Examples of PPAR alpha / gamma agonists that can be used in the methods described herein include saroglitazar, aleglitazar, muraglitazar, tesaglitazar, or DSP-8658.

[0112] Examples of PPAR alpha / delta agonists that can be used in the methods described herein include elafibranor or T913659.

[0113] Examples of PPARγ / δ agonists that can be used in the methods described herein include conjugated linoleic acid (CLA) or T3D-959.

[0114] Examples of PPARα / γ / δ agonists that can be used in the methods described herein include IVA337 (lanifibranor), TTA (tetradecylthioacetic acid), bavachinin, GW4148, GW9135, bezafibrate, lobeglitazone, 2-(4-(5,6-methylenedioxybenzo[d]thiazol-2-yl)-2-methylphenoxy)-2-methylpropanoic acid (MHY2013) and CS038.

[0115] 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-oxido-[1,3,2]-dioxaphosphinane).

[0116] 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.

[0117] In another embodiment, a method for treating a subject suffering from an itch-related condition is provided, the method comprising administering to the subject a pharmaceutically effective amount of a compound and a pharmaceutical composition thereof, the compound having a structure of formula (I), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof. In one embodiment, the itch-related condition is cholestatic pruritus, uremic pruritus, atopic dermatitis, dry skin, psoriasis, contact dermatitis or eczema.

[0118] In one embodiment of formula (I), n is 1, R 1 is H, Z is O, R is -C(=O)OR 12 , and the compound has the structure of formula (II):

[0119]

[0120] or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof, wherein x, A, Q 1 , Q 2 , R 2 , R 3 , R 4 , R 5 and R 12 As defined above.

[0121] In one embodiment of Formula (I), n is 0, Z is O, and the compound has the structure of Formula (III):

[0122]

[0123] or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof, wherein x, A, Q 1 , Q 2 , R 2 , R 3 , R 4 , R 5 and R 12 As defined above.

[0124] In one embodiment of formula (II), x is 0, and the compound has the structure of formula (IV):

[0125]

[0126] or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof, wherein A, Q 1 , Q 2 , R 3 , R 4 , R 5 and R 12 As defined above.

[0127] In one embodiment of Formula (II), x is 1, and the compound has the structure of Formula (V):

[0128]

[0129] or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof, wherein A, Q 1 , Q 2 , R 2 , R 3 , R 4 , R 5 and R 12As defined above.

[0130] In one embodiment of Formula (III), x is 0, and the compound has the structure of Formula (VI):

[0131]

[0132] or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof, wherein x, A, Q 1 , Q 2 , R 3 , R 4 , R 5 and R 12 As defined above.

[0133] In one embodiment of Formula (III), x is 1, and the compound has the structure of Formula (VII):

[0134]

[0135] or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof, wherein x, A, Q 1 , Q 2 , R 2 , R 3 , R 4 , R 5 and R 12 As defined above.

[0136] In another embodiment, when R in each of formulas (II) to (VII) is 12 When is hydrogen, the resulting carboxylic acid group (-COOH) is replaced by a carboxylic acid isostere as defined herein.

[0137] In one embodiment of formula (I), n is 1, R 1 is H, Z is O, R is -(C=O)NHR 15 、-CH 2 OH, -CH 2 NH 2 or -CN, and the compound has the structure of Formula (VIII), (IX), (X) or (XI) below, respectively:

[0138]

[0139] or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof, wherein x, A, Q 1 , Q 2 , R 2 , R 3 , R4 , R 5 and R 15 As defined above.

[0140] In one embodiment of formula (I), n is 0, Z is O, and R is -(C=O)NHR 15 、-CH 2 OH, -CH 2 NH 2 or -CN, and the compound has the structure of Formula (XII), (XIII), (XIV) or (XV) below, respectively:

[0141]

[0142] or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof, wherein x, A, Q 1 , Q 2 , R 2 , R 3 , R 4 , R 5 and R 15 As defined above.

[0143] In one embodiment of Formula (I), Z is -S-, -N(R 11 )-、-CH 2 - or -C≡C-, and the compound has the structure of Formula (XVI), (XVII), (XVIII) or (IX) below, respectively:

[0144]

[0145] or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof, wherein n, x, A, Q 1 , Q 2 , R, R 1 , R 2 , R 3 , R 4 , R 5 and R 11 As defined above.

[0146] In one embodiment of any one of Formulae (I) to (XIX), A is aryl.

[0147] In one embodiment of any one of Formulas (I) to (XIX), A is phenyl.

[0148] In one embodiment of any one of Formulas (I) to (XIX), A is a phenyl group having the following points of attachment:

[0149]

[0150] In one embodiment of any one of Formulae (I) to (XIX), A is heteroaryl.

[0151] In one embodiment of any one of Formulae (I) to (XIX), A is pyridine or pyrazine.

[0152] In one embodiment of any one of Formulae (I) to (XIX), A is pyridine or pyrazine having the following attachment points, respectively:

[0153]

[0154] In one embodiment of any one of Formulae (I) to (XIX), A is furan, thiophene, or isoxazole.

[0155] In one embodiment of any one of Formulae (I) to (XIX), A is furan, thiophene, or isoxazole, respectively, having the following points of attachment:

[0156]

[0157] In one embodiment of any one of Formulas (I) to (XIX), Q 1 and Q 2 All are CH.

[0158] In one embodiment of any one of Formulas (I) to (XIX), Q 1 is CH and Q 2 It is N.

[0159] In one embodiment of any one of Formulas (I) to (XIX), Q 1 is N and Q 2 It is CH.

[0160] In one embodiment of any one of Formulae (I) to (XIX), R 1 It's hydrogen.

[0161] In one embodiment of any one of Formulae (I) to (XIX), R 1 It is an alkyl group.

[0162] In one embodiment of any one of Formulae (I) to (XIX), R 1 It's methyl.

[0163] In one embodiment of Formula (I), the compound has the structure of Formula (XX):

[0164]

[0165] or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof, wherein x, R 2 , R 3 , R 4 , R 5 and R 12 As defined above.

[0166] In one embodiment of Formula (I), the compound has the structure of Formula (XXI):

[0167]

[0168] or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof, wherein R 3 , R 4 , R 5 and R 12 As defined above.

[0169] In one embodiment of Formula (I), the compound has the structure of Formula (XXII):

[0170]

[0171] or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof, wherein R 2 , R 3 , R 4 , R 5 and R 12 As defined above.

[0172] In another embodiment, when R in each of the above formulae (XX) to (XXII) is 12 When is hydrogen, the resulting carboxylic acid group (-COOH) is replaced by a carboxylic acid isostere as defined herein.

[0173] In one embodiment of Formula (I), the compound has the structure of Formula (XXIII):

[0174]

[0175] or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof, wherein R 3 , R 4 and R 5 As defined above.

[0176] In one embodiment of Formula (I), the compound has the structure of Formula (XXIV):

[0177]

[0178] or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof, wherein R 2 , R 3 , R 4 and R 5 As defined above.

[0179] In another embodiment, the carboxylic acid group (—COOH) of each of Formulas (XXIII) and (XXIV) above is replaced with a carboxylic acid isostere as defined herein.

[0180] In one embodiment of any one of Formulae (I) to (XXIV), n is 0.

[0181] In one embodiment of any one of Formulae (I) to (XXIV), n is 1.

[0182] In one embodiment of any one of Formulae (I) to (XXIV), x is 0.

[0183] In one embodiment of any one of Formulae (I) to (XXIV), x is 1.

[0184] In one embodiment of any one of Formulae (I) to (XXIV), x is 2.

[0185] In one embodiment of any one of Formulas (I) to (XXIV), A is aryl.

[0186] In one embodiment of any one of Formulas (I) to (XXIV), A is heteroaryl.

[0187] In one embodiment of any one of Formulae (I) to (XXIV), Z is -O-.

[0188] In one embodiment of any one of Formulae (I) to (XXIV), Z is -S-.

[0189] In one embodiment of any one of Formulae (I) to (XXIV), Z is -N(R 11 )-.

[0190] In one embodiment of any one of Formulae (I) to (XXIV), Z is -CH 2 -.

[0191] In one embodiment of any one of Formulae (I) to (XXIV), Z is or -C≡C-.

[0192] In one embodiment of any one of Formulae (I) to (XXIV), R is -(CH 2 ) m C(=O)OR12 .

[0193] In one embodiment of any one of Formulae (I) to (XXIV), R is -(CH 2 ) m NHR 13 .

[0194] In one embodiment of any one of formulae (I) to (XXIV), R is -(C=O)NR 14 R 15 .

[0195] In one embodiment of any one of Formulae (I) to (XXIV), Z is -CH 2 OH.

[0196] In one embodiment of any one of Formulae (I) to (XXIV), R is -CN.

[0197] In one embodiment of any one of Formulas (I) to (XXIV), R is haloalkyl.

[0198] In one embodiment of any one of Formulae (I) to (XXIV), R is a carbocyclic ring.

[0199] In one embodiment of any one of Formulae (I) to (XXIV), R is a heterocycle.

[0200] In one embodiment of any one of Formulae (I) to (XXIV), m is 0.

[0201] In one embodiment of any one of Formulae (I) to (XXIV), m is 1.

[0202] In one embodiment of any one of Formulae (I) to (XXIV), R 14 is H, and R 15 It is H, -SO 2 CH 3 , carbocyclic, heterocyclic or alkyl substituted by 0, 1, 2 or 3 substituents selected from the following: -OH, -CN, -NR'R", C(=O)OH, C(=O)NR'R", -SO 2 OH, alkoxy, carbocycle or heterocycle, wherein R' and R" are independently H or alkyl.

[0203] In one embodiment of any one of Formulae (I) to (XXIV), R 14 and R 15 Together with the nitrogen atom to which it is attached, it forms a heterocyclic ring.

[0204] In one embodiment of any one of Formulae (I) to (XXIV), R 1It's H.

[0205] In one embodiment of any one of Formulae (I) to (XXIV), R 1 It is an alkyl group.

[0206] In one embodiment of any one of Formulae (I) to (XXIV), R 2 It is halogenated.

[0207] In one embodiment of any one of Formulae (I) to (XXIV), R 2 It's cyano.

[0208] In one embodiment of any one of Formulae (I) to (XXIV), R 2 It's amino.

[0209] In one embodiment of any one of Formulae (I) to (XXIV), R 2 It is an alkyl group.

[0210] In one embodiment of any one of Formulae (I) to (XXIV), R 2 It is an alkoxy group.

[0211] In one embodiment of any one of Formulae (I) to (XXIV), R 2 It is a carbon ring.

[0212] In one embodiment of any one of Formulae (I) to (XXIV), R 2 It is a heterocycle.

[0213] In one embodiment of any one of Formulae (I) to (XXIV), R 3 , R 4 and R 5 are the same or different and are absent or, when present, are cyano, cyanoalkyl, nitro, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, -(C=O)alkyl, -(C=O)NHalkyl, carbocycle, heterocycle, -O-carbocycle or -O-heterocycle.

[0214] In one embodiment of any one of Formulae (I) to (XXIV), R 3 , R 4 and R 5 are the same or different and are absent or, when present, are cyano, nitro, halogen, alkyl, haloalkyl, alkoxy or haloalkoxy.

[0215] In one embodiment of any one of Formulae (I) to (XXIV), R 3 , R 4 and R 5The same or different and not present, or when present, -CN, -NO 2 , -F, -Cl, -Br, -CH 3 , -CF 3 , -CHF 2 、-C(CH 3 ) 3 、-OCH 3 or -OCF 3 .

[0216] In one embodiment of any one of Formulae (I) to (XXIV), R 3 , R 4 and R 5 Any two of the carbonyl groups together with the atoms to which they are attached form a carbocyclic or heterocyclic ring, which is unsubstituted or substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, hydroxy, oxo, halo, alkyl, haloalkyl, alkoxy, haloalkoxy, carbonyl group or heterocyclic ring.

[0217] In one embodiment of any one of Formulae (I) to (XXIV), R 3 and R 4 Together with the atoms to which it is attached, it forms a heterocyclic ring as shown below, which is unsubstituted or substituted by 1, 2 or 3 substituents independently selected from the following: halogen, hydroxy, oxo, halo, alkyl, haloalkyl, alkoxy, haloalkoxy, carbocyclic ring or heterocyclic ring:

[0218]

[0219] In one embodiment of any one of Formulae (I) to (XXIV), R 3 and R 4 Together with the atoms to which it is attached, it forms a carbocyclic ring as shown below, which is unsubstituted or substituted by 1, 2 or 3 substituents independently selected from the following: halogen, oxy, halo, alkyl, haloalkyl, alkoxy, haloalkoxy, carbocyclic ring or heterocyclic ring:

[0220]

[0221] Where applicable, representative compounds of formula (I) and formula (II) to (XXIV) include any of the compounds listed 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 corresponding "compound number", sometimes abbreviated as "compound number" or "compound number (Cpd. No.)".

[0222] Table A

[0223] Representative compounds

[0224]

[0225]

[0226]

[0227]

[0228]

[0229]

[0230]

[0231]

[0232]

[0233]

[0234]

[0235]

[0236]

[0237]

[0238]

[0239]

[0240]

[0241]

[0242]

[0243]

[0244]

[0245]

[0246]

[0247] In more specific embodiments, the compound has the following structure or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof:

[0248]

[0249] In more specific embodiments, the compound has the following structure or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof:

[0250]

[0251] In more specific embodiments, the compound has the following structure or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof:

[0252]

[0253] In more specific embodiments, the compound has the following structure or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof:

[0254]

[0255] In more specific embodiments, the compound has the following structure or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof:

[0256]

[0257] In more specific embodiments, the compound has the following structure or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof:

[0258]

[0259] In more specific embodiments, the compound has the following structure or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof:

[0260]

[0261] In more specific embodiments, the compound has the following structure or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof:

[0262]

[0263] In more specific embodiments, the compound has the following structure or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof:

[0264]

[0265] In more specific embodiments, the compound has the following structure or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof:

[0266]

[0267] In more specific embodiments, the compound has the following structure or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof:

[0268]

[0269] In more specific embodiments, the compound has the following structure or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof:

[0270]

[0271] In more specific embodiments, the compound has the following structure or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof:

[0272]

[0273] In more specific embodiments, the compound has the following structure or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof:

[0274]

[0275] In more specific embodiments, the compound has the following structure or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof:

[0276]

[0277] In more specific embodiments, the compound has the following structure or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof:

[0278]

[0279] In more specific embodiments, the compound has the following structure or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof:

[0280]

[0281] In more specific embodiments, the compound has the following structure or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof:

[0282]

[0283] In another embodiment, where applicable, certain compounds of formula (I) and formula (II) to (XXIV) may have their carboxylic acid moieties substituted with carboxylic acid isosteric groups, as described herein. Representative carboxylic acid isosteric compounds derived from the representative compounds listed in the table below are presented in Table B.

[0284]

[0285] For this purpose, the carboxylic acid isostere groups used for the compounds of Table B are as follows:

[0286]

[0287] Table B

[0288] Representative carboxylic acid isostere compounds

[0289]

[0290]

[0291]

[0292]

[0293] In other embodiments, prodrugs and / or metabolites of compounds of Formula (I) and Formulas (II) to (XXIV) are provided.

[0294] Therefore, in one embodiment, there is provided a prodrug of a compound of the present invention, which, after being applied to a subject, is chemically transformed into an active pharmacological substance by metabolism or other physiological processes. The conversion by metabolism or other physiological processes includes but is not limited to the enzymatic (e.g., specific enzymatic catalysis) and non-enzymatic (e.g., general or specific acid or base induction) chemical conversion of prodrugs to active pharmacological substances. Generally speaking, such prodrugs will be functional derivatives of the compounds of the present invention, which are easily converted into compounds of the present invention in vivo. The conversion procedures for selecting and preparing suitable prodrug derivatives are described in, for example, "Prodrug Design (Design of Prodrugs)", edited by H.Bundgaard, Elsevier Press (Elsevier), 1985.

[0295] Therefore, a "prodrug" is a substance that, after being administered to a subject, is converted into an active pharmaceutical ingredient in vivo by the action of biochemical substances (such as enzymes) in the subject. 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 that can be administered to a subject is provided, which is then converted in the subject to obtain a compound having a structure of any one of formula (I) or formula (II) to (XXIV).

[0296] In this regard, the prodrugs of carboxylic acids are typically esters and amides, which can be easily prepared by the corresponding carboxylic acids by known techniques. For example, in one embodiment, the prodrug can be generated by converting the carboxylic acid moiety of the compound of formula (I) to (VII) and (XVI) to (XXIV) into the following ester functional group: comprising alkyl esters, such as methyl, ethyl, isopropyl and n-butyl esters; aryl esters, such as phenyl and indanyl esters; diesters, such as (acyloxy) alkyl or [(alkoxycarbonyl) oxy] methyl esters; and cyclic carbonates, such as (oxydioxo) methyl esters. In another embodiment, the carboxylic acid moiety can be combined with carbamoylmethyl, aminoalkyl or amidoalkyl moieties to provide carbamoylmethyl, aminoalkyl and amidoalkyl esters, respectively. In yet another embodiment, the carboxylic acid moiety can be combined with esters of acylglycerol and bis(acyl-amino) propan-2-ol. In a further embodiment, the carboxylic acid moiety can be combined with amide groups, comprising N-hydroxyamides, N-acylsulfonamides and N-acylsulfonylureas.

[0297] As used herein, "metabolites" are compounds that are converted in the subject to produce active substances after administration to the subject. Such conversions typically involve hydrolysis, phosphorylation, and / or oxidation / reduction processes and may be mediated by any number of enzymes (e.g., esterases, phosphatases, cytochrome P450, etc.) and different environments in the body (e.g., changes in pH).

[0298] In one embodiment, where applicable, compounds of formula (I) and (II) to (XXII) are modified to encompass metabolites of the parent compound. In another embodiment, compounds of formula (I) and (II) to (XXII) are modified to have the "A ring" carboxylic acid of formula (I) derivatized with a carbohydrate or amino acid compound. In additional embodiments, the A-ring carboxylic acid moiety is derivatized with glucuronic acid or the amino acid glycine to provide compounds of formula (XXV) and (XXVI), respectively:

[0299]

[0300] In certain embodiments, the present invention provides a pharmaceutical composition comprising a compound of any one of formula (I) to (XIV) and at least one pharmaceutically acceptable carrier, diluent or excipient. For example, the active compound is typically mixed with a carrier or diluted by a carrier or encapsulated in a carrier, and the carrier 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 is used as a diluent, the carrier may be a solid, semisolid or liquid material that serves as a vehicle, excipient or medium for the active compound. The active compound may be adsorbed on a granular solid carrier, such as contained in a sachet. Some examples of suitable carriers are water, saline solution, alcohol, polyethylene glycol, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatin, lactose, clay, sucrose, dextrin, magnesium carbonate, sugar, cyclodextrin, straight-chain starch, magnesium stearate, talc, gelatin, agar, pectin, gum arabic, lower alkyl ethers of stearic acid or cellulose, silicic acid, fatty acid, fatty acid amine, fatty acid monoglyceride and diglyceride, pentaerythritol fatty acid ester, polyoxyethylene, hydroxymethylcellulose and polyvinylpyrrolidone. Similarly, the carrier or diluent can include any sustained-release material known in the art such as glyceryl monostearate or glyceryl distearate, either alone or mixed with wax.

[0301] As used herein, the term "pharmaceutical composition" refers to a composition containing one or more of the compounds described herein or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof, formulated with a pharmaceutically acceptable carrier, which may also contain other additives, and is manufactured or sold with the approval of a governmental regulatory agency as part of a therapeutic regimen for treating a mammalian disease. The pharmaceutical composition may be formulated, for example, for oral administration in a unit dosage form (e.g., tablets, capsules, caplets, soft gels or syrups); for topical administration (e.g., as a cream, gel, lotion or ointment); for intravenous administration (e.g., as a sterile solution without particle plugs and a solvent system suitable for intravenous use); or in any other formulation described herein. Conventional procedures and ingredients for selecting and preparing suitable formulations are described, for example, in Remington: The Science and Practice of Pharmacy, 21st edition, Gennaro ed., Lippencott Williams & Wilkins (2005) and The United States Pharmacopeia: The National Formulary (USP 36NF31), published in 2013.

[0302] In some embodiments, the pharmaceutical composition includes a compound of any one of formula (I) to (XIV) and at least one pharmaceutically acceptable carrier, diluent or excipient, and the pharmaceutical composition further comprises a second therapeutic agent. In one embodiment, the second therapeutic agent is a liver disease therapeutic agent. In one embodiment, the liver disease therapeutic agent is ursodeoxycholic acid (UDCA), norursodeoxycholic acid, cholestyramine, stanozolol, naltrexone, rifampicin, alismatol B 23-acetate (AB23A), curcumin, dihydroartemisinin, fenofibrate, bezafibrate, metronidazole, methotrexate, colchicine, metformin, betaine, glucagon, naltrexone, farnesoid X-receptor (FXR) agonist, peroxisome proliferator-activated receptor (PPAR) agonist, thyroid hormone receptor β (TRβ) agonist or any combination thereof.

[0303] Examples of FXR agonists that can be used in the pharmaceutical compositions described herein include obeticholic acid, trofibride isopropyl (WAY-362450), 3-(2,6-dichlorophenyl)-4-(3'-carboxy-2-chlorostilbene-4-yl)oxymethyl-5-isopropylisoxazole (GW4064), PX20606 (PX-102), PX-101, INT-767, INT-787, TERN-101, tricholamine, tropifil (LJN452), nidofil, Troferid isopropyl, phenoxamine, silymarin, silybin, herzognic acid, cafestol, zlofil (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 an analog thereof (e.g., obeticholic acid, INT-767, INT-787, troferidopropyl (WAY-362450) or BAR704) or a non-bile acid agonist (e.g., EDP-305, tropifil, nidofil, zrofil, GW4064, troferidopropyl, fexamine, PX20606 (PX-102), TERN-101, silymarin, silybin, herzognic acid, BAR502, EYP-001, RDX023-2, AGN-242266, HPG-1860, MET-409, EP-024297, M-480 or cafestol).

[0304] In one embodiment, the PPAR agonist is a PPAR-α agonist, a PPAR-γ agonist, a PPAR-δ agonist, a PPAR-α / γ dual agonist, a PPARα / δ dual agonist, a PPARγ / δ dual agonist, a PPARα / γ / δ pan agonist, or any combination thereof.

[0305] Examples of PPARα agonists that can be used in the pharmaceutical compositions described herein include fenofibrate, ciprofibrate, pemafibrate, gemfibrozil, clofibrate, binifibrate, clinfibrate, clofibric acid, nicofibrate, pilifibrate, prafibride, ronifibrate, terfibrate, tocofibrate, or SRI 0171.

[0306] Examples of PPARγ agonists that can be used in the pharmaceutical compositions described herein include rosiglitazone, pioglitazone, deuterium-stabilized R-pioglitazone, ivaglitazone, ATx08-001, OMS-405, CHS-131, THR-0921, SER-150-DN, KDT-501, GED-0507-34-levorotatory, CLC-3001, or ALL-4.

[0307] Examples of PPARδ agonists that can be used in the pharmaceutical compositions described herein include GW501516 (Anthurab or ({4-[({4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}acetic acid)), MBX8025 (Ceradelpa or {2-methyl-4-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethylsulfanyl]-phenoxy}-acetic acid), GW0742 ([4-[[[2-[3-fluoro-4-(trifluoromethyl)phenyl]-4-methyl-5-thiazolyl]methyl]thio]-2-methylphenoxy]acetic acid), L165041, HPP-593, and NCP-1046.

[0308] Examples of PPAR alpha / gamma agonists that can be used in the pharmaceutical compositions described herein include sarolitazar, aleglitazar, muraglitazar, teglitazar, or DSP-8658.

[0309] Examples of PPAR alpha / delta agonists that can be used in the pharmaceutical compositions described herein include elafibrano or T913659.

[0310] Examples of PPAR gamma / delta agonists that can be used in the pharmaceutical compositions described herein include conjugated linoleic acid (CLA) or T3D-959.

[0311] Examples of PPARα / γ / δ agonists that can be used in the pharmaceutical compositions described herein include IVA337 (lanifebrano), TTA (tetradecylthioacetic acid), methyl psoralen, GW4148, GW9135, bezafibrate, lobeglitazone, 2-(4-(5,6-methylenedioxybenzo[d]thiazol-2-yl)-2-methylphenoxy)-2-methylpropanoic acid (MHY2013) and CS038.

[0312] Examples of thyroid hormone receptor beta agonists that can be used in the pharmaceutical compositions described herein include subitero, ilotero, GC-24, MGL-3196, MGL-3745, VK-2809, KB141 [3,5-dichloro-4-(4-hydroxy-3-isopropylphenoxy)phenylacetic acid], and MB07811 ((2R,4S)-4-(3-chlorophenyl)-2-[(3,5-dimethyl-4-(4'-hydroxy-3'-isopropylbenzyl)phenoxy)methyl]-2-oxido-[1,3,2]-dioxaphosphinane).

[0313] As used herein, the term "pharmaceutically acceptable carrier" refers to any component other than a disclosed compound or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof (e.g., a carrier capable of suspending or dissolving the active compound) and has the properties of being non-toxic and non-inflammatory to the patient. Excipients may include, for example: anti-adherents, antioxidants, binders, coatings, compression aids, disintegrants, dyes (colorants), emollients, emulsifiers, fillers (diluents), film formers or coatings, flavorings, fragrances, glidants (flow enhancers), lubricants, preservatives, printing inks, adsorbents, suspending or dispersing agents, sweeteners or water of hydration. Exemplary excipients include, but are not limited to, butylated hydroxytoluene (BHT), calcium carbonate, calcium phosphate (dibasic), calcium stearate, cross-linked carboxymethylcellulose, cross-linked polyvinyl pyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methylparaben, microcrystalline cellulose, polyethylene glycol, polyvinyl pyrrolidone, 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.

[0314] The formulation may be mixed with auxiliary agents that do not react adversely with the active compound. Such additives may include wetting agents, emulsifiers and suspending agents, salts that affect osmotic pressure, buffers and / or coloring substances, preservatives, sweeteners or flavoring agents. If desired, the composition may also be sterilized.

[0315] The route of administration can be any route that effectively transports the active compound of the 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.

[0316] The dosage form can be administered once a day, or more than once a day, such as twice or three times a day. Alternatively, if the prescribing physician or the prescription information of the drug considers it desirable, the dosage form can be administered at a frequency shorter than that of a day, such as once every other day or once a week. The dosage regimen includes, for example, titrating the dose to the required or useful degree for the indication to be treated, so that the patient's body adapts to the treatment, to minimize or avoid unwanted side effects associated with the treatment, and / or to maximize the therapeutic effect of the compounds of the invention. Other dosage forms include delayed or controlled release forms. Suitable dosage regimens and / or forms include, for example, those listed in the latest version of the Physicians' Desk Reference, which is incorporated herein by reference.

[0317] In one embodiment, the present invention provides an oral pharmaceutical composition comprising a compound of any one of formula (I) to (XXIV) and at least one pharmaceutically acceptable oral carrier, diluent or excipient. In another embodiment, the present invention provides a topical pharmaceutical composition comprising a compound of any one of formula (I) to (XXIV) and at least one pharmaceutically acceptable topical carrier, diluent or excipient. For example, an oral pharmaceutical composition is provided for the treatment of cholestatic pruritus, wherein the dosage regimen is, for example, once a day. In one embodiment, a topical pharmaceutical composition is provided for the treatment of atopic dermatitis.

[0318] In another embodiment, a method for preparing a composition of a compound described herein is provided, the method comprising formulating a compound of the 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 may further comprise the step of 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 the step of lyophilizing the composition to form a lyophilized formulation.

[0319] In certain embodiments, the present invention provides compounds having the structure of any one of formula (I) to (XXIV). Such compounds can be synthesized using standard synthesis techniques known to those skilled in the art. For example, the compounds of the present invention can be synthesized using the appropriately modified synthesis procedures described in the following examples and reaction schemes. To this end, standard synthesis techniques known to those skilled in the art can also be used to achieve carboxylic acid isosteres and substituents thereof that replace the carboxylic acids disclosed herein.

[0320] For this reason, the reactions, processes and synthetic methods described herein are not limited to the specific conditions described in the following experimental section, but are intended to be used as guidance to a suitable technician in the field. For example, the reaction can be carried out in any suitable solvent or other reagent to carry out the necessary conversion. Generally, a suitable solvent is a protic or aprotic solvent that does not react with reactants, intermediates or products at a temperature (i.e., a temperature that can be frozen to a boiling temperature range) for the reaction. A given reaction can be carried out in a solvent or a mixture of more than one solvent. Depending on the specific reaction, a suitable solvent for specific post-treatment after the reaction can be used.

[0321] All reagents that the experimental section does not describe the synthesis are commercially available, or are known compounds, or can be formed from known compounds by known methods by those skilled in the art. The compounds and intermediates produced according to the method of the present invention may need to be purified. The purification of organic compounds is well known to those skilled in the art, and there may be several methods to purify the same compound. In some cases, purification may not be required. In some cases, the compound can be purified by crystallization. In some cases, impurities can be stirred out using a suitable solvent. In some cases, the compound can be purified by chromatography, specifically flash column chromatography, using a special or pre-loaded silica gel column and an eluent such as a solvent gradient, such as heptane, ether, ethyl acetate, acetonitrile, ethanol, etc. In some cases, the compound can be purified by preparative HPLC using a method as described herein.

[0322] The purification methods as described herein can provide compounds of the invention having sufficient basic or acidic functionality in the form of salts, such as trifluoroacetate or formate salts in the case of sufficiently basic compounds of the invention, or ammonium salts in the case of sufficiently acidic compounds of the invention. Salts of this type can be converted to their free base or free acid forms, respectively, by various methods known to those skilled in the art, or used as salts in subsequent bioassays. It should be understood that a particular form of a compound of the invention as isolated and as described herein is not necessarily the only form in which the compound can be used in a bioassay to quantify a particular biological activity.

[0323] Chemical names were generated using ChemDraw nomenclature software (version 17.0.0.206) from PerkinElmer Informatics, Inc. In some cases, generally accepted commercially available reagent names were used in place of names generated by the nomenclature software.

[0324] Examples

[0325] General approach

[0326] 1 H NMR (400 MHz) spectra were obtained in deuterated chloroform (CDCl3), deuterated methanol (CD3OD), or dimethyl sulfoxide-D6 (DMSO) solutions. HPLC retention time, purity, and mass spectra (LCMS) were obtained using one of the following methods:

[0327] Method 1 Agilent 1260 Infinity II system equipped with an Agilent Poroshell 120EC-18, 2.7 μm, 4.6 × 100 mm column was used with 0.1% formic acid in HO. 2 O was used as mobile phase A, and MeCN containing 0.1% formic acid was used as mobile phase B. The ESI detector in positive mode was used. The gradient was 20-95% mobile phase B in 5 minutes, then maintained at 95% for 3.8 minutes, and then returned to 20% mobile phase B in 0.2 minutes. The flow rate was 1 ml / min.

[0328] Method 2 Agilent 1260 Infinity II system equipped with an Agilent Poroshell 120EC-18, 2.7 μm, 4.6 × 100 mm column was used with 0.1% formic acid in HO. 2 O was used as mobile phase A, and MeCN containing 0.1% formic acid was used as mobile phase B. The ESI detector in negative mode was used. The gradient was 20-95% mobile phase B in 5 minutes, then held at 95% for 3.8 minutes, and then returned to 20% mobile phase B in 0.2 minutes. The flow rate was 1 ml / min.

[0329] Method 3 Agilent 1260 Infinity II system equipped with an Agilent Poroshell 120EC-18, 2.7 μm, 4.6 × 100 mm column was used with 0.1% formic acid in HO. 2 O was used as mobile phase A, and MeCN containing 0.1% formic acid was used as mobile phase B. The ESI detector in positive mode was used. The gradient was 20-95% mobile phase B in 5 minutes, then maintained at 95% for 3.8 minutes, and then returned to 20% mobile phase B in 0.2 minutes. The flow rate was 1 ml / min.

[0330] Method 4 Agilent 1260 Infinity II system equipped with an Agilent Poroshell 120EC-18, 2.7 μm, 4.6 × 100 mm column was used with 0.1% formic acid in HO. 2O was used as mobile phase A, and MeCN containing 0.1% formic acid was used as mobile phase B. The ESI detector in negative mode was used. The gradient was 10-95% mobile phase B in 12 minutes, then held at 95% for 2 minutes, and then returned to 10% mobile phase B in 1 minute. The flow rate was 1 mL / min.

[0331] Method 5 A Shimadzu LCMS-2020 system equipped with a KinetiX EVO C18 2.1×30 mm, 5 μm column was used with 0.025% NH 3 -H 2 O'H 2 O was used as mobile phase A and MeCN was used as mobile phase B. The flow rate was 1.5 ml / min. An ESI mass detector in negative mode was used. The gradient was 0-60% B in 0.8 min, then held at 60% B for 0.4 min, then returned to 0% B in 0.01 min and then held at 0% B for 0.34 min.

[0332] Method 6 : Agilent 1200 / G6110A system equipped with a Chromolith Flash RP-18e 25×2.0 mm column, using 0.0375% TFA in H 2 O was used as mobile phase A and MeCN containing 0.01875% TFA was used as mobile phase B. An ESI mass detector was used set in positive mode. The gradient was 5-95% B in 0.8 minutes, held at 95% B for 0.4 minutes, then returned to 5% B in 0.01 minutes and then held at 5% B for 0.29 minutes.

[0333] Method 7 A Shimadzu LCMS-2020 system equipped with a KinetiX EVO C18 2.1×30 mm, 5 μm column was used with 0.025% NH 3 H 2 O was used as mobile phase A and MeCN was used as mobile phase B. The flow rate was 1.5 ml / min. An ESI mass detector in negative mode was used. The gradient was 5-95% B in 0.8 min, held at 95% B for 0.4 min, then returned to 5% B in 0.01 min and then held at 5% B for 0.34 min.

[0334] Method 8 : Agilent 1200 / G6110A system equipped with ACE Excel C18, 2.1×30 mm, 5 μm column, using 0.025% NH 3 H 2O was used as mobile phase A and MeCN was used as mobile phase B. An ESI mass detector set in negative mode was used. The gradient was 10-80% B in 1.2 minutes, held at 80% B for 0.4 minutes, then returned to 5% B in 0.01 minutes and then held at 5% B for 0.39 minutes.

[0335] Method 9 The Agilent 1100 system was equipped with an Agilent Eclipse XDB-C18, 3.5 μm, 4.6 × 150 mm column and 0.1% trifluoroacetic acid in HO. 2 O was used as mobile phase A, and methanol containing 0.1% trifluoroacetic acid was used as mobile phase B. The gradient was 5-95% mobile phase B in 12 minutes, then held at 95% mobile phase B for 3 minutes, and then returned to 5% mobile phase B in 1 minute. The flow rate was 1 mL / min.

[0336] Method 10 A Shimadzu SCL-10A system equipped with an Agilent Eclipse XDB-C18, 3.5 μm, 4.6 × 150 mm column and a PE Sciex API150EX column was used with 0.1% trifluoroacetic acid in HO. 2 O was used as mobile phase A, and methanol containing 0.1% trifluoroacetic acid was used as mobile phase B. The gradient was 5-95% mobile phase B in 12 minutes, then held at 95% mobile phase B for 3 minutes, and then returned to 5% mobile phase B in 1 minute. The flow rate was 1 mL / min.

[0337] Method 11 A Shimadzu SCL-10A system equipped with an Agilent Eclipse XDB-C18, 3.5 μm, 4.6 × 150 mm column and a PE Sciex API150EX column was used with 0.1% trifluoroacetic acid in HO. 2 O was used as mobile phase A, and methanol containing 0.1% trifluoroacetic acid was used as mobile phase B. The gradient was 50-95% mobile phase B in 4 minutes, then held at 95% mobile phase B for 4 minutes, and then returned to 50% mobile phase B in 0.1 minutes. The flow rate was 1 mL / min.

[0338] Method 12 : Waters Acquity system equipped with an Acquity UPLC BEH C18 1.7 μm, 2.1×50 mm column, using 0.1% ammonium formate in H2O adjusted to pH 3.8, with formic acid as mobile phase A and acetonitrile as mobile phase B. The gradient was 5-100% in 9 minutes, followed by a 1 minute hold at 100% mobile phase B. The flow rate was 0.7 mL / min.

[0339] Method 13 : A Waters Acquity system equipped with EVO C18 (5 μm, 3.0×50 mm) was used with a low pH buffer gradient of 5% to 100% MeCN / H2O in 2.5 min at 2.2 ml / min. 2 O (0.1% HCOOH) and maintained at 100% for a total time of 3.5 minutes.

[0340] The pyridine, dichloromethane (DCM), tetrahydrofuran (THF), and toluene used in the procedure were obtained from nitrogen (N 2 ) in Aldrich Sure-Seal bottles. All reactions were stirred magnetically and at the external reaction temperature. Chromatography was typically performed using a column chromatography column equipped with Redisep (Teledyne Isco) Rf gold normal phase silica gel (SiO 2 ) column using a Combiflash Rf Flash Purification System (Teledyne Isco) or by using a similar system.

[0341] Preparative HPLC purifications were typically performed using one of the following systems: 1) a Waters system equipped with a Waters 2489 uv / vis detector, an Aquity QDA detector, a Waters xBridge Prep C18 5 μm OBD, 30×1560 mm column, and various gradients of H 2 O / MeCN (0.1% formic acid) for elution, or 2) column: Phenomenex Synergi C18 150×30mm-4μm; mobile phase: [H 2 O (0.225% formic acid)-MeCN]; B: 55%-85%, 12 min), typically concentrated using a Genevac EZ-2.

[0342] The following additional abbreviations are used: ethyl acetate (EA), triethylamine (TEA), dimethyl sulfoxide (DMSO), silica gel (SiO 2), 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 tetramethylurea hexafluorophosphate (HATU), hydroxybenzotriazole (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), isopropyl alcohol (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), hours (h), and not applicable (N / A).

[0343] Example 1:

[0344] Synthesis of Compound 1-0, Compound 1-16 and other representative compounds

[0345]

[0346] Solution 1

[0347]

[0348] Reagents: (i) Base (Na 2 CO 3 , K 2 CO 3 KO t Bu), solvent (THF or DMF); ii. NaOH, solvent (THF, MeOH or DMF)

[0349] Step 1-1. Synthesis of methyl 3-((4-chloro-2-(trifluoromethyl)phenoxy)methyl)benzoate (Compound 1-0)

[0350]

[0351] 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 K 2 CO 3(118 mg, 0.85 mmol). The reaction mixture was heated at 60 °C for 3 h, then cooled to room temperature and precipitated with H 2 O (3 mL). The aqueous layer was diluted with Et 2 O (2 x 6 mL) and EA (1 x 6 mL), and the combined organic layers were dried (Na 2 SO 4 ), filtered, concentrated and passed through SiO 2 Chromatography (EA / hexane) purification gave 203 mg (77.4%) of methyl 3-((2-methyl-4-(trifluoromethyl)phenoxy)methyl)benzoate (Compound 1-0) as a white solid. 17 H 15 F 3 O 3 LCMS-ESI (m / z) calculated value: 324.3; found value: 346.1 [M+Na] + , t R = 6.68 minutes (method 1).

[0352] The compounds listed in Table 1A were prepared using the procedure of Scheme 1.

[0353] Table 1A

[0354]

[0355]

[0356] Step 1-2. Synthesis of 3-((2-methyl-4-(trifluoromethyl)phenoxy)methyl)benzoic acid (Compound 1-16)

[0357]

[0358] 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 washed with EA and Et 2 O extraction, drying (Na 2 SO 4 ), filtered and concentrated to give a crude solid which was purified by reverse phase SiO 2 Chromatography was performed 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 F 3 O3 LCMS-ESI (m / z) calculated value: 310.2; found value: 333.1 [M+Na] + , t R = 10.4 minutes (Method 3).

[0359] The compounds listed in Table 1B were prepared using the procedure of Scheme 1.

[0360] Table 1B:

[0361]

[0362]

[0363]

[0364]

[0365]

[0366]

[0367]

[0368]

[0369]

[0370]

[0371]

[0372]

[0373]

[0374]

[0375]

[0376]

[0377]

[0378]

[0379] Example 2:

[0380] Synthesis of compound 2-1 and other representative compounds

[0381]

[0382] Solution 2

[0383]

[0384] Reagents: (i) PPh 3 , DIAD, THF; (ii) NaOH, solvent (THF, MeOH or DMF)

[0385] Step 2-1. Synthesis of methyl 3-chloro-5-((2,4-dichlorophenoxy)methyl)benzoate (INT 2-A)

[0386]

[0387] 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 stirred with N 2 Purge (3 times) and stir at 10 °C for 16 h (under N 2 atmosphere), then concentrated and filtered through a fast SiO 2 Chromatography (EA / petroleum ether) gave 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 (400 MHz, CDCl 3 -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).

[0388] Step 2-2. Synthesis of 3-chloro-5-((2,4-dichlorophenoxy)methyl)benzoic acid (Compound 2-1)

[0389]

[0390] 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 2M NaOH (0.43 mL, 0.87 mmol). The reaction mixture was heated at 30 °C for 1 hour and then concentrated in vacuo. The resulting residue was purified by reverse phase HPLC to give 12.6 mg (13%) of 3-chloro-5-((2,4-dichlorophenoxy)methyl)benzoic acid (Compound 2-1) as a white solid. 14 H 9 Cl 3 O 3 LCMS-ESI (m / z) calculated value: 331.5; found value: 328.8 [MH] + , t R =0.72 minutes. 1 H NMR (400 MHz, DMSO-d 6 )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).

[0391] The compounds listed in Table 2 were prepared using the procedure of Scheme 2.

[0392] Table 2

[0393]

[0394] Example 3:

[0395] Synthesis of Compound 3-1, Compound 3-2 and other representative compounds

[0396]

[0397] Solution 3

[0398]

[0399] Reagents: (i) Base (Na 2 CO 3 , K 2 CO 3 KO t Bu), DMF; (ii) NaOH, solvent (THF, MeOH or DMF).

[0400] Step 3-1. Synthesis of 3-((2-chloro-4-methylphenoxy)methyl)benzonitrile (INT 3-A)

[0401]

[0402] 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 Na 2 CO 3 (0.81 g, 7.65 mmol). The reaction mixture was stirred at room temperature overnight and then washed with 150 mL of H 2 O quenched. The resulting precipitate was collected and washed with H 2 O (2×20 mL) and dried to give 600 mg (91.3%) of 3-((2-chloro-4-methylphenoxy)methyl)benzonitrile (INT 3-A). 15 H 12 LCMS-ESI (m / z) calculated value of C1NO: 257.7; found value: 258.0 [M+H] + , t R =5.43 minutes (Method 11).

[0403] The compounds listed in Table 3A were prepared using procedure step 3-1 of Scheme 3 using 3-(bromomethyl)benzonitrile and 2,4-dichlorophenol.

[0404] Table 3A

[0405]

[0406] Step 3-2. Synthesis of 3-((2-chloro-4-methylphenoxy)methyl)benzoic acid (Compound 3-2)

[0407]

[0408] To a stirred solution of 3-((2-chloro-4-methylphenoxy)methyl)benzonitrile (INT 3-A) (300 mg, 0.12 mmol) in MeOH (5 mL) was added NaOH (375 mg, 9.4 mmol) in H 2 O (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 4N HCl. The resulting precipitate was collected to give 210 mg (65%) of 3-((2-chloro-4-methylphenoxy)methyl)benzoic acid (Compound 3-2). 15 H 13 C1 1 O 3 LCMS-ESI (m / z) calculated value: 276.7; found value: 277.3 [M+H] + ,tR =14.01 minutes. 1 HNMR (400MHz, CDCl 3 ):8.19(s,1H),8.06(d,J=8Hz,1H),7.77(d,J=8Hz,1H),7.53(t,J=8Hz,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).

[0409] The compounds listed in Table 3B were prepared using procedure step 3-2 of Scheme 3.

[0410] Table 3B

[0411]

[0412] Example 4:

[0413] Synthesis of compound 4-1 and other representative compounds

[0414]

[0415] Solution 4

[0416]

[0417] Reagents: (i) NBS, AIBN, CCl 4 , 100° C. (ii) See Scheme 1.

[0418] Step 4-1. Synthesis of methyl 3-(bromomethyl)-2-fluorobenzoate (INT-4A)

[0419]

[0420] To methyl 2-fluoro-3-methylbenzoate (1.0 g, 5.95 mmol) in CCl 4 To a stirred solution of 4% paraformaldehyde (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 filtered through SiO 2 Chromatography purification gave 858 mg (58%) of methyl 3-(bromomethyl)-2-fluorobenzoate (INT-4A) as a white solid. TLC (10% EA / petroleum ether): R f =0.50. C 9 H 8 BrF 2LCMS-ESI (m / z) calculated value: 245.97; found value: 247.0 [M+H] + , t R = 0.86 min (Method 6).

[0421] Step 4-2. Synthesis of methyl 3-((2,4-dichlorophenoxy)methyl)-2-fluorobenzoate (INT 4-B)

[0422]

[0423] To a stirred solution of methyl 3-(bromomethyl)-2-fluorobenzoate (INT-4A) (500 mg, 2.02 mmol) in MeCN (2 mL) was added K 2 CO 3 (559.4 mg, 4.05 mmol) and 2,4-dichlorophenol (329.9 mg, 2.02 mmol). After stirring at 50 °C for 16 hours, the reaction mixture was concentrated and the resulting residue was purified by flash SiO 2 Chromatography purification gave 537 mg (81%) of methyl 3-((2,4-dichlorophenoxy)methyl)-2-fluorobenzoate (INT 4-B) as a white solid. TLC (10% EA / petroleum ether): R f =0.45. C 15 H 11 Cl 2 BrF 3 The LCMS-ESI (m / z) calculated value is: 328.01; the found value is: 329.1 [M+H] + , t R = 1.03 min (Method 6).

[0424] Step 4-3. Synthesis of 3-((2,4-dichlorophenoxy)methyl)-2-fluorobenzoic acid (Compound 4-1)

[0425]

[0426] To a stirred solution of methyl 3-((2,4-dichlorophenoxy)methyl)-2-fluorobenzoate (INT 4-B) (100 mg, 0.303 mmol) in MeOH (1 mL) and THF (1 mL) was added 2M NaOH solution (455.7 μL, 0.9 mmol). After stirring at 10 °C for 16 hours, 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 H 9 Cl 2 FO 3LCMS-ESI (m / z) calculated value: 313.99; found value: 312.9 [MH] + , t R = 0.663 min (Method 7). 1 H NMR (400MHz, DMSO-d6) δ7.84 (t, J = 6.7 Hz, 1H), 7.75 (br t, J = 7.0 Hz, 1H), 7.60 (d, J = 2.4 Hz, 1H), 7.42-7.30 (m, 3H), 5.28 (s, 2H).

[0427] Synthesis of Compound 1-55

[0428]

[0429] Step 4-4. Synthesis of methyl 3-(bromomethyl)-2-fluorobenzoate (INT 4-C)

[0430]

[0431] To methyl 2-fluoro-3-methylbenzoate (1.0 g, 5.9 mmol) in CCl 4 To a stirred solution in 4% paraformaldehyde (20 mL) was added NBS (1.2 g, 6.5 mmol) and AIBN (98 mg, 0.59 mmol). The reaction mixture was heated at reflux for 3 h, then cooled to room temperature and concentrated in vacuo to give the crude product. The crude product was filtered through SiO 2 Chromatography (EA / hexanes) gave 399 mg (27%) of methyl 3-(bromomethyl)-2-fluorobenzoate (INT 4-C) as a white solid. LCMS-ESI (m / z), t R =5.05 minutes (method 7 minutes).

[0432] Step 4-5. Preparation of methyl 3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-2-fluorobenzoate (INT 4-D) synthesis

[0433]

[0434] To a stirred solution of INT 4-C (449 mg, 1.82 mmol) in MeCN (4 mL) were added 2-chloro-4-(trifluoromethyl)phenol (357 mg, 1.82 mmol) and K 2 CO 3 (327 mg, 2.36 mmol). After heating at 60 °C for 18 h, the reaction mixture was cooled to room temperature and precipitated with H 2 The aqueous layer was diluted with Et 2 O (2 x 6 mL) and EA (6 mL). The combined organic layers were dried (Na 2 SO4 ), filtered and concentrated in vacuo to give a crude white solid which was filtered through SiO 2 Chromatography (EA / hexanes) gave 551.6 mg (83.7%) of methyl 3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-2-fluorobenzoate (INT 4-D) as a white solid. 16 H 11 CIF 4 O 3 The LCMS-ESI (m / z) calculated value is: 362.7; the found value is: 363.1 [M+H] + , (method 7 minutes).

[0435] Step 4-6. Synthesis of 3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-2-fluorobenzoic acid (1-55)

[0436]

[0437] 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, washed with EA and Et 2 O extraction, drying (Na 2 SO 4 ), filtered and concentrated in vacuo. The resulting white solid was dissolved in MeCN (5 mL) and H 2 O (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. 15 H 9 CIF 4 O 3 LCMS-ESI (m / z) calculated value: 348.68; found value: 349.1 [M+H] + , t R = 10.28 min (15 min purity). 1 H 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).

[0438] Synthesis of Compound 1-65

[0439]

[0440] Step 4-7. Methyl 3-fluoro-5-methylbenzoate (INT Synthesis of 4-E)

[0441]

[0442] 3-Fluoro-5-methyl-benzoic acid (5 g, 32.4 mmol) and H 2 SO 4 A solution of 1,4-dihydro-2-nitropropene (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 H 2 O (100 mL) and extracted into EA. The combined organic phases were dried and concentrated to give a residue which was purified by SIO 2 Chromatography (PE / EA) gave 4.5 g (82.5%) of 3-fluoro-5-methyl-benzoic acid methyl ester (INT 4-E) as a yellow oil. 1 H NMR (400 MHz, CDCl 3 )δppm 2.40(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).

[0443] Step 4-8. Synthesis of methyl 3-(bromomethyl)-5-fluorobenzoate (INT 4-F)

[0444]

[0445] 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) were dissolved in CCl 4 The solution in 50 mL was stirred at 70 °C for 12 h. The reaction was concentrated and filtered through SiO 2 Chromatography (PE / EA) purification gave 4.9 g (74%) of crude 3-(bromomethyl)-5-fluoro-benzoic acid methyl ester (INT4-F) as a yellow oil. TLC (10:1 petroleum ether:EA): R f =0.70. 1H NMR (400MHz, CDCl 3 )δppm 7.86(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).

[0446] Step 4-9. Preparation of methyl 3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-5-fluorobenzoate (INT 4-G) synthesis

[0447]

[0448] INT 4-F (3 g, 12.1 mmol), 2-chloro-4-(trifluoromethyl)phenol (3.58 g, 18.2 mmol) and K 2 CO 3 A mixture of (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 which was filtered through SiO 2 Chromatography (PE / EA) gave 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.

[0449] Step 4-10. Synthesis of 3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-5-fluorobenzoic acid (1-65)

[0450]

[0451] INT 4-G (2.4 g, 6.6 mmol) and NaOH (794 mg, 19.9 mmol) were dissolved in THF (1 mL) and H 2 The mixture in 2% O (0.5 mL) was stirred at 30° C. for 2 h. The reaction mixture was acidified with 1N HCl and extracted with EA. The combined organic layers were dried (Na 2 O) and purified by centrifugation. 2 SO 4 ) and concentrated to give a residue which was dissolved in PE / EA and filtered. The filter cake was washed with MeCN / H 2 O 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 H 9 CIF 4 O 3 LCMS-ESI (m / z) calculated value: 348.6; found value: 347.0 [MH] + , t R = 0.958 min (Method 8). 1 H NMR (400 MHz, CDCl 3-d)δppm 7.99(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).

[0452] Synthesis of Compound 1-85

[0453]

[0454] Step 4-11. Synthesis of methyl 2-fluoro-5-methylbenzoate (INT 4-H)

[0455]

[0456] 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 mol) dropwise at 25° C. After 0.5 h at 25° C., the mixture was concentrated and filtered through SiO 2 Chromatography (PE / EA) gave 10.6 g (97%) of methyl 2-fluoro-5-methylbenzoate (INT4-H) as a colorless oil. TLC (1:1 petroleum ether:EA): R f =0.90.

[0457] Step 4-12. Synthesis of methyl 5-(bromomethyl)-2-fluorobenzoate (INT 4-I)

[0458]

[0459] INT 4-H (8 g, 47.6 mmol) was dissolved in CHCl 3 NBS (10.16 g, 57.1 mmol) and AIBN (781.2 mg, 4.76 mmol) were added to a solution of 1% ethanol (200 mL). After 12 h at 70 °C, the reaction was heated with H 2 O (200 mL) and extracted with EA (3×100 mL). The combined organic layers were dried (Na 2 SO 4 ), concentrated and passed through SiO 2 Chromatography (PE / EA) gave 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. C 9 H 8 BrF 2LCMS-ESI (m / z) calculated value: 247.06; found value: 248.8 [MH] + , t R =0.702 minutes. 1 H NMR (400 MHz, CDCl 3 -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).

[0460] Step 4-13. Preparation of methyl 5-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-2-fluorobenzoate (INT 4-J) synthesis

[0461]

[0462] 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 3 (6.71 g, 48.57 mmol). After 2 h at 50 °C, the reaction mixture was filtered, concentrated and filtered through SiO 2 Chromatography (PE) purification afforded 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 CIF 4 O 3 LCMS-ESI (m / z) calculated value: 362.7; found value: 363.0 [MH] + , t R = 1.07 min (Method 6). 1 H NMR (400 MHz, CDCl 3 -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).

[0463] Step 4-14. Synthesis of 5-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-2-fluorobenzoic acid (1-85)

[0464]

[0465] INT 4-J (1.7 g, 4.63 mmol) was dissolved in H2 To a solution of 2% CO (10 mL), THF (10 mL) and MeOH (5 mL) was added LiOH. 2 O (582.33 mg, 13.88 mmol). After 2 hours at 25 °C, H 2 O (30 μL) was added to the reaction mixture and the organic solvent was removed by reduced pressure to give 1.57 g (97%) of 5-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-2-fluorobenzoic acid (Compound 1-85) as a white solid. 15 H 9 CIF 4 O 3 LCMS-ESI (m / z) calculated value: 348.68; found value: 349.0 [MH] + , t R = 0.925 min (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).

[0466] Synthesis of Compound 1-101

[0467]

[0468] Step 4-15. 4,4,5,5-Tetramethyl-2-(2-methyl-4-(trifluoromethyl)phenyl)-1,3,2-dioxaborolane Synthesis of INT 4-K

[0469]

[0470] To a solution of 1-bromo-2-methyl-4-(trifluoromethyl)benzene (7.3 g, 30.5 mmol) in dioxane (100 mL) were added AcOK (11.99 g, 122.16 mmol, 4 equiv), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborolane) (15.51 g, 61.1 mmol) and Pd(dppf)Cl 2 .CH 2 Cl 2 (2.49 g, 3.05 mmol). 2 After stirring at 100° C. for 12 hours, the mixture was filtered and the filtrate was concentrated to give a crude product, which was filtered through SiO 2Chromatography (PE) purification gave 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 (400 MHz, CDCl 3 -d) δ7.93-7.84(m,1H),7.46-7.39(m,2H),2.61(s,3H),1.38(s,13H).

[0471] Step 4-16. Synthesis of 2-methyl-4-(trifluoromethyl)phenol (INT 4-L)

[0472]

[0473] To a solution of INT 4-K (5.8 g, 20.27 mmol) in EtOH (40 mL) and H2O (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 Na2SO 3 (100 mL) and concentrated to remove volatiles. The resulting solution was washed with H 2 O (50 mL) and extracted with EA (3×80 mL). The combined organic layers were washed with saturated NaHCO 3 The solution (2×50 mL) and brine (100 mL×2) were washed and then dried (Na 2 SO 4 ), concentrated and passed through SiO 2 Chromatographic purification afforded 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 (400 MHz, CDCl 3 -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).

[0474] Step 4-17. Methyl 2-fluoro-3-((2-methyl-4-(trifluoromethyl)phenoxy)-methyl)benzoate (INT 4- Synthesis of M)

[0475]

[0476] 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 K2 CO 3 (2.04 g, 14.7 mmol). After 12 h at 60 °C, the reaction mixture was filtered, concentrated and filtered through SiO 2 Chromatography (EA / PE) gave 3.0 g (77%) of methyl 2-fluoro-3-((2-methyl-4-(trifluoromethyl)phenoxy)methyl)benzoate (INT 4-M) as a colorless oil. 17 H 14 F 4 O 3 LCMS-ESI (m / z) calculated value: 342.29; found value: 343.0 [M+H] + , t R = 1.04 min (Method 6). 1 H NMR (400 MHz, CDCl 3 -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).

[0477] Step 4-18. Synthesis of 5-((2-methyl-4-(trifluoromethyl)phenoxy)methyl)-2-fluorobenzoic acid (1-101)

[0478]

[0479] 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 hours at 40 °C, the pH was adjusted to pH 5 with HCl (1 M) to produce a solid precipitate that was filtered and collected. The resulting product was dissolved in EA (500 mL), dried (Na 2 O) and eluted. 2 SO 4 ), filtered and concentrated to give 2.35 g (81%) of 5-((2-methyl-4-(trifluoromethyl)phenoxy)methyl)-2-fluorobenzoic acid (1-101) as a light yellow solid. 16 H 12 F 4 O 3 LCMS-ESI (m / z) calculated value: 328.2; found value: 326.9 [MH] + , t R = 0.73 min (Method 7). 1 H NMR (400MHz, CD 4OD)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).

[0480] Synthesis of Compound 4-10

[0481]

[0482] Step 4-19. Synthesis of methyl 3-(bromomethyl)-5-methylbenzoate (INT 4-N)

[0483]

[0484] To methyl 3,5-dimethylbenzoate (5 g, 30.5 mmol) in CCl 4 NBS (5.96 g, 33.5 mmol) and AIBN (1.00 g, 6.1 mmol) were added to a solution of 1% ethanol (200 mL). After stirring at 80 °C for 12 h, the reaction mixture was concentrated and filtered through SiO 2 Chromatography (PE / EA) gave 8.4 g (79%) of crude methyl 3-(bromomethyl)-5-methylbenzoate (INT 4-N) as a colorless oil with a purity of 70%. 10 H 11 B O 2 The LCMS-ESI (m / z) calculated value is: 243.1; the found value is: 245 [M+H] + , t R =0.873 minutes. 1 H NMR (400 MHz, CDCl 3 -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).

[0485] Step 4-20. Methyl 3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-5-methylbenzoate (INT 4-O) Synthesis

[0486]

[0487] INT 4-N (3 g, 8.64 mmol), 2-chloro-4-(trifluoromethyl)phenol (1.7 g, 8.64 mmol) and K 2 CO 3A mixture of (5.03 g, 36.4 mmol) in MeCN (30 mL) was stirred at 60 ° C for 12 hours. The reaction mixture was filtered and concentrated to give a residue, which was purified by SiO2 chromatography (PE / EA) to give 2.8 g (90%) of methyl 3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-5-methylbenzoate (INT 4-0) as a white solid. TLC (5:1 petroleum ether:EA): R f =0.60. C 17 H 14 CIF 3 O 3 The LCMS-ESI (m / z) calculated value is: 358.7; the found value is: 359 [M+H] + , t R =1.06 minutes.

[0488] Step 4-21. Synthesis of 3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-5-methylbenzoic acid (4-10)

[0489]

[0490] A mixture of INT 4-0 (2.8 g, 7.81 mmol) and 2M NaOH (30 mL, 30 mmol) in THF (30 mL) and MeOH (30 mL) was stirred at 30° C. for 12 hours. The volatile solvents were removed in vacuo, and the resulting solution was acidified to pH 5 with 1N 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. 16 H 12 CIF 3 O 3 The LCMS-ESI (m / z) calculated value is: 344.71; the found value is: 342.9 [M+H] + , t R = 0.761 min (Method 7). 1 H NMR (400MHz, CD 4 OD)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).

[0491] The compounds listed in Table 4 were prepared using the procedure of Scheme 4:

[0492] Table 4

[0493]

[0494]

[0495]

[0496]

[0497] Example 5:

[0498] Synthesis of compound 5-1 and other representative compounds

[0499]

[0500] Solution 5

[0501]

[0502] Reagents: (i) Zn(CN) 2 , Zn, Pd 2 (dba) 3 , dppf, DMF, 120°C; (ii) NaOH, solvent (THF, MeOH or DMF).

[0503] Step 5-1. Synthesis of methyl 3-cyano-5-((2,4-dichlorophenoxy)methyl)benzoate (INT 5-B)

[0504]

[0505] To a stirred solution of methyl 3-bromo-5-((2,4-dichlorophenoxy)methyl)benzoate INT 5-A (100 mg, 256.37 μmol, prepared from methyl 3-bromo-5-(bromomethyl)benzoate and 2,4-dichlorophenol via Scheme 1) in DMF (2 mL) was added Zn (33.53 mg, 512.75 μmol), Pd 2 (dba) 3 (23.48mg, 25.64μmol), DPPF (28.43mg, 51.27μmol) and Zn(CN) 2 (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 NO 3LCMS-ESI (m / z) calculated value: 336.2; no m / z observed, t R = 1.1 min (Method 6). 1 H NMR (400 MHz, CDCl 3 )δ8.34(s,1H),8.31(s,1H),7.99(s,1H),7.44(d,J=2.4Hz,1H),7.24-7.17(m,1H),6.89(d,J=8.8Hz,1H),5.19(s,2H),3.99(s,3H).

[0506] Step 5-2. Synthesis of 3-cyano-5-((2,4-dichlorophenoxy)methyl)benzoic acid (Compound 5-1)

[0507]

[0508] To a stirred solution of 3-cyano-5-[(2,4-dichlorophenoxy)methyl]-benzoic acid methyl ester (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 H 2 O (20 mL) and acidified (1 M HCl) to pH 5, and 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 H 9 C1 2 NO 3 The LCMS-ESI (m / z) calculated value is: 322.14; the found value is: 319.9 [MH] + , t R = 0.727 min (Method 6). 1 H NMR (400 MHz, DMSO-d 6 )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).

[0509] The compounds listed in Table 5 were prepared using the procedure of Scheme 5.

[0510] Table 5

[0511]

[0512] Example 6:

[0513] Synthesis of compound 6-1

[0514]

[0515] Solution 6

[0516]

[0517] Reagents: (i) CH 3 I.DMF.K 2 CO 3 , 10°C; (ii) see Scheme 4; (iii) see Scheme 1.

[0518] Step 6-1. Methyl 2-methoxy-3-methylbenzoate (INT 6-A) Synthesis

[0519]

[0520] To a solution of 2-hydroxy-3-methyl-benzoic acid (1 g, 6.6 mmol) in DMF (15 mL) was added K 2 CO 3 (2.73 g, 19.7 mmol) and CH 3 I (4.66 g, 32.86 mmol, 2.1 mL). The mixture was stirred at 10 °C for 2 h. Additional CH 3 I (2.33 g, 16.43 mmol, 1.0 mL) and the mixture was stirred for another 16 h. 2 The reaction mixture was quenched with 1% O (50 mL), and then extracted with EA (100 mL×3). The combined organic layers were dried (Na 2 SO 4 ), filtered and concentrated under vacuum pressure to obtain a residue which was passed through SiO 2 Chromatography purification gave 1.0 g (85%) of methyl 2-methoxy-3-methylbenzoate (INT 6-A) as a colorless oil. TLC (33% EA / petroleum ether), Rf=0.45. 1 HNMR (400MHz, CDCl 3 )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).

[0521] Step 6-2. Synthesis of 3-((2,4-dichlorophenoxy)methyl)-2-methoxybenzoic acid (Compound 6-1)

[0522]

[0523] Compound 6-1 was prepared from INT 6-A according to Scheme 4 and then by the procedure of Scheme 1 to give 1.0 g (85%) of 3-((2,4-dichlorophenoxy)methyl)-2-methoxybenzoic acid (6-1) as a colorless oil. 10 H 12 O 3 LCMS-ESI (m / z) calculated value: 180.2; no m / z observed, t R = 0.70 min (Method 7). 1 H NMR (400 MHz, DMSO-d 6 )δppm 3.82(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).

[0524] The compounds listed in Table 6 were prepared using the procedure of Scheme 6.

[0525] Table 6

[0526]

[0527] Example 7:

[0528] Synthesis of compound 7-1

[0529]

[0530] Solution 7

[0531]

[0532] Reagents: (i) Base (Na 2 CO 3 , K 2 CO 3 KO t Bu), MeCN, 60°C; (ii) 4M HCl / dioxane.

[0533] Step 7-1. Synthesis of tert-butyl (3-((2,4-dichlorophenoxy)methyl)benzyl)carbamate (INT 7-A)

[0534]

[0535] 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 K 2 CO 3 (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 and heated with H 2 O (10 mL) and diluted with Et 2 O (2 × 10 mL), and dried (Na 2 SO 4 ), filtered through celite, and concentrated under vacuum to give 627 mg (96%) of tert-butyl (3-((2,4-dichlorophenoxy)methyl)benzyl)carbamate (INT 7-A). 19 H 21 Cl 2 NO 3 LCMS-ESI (m / z) calculated value: 381; found value: 404.1 [M+Na] + , t R = 12.2 minutes (Method 3). 1 H NMR (500 Hz, CDCl 3 )7.37(d,J=2.5,1H),7.34-7.33(m,3H),7.25-7.22(m,1H),7.134(dd,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).

[0536] Step 7-2. Synthesis of (3-((2,4-dichlorophenoxy)methyl)phenyl)methanamine (Compound 7-1)

[0537]

[0538] To a stirred solution of tert-butyl (3-((2,4-dichlorophenoxy)methyl)-benzyl)carbamate (INT 7-A) (200 mg, 523 μmol) in dioxane (5 mL) was added 4M hydrogen chloride / dioxane (5 mL, 20.9 mmol). After 3 hours, 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 Cl2 LCMS-ESI (m / z) calculated value of NO: 281; found value: 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).

[0539] The compounds listed in Table 7 were prepared using the procedure of Scheme 7.

[0540] Table 7

[0541]

[0542] Example 8:

[0543] Synthesis of compound 8-1 and other representative compounds

[0544]

[0545] Solution 8

[0546]

[0547] Reagents (i) NBS, AIBN, CCl 4 , 100℃; (ii) alkali (K 2 CO 3 KO t Bu), solvents (MeCN, DMF, DCM); (iii) Pd(dppf)Cl 2 , boric acid, K 2 CO 3 , dioxane; (iv) NaOH, solvent (THF, MeOH or DMF).

[0548] Step 8-1. Synthesis of methyl 5-(bromomethyl)-2-iodobenzoate (INT 8-A)

[0549]

[0550] To 2-iodo-5-methyl-benzoic acid methyl ester (1 g, 3.62 mmol) in CCl 4NBS (644.7 mg, 3.62 mmol) and AIBN (11.9 mg, 72.5 μmol) were added to a solution of 1% ethyl acetate (10 mL). The mixture was stirred at 100 °C for 2 hours and concentrated under reduced pressure to give a residue, which was purified by flash SiO 2 Chromatography (EA / petroleum ether) gave 733 mg (57.0%) of methyl 5-(bromomethyl)-2-iodobenzoate (INT 8-A) as a brown solid. TLC: (10% EA / petroleum ether), Rf: 0.5. 1 H NMR (400 MHz, CDCl 3 )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).

[0551] Step 8-2. Synthesis of 5-((2,4-dichlorophenoxy)methyl)-2-iodo-benzoic acid methyl ester (INT 8-B)

[0552]

[0553] To a solution of methyl 5-(bromomethyl)-2-iodobenzoate (INT 8-A) (733 mg, 2.06 mmol) in MeCN (5 mL) was added K 2 CO 3 (571 mg, 4.13 mmol) and 2,4-dichlorophenol (337 mg, 2.06 mmol). After stirring at 50 °C for 16 hours, the reaction mixture was concentrated in vacuo and filtered through a flash SiO 2 Chromatography purification gave 780 mg (86.4% yield) of 5-((2,4-dichlorophenoxy)methyl)-2-iodo-benzoic acid methyl ester (INT 8-B) as a white solid. TLC: (10% EA / petroleum ether), R: 0.3. 1 H NMR (400 MHz, CDCl 3 )δ8.02(d,J=8.2Hz,1H),7.88(d,J=2.1Hz,1H),7.41(d,J=2.4Hz,1H),7.30-7.28(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).

[0554] Step 8-3. Synthesis of methyl 5-((2,4-dichlorophenoxy)methyl)-2-methylbenzoate (INT 8-C)

[0555]

[0556] To 5-((2,4-dichlorophenoxy)methyl)-2-iodo-benzoic acid methyl ester (INT 8-B) (200 mg, 457.6 μmol) in dioxane (1 mL) and H 2 Pd(dppf)Cl was added to the solution in O (1 mL). 2 (16.7 mg, 22.9 μmol), K 2 CO 3 (189.7 mg, 1.4 mmol) and MeB(OH) 2 (54.8 mg, 915 μmol). The mixture was stirred at 100 °C for 2 h, concentrated and filtered through a flash SiO 2 Chromatography (EA / petroleum ether) gave 100 mg (67.2%) of 5-((2,4-dichlorophenoxy)methyl)-2-methyl-benzoic acid methyl ester (INT 8-C) as a white solid. TLC: (10% EA / petroleum ether), R f =0.4. 1 H NMR (400 MHz, CDCl 3 )δ7.98(d,J=1.6Hz,1H),7.51(dd,J=1.7,7.8Hz,1H),7.40(d,J=2.6Hz,1H),7.31-7.28(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).

[0557] Step 8-4. Synthesis of 5-((2,4-dichlorophenoxy)methyl)-2-methylbenzoic acid (Compound 8-1)

[0558]

[0559] To a solution of 5-[(2,4-dichlorophenoxy)methyl]-2-methyl-benzoic acid methyl ester (INT 8-C) (100 mg, 307.52 μmol) in MeOH (1 mL) and THF (1 mL) was added NaOH (2M, 461.27 μL). After stirring at 10 °C for 16 hours, the mixture was concentrated in vacuo and purified by preparative HPLC to give 29 mg (30.3%) of 5-((2,4-dichlorophenoxy)methyl)-2-methylbenzoic acid (Compound 8-1) as a white solid. 15 H 12 Cl 2 O 3 The LCMS-ESI (m / z) calculated value is: 310.02; the measured value is: 308.9 [MH] + , t R= 0.718 min (Method 7). 1 H NMR (400 MHz, CDCl 3 )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).

[0560] The compounds listed in Table 8 were prepared using the procedure of Scheme 8.

[0561] Table 8

[0562]

[0563] Example 9:

[0564] Synthesis of compound 9-1

[0565]

[0566] Solution 9

[0567]

[0568] Reagent (i) NaBH 4 , DCM, MeOH; (ii) PPh 3 ,NEt 3 , DEAD, THF; (iii) NaOH, solvent (THF, MeOH or DMF).

[0569] Step 9-1. Synthesis of methyl 4-bromo-6-(hydroxymethyl)picolinate (INT 9-A)

[0570]

[0571] 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) was added sodium borohydride (0.17 g, 4.4 mmol) in 3 batches at 0 °C. The reaction mixture was warmed to room temperature and stirred overnight. Additional sodium borohydride (0.17 g, 4.4 mmol) was added. After 2 hours, the reaction mixture was washed with NH 4 The aqueous layer was extracted with DCM (2×10 mL) and EA (10 mL), and dried (Na 2 O ) and the mixture was stirred for 2 h. 2 SO 4), filtered through celite, and concentrated in vacuo to give a crude white solid which was filtered through SiO 2 Chromatography (10% MeOH in EA / hexanes) gave 514 mg (57%) of methyl 4-bromo-6-(hydroxymethyl)picolinate (INT 9-A) as a white solid. 9 H 10 BrNO 3 LCMS-ESI (m / z) calculated value: 258.98; no m / z observed, t R = 3.21 minutes (method 1).

[0572] Step 9-2. 4-bromo-6-((2-chloro-4-(trifluoromethyl)phenoxy)-methyl)picolinic acid methyl ester (INT 9-B) Synthesis

[0573]

[0574] 4-bromo-6-(hydroxymethyl)picolinic acid methyl ester (INT 9-A) (100mg, 0.406mmol), triphenylphosphine (107mg, 0.406mmol) and TEA (56.7μL, 406μmol) are added to a stirred solution of 2-chloro-4-(trifluoromethyl)phenol (87.9mg, 0.447mmol) in THF (10mL). The reaction mixture is cooled to 0°C and diisopropyl azodicarboxylate (82.2mg, 80.0μL, 0.406mmol) is added dropwise. The reaction mixture is stirred at 0°C for 30 minutes, warmed to room temperature and stirred overnight. The reaction mixture is concentrated in vacuo to obtain a crude product, which is passed through SiO 2 Chromatography (EA / hexanes) gave 94 mg (55%) of methyl 4-bromo-6-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)picolinate (INT 9-B) as an off-white solid. 15 H 10 BrClF 3 NO 3 LCMS-ESI (m / z) calculated value: 422.95; no m / z observed, t R = 6.73 minutes (method 1).

[0575] Step 9-3. Synthesis of 4-bromo-6-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)picolinic acid (Compound 9-1) become

[0576]

[0577] 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 THF (2 mL) was added 1 M NaOH (1 mL, 1.11 mmol). The reaction mixture was heated at 60 °C overnight, cooled, and then acidified with 3 M HCl. The mixture was washed with EA and Et 2 O extraction, and the combined organic matter was dried (Na 2 SO 4 ), filtered and concentrated in vacuo to give 77.6 mg (85%) of 4-bromo-6-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)picolinic acid (Compound 9-1) as a white solid. 14 H 18 BrClF 3 NO 3 LCMS-ESI (m / z) calculated value: 408.93; found value: 410.0 [MH] + , t R = 10.7 minutes (Method 3).

[0578] The compounds listed in Table 9 were prepared using the procedure of Scheme 9:

[0579] Table 9

[0580]

[0581] Example 10:

[0582] Synthesis of compound 10-1

[0583]

[0584] Solution 10

[0585]

[0586] Reagent(i)KO t Bu, dioxane; (ii) NaOH, solvent (THF, MeOH or DMF).

[0587] Step 10-1. 3-(((5-(Trifluoromethyl)pyridin-2-yl)oxy)methyl)-benzoic acid methyl ester (INT 10-A) Synthesis

[0588]

[0589] 2-Chloro-5-(trifluoromethyl)pyridine (363 mg, 2.00 mmol) and potassium tert-butoxide (337 mg, 3.00 mmol) were added to a pressure vessel containing a solution of methyl 3-(hydroxymethyl)benzoate (499 mg, 3.00 mmol) in 1,4-dioxane (9 mL). The vessel was sealed and the reaction mixture was heated and stirred at 90 ° C overnight and then cooled to room temperature. The reaction mixture was heated in Et 2 O and H 2 The phases were separated and the aqueous layer was further extracted with diethyl ether (2 times). The organic phases were combined, washed with brine, and dried (Na 2 SO 4 ), filtered and concentrated under reduced pressure. The resulting colorless oil was purified by rapid SiO 2 Chromatography (EA / hexanes) gave 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 F 3 NO 3 LCMS-ESI (m / z) calculated value: 311.1; found value: 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).

[0590] Step 10-2. Synthesis of 3-(((5-(trifluoromethyl)pyridin-2-yl)oxy)methyl)benzoic acid (Compound 10-1) become

[0591]

[0592] 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 charged 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 H 2 O and acidified to pH 4-5 using 3M HCl. The resulting white precipitate was washed with Et 2 The combined organic layers were washed with brine and dried (Na 2 SO 4 ) and concentrated in vacuo to give 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 F 3 NO 3 LCMS-ESI (m / z) calculated value: 297.2; found value: 298.1 [M+H] + , t R =9.33 minutes (Method 3). 1 H NMR (500 MHz, DMSO-d 6 )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).

[0593] The compounds listed in Table 10 were prepared using the procedure of Scheme 10:

[0594] Table 10

[0595]

[0596] Example 11:

[0597] Synthesis of compound 11-1

[0598]

[0599] Solution 11

[0600]

[0601] Reagent (i) tricyclohexylphosphine, Pd(OAc) 2 , cyclopropylboronic acid, potassium phosphate, toluene; (ii) NaOH, solvent (THF, MeOH or DMF).

[0602] Step 11-1. Methyl 3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-5-cyclopropylbenzoate (INT 11-B) Synthesis

[0603]

[0604] 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 by 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 hours, 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 (Na 2 SO 4 ), filtered, and concentrated in vacuo to give the crude material, which was filtered through SiO 2 Chromatography (EA / hexane) gave 132 mg (72%) of methyl 3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-5-cyclopropylbenzoate (INT 11-B). 19 H 16 CIF 3 O 3 LCMS-ESI (m / z) calculated value: 384.1; no m / z observed, t R =7.02 min (Method 1). 1H 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).

[0605] Step 11-2 3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-5-cyclopropylbenzoic acid (Compound 11-1) Synthesis

[0606]

[0607] 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 washed with EA and Et 2 O extraction, drying (Na 2 SO 4 ), 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. 18 H 14 CIF 3 O 3 The LCMS-ESI (m / z) calculated value is: 370.7; the measured value is: 393.1 [M+Na] + , t R = 11.25 minutes (Method 3). 1 HNMR (500 Hz, DMSO-d 6 )δ13.00(s,1H),7.87(s,1H),7.82(s,1H),7.71(d,J=8.0,1H),7.62(s,1H),7.4 3-7.41(m,2H),5.34(s,2H),2.04(m,1H),1.01(d,J=7.0,2H),0.72-0.71(m,2H).

[0608] The compounds listed in Table 11 were prepared using the procedure of Scheme 11.

[0609] Table 11

[0610]

[0611] Example 12:

[0612] Synthesis of compound 12-1

[0613]

[0614] Solution 12

[0615]

[0616] Reagents: (i) NaH, DMF; (ii) NaOH, solvent (THF, MeOH or DMF).

[0617] Step 12-1. Synthesis of methyl 3-(((2,4-dichlorophenyl)amino)methyl)benzoate (INT 12-A)

[0618]

[0619] 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) was added NaH (60% in mineral oil, 38 mg, 0.95 mmol) at 0° C. After 1 h at 0° C., the mixture was washed with H 2 O (20 mL) and extracted with EA (2×50 mL). The organic layers were combined, washed with brine, and dried (Na 2 SO 4 ), filtered and concentrated to obtain a crude product, which was passed through SiO 2 Chromatography gave 230 mg (56%) of methyl 3-(((2,4-dichlorophenyl)amino)methyl)benzoate (INT 12-A) with a purity of 30% and used without further purification. 15 H 13 C1 2 NO 2 LCMS-ESI (m / z) calculated value: 310.2; found value: 311.2 [M+H] + , t R =5.7 minutes (Method 11).

[0620] Step 12-2. Synthesis of 3-(((2,4-dichlorophenyl)amino)methyl)benzoic acid (Compound 12-1)

[0621]

[0622] 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 NaOH (290 mg, 7.4 mmol) in H 2 The reaction was heated to reflux for 2 hours, cooled to room temperature and concentrated in vacuo to remove MeOH. The aqueous layer was acidified to pH 2 with 4N HCl (aq) and extracted with EA (2×50 mL). The combined organic layers were washed with H 2 O, washed with brine, dried (MgSO 4 ), filtered and concentrated in vacuo to give the crude material which was filtered through SiO 2 Chromatography was used to obtain 5 mg (2.3%) of 3-(((2,4-dichlorophenyl)amino)methyl)benzoic acid (Compound 12-1). 14 H 11 C 11 NO 2 LCMS-ESI (m / z) calculated value: 296.2; found value: 296.5 [M+H] + , t R = 13.88 minutes (Method 9). 1 H NMR (400 MHz, DMSO-d 6 )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).

[0623] The compounds listed in Table 12 were prepared using the procedure of Scheme 12.

[0624] Table 12

[0625]

[0626] Example 13:

[0627] Synthesis of compound 13-1

[0628]

[0629] Solution 13

[0630]

[0631] Reagents (i) NaOH, MeOH, heating.

[0632] Step 13-1. Synthesis of 3-((2,3-dichlorophenoxy)methyl)benzamide (Compound 13-1)

[0633]

[0634] To a stirred solution of INT 13-1 (0.3 g, 1.1 mmol, prepared by Scheme 3 from 3-(bromomethyl)benzonitrile and 2,3-dichlorophenol) in MeOH (5 mL) was added NaOH (0.34 g, 8.6 mmol) in H 2 After heating at 90 °C for 4 h, the reaction mixture was cooled to room temperature and the resulting solid was collected and precipitated with H 2 O (10 mL). The material was dried under high vacuum to give 68.8 mg (21%) of 3-((2,3-dichlorophenoxy)methyl)benzamide (Compound 13-1). 14 H 11 Cl 2 NO 2 LCMS-ESI (m / z) calculated value: 296.2; found value: 297.2 [M+H] + , t R = 11.8 minutes (Method 10). 1 H NMR (400 MHz, CDCl 3 )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).

[0635] The compounds listed in Table 13 were prepared using the procedure of Scheme 13.

[0636] Table 13

[0637]

[0638] Example 14:

[0639] Synthesis of compound 14-1

[0640]

[0641] Solution 14

[0642]

[0643] Reagents: (i) PPh 3,NEt 3 , DIAD, THF.

[0644] Step 14-1. Synthesis of (3-((2,4-dichlorophenoxy)methyl)phenyl)methanol (Compound 14-1)

[0645]

[0646] 1,3-benzenedimethanol (250mg, 1.81mmol), triphenylphosphine (475mg, 1.81mmol) and TEA (183mg, 252μL, 1.81mmol) were added to a stirred solution of 2,4-dichlorophenol (324mg, 1.99mmol) in THF (15mL). The reaction mixture was cooled to 0°C and diisopropyl azodicarboxylate (356μL, 1.81mmol) 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 obtain a crude product, which was filtered through SiO 2 Chromatography (EA / hexanes) gave 90.9 mg (17.7%) (3-((2,4-dichlorophenoxy)methyl)phenyl)methanol (Compound 14-1) as an off-white solid. 14 H 12 Cl 2 O 2 LCMS-ESI (m / z) calculated value: 282.0; found value: 282.21 [M+H] + , t R = 10.08 min (Method 3).

[0647] The compounds listed in Table 14 were prepared using the procedure of Scheme 14:

[0648] Table 14

[0649]

[0650] Example 15:

[0651] Synthesis of compound 15-1

[0652]

[0653] Solution 15

[0654]

[0655] Reagents: (i) Base (Na 2 CO 3 , K 2 CO 3 KO tBu), solvent (THF or DMF); ii. NaOH, solvent (THF, MeOH or DMF).

[0656] Step 15-1. Synthesis of methyl 3-(((2,4-dichlorophenyl)thio)methyl)benzoate (INT 15-A)

[0657]

[0658] 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, and washed with H 2 O (20 mL) and washed with Et 2 O (2×20 mL). The combined organic layers were dried (Na 2 SO 4 ), filtered and concentrated to give 1.3 g (94%) of methyl 3-(((2,4-dichlorophenyl)thio)methyl)benzoate (INT 15-A) as a yellow oil which solidified upon standing. 15 H 12 Cl 2 O 2 LCMS-ESI (m / z) calculated value of S: 325.9; found value: 327.1 [M+H] + , t R = 12.5 minutes (Method 3).

[0659] Step 15-2. Synthesis of 3-(((2,4-dichlorophenyl)thio)methyl)benzoic acid (15-1)

[0660]

[0661] 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, the aqueous layer was extracted with EA (2 x 5 mL), dried (Na 2 SO 4 ), 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 Cl 2 O 2LCMS-ESI (m / z) calculated value of S: 311.97; found value: 313.1 [M+Na] + , tR = 10.59 min (Method 3).

[0662] The compounds listed in Table 15 were prepared using the procedure of Scheme 15.

[0663] Table 15

[0664]

[0665] Example 16:

[0666] Compound 16-1 and

[0667] Synthesis of other representative compounds

[0668]

[0669] Scheme 16

[0670]

[0671] Reagents: (i) Base, Cu(OAc) 2 , DCM; ii. NaOH, solvent (THF, MeOH or DMF).

[0672] Step 16-1. Synthesis of methyl 3-(2,4-dichlorophenoxy)benzoate (INT 16-A)

[0673]

[0674] 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) 2 (111 mg, 0.61 mmol) and TEA (0.86 mL, 0.61 mmol). After stirring overnight, the reaction mixture was filtered, concentrated and filtered through SiO 2 Chromatography (EA / hexane) gave 182 mg (27%) of methyl 3-(2,4-dichlorophenoxy)benzoate (INT 16-A). 14 H 10 Cl 2 O 3 LCMS-ESI (m / z) calculated value: 296; found value: 297.5 [M+H] + , t R =5.96 minutes (Method 11).

[0675] Step 16-2. Synthesis of 3-(2,4-dichlorophenoxy)benzoic acid (16-1)

[0676]

[0677] 1M NaOH (67 mg, 1.68 mmol) was added to a stirred solution of methyl 3-(2,4-dichlorophenoxy)benzoate (INT 16-A) (50 mg, 0.17 mmol) in MeOH (3 mL). The reaction mixture was heated under reflux for 2 hours. The pH was adjusted to 2 by adding 4N HCl (aqueous solution) and then extracted with EA. The organic layer was washed with brine, dried (MgSO 4 ), filtered and concentrated in vacuo to give a crude solid which was filtered through SiO 2 Chromatography (EA / hexane) purification gave 10 mg (21%) of 3-(2,4-dichlorophenoxy)benzoic acid (Compound 16-1) as a white solid. 13 H 8 Cl 2 O 3 LCMS-ESI (m / z) calculated value: 281.99; found value: 283.6 [M+H] + , t R = 14.15 minutes (Method 10).

[0678] The compounds listed in Table 16 were prepared using the procedure of Scheme 16.

[0679] Table 16

[0680]

[0681] Example 17:

[0682] Synthesis of Compound 17-1, Compound I-31 and Other Representative Tetrazolyl Isosteres

[0683]

[0684]

[0685] Reagents: (i) Base (Na 2 CO 3 , K 2 CO 3 KO t Bu), solvents (acetone, MeCN, DMF); (ii) NaN 3 NH 4 Cl, DMF.

[0686] Step 17-1: 3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)benzonitrile (INT-17-1)

[0687]

[0688] 3-(Bromomethyl)benzonitrile (500 mg, 2.55 mmol), 2-chloro-4-(trifluoromethyl)phenol (0.551 g, 2.81 mmol) and K 2 CO 3 A mixture of 4-(1-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)benzonitrile (compound 17-1) (1.06 g, 7.65 mmol) in acetone (10.0 mL) was heated at 80 ° C for 1 hour. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (40 g cartridge) eluted 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).

[0689] Step 17-2: 5-(3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)phenyl)-1H-1,2,3,4-tetrazolyl (INT-31)

[0690]

[0691] Compound 17-1 (100 mg, 0.321 mmol), NaN 3 (31.3 mg, 0.481 mmol) and NH 4 A mixture of Cl (27.5 mg, 0.513 mmol) in DMF (1.00 mL) was heated at 130 ° C for 12 hours. The mixture was cooled to room temperature and poured into 2M HCl at 0 ° C. The mixture was filtered and the solid was dried to give 5-(3-((2-chloro-4-(trifluoromethyl)-phenoxy)methyl)phenyl)-1H-1,2,3,4-tetrazole (INT-31) (102 mg, 90%) as a solid. 1 HNMR (400MHz, CD 3OD) δ8.17 (s, 1H), 8.00 (d, J = 7.8 Hz, 1H), 7.72 (dd, J = 8.1, 5.0 Hz, 2H), 7.67,–7.53 (m, 2H), 7.33 (d, J = 8.7 Hz, 1H), 5.37 (s, 2H); LCMS: for C 15 H 10 CIF 3 N 4 O Calculated: 354; Measured: 355.06, [MH] + , t R =4.35 minutes (Method 12).

[0692] The compounds listed in Table 17 were prepared using the procedure of Scheme 17.

[0693] Table 17

[0694]

[0695]

[0696] Example 18:

[0697] General Synthesis of Representative Arylsulfonamide Isosteres

[0698]

[0699] Reagents: (i) NaH, DMF, BnBr; (ii) ArSO 2 Cl, pyr, CHCl 2 (iii) H 2 , Pd / C, MeOH; (iv) See Scheme 2, Step 1.

[0700] A solution of 3-aminobenzyl alcohol in DMF was treated with NaH and benzyl bromide to form 3-((benzyloxy)methyl)aniline. After separation, 3-((benzyloxy)-methyl)aniline was dissolved in CH 2 Cl 2 In the reaction, pyridine and arylsulfonyl chloride (ArSO 2 Cl) to give the O-benzyl protected arylsulfonamide, which was deprotected by catalytic hydrogenation to give the alcohol intermediate 18-A. The preparation of the final compound was accomplished according to the Mitsunobu conditions described in Scheme 2, Step 1.

[0701] Example 19:

[0702] General Synthesis of Representative Sulfonylurea Isosteres

[0703]

[0704] Reagents: (i) NaH, DMF, BnBr; (ii) Mg, THF; DABSO; SO 2 Cl 2 NH 4 OH; (iii) base (K 2 CO 3 , Et 3 N, i-Pr 2 EtN), DPPA, HOAc; (iv) H 2 , Pd / C, MeOH; (v) See Scheme 2, Step 1.

[0705] A solution of 3-bromobenzyl alcohol in DMF was treated with NaH and benzyl bromide to form 1-((benzyloxy)methyl)-3-bromobenzene, which was converted to the Grignard reagent in a separate step by dissolving in dry THF and treating with Mg. The Grignard reagent was reacted with DABSO, sulfonyl chloride and ammonium hydroxide according to Woolven, H. et al. (Org. Lett. 13:4876, 2011) to give the O-benzyl protected sulfonamide intermediate 19-A. INT 19-A was treated with base, DPPA and acetic acid according to the method of Lockhurst, Ca et al. (Tet. Lett. 48:8878, 2007) to give the O-benzyl protected sulfonylurea, intermediate 19-B. INT 19-B was deprotected by catalytic hydrogenation to give the free alcohol intermediate, which was converted to the final compound according to the Mitsunobu conditions described in Scheme 2, Step 1.

[0706] Example 20:

[0707] General Synthesis of Representative N-Acylsulfonamide Isosteres

[0708]

[0709] Reagents: (i) ZnCl 2 ,Ac 2 O; (ii) H 2 , Pd / C, MeOH; (iii) See Scheme 2, Step 1.

[0710] According to Pham, MV et al., Angew. Chem IE 51:10610, 2012), intermediate 19-A (see Example 19) was reacted with ZnCl 2 and acetic anhydride (Ac 2O) to give 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 conditions described in Scheme 2, Step 1.

[0711] Example 21:

[0712] General Synthesis of Representative N-Hydroxyamide Isosteres

[0713]

[0714] Reagents: (i) EtCO 2 Cl, NMM, DMF; (ii) NH 2 OHMeOH.

[0715] The compound of formula (I) wherein A is phenyl and R is carboxylic acid is dissolved in DMF and cooled to 0°C. Ethyl chloroformate (1.2 equivalents) and N-methylmorpholine (1.3 equivalents) are added successively and the mixture is stirred for 10 minutes. Hydroxylamine (2 equivalents) is added in methanol and the reaction is warmed to room temperature and stirred overnight. Conventional post-treatment and purification are to obtain the desired N-hydroxyamide product.

[0716] Example 22:

[0717] General Synthesis of Representative Phosphinic Acid Isosteres

[0718]

[0719] Reagents: (i) see Scheme 2, Step 1; (ii) methyl phosphinate, Pd(OAc) 2 PPh 3 , NMM, MeCN; (iii) HCl, H 2 O.

[0720] 3-Iodobenzyl alcohol was converted to intermediate 22-A according to Mitsunobu conditions described in Scheme 2, Step 1. A palladium-catalyzed cross-coupling reaction (Pd(OAc)) was used as described by Grady, HL ("Preparation of arylphosphinic acid derivatives as building blocks for binding sites", Retrospective Thes and Dissertations, 10373, 1992) to obtain 22-A. 2 and PPh 3 The aryl iodide is converted to an alkyl phosphinate using methyl phosphinate in acetonitrile in the presence of NMM as a base. The aryl phosphinic acid product is obtained by hydrolysis of the alkyl phosphinate in aqueous HCl.

[0721] Example 23:

[0722] General Synthesis of Representative Phosphonic Acid Isosteres

[0723]

[0724] Reagents: (i) See Scheme 2, Step 1; (ii) HPO(Oi-Pr) 2 、Pd(OAc) 2 , CM-Phos, t-BuOH / i-PrOH, DIPEA; (iii) HCl, H 2 O.

[0725] 3-Bromobenzyl alcohol was converted to intermediate 23-A according to the Mitsunobu conditions described in Scheme 2, Step 1. The palladium-catalyzed cross-coupling reaction (Pd(OAc)) described by Fu, CW et al., (Organ Express 17:5906, 2015) was used. 2 The aryl bromide was converted into a dialkylphosphonate by using a phosphonic acid ester (with CM-phosphorus as a ligand) in which an alcohol solvent containing diisopropyl phosphite was used with DIPEA as a base. The arylphosphonic acid product was obtained by hydrolysis of the dialkylphosphonate in aqueous HCl.

[0726] Example 24:

[0727] General Synthesis of Representative Pyrrolidine-2,4-dione Isosteres

[0728]

[0729] Reagents: (i) ethylmalonyl chloride, CH 2 Cl 2 , Et 3 N; (ii) KHMDS, toluene; (iii) HBr, water; (iv) H 2 , Pd / C, MeOH; (v) See Scheme 2, Step 1.

[0730] The conversion of the starting phenylglycine amino acid derivative to pyrrolidine-2,4-dione is accomplished by a three-step addition / cyclization / decarboxylation sequence described in WO2007 / 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 conditions described in step 1 of Scheme 2. The starting material amino acid methyl esters can be prepared by various methods known to those skilled in the art; for example, synthesized from 3-((benzyloxy)methyl)benzaldehyde (as described below) by Strecker amino acid synthesis and esterification.

[0731] Example 25:

[0732] General Synthesis of Representative Pyrfuran-2,4-dione Isosteres

[0733]

[0734] Reagents: (i) NaH, DMF, BnBr; (ii) LDA, THF, (iii) HBr, water; (iv) H 2 , Pd / C, MeOH; (v) See Scheme 2, Step 1.

[0735] 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 as described in WO2007 / 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 conditions described in Scheme 2, Step 1.

[0736] Example 26:

[0737] General Synthesis of Representative Cyclopentane-1,3-dione Isosteres

[0738]

[0739] Reagents: (i) NaH, DMF, BnBr; (ii) t -BuLi, Et 2 O; CuI; (iii) HF / pyridine, CH 3 CN; (iv) Jones reagent, acetone; (v) H 2 , Pd / C, MeOH; (vi) See Scheme 2, Step 1.

[0740] A solution of 3-bromobenzyl alcohol in DMF was treated with NaH and benzyl bromide to form 1-((benzyloxy)methyl)-3-bromobenzene. This intermediate was 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 was deprotected by catalytic hydrogenation to give the free alcohol, which was converted to the final compound according to the Mitsunobu conditions described in Scheme 2, Step 1.

[0741] Example 27:

[0742] General Synthesis of Representative Difluorophenol Isosteres

[0743]

[0744] Reagents: (i) See Scheme 11, Step 1; (ii) See Scheme 2, Step 1.

[0745] 3-Bromobenzyl alcohol and commercially available 4-hydroxy-3,5-difluorophenylboronic acid were coupled according to the Suzuki coupling method described in Example 11 to give intermediate 27-A, which was converted to the final compound according to Mitsunobu conditions described in Scheme 2, Step 1.

[0746] Example 28:

[0747] General Synthesis of Representative 3-Substituted 5-Oxo-Thiadiazole Isosteres

[0748]

[0749] Reagents: (i) NaH, DMF, BnBr; (ii) NH 2 OH.HCl, Et 3 N, EtOH; (iii) TCDI, THF; BF 3 -OEt 2 / THF; (iv)H 2 , Pd / C, MeOH; (v) See Scheme 2, Step 1.

[0750] A solution of 3-cyanobenzyl alcohol in DMF is treated with NaH and benzyl bromide to form 3-((benzyloxy)methyl)benzonitrile. According to Kohara, Y. et al. (J. Hetercyclic Chem. 37:1419, 2000), the aryl cyanide is then converted to the 3-substituted 5-oxo-thiadiazole in two steps 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 conditions described in Scheme 2, Step 1.

[0751] Example 29:

[0752] General Synthesis of Representative 3-Substituted Oxadiazolone Isosteres

[0753]

[0754] Reagents: (i) NaH, DMF, BnBr; (ii) NH 2 OH.HCl, Et 3 N, EtOH; (iii) CDI, DBU, 1,4-dioxane; (iv) H 2 , Pd / C, MeOH; (v) See Scheme 2, Step 1.

[0755] A solution of 3-cyanobenzyl alcohol in DMF was treated with NaH and benzyl bromide to form 3-((benzyloxy)methyl)benzonitrile. The aryl cyanide was then converted to the 3-substituted oxadiazolone in two steps to give intermediate 29-A according to Yu, X. et al. (Organic Express 18:5412, 2-016). This intermediate was deprotected by catalytic hydrogenation to give the free alcohol, which was converted to the final compound according to the Mitsunobu conditions described in Scheme 2, Step 1.

[0756] Example 30:

[0757] General Synthesis of Representative Thiazolidine 2,4-Dione Isosteres

[0758]

[0759] Reagents: (i) NaH, DMF, BnBr; (ii) ZnI 2 、TMSCN;HCl(concentration);(iii)MeOH, type salicylaldehyde;(iv)SOCl 2 , pyridine; thiourea, NaOAc, EtOH; HCl (aqueous solution), EtOH; (v) H 2 , Pd / C, MeOH; (vi) See Scheme 2, Step 1.

[0760] Commercially available 3-hydroxymethylbenzaldehyde is reacted with NaH and benzyl bromide to form 3-((benzyloxy)methyl)benzaldehyde. According to Sirimanne and Patterson (J. Label. Cmpd. Radiopharm. 33:725, 1993), the resulting ether aldehyde is converted to mandelic acid to first give a mandelic acid derivative, which is esterified to give intermediate 30-A. According to Koyama et al. (Biorg. Med. Chem. Lett. 13:1801, 2003), intermediate 30-A is converted to thiazolidine-2,4-dione and catalytic hydrogenation is used to deprotect the alcohol to give intermediate 30-B. Alcohol 30-B is converted to the final compound according to the Mitsunobu conditions described in Scheme 2, Step 1.

[0761] Example 31:

[0762] Alternative synthesis of compound 1-56 and synthesis of 31-2

[0763]

[0764] Scheme 31

[0765]

[0766] Reagent (i) NaBH 4 , DCM, MeOH; (ii) SOCl 2 , DCM; (iii) K 2 CO 3 , CH 3 CN; (iv) NaOH, solvent (THF, MeOH or DMF).

[0767] Step 31-1. Synthesis of methyl 6-(hydroxymethyl)picolinate (INT 31-A)

[0768]

[0769] To a stirred solution of dimethyl pyridine-2,6-dicarboxylate (20 g, 102.5 mmol) in MeOH (20 mL) was added sodium borohydride (5.81 g, 153.7 mmol) in 3 portions at 0°C. The reaction mixture was warmed to room temperature and stirred for 1 hour. The reaction mixture was washed with NH 4 The mixture was diluted with Cl(aq) (10 mL) and extracted with EA (3 x 500 mL) and EA (10 mL). The combined organic layers were dried (Na 2 SO 4 ), concentrated in vacuo and filtered through SiO 2 Chromatography (10% MeOH in EA / hexanes) gave 12 g (70%) of methyl 6-(hydroxymethyl)pyridine-2-carboxylate (INT 31-A) as a white solid. TLC (EA): R f =0.60.

[0770] Step 31-2. Synthesis of methyl 6-(chloromethyl)picolinate (INT 31-B)

[0771]

[0772] To a flask containing a stirred solution of INT 31-A (5.00 g, 29.9 mmol) in DCM (62.5 mL) was charged with thionyl chloride (4.36 mL, 59.8 mmol) at room temperature. After stirring for 14 h, saturated K 2 CO 3 The aqueous solution was added to adjust the pH to 10-11. The organic layer was collected and the aqueous layer was back extracted twice with DCM. The organic layers were combined, washed with brine, and dried (Na2O3). 2 SO 4 ), and through SiO 2 Purification by chromatography (EA / hexanes) gave 3.9 g (69.7%) of methyl 6-(chloromethyl)picolinate (INT 31-B) as a colorless oil which solidified upon standing to give a white crystalline powder. 8 H 8ClNO 2 LCMS-ESI (m / z) calculated value: 185.61; m / z 186.1 (M+H) + , t R = 3.64 minutes (method 1). 1 HNMR (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).

[0773] Step 31-3. Preparation of methyl 6-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)picolinate (Compound 31-C) synthesis

[0774]

[0775] A flask containing INT 31-C (3.861 g, 20.8 mmol) was charged with a solution of 2-chloro-4-(trifluoromethyl)phenol (4.497 g, 22.9 mmol) in MeCN (70 mL) and then K 2 CO 3 (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 hours, the reaction mixture was cooled to room temperature and treated with H 2 O diluted and Et 2 O was extracted 3 times. The organic layers were combined, washed with brine, and dried (Na 2 SO 4 ), and through SiO 2 Chromatography (EA / hexanes) gave 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 CIF 3 NO 3 LCMS-ESI (m / z) calculated value: 345.70; found value: 346.1 [M+H] + , t R =5.99 minutes (method 1).

[0776] Step 31-4. Synthesis of 6-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)picolinic acid (Compound 1-56)

[0777]

[0778] To a flask containing a stirred solution of INT 31-C (500 mg, 1.45 mmol) in THF (7.23 mL) was charged 1 M NaOH (7.23 mL, 7.23 mmol). After stirring at 50 °C for 17 h, the mixture was washed with THF and H 2 O dilution, however, no distinct layer was observed. Addition of Et 2 O to achieve separation of the organic layer and the aqueous layer. The aqueous layer was collected and acidified to pH 3-4 using 3M HCl. The resulting white precipitate was washed with Et 2 O was extracted 3 times, and the combined organic extracts were washed with brine, dried (Na 2 SO 4 ) 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 H 9 CIF 3 NO 3 The LCMS-ESI (m / z) calculated value is: 331.68; the found value is: 332.1 [M+H] + , t R =5.34 minutes (Method 1).

[0779] Synthesis of compound 31-2

[0780]

[0781] Step 31-5. Synthesis of dimethyl 4-ethylpyridine-2,6-dicarboxylate (INT 31-D)

[0782]

[0783] To dimethyl pyridine-2,6-dicarboxylate (10 g, 51.2 mmol) and propionaldehyde (18.7 mL, 256.2 mmol) was added H 2 SO 4 FeSO (100 mL) was added dropwise to the solution 4 (5.70 g, 20.49 mmol) and 30% H 2 O 2 (9.9 mL, 102.5 mmol) for 15 minutes. After stirring at 0°C for 15 minutes, the mixture was washed with saturated K 2 CO 3 The organic layer was dried (Na2O3) and diluted with EA. 2 SO 4 ), concentrated in vacuo and filtered through SiO 2Chromatography (petroleum ether / EA) gave 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 HNMR (400MHz, CDCl 3 )δ8.13-8.20(m,2H)4.00-4.03(m,6H)2.78-2.87(m,2H)1.29-1.37(m,3H).

[0784] Step 31-6. Synthesis of methyl 4-ethyl-6-(hydroxymethyl)picolinate (INT 31-E)

[0785]

[0786] To a solution of INT-31-D (4.5 g, 20.2 mmol) in MeOH (80 mL) and DCM (20 mL) was added NaBH 4 (1.14 g, 30.24 mmol). After stirring at 20°C for 12 hours, the mixture was washed with saturated NH 4 The organic layer was dried (Na2O3) and diluted with aqueous Cl solution and extracted with EA. 2 SO 4 ), concentrated in vacuo and filtered through SiO 2 Chromatography (petroleum ether / EA) gave 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 (400 MHz, CDCl 3 )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).

[0787] Step 31-7. Synthesis of methyl 6-(chloromethyl)-4-ethylpicolinate (INT 31-F)

[0788]

[0789] To a solution of INT-31-E (2.8 g, 14.34 mmol) in DCM (100 mL) was added SOCl at 0 °C. 2(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 any further purification. 10 H 12 ClNO 2 LCMS-ESI (m / z) calculated value: 213.66; found value: 214.0 [M+H] + , t R = 0.842 min (Method 6).

[0790] Step 31-8. 6-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-4-ethylpicolinate (INT Synthesis of 31-G)

[0791]

[0792] 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 K 2 CO 3 (4.85 g, 35.10 mmol). The suspension was stirred at 80°C for 12 hours, cooled and filtered to collect the residue, which was passed through SiO 2 Chromatography (PE:EA) purification gave 4 g (82%) of methyl 6-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-4-fluorobenzoate (INT-31-G) as a light yellow solid. TLC (3:1 petroleum ether:EA): R f =0.55. 1 H NMR (400 MHz, CDCl 3 )δppm 1.32(t,J=7.58Hz,3H)2.79(q,J=7.62Hz,2H)4.03-4.05(m,3H)5.40(s,2H)7.0 6(d,J=8.56Hz,1H)7.50(dd,J=8.68,1.59Hz,1H)7.67-7.74(m,2H)7.97(s,1H).

[0793] Step 31-9. 6-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-4-ethylpicolinic acid (Compound 31-2) Synthesis

[0794]

[0795] INT-31-G (3.4 g, 9.1 mmol) and LiOH-H 2 O (1.15 g, 27.3 mmol) in THF (5 mL) and H2 The solution in 2% O (1 mL) was stirred at 30° C. for 12 h. The reaction mixture was acidified to pH 6 with 1N HCl and then extracted into EA. The combined organic extracts were dried (Na 2 O). 2 SO 4 ), concentrated and dissolved in MeCN. H 2 O to produce a white precipitate, which was collected by filtration and washed with H 2 The resulting filter cake was lyophilized to give 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 CIF 3 NO 3 LCMS-ESI (m / z) calculated value: 359.7; found value: 360.0 [M+H] + , t R = 0.95 min (Method 5-95AB_R_220&254.1 cm). 1 H NMR (400 MHz, CDCl 3 )δppm 8.07(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).

[0796] Example 32:

[0797] Synthesis of compound 32-1

[0798]

[0799] Scheme 32

[0800]

[0801] Reagent (i) Thionyl-Cl, POCl 3 、MeOH;(ii)SOCl 2 , DCM; (iii) K 2 CO 3 , CH 3 CN; (iv) NaOH, solvent (THF, MeOH or DMF).

[0802] Step 32-1. Synthesis of methyl 3-cyano-5-methylbenzoate (INT 32-A)

[0803]

[0804] Thionyl chloride (7 mL) was added to 3-(methoxycarbonyl)-5-methylbenzoic acid (1.5 g, 7.7 mmol). After stirring at reflux for 1 hour, the reaction mixture was dissolved and concentrated with toluene three times. The residue was dissolved in DCM (5 mL) and added to NH 4 OH (5 mL) was added to give a white precipitate. The reaction mixture was stirred at 0 °C for 5 minutes. H 2 O and EA, and the mixture was filtered to obtain 1.40 g of a white solid. POCl was added to the filtered solid 3 (4.7 mL) and the reaction mixture was heated at 100 °C for 1 h. The reaction mixture was cooled, concentrated in vacuo, dissolved in DCM, and washed with saturated NaHCO 3 The mixture was extracted with EA (2×20 mL) and dried (Na 2 SO 4 ), filtered and concentrated in vacuo to give 1.15 g of crude material. The crude material was filtered through SiO 2 Chromatography (EA / hexanes) gave 952 mg (70%) of methyl 3-cyano-5-methylbenzoate (INT 32-A) as a white solid. 10 H 9 NO 2 The LCMS-ESI (m / z) calculated value is: 175.19; the found value is: 176.2 [M+H] + , t R =4.87 minutes (Method 1). 1 HNMR (500MHz, CDCl 3 )δ8.12(br s,1H),8.07(brs,1H),7.63(br s,1H),3.94(s,3H),2.45(s,3H).

[0805] Step 32-2. Synthesis of methyl 3-(bromomethyl)-5-cyanobenzoate (INT 32-B)

[0806]

[0807] INT 32-A (0.50 g, 2.9 mmol) was dissolved in CCl 4 To a stirred solution of 1% ethyl acetate (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 filtered through SiO 2Chromatography (EA / hexanes) gave 247 mg (34%) of methyl 3-(bromomethyl)-5-fluorobenzoate (INT 32-B) as a white solid. 10 H 8 BrNO 2 LCMS-ESI (m / z) calculated value: 254.08; m / z 255.2 (M+H) + , t R =5.05 min (Method 1).

[0808] Step 32-3. Methyl 3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-5-cyanobenzoate (INT 32- C) Synthesis

[0809]

[0810] 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 K 2 CO 3 (87.7 mg, 634 μmol). After heating at 60 °C for 12 h, the reaction mixture was cooled to room temperature and precipitated with H 2 The aqueous layer was diluted with Et 2 O (2 × 6 mL) and EA (6 mL), dried (Na 2 SO 4 ), 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 CIF 3 NO 3 The LCMS-ESI (m / z) calculated value is: 369.72; the found value is: 370.0 [M+H] + , t R = 6.39 minutes (method 1).

[0811] Step 32-3. 3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-5-cyanobenzoic acid (Compound 32-1) Synthesis

[0812]

[0813] To a vial containing a stirred solution of INT 32-C (146.1 mg, 395.2 μmol) in MeOH (2 mL) and THF (2 mL) was charged solid NaOH (79 mg, 1.98 mmol). After stirring at 50 °C for 12 h, the reaction mixture was treated with H 2O and acidified to pH 4-5 using 3M HCl. The resulting white precipitate was washed with Et 2 O (3×10 mL) and EA (2×10 mL). The organic layers were combined, washed with brine, and dried (Na 2 SO 4 ) and concentrated under reduced pressure to give a crude solid which was purified by reverse phase HPLC (H 2 O / CH 3 CN). The combined pure fractions were lyophilized to give 82.6 mg (59%) of 3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-5-cyanobenzoic acid (Compound 32-1) as a white solid. 16 H 9 CIF 3 NO 3 LCMS-ESI (m / z) calculated value: 355.0; found value: 354.0 [M+H] + , t R = 10.07 min (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).

[0814] The compounds listed in Table 32 were prepared using the procedure of Scheme 32.

[0815] Table 32

[0816]

[0817] Example 33:

[0818] Synthesis of compound 33-1

[0819]

[0820] Scheme 33

[0821]

[0822] Reagents: (i) Base (Na 2 CO 3 , K 2 CO 3 KO tBu), solvent (THF or DMF); ii. diethylaminosulfur trifluoride, DCM; iii. NaOH, solvent (THF, MeOH or DMF).

[0823] Step 33-1. Synthesis of methyl 3-((2-formylphenoxy)methyl)benzoate (INT 33-A)

[0824]

[0825] 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 K 2 CO 3 (235 mg, 1.70 mmol). After heating at 60 °C for 18 h, the mixture was cooled to room temperature and precipitated with H 2 O (6 mL), and the aqueous layer was washed with Et 2 O (2 x 6 mL) and EA (6 mL). The combined organic layers were dried (Na 2 SO 4 ), filtered through celite and passed through SiO 2 Chromatography (EA / hexanes) gave 315 mg (89%) of methyl 3-((2-formylphenoxy)methyl)benzoate (INT 33-A) as a white solid. 16 H 14 O 4 The LCMS-ESI (m / z) calculated value is: 270.1; the measured value is: 271.5 (M+H) + , t R =5.4 minutes (Method 1).

[0826] Step 33-2. Synthesis of methyl 3-((2-(difluoromethyl)phenoxy)methyl)benzoate (INT 33-B)

[0827]

[0828] 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 room temperature and quenched with H 2 O and extracted with DCM (3×5 mL). The combined organic extracts were dried (Na 2 SO 4 ), filtered, concentrated in vacuo and filtered through SiO 2Chromatography (EA / hexane) gave 28.7 mg (53%) of methyl 3-((2-(difluoromethyl)phenoxy)methyl)benzoate (INT33-B). 16 H 14 F 2 O 3 The LCMS-ESI (m / z) calculated value is: 292.28; the measured value is: 273.2 (M+H) + , t R =5.94 minutes (Method 1). 1 H NMR (500 MHz, CDCl 3 )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).

[0829] Step 33-3. Synthesis of 3-((2-(difluoromethyl)phenoxy)methyl)benzoic acid (Compound 33-1)

[0830]

[0831] 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 Et 2 The combined organic layers were dried (Na 2 SO 4 ), 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. 15 H 12 F 2 O 3 LCMS-ESI (m / z) calculated value: 278.3; found value: 277.2 [M+H] + , t R = 8.02 min (Method 4). 1H 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).

[0832] The compounds listed in Table 33 were prepared using the procedure of Scheme 33.

[0833] Table 33

[0834]

[0835] Example 34:

[0836] Synthesis of compound 34-1

[0837]

[0838] Scheme 34

[0839]

[0840] Reagents: (i) Base (Na 2 CO 3 , K 2 CO 3 KO t Bu), solvent (THF or DMF); ii. tricyclohexylphosphine, potassium phosphate, Pd(OAc) 2 , boric acid, toluene; iii. NaOH, solvent (THF, MeOH or DMF).

[0841] Step 34-1. Synthesis of methyl 3-((2-bromo-4-(trifluoromethyl)phenoxy)methyl)benzoate (INT 34-A)

[0842]

[0843] To a vial containing a stirred solution of 2-bromo-4-(trifluoromethyl)phenol (316 mg, 1.31 mmol) in MeCN (5 mL) was charged methyl 3-(bromomethyl)benzoate (300 mg, 1.31 mmol) and K 2 CO 3 (235 mg, 1.70 mmol). The resulting yellow suspension was stirred at 60 °C for 16 h, cooled to room temperature, and quenched with H 2 O diluted and Et 2 O was extracted 3 times. The organic layers were combined, washed with brine, concentrated under reduced pressure, and filtered through SiO 2Chromatography (EA / hexanes) gave 451 mg (88.5%) of methyl 3-((2-bromo-4-(trifluoromethyl)phenoxy)methyl)benzoate (INT 34-A) as a white solid. 16 H 12 F 3 O 3 The LCMS-ESI (m / z) calculated value is: 389.2; the found value is: 391.0 (M+H) + , t R = 6.7 minutes (method 1).

[0844] Step 34-2. Preparation of methyl 3-((2-cyclopropyl-4-(trifluoromethyl)phenoxy)methyl)benzoate (INT 34-B) synthesis

[0845]

[0846] To a 15 mL pressure tube containing a mixture of INT 34-A (300 mg, 771 μmol) in toluene (4 mL) was charged 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 heated in Et 2 O and H 2 The aqueous layer was partitioned with Et 2 O back extraction (2 times). The organic layers were combined, washed with brine, and dried (Na 2 SO 4 ), concentrated under reduced pressure, and filtered through SiO 2 Chromatography (EA / hexane) gave 201 mg (74%) of methyl 3-((2-cyclopropyl-4-(trifluoromethyl)phenoxy)methyl)benzoate (INT 34-B). 19 H 17 F 3 O 3 The LCMS-ESI (m / z) calculated value is: 350.34; the measured value is: 373.2 (M+Na) + , t R = 6.8 minutes (method 1). 1H 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,J=8.6Hz,1H),7.15(d,J=2.3Hz,1H),5.34(s,2H),3.86(s,3H),2.18(tt,J=8.5,5.3Hz,1H),1.01–0.91(m,2H),0.76–0.69(m,2H).

[0847] Step 34-3. Synthesis of 3-((2-cyclopropyl-4-(trifluoromethyl)phenoxy)methyl)benzoic acid (Compound 34-1) become

[0848]

[0849] To a stirred solution of INT 34-B (195 mg, 557 μmol) in THF (5 mL) was added 1 M NaOH solution (2.23 mL, 2.23 mmol). The solution was stirred at 50 °C overnight for 12.5 h, concentrated under reduced pressure, dissolved in H 2 O and acidified to pH 4-5 using 3M HCl. The resulting white precipitate was extracted three times into Et 2 The organic layers were combined, washed with brine, and dried (Na 2 SO 4 ) and concentrated under reduced pressure to give a crude product which was purified by preparative HPLC (CH 3 CN / H 2 O) 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 F 3 O 3 LCMS-ESI (m / z) calculated value: 336.3; found value: 335.2 [M+H] + , t R = 10.83 minutes (Method 4). 1 H NMR (499 MHz, DMSO-d 6)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 (376 MHz, DMSO-d 6 )δ-59.98.

[0850] Example 35:

[0851] Synthesis of compound 35-1

[0852]

[0853] Scheme 35

[0854]

[0855] Reagents: (i) Base (Na 2 CO 3 , K 2 CO 3 KO t Bu), solvent (THF, dioxane or DMF); iii. NaOH, solvent (THF, MeOH or DMF).

[0856] Step 35-1. Methyl 3-(((3-chloro-5-(trifluoromethyl)pyridin-2-yl)oxy)methyl)benzoate (INT Synthesis of 35-A)

[0857]

[0858] 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, the reaction mixture was heated at 90 ° C for 15.5 hours, and then cooled to room temperature. The reaction mixture was heated in Et 2 O and H 2 The phases were separated and the aqueous layer was washed with Et 2 O extraction (2 times). The organic phases were combined, washed with brine, and dried (Na 2 SO 4), concentrated, and passed through SiO 2 Chromatography (EA / hexanes) gave 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 CIF 3 NO 3 The LCMS-ESI (m / z) calculated value is: 345.7; the found value is: 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).

[0859] Step 35-2. 3-(((3-chloro-5-(trifluoromethyl)pyridin-2-yl)oxy)methyl)benzoic acid (Compound 35- 1) Synthesis

[0860]

[0861] To a 20 mL vial containing a stirred solution of INT 35-A (190 mg, 550 μmol) in THF (5 mL) was charged 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 H 2 O and acidified to pH 4-5 using 3M HCl. The resulting white precipitate was washed with Et 2 O extraction (3 times). The organic layers were combined, washed with brine, and dried (Na 2 SO 4 ) 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 solid. 14 H 9 CIF 3 NO 3 The LCMS-ESI (m / z) calculated value is: 331.7; the measured value is: 333.2 (M+Na) + , t R = 10.1 min (Method 3). 1H 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 (376 MHz, DMSO-d 6 )δ-60.02.

[0862] Example 36:

[0863] Synthesis of compound 36-1

[0864]

[0865] Scheme 36

[0866]

[0867] Reagents: (i) Base (Na 2 CO 3 , K 2 CO 3 KO t Bu), solvent (THF, dioxane or DMF); (ii) ethynyl(trimethyl)silane, dichloropalladium, triphenylphosphine, CuI, TEA, THF; (iii) NaOH, solvent (THF, MeOH or DMF).

[0868] Step 36-1. Methyl 2-fluoro-3-((2-iodo-4-(trifluoromethyl)phenoxy)-methyl)benzoate (INT 36- A) Synthesis

[0869]

[0870] INT 4-A (300 mg, 1.21 mmol) and 2-iodo-4-(trifluoromethyl)phenol (349.72 mg, 1.21 mmol) were stirred in CH 3 K was added to the solution in CN (10 mL) 2 CO 3 (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 give 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 F 4 IO 3LCMS-ESI (m / z) calculated value: 454.16; found value: 454.9 (M+H) + , t R = 1.04 min (Method 6).

[0871] Step 36-2. 2-Fluoro-3-((4-(trifluoromethyl)-2-((trimethylsilyl)ethynyl)phenoxy)methyl Synthesis of methyl benzoate (INT 36-B)

[0872]

[0873] 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 12 h at 40 °C, the mixture was poured into H 2 O (20 mL) and extracted with EA (3×20 mL). The organic layer was dried (Na 2 SO 4 ) was dried, concentrated, and filtered through SiO 2 Chromatography (PE, EA) gave 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 HNMR (400MHz, CDCl 3 )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).

[0874] Step 36-3. 3-((2-ethynyl-4-(trifluoromethyl)phenoxy)methyl)-2-fluorobenzoic acid (Compound 36- 1) Synthesis

[0875]

[0876] INT 36-B (185 mg, 0.44 mmol) was dissolved in MeOH (5 mL) and H 2To a suspension of 1% dHO (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 (HPLC). 2 O / CH 3 CN, containing formic acid) to give 59 mg (48%) of 3-((2-ethynyl-4-(trifluoromethyl)phenoxy)methyl)-2-fluorobenzoic acid (Compound 36-1) as a white solid. 17 H 10 F 4 O 3 The LCMS-ESI (m / z) calculated value is: 338.3; the measured value is: 339.1 (M+Na) + , t R = 0.786 min (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).

[0877] Example 37:

[0878] Synthesis of compound 37-1

[0879]

[0880] Scheme 37

[0881]

[0882] Reagents: (i) dioxaborane or boric acid, Pd(dppf)Cl 2 -CH 2 Cl 2 , dioxane; (ii) H 2 , Pd / C, MeOH; (iii) NaBH 4 , MeOH; (iv) SOCl 2 , DCM; (v) alkali (Na 2 CO 3 , K 2 CO 3 KO t Bu), solvent (THF, dioxane or DMF); (iv) NaOH, solvent (THF, MeOH or DMF).

[0883] Step 37-1. Synthesis of methyl 3-(hydroxymethyl)-2-vinylbenzoate (INT 37-A)

[0884]

[0885] To dimethyl 2-bromobenzene-1,3-dicarboxylate (1 g, 3.66 mmol) and Na 2 CO 3 (776.25 mg, 7.32 mmol) in 1,4-dioxane (20 mL) and H 2 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (683.25 μL, 4.03 mmol) was added to the suspension in 2% CO (4 mL). The reaction mixture was treated with Pd(dppf)Cl 2 -CH 2 Cl 2 (149.5 mg, 183.1 μmol) and stirred at 100°C for 12 hours. The mixture was filtered. The filtrate was stirred in EA (30 ml) and H 2 The aqueous layer was back extracted with EA (30 ml). The combined organic extracts were dried (Na 2 SO 4 ), filtered and concentrated in vacuo to give a residue which was filtered through SiO 2 Chromatography gave 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.

[0886] Step 37-2. Synthesis of methyl 2-ethyl-3-(hydroxymethyl)benzoate (INT 37-B)

[0887]

[0888] At 30 °C, H 2 (15 psi) was bubbled into a solution of INT 37-A (680 mg, 3.09 mmol), Pd / C (70 mg, 308.8 umol, 10% purity) in MeOH (10 mL) for 12 h. The reaction mixture was filtered and the filtrate was concentrated to give the crude product, which was filtered through SiO 2 Chromatography (EA / PE) gave 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 HNMR (400MHz, CDCl 3)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).

[0889] Step 37-3. Synthesis of methyl 2-ethyl-3-(hydroxymethyl)benzoate (INT 37-C)

[0890]

[0891] To a solution of INT 37-B (0.4 g, 1.80 mmol) in THF (10 mL) was added NaBH at 0 °C. 4 (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 4 Cl (20 mL aqueous solution) and extracted with EA (3×20 mL). The combined organic layers were dried (Na 2 SO 4 ), concentrated in vacuo and purified by preparative TLC to give 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.

[0892] Step 37-4. Synthesis of methyl 3-(chloromethyl)-2-ethylbenzoate (INT 37-D)

[0893]

[0894] To a solution of INT 37-C (70 mg, 360.4 μmol) in DCM (2 mL) was added SOCl at 0 °C. 2 (130.7 μL, 1.80 mmol). After stirring at 30°C for 1 hour, the reaction mixture was concentrated in vacuo to give 72 mg (94%) of 3-(chloromethyl)-2-ethyl-benzoic acid methyl ester (INT 37-D) as a brown gum, which was used in the next step without any further purification. TLC (5:1 PE:EA): R f =0.7.

[0895] Step 37-5. Methyl 3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-2-ethylbenzoate (INT 37- E) Synthesis

[0896]

[0897] INT 37-D (70 mg, 329.15 μmol) and K 2 CO 3(136.47 mg, 987.44 μmol) in CH 3 To the suspension in CN (2 mL) was added 2-chloro-4-(trifluoromethyl)phenol (71.16 mg, 362.06 μmol, 1.1 eq.). After stirring at 80 °C for 12 h, the reaction mixture was filtered and the filtrate was concentrated in vacuo to give a residue which was filtered through SiO 2 Chromatography (PE / EA) gave 59 mg (48%) of methyl 3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-2-fluorobenzoate (INT 37-E) as a light yellow gum. TLC (10:1 PE:EA): R f =0.75. C 18 H 16 CIF 3 O 3 LCMS-ESI (m / z) calculated value: 372.7; found value: 373.4 (M+H) + , t R = 1.14 minutes (Method 6). 1 H NMR (400 MHz, CDCl 3 )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).

[0898] Step 37-6. 3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-2-ethylbenzoic acid (Compound 37-1) Synthesis

[0899]

[0900] INT 37-E (156 mg, 418.5 umol) was dissolved in THF (3 mL), MeOH (1 mL) and H 2 To the solution in 1% HCl (1 mL) was added NaOH (42.92 mg, 1.07 mmol). After stirring at 50 °C for 12 h, the mixture was acidified with 3 M HCl and then stirred in EA (10 ml) and H 2 The organic layer was dried (Na2O3) and partitioned between 1% paraformaldehyde and 1% paraformaldehyde. 2 SO 4 ), filtered and concentrated in vacuo. The resulting residue was purified by preparative HPLC (H 2 O(0.225%FA)-CH3 CN) to obtain 144 mg (77%) of 3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-2-ethylbenzoic acid (Compound 37-1). 17 H 14 CIF 3 O 3 The LCMS-ESI (m / z) calculated value is: 358.7; the measured value is: 357.0 (MH) + , t R = 0.95 min (Method 8). 1 H NMR (400 MHz, CDCl 3 )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

[0901] Example 38:

[0902] Synthesis of compound 38-1

[0903]

[0904] Scheme 38

[0905]

[0906] Reagents: (i) Boc 2 O、DMAP、CH 3 CN; (ii) NBS, AIBN or BPO, CCl 4 ; (iii) Base (Na 2 CO 3 , K 2 CO 3 KO t Bu), solvent (THF, dioxane or DMF); (iv) acid (HCl, TFA), solvent (dioxane, THF); (v) MeI, K 2 CO 3 , CH 3 CN; (vi) NaOH, solvent (THF, MeOH or DMF).

[0907] Step 38-1 Synthesis of methyl 3-((tert-butyloxycarbonyl)amino)-5-methylbenzoate (INT 38-A)

[0908]

[0909] To 3-amino-5-methyl-benzoic acid methyl ester (1 g, 6.05 mmol, 1), di-tert-butyl dicarbonate (2.64 g, 12.11 mmol) and TEA (1.69 mL, 12.11 mmol) was added in CH 3 4-Dimethylaminopyridine (73.96 mg, 605.37 μmol) was added to a solution in CN (15 mL). The reaction mixture was stirred at 50 °C for 12 h and then filtered. The filtrate was concentrated and filtered through SiO 2 Chromatography (EA / PE) gave 850 mg (53%) of methyl 3-((tert-butyloxycarbonyl)amino)-5-methylbenzoate (INT 38-A) as a yellow gum. TLC (5:1 PE:EA): R f =0.7. 1 H NMR (400 MHz, CDCl 3 )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).

[0910] Step 38-2 Synthesis of methyl 3-(bromomethyl)-5-((tert-butoxycarbonyl)amino)benzoate (INT 38-B)

[0911]

[0912] INT 38-A (750 mg, 2.83 mmol) and NBS (604 mg, 3.39 mmol) were dissolved in CCl 4 AIBN (46 mg, 282 μmol) was added to the solution in 10 mL of 1% ethanol. After stirring at 80 °C for 12 h, the reaction mixture was filtered and filtered through SiO 2 Purification by chromatography (EA / PE) gave 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.

[0913] Step 38-3 3-((tert-Butyloxycarbonyl)amino)-5-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)benzyl Synthesis of methyl ester of INT38-C

[0914]

[0915] INT 38-B (560 mg, 1.63 mmol) and K 2 CO 3 (674.57 mg, 4.88 mmol) in CH 32-Chloro-4-(trifluoromethyl)phenol (351.76 mg, 1.79 mmol) was added to the suspension in CN (10 mL). After stirring at 80 °C for 12 h, the reaction mixture was filtered, concentrated and filtered through SiO 2 Chromatography gave 140 mg (18%) of methyl 3-((tert-butoxycarbonyl)amino)-5-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)benzoate (INT 38-C) as a light yellow gum. TLC (10:1 PE:EA): R f =0.60. C 21 H 21 CIF 3 NO 5 LCMS-ESI (m / z) calculated value: 459.85; found value: 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).

[0916] Step 38-4 Methyl 3-amino-5-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)benzoate (INT 38-D) Synthesis

[0917]

[0918] 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 hour. 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 grey solid which was used in the next step without further purification. TLC (10:1 PE:EA): R f =0.65.

[0919] Step 38-5 Methyl 3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-5-(dimethylamino)benzoate Synthesis of (INT 38-E)

[0920]

[0921] INT 38-D (50 mg, 138.99 μmol) and K 2 CO 3To a suspension of 1,4-dihydro- ... 2 Chromatography gave 12 mg (22%) of methyl 3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-5-(dimethylamino)benzoate (INT 38-E) as a light yellow gum. TLC (5:1 PE:EA): R f =0.8. C 18 H 17 CIF 3 NO 3 The LCMS-ESI (m / z) calculated value is: 387.8; the measured value is: 388 (MH) + , t R = 0.99 min (Method 6). 1 HNMR (400MHz, CDCl 3 )δppm 7.66(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).

[0922] Step 38-6 3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-5-(dimethylamino)benzoic acid (Compound Synthesis of 38-1)

[0923]

[0924] INT 38-E (12 mg, 30.95 μmol) was dissolved in THF (1 mL), MeOH (0.5 mL) and H 2 To the solution in 1% 4% HCl (0.5 mL) was added NaOH (4.95 mg, 123.78 μmol). After stirring at 50 °C for 4 h, the mixture was acidified with 3 M hydrochloric acid. The mixture was then stirred in EA (10 ml) and H 2 O (10 ml), and the resulting organic layer was dried (Na 2 SO 4 ), filtered and purified by preparative HPLC (H 2 O(0.225%FA)-CH 3 CN) to give 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 CIF 3 NO3 The LCMS-ESI (m / z) calculated value is: 373.76; the measured value is: 374.1 (MH) + , t R = 0.93 min (Method 6). 1 H NMR (400 MHz, CDCl 3 )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).

[0925] Example 39:

[0926] Synthesis of compound 39-1

[0927]

[0928] Scheme 39

[0929]

[0930] Reagents: (i) i PrMgCl-LiCl, 3-bromoprop-1-ene, CuCN, THF; (ii) Pd(dppf)Cl 2 , CO (gas), TEA, MeOH, DCM; (iii) Pd / C, H 2 (gas), MeOH; (ii) See Scheme 31.

[0931] Step 39-1. Synthesis of 4-allyl-2,6-dichloropyridine (INT 39-A)

[0932]

[0933] At -60°C i To a mixture of PrMgCl-LiCl (1 M, 12.78 mL) in THF (100 mL) 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. By adding H 2The reaction mixture was quenched with 4-allyl-2,6-dichloropyridine (INT 39-A) and quenched with 1,2-dihydro-2-nitropropene (2,4-dichloropyridine) (100 mL) and extracted with EA (3×50 mL). The combined organic layers were dried and concentrated to give a residue, which 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.

[0934] Step 39-2. Synthesis of dimethyl 4-allylpyridine-2,6-dicarboxylate (INT 39-B)

[0935]

[0936] To INT 39-A (1.4g, 7.44mmol), Pd(dppf)Cl 2 -CH 2 Cl 2 CO gas (20.85 g, 744.47 mmol) was bubbled into a solution of 4-(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 filtered through SiO 2 Chromatography (EA / PE) gave 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.

[0937] Step 39-3. Synthesis of dimethyl 4-propylpyridine-2,6-dicarboxylate (INT 39-C)

[0938]

[0939] 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 at 4 °C for 1 h. 2 The mixture was stirred at 25° C. for 12 h under 40 psi. The reaction mixture was filtered and concentrated to give a residue which was filtered through SiO 2 Chromatography (EA) gave 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 (400 MHz, CDCl 3)δppm 8.14(s,2H)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).

[0940] Step 39-4. 6-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-4-propylpicolinic acid (Compound 39- 1) Synthesis

[0941]

[0942] As shown in Scheme 31, the synthesis of compound 39-1 was completed by INT 39-C. 17 H 15 CIF 3 NO 3 LCMS-ESI (m / z) calculated value: 373.76; found value: 373.8 (M+H) + , t R = 0.786 min (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).

[0943] Example 40:

[0944] Synthesis of Compound 40-1

[0945]

[0946] Scheme 40

[0947]

[0948] Reagents: (i) Base (Na 2 CO 3 , K 2 CO 3 KO t Bu), solvent (THF, dioxane or DMF); (ii) NaOH, solvent (THF, MeOH or DMF).

[0949] Step 40-1. Synthesis of 3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)benzenesulfonamide (INT 40-A)

[0950]

[0951] 3-(Bromomethyl)benzenesulfonamide (100 mg, 400 μmol) was dissolved in CH 3 To a solution in CN (3 mL) was added 2-chloro-4-(trifluoromethyl)phenol (78.6 mg, 400 μmol) and K 2 CO 3 (111 mg, 800 μmol). After stirring at 30° C. for 12 hours, the mixture was concentrated to give a crude product, which was purified by preparative HPLC (H 2 O(0.225%FA) / CH 3 CN) to give 70 mg (48%) of 3-((2-chloro-4-(trifluoromethyl)phenoxy)-methyl)benzenesulfonamide (INT40-A) as a white solid. 14 H 11 CIF 3 NO 3 LCMS-ESI (m / z) calculated value of S: 365.8; found value: 364.0 (MH) + , t R = 0.967 min (Method 7).

[0952] Step 40-2. Synthesis of 3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)benzenesulfonic acid (Compound 40-1)

[0953]

[0954] 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 2 (9.6 mg, 139 μmol). After stirring at 40° C. for 12 hours, the mixture was concentrated to give a crude product, which was purified by preparative HPLC (H 2 O(0.1%TFA) / CH 3 CN) to give 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 CIF 3 O 4 LCMS-ESI (m / z) calculated value of S: 366.7; found value: 365.0 (MH) + , t R = 0.708 min (Method 7).

[0955] Example 41:

[0956] Synthesis of compound 41-1

[0957]

[0958] Scheme 41

[0959]

[0960] Reagents: (i) Pd(dppf)Cl 2 -CH 2 Cl 2 , CO (gas), TEA; (ii) see Scheme 31.

[0961] Step 41-1. Synthesis of dimethyl 4-methylpyridine-2,6-dicarboxylate (INT 41-A)

[0962]

[0963] 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 2 -CH 2 Cl 2 (504.05 mg, 617.22 μmol) and TEA (3.44 mL, 24.69 mmol). After stirring at 80 °C for 16 h under a CO (50 PSI) atmosphere, the reaction mixture was filtered, concentrated, and washed with H 2 O and extracted with EA (2×50 mL). The combined organic layers were dried (Na 2 SO 4 ), filtered, concentrated, and passed through SiO 2 Chromatography (EA / PE) gave 900 mg (68%) of dimethyl 4-methylpyridine-2,6-dicarboxylate (INT 41-A) as a yellow solid. TLC (2:1 EA:PE): R f =0.20. C 10 H 11 NO 4 The LCMS-ESI (m / z) calculated value is: 209.2; the measured value is: 210.6 (MH) + , t R = 0.756 min (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).

[0964] Step 41-2. Synthesis of 4-methyl-6-((naphthalen-2-yloxy)methyl)picolinic acid (Compound 41-1)

[0965]

[0966] 4-Methyl-6-((naphthalen-2-yloxy)methyl)picolinic acid (compound 41-1) was synthesized from INT41-A and naphthalen-2-ol according to Scheme 31 (steps i-iv) to give a white solid. 18 H 15 NO 3 The LCMS-ESI (m / z) calculated value is: 293.3; the measured value is: 294.2 (MH) + , t R = 0.789 min (Method 7). 1 H 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).

[0967] The compounds listed in Table 41 were prepared using the procedure of Scheme 41.

[0968] Table 41

[0969]

[0970] Example 42:

[0971] Synthesis of compound 42-1

[0972]

[0973] Scheme 42

[0974]

[0975] Reagents: (i) Aldehyde, aqueous solution, H 2 SO 4 、FeSO 4 、30%H 2 O 2 ; (ii) See Scheme 31.

[0976] Step 42-1. Synthesis of dimethyl 4-ethylpyridine-2,6-dicarboxylate (INT 42-A)

[0977]

[0978] Dimethyl pyridine-2,6-dicarboxylate (10 g, 51.2 mmol) and propionaldehyde (18.65 mL, 256.2 mmol) were added to H2O over 15 min. 2 SO 4FeSO (100 mL) was added dropwise to the solution 4 (5.70 g, 20.49 mmol) and 30% H 2 O 2 (9.85 mL, 102.47 mmol). After stirring at 0°C for 15 min, the mixture was washed with saturated K 2 CO 3 The solution was diluted with EA (3×200 mL) and the combined organic layers were dried (Na 2 SO 4 ), concentrated, through SiO 2 Chromatography (EA / PE) gave 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 (400 MHz, CDCl 3 )δ8.13-8.20(m,2H)4.00-4.03(m,6H)2.78-2.87(m,2H)1.29-1.37(m,3H).

[0979] Step 42-2. Synthesis of 4-ethyl-6-((naphthalen-2-yloxy)methyl)picolinic acid (Compound 42-1)

[0980]

[0981] 4-Ethyl-6-((naphthalen-2-yloxy)methyl)picolinic acid (compound 42-1) was synthesized from INT42-A and naphthalen-2-ol according to Scheme 31 (steps i-iv) and obtained as a pale yellow solid. 19 H 17 NO 3 LCMS-ESI (m / z) calculated value: 307.4; found value: 307.9 (MH) + , t R = 0.743 min (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).

[0982] The compounds listed in Table 42 were prepared using the procedure of Scheme 42.

[0983] Table 42

[0984]

[0985] Example 43:

[0986] Synthesis of compound 43-1

[0987]

[0988] Scheme 43

[0989]

[0990] Reagents: (i) PBr 3 Br 2 , hexane; (ii) NaBH 4 , MeoH, DCM; (iii) PBr 3 , CHCl 3 (iv) alkali (Na 2 CO 3 , K 2 CO 3 KO t Bu), solvent (THF, dioxane or DMF); (iv) Zn(CN) 2 、Pd(PPh 3 ) 4 , DMF; (v) NaOH, solvent (THF, MeOH or DMF).

[0991] Step 43-1. Synthesis of dimethyl 4-bromopyridine-2,6-dicarboxylate (INT 43-A)

[0992]

[0993] At 0°C, PBr 3 (1.61 mL, 16.9 mmol) was added to Br 2 (700 μL, 13.7 mmol) in hexane (10.0 mL). The mixture was stirred at 22 °C for 1 hour. 4-Hydroxypyridine-2,6-dicarboxylic acid (1.00 g, 5.46 mmol) was added and the mixture was stirred at 90 °C for 6 hours. The mixture was cooled and washed with CHCl 3 The mixture was concentrated and the residue was dissolved in DCM (50 mL) and washed with saturated NaHCO 3 The aqueous phase was extracted with DCM (4 x 50 mL) and the combined organic layers were dried (Na 2 SO4 ), filtered and concentrated under reduced pressure. The residue was filtered through SiO 2 Chromatography (EA / hexanes) gave 924 mg (62%) of dimethyl 4-bromopyridine-2,6-dicarboxylate (INT 43-A) as a solid. 9 H 8 BrNO 4 The LCMS-ESI (m / z) calculated value is: 274.07; the measured value is: 276.1 (MH) + , t R = 2.04 min (Method 13).

[0994] Step 43-2. ​​Synthesis of methyl 4-bromo-6-(hydroxymethyl)pyridine-2-carboxylate (INT 43-B)

[0995]

[0996] NaBH 4 (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). The mixture was stirred at 0 °C for 30 min. Saturated NaHCO 3 The aqueous solution (50 mL) was added and the aqueous phase was extracted with DCM (4 x 30 mL). The combined organic layers were dried (Na 2 SO 4 ), filtered, and concentrated to give 690 mg (83%) of methyl 4-bromo-6-(hydroxymethyl)pyridine-2-carboxylate (INT 43-B) as a solid. 8 H 8 BrNO 3 The LCMS-ESI (m / z) calculated value is: 246.06; the measured value is: 246.1 (MH) + , t R = 1.78 minutes (Method 13).

[0997] Step 43-3. Synthesis of methyl 4-bromo-6-(bromomethyl)pyridine-2-carboxylate (INT 43-C)

[0998]

[0999] At 0°C, PBr 3 (450 μL, 4.74 mmol) was added to INT 43-B (690 mg, 2.80 mmol) in CHCl 3 The mixture was stirred at 22 °C for 5 h, cooled to 0 °C and heated with saturated K 2 CO 3The aqueous phase was extracted with EA (3 x 30 mL), and the combined organic layers were washed with brine (20 mL), dried (Na 2 SO 4 ), filtered and concentrated. The residue was filtered through SiO 2 Purification by chromatography (EA / hexanes) afforded 700 mg (81%) of dimethyl 4-bromopyridine-2,6-dicarboxylate (INT 43-C) as a solid. 8 H 7 Br 2 NO 2 The LCMS-ESI (m / z) calculated value is: 308.96; the found value is: 246.1 (M+H) + , t R = 2.22 minutes (Method 13).

[1000] Step 43-4. 4-bromo-6-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)pyridine-2-carboxylic acid methyl ester (INT Synthesis of 43-D)

[1001]

[1002] 2-Chloro-4-(trifluoromethyl)phenol (490 mg, 2.49 mmol) and Cs 2 CO 3 (1.48 g, 4.53 mmol) was added to a solution of INT 43-C (700 mg, 2.27 mmol) in anhydrous DMF (5 mL). The mixture was stirred at 50 °C for 18 h, cooled to room temperature and treated with H 2 The aqueous phase was extracted with EA (3×30 mL), and the combined organic layers were washed with brine (20 mL), dried (Na 2 SO 4 ), filtered and concentrated. The residue was filtered through SiO 2 Chromatography (EA / hexanes) gave 750 mg (78%) of methyl 4-bromo-6-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)pyridine-2-carboxylate (INT 43-D) as a solid. 15 H 10 BrClF 3 NO 3 LCMS-ESI (m / z) calculated value: 422.95; found value: 424.4 (M+H) + , t R = 2.78 minutes (Method 13).

[1003] Step 43-5. 4-bromo-6-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)pyridine-2-carboxylic acid methyl ester (INT Synthesis of 43-E)

[1004]

[1005] Zn(CN) 2 (59.7 mg, 0.509 mmol) and Pd(PPh 3 ) 4 (44.1 mg, 0.038 mmol) was added to a solution of INT 43-D (108 mg, 0.254 mmol) in non-degassed DMF (2.00 mL). The mixture was washed with N 2 The mixture was concentrated and the residue was purified by purging for 5 minutes and stirring at 150°C for 6 hours. 2 Chromatography (EA / hexanes) gave 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 CIF 3 N 2 O 3 The LCMS-ESI (m / z) calculated value is: 370.03; + No m / z, t was observed R = 2.78 minutes (Method 13).

[1006] Step 43-6. 6-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-4-cyano-pyridine-2-carboxylic acid (Compound Synthesis of 43-1)

[1007]

[1008] 2M NaOH aqueous solution (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 HCl aqueous solution (pH about 2) and washed with H 2 The aqueous phase was extracted with EA (3 x 10 mL), and the combined organic layers were washed with brine (10 mL), dried (Na 2 SO 4 ), filtered and concentrated. The residue was purified by reverse phase chromatography (H 2 O(+0.1% formic acid) / CH 3 CN) to give 63 mg (89%) of 6-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-4-cyano-pyridine-2-carboxylic acid (Compound 43-1) as a solid. 15 H 8 CIF3 N 2 O 3 LCMS-ESI (m / z) calculated value: 356.7; found value: 357.1 (M+H) + , t R = 3.91 minutes (Method 12). 1 HNMR(500MHz,DMSO-d6)δ13.84(brs,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).

[1009] Example 44:

[1010] Synthesis of compound 44-1

[1011]

[1012] Scheme 44

[1013]

[1014] Reagents: (i) Base (Na 2 CO 3 , K 2 CO 3 KO t Bu), solvent (THF, dioxane or DMF); (ii) 2-methyloxazole, Pd(PPh 3 ) 4 , KOAc, DMF; (v) NaOH, solvent (THF, MeOH or DMF).

[1015] Step 44-1. Methyl 3-bromo-5-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)benzoate (INT 44-A) Synthesis

[1016]

[1017] Methyl 3-bromo-5-(bromomethyl)benzoate (3.60 g, 11.7 mmol), 2-chloro-4-(trifluoromethyl)phenol (1.48 mL, 11.1 mmol) and K 2 CO 3 A mixture of (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 filtered through SiO 2Chromatography (EA / hexanes) gave 2.36 g (48%) of methyl 3-bromo-5-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)benzoate (INT 44-A) as a solid. 16 H 11 BrClF 3 O 3 The LCMS-ESI (m / z) calculated value is: 423.61; the measured value is: 442.2 (M+H 2 O) + , t R = 3.29 minutes (Method 13). 1 H NMR (400 MHz, CDCl 3 )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(d t,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).

[1018] Step 44-2. 3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-5-(2-methyloxazol-5-yl)benzoic acid Synthesis of methyl ester (INT 44-B)

[1019]

[1020] INT 44-A (150 mg, 0.354 mmol), 2-methyloxazole (58.0 μL, 0.708 mmol), Pd(PPh 3 ) 4 A mixture of 2-(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 washed with H 2 The aqueous phase was extracted with EA (3×20.0 mL), and the combined organic layers were washed with brine (20 mL), dried (MgSO 4 ), filtered and concentrated. The residue was filtered through SiO 2 Chromatography (EA / hexanes) gave 98 mg (65%) of methyl 3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-5-(2-methyloxazol-5-yl)benzoate (INT 44-B) as a solid. 20 H 15 CIF 3 NO 4 LCMS-ESI (m / z) calculated value: 425.06; found value: 426.25 (MH)+ , t R = 2.79 minutes (Method 13). 1 H NMR (500 MHz, CDCl 3 )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).

[1021] Step 44-3. 3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-5-(2-methyloxazol-5-yl)benzoic acid Synthesis of (Compound 44-1)

[1022]

[1023] NaOH (1 M in H 2 O, 676 μL, 0.676 mmol) was added to a solution of INT 44-B (96.0 mg, 0.225 mmol) in THF and H 2 O (3: 1 v / v, 4.00 mL). The mixture was stirred at 22 ° C for 4 hours. The mixture was acidified with 1M HCl aqueous solution (pH 2) and diluted with EA (20 mL). The aqueous phase was extracted with EA (2×30 mL), and the combined organic layer was washed with brine (20 mL), dried (MgSO 4 ), filtered and concentrated. The residue was filtered through SiO 2 Chromatography (MeOH / DCM) gave 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. 19 H 13 CIF 3 NO 4 The LCMS-ESI (m / z) calculated value is: 411.05; the measured value is: 412.2 (MH) + , t R =4.59 minutes (Method 12). 1H 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).

[1024] Example 45:

[1025] Synthesis of Compounds 45-1 and 45-2

[1026]

[1027] Scheme 45

[1028]

[1029] Reagents: (i) Base (NaH, Na 2 CO 3 , K 2 CO 3 KO t Bu), solvent (THF, dioxane or DMF); (ii) dimethylformamide dimethyl acetal, N 2 H 4 -H 2 O, AcOH.

[1030] Step 45-1. Synthesis of 3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)benzamide (Compound 45-1)

[1031]

[1032] To a solution of 3-(bromomethyl)benzamide (254 mg, 1.29 mmol) in DMF (5 mL) was added NaH at 0°C. After the reaction mixture was stirred and warmed to room temperature over 30 min, 2-chloro-4-(trifluoromethyl)phenol (250 mg, 1.17 mmol) was added. After 4 h, the reaction mixture was diluted with EA and washed with H 2 O, 1M HCl, 1M NaOH, H 2 O, washed with brine, dried (Na 2 SO 4 ), filtered and concentrated. The resulting crude residue was purified by reverse phase SiO 2 Chromatography (MeOH / H 2 O) to give a material which was mixed with MeOH / H 2O were triturated together, filtered and dried in vacuo to give 260 mg (67%) of 3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)benzamide (Compound 45-1). 15 H 11 CIF 3 NO 2 The LCMS-ESI (m / z) calculated value is: 329.04; the measured value is: 330.1 (MH) + , t R = 12.14 minutes (Method 10). 1 H NMR (300 MHz, CDCl 3 )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).

[1033] Step 45-2. 3-(3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)phenyl)-1H-1,2,4-triazole (Chem. Synthesis of Compound 45-2)

[1034]

[1035] A solution of compound 45-1 (260 mg, 0.079 mmol) in dimethylformamide dimethyl acetal (4 mL) was heated at 120 °C for 2 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo. The resulting residue was dissolved in AcOH (4 mL) and N 2 H 4 -H 2 O (47 mg, 0.946 mmol). After stirring at 90°C for 2 hours, the mixture was concentrated and washed with Et 2 O and cooled to 0 °C. The resulting precipitate was collected by filtration and passed through SiO 2 Chromatography (EA / hexane) purification provided 125 mg (45%) of 3-((2-chloro-4-(trifluoromethyl)phenoxy)m)methyl)benzamide (Compound 45-2). 16 H 11 CIF 3 N 3 LCMS-ESI (m / z) calculated value of O: 353.05; found value: 354.5 (MH) + , t R = 13.56 minutes (Method 10). 1 H NMR (300 MHz, 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).

[1036] The compounds listed in Table 45 were prepared using the procedure of Scheme 45.

[1037] Table 45

[1038]

[1039] Example 46:

[1040] Synthesis of compound 46-1

[1041]

[1042] Scheme 46

[1043]

[1044] Reagents: (i) N,O-dimethylhydroxylamine hydrochloride, HATU, DIPEA, DMF; (ii) DIBAL, THF, -78°C; (iii) glyoxal, NH 4 OH, EtOH.

[1045] Step 46-1. 3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-N-methoxy-N-methylbenzamide Synthesis of (INT 46-A)

[1046]

[1047] 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 the reaction mixture was stirred for 18 hours, the reaction mixture was acidified with TFA and filtered through a reverse phase SiO 2 Chromatography (MeOH / H 2 (0, 0 / 1% TFA) to give 530 mg (94%) of 3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-N-methoxy-N-methylbenzamide (INT 46-A). 17 H 15 CIF 3 NO 3LCMS-ESI (m / z) calculated value: 373.07; no m / zt observed R = 6.2 minutes (Method 11).

[1048] Step 46-2. Synthesis of 3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)benzaldehyde (INT 46-B)

[1049]

[1050] To a solution of INT 46-A (1000 mg, 2.68 mmol) in THF (10 mL) was added DIBAL (3.21 mL of 1 M / THF solution, 3.21 mmol) at -78 °C. After the reaction mixture was stirred for 30 min, H 2 O, and the solution was extracted with EA, dried (Na 2 SO 4 ), and through SiO 2 Chromatography (EA / hexane) gave 600 mg (71.1%) of 3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)benzaldehyde (INT 46-B). 15 H 10 CIF 3 O 2 LCMS-ESI (m / z) calculated value: 314.03; no m / z observed, t R = 6.3 minutes (Method 11).

[1051] Step 46-3. 2-(3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)phenyl)-1H-imidazole (Compound 46- 1) Synthesis

[1052]

[1053] To a solution of INT 46-B (100 mg, 0.32 mmol) in EtOH (5 mL) was added glyoxal (0.04 mL 8.8 M / H 2 O) at 0 °C. 2 O solution, 0.35 mmol) and NH 4 OH (0.053 mL 29% EtOH solution, 0.44 mmol). After stirring for 48 h, the mixture was concentrated and filtered through SiO 2 Chromatography (EA / hexanes) gave 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 CIF 3 N 2 LCMS-ESI (m / z) calculated value of O: 352.74; found value: 353.2 (MH)+ , 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).

[1054] Example 47:

[1055] Synthesis of compound 47-1

[1056]

[1057] Scheme 47

[1058]

[1059] Reagents: (i) MeMgBr, Et 2 O; (ii) Br 2 , DCM; (iii) formamide.

[1060] Step 47-1. 1-(3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)phenyl)ethan-1-one (INT 47-A) Synthesis

[1061]

[1062] INT 46-A (480 mg, 1.28 mmol) was dissolved in Et 2 O (20 mL) was added with MeMgBr (0.557 mL 3MEt 2 O solution, 1.67 mmol). After the reaction mixture was stirred for 6 hours, 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 (Na 2 SO 4 ), filtered, concentrated, and passed through SiO 2 Chromatography (EA / hexane) gave 224 mg (53%) of 1-(3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)phenyl)ethan-1-one (INT 47-A). 17 H 15 CIF 3 NO 3 LCMS-ESI (m / z) calculated value: 373.07; no m / zt observed R = 6.2 minutes (Method 11).

[1063] Step 47-2. 2-Bromo-1-(3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)phenyl)ethan-1-one (INT Synthesis of 47-B)

[1064]

[1065] To a solution of INT 47-A (224 mg, 0.68 mmol) in DCM (15 mL) was added Br 2 (0.035 mL, 0.68 mmol). After stirring the reaction mixture for 30 minutes, the reaction mixture was washed with NH 4 Cl (aq.) was quenched and extracted into DCM. The resulting organic layer was washed with NaHCO 3 (saturated aqueous solution), water and brine, dried (Na 2 SO 4 ), concentrated, and passed through SiO 2 Chromatography (EA / hexanes) gave 140 mg (50%) of 2-bromo-1-(3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)phenyl)ethan-1-one (INT 47-B). 16 H 11 BrClF 3 O 2 LCMS-ESI (m / z) calculated value: 405.96; found value: 407.2 (M+H) + ;t R =5.529 minutes (Method 11).

[1066] Step 47-3. 5-(3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)phenyl)-1H-imidazole (Compound 47- 1) Synthesis

[1067]

[1068] A solution of INT 47-B (100 mg, 0.3 mmol) in formamide (5 mL) was stirred at 170 °C for 4 h, the reaction mixture was concentrated and purified by reverse phase C18 chromatography (H 2 O / MeOH) to give 6 mg (5%) of 5-(3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)phenyl)-1H-imidazole (Compound 47-1). 17 H 12 CIF 3 N 2 LCMS-ESI (m / z) calculated value of O: 352.06; found value: 353.4 (M+H) + ;t R = 12.14 minutes (Method 10).

[1069] Example 48:

[1070] Synthesis of compound 48-1

[1071]

[1072] Scheme 48

[1073]

[1074] Reagents: (i) ethynyltrimethylsilane, Pd(OAc) 2 PPh 3 (ii) DEAD, PPh 3 , THF; (iii) CuI, TMSN 3 , DMF, EtOH.

[1075] Step 48-1. Synthesis of (3-ethynylphenyl)methanol (INT 48-A)

[1076]

[1077] To a solution of (3-ethynylphenyl)methanol (1.5 g, 8.02 mmol) in TEA (8 mL) were added ethynyltrimethylsilane (1.58 g, 16 mmol), palladium acetate (180 mg, 0.8 mmol) and PPh 3 (422 mg, 1.6 mmol). After heating at 95° C. for 1 hour, the reaction mixture was filtered through celite and washed with EA. The resulting organic layer was washed with H 2 O (3 times) and brine, dried (Na 2 SO 4 ), filtered, concentrated, and passed through SiO 2 Chromatography (EA / hexane) gave 800 mg (76%) of (3-ethynylphenyl)methanol (INT 48-A). 9 H 8 LCMS-ESI (m / z) calculated value of O: 132.06; found value: 133.3 (M+H) + , t R = 3.1 minutes (Method 11).

[1078] Step 48-2. Synthesis of 2-chloro-1-((3-ethynylbenzyl)oxy)-4-(trifluoromethyl)benzene (INT 48-B):

[1079]

[1080] To a solution of DEAD (55 mg of a 40% solution, 2.7 mmol) in THF (3 mL) was added PPh 3(71.2 mg, 2.7 mmol) and INT 48-A (30 mg, 8.02 mmol). After the reaction mixture was stirred for 1 hour, the reaction mixture was concentrated and filtered through SiO 2 Chromatography (EA / hexanes) gave 65 mg (93%) of crude 2-chloro-1-((3-ethynylbenzyl)oxy)-4-(trifluoromethyl)benzene (INT 48-B) which was used in the next step without further purification.

[1081] Step 48-3. 4-(3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)phenyl)-2H-1,2,3-triazole (compound Synthesis of Compound 48-1)

[1082]

[1083] 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 washed with N 2 Purge and add TMSN 3 (741 mg, 6.4 mmol). After stirring at 120 °C for 18 h, the reaction mixture was filtered through celite, concentrated, and filtered through SiO 2 Chromatography (EA / hexane) and reverse phase chromatography (MeOH / H 2 O) to obtain 65 mg (93%) of 4-(3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)phenyl)-2H-1,2,3-triazole (Compound 48-1). 16 H 11 CIF 3 N 3 LCMS-ESI (m / z) calculated value of O: 353.05; found value: 354.4 (M+H) + , t R =5.39 minutes (Method 11).

[1084] Example 49:

[1085] Synthesis of compound 49-1

[1086]

[1087] Scheme 49

[1088]

[1089] Reagents: (i) DEAD, PPh 3 , THF.

[1090] Step 49-1. 5-(3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)phenyl)-3-methyl-1,2,4-oxadiazole Synthesis of azole (compound 49-1)

[1091]

[1092] 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) were 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 and washed with saturated NaHCO 3 , H 2 O and brine, then dried (Na 2 SO 4 ), concentrated and passed through SiO 2 Chromatography (EA / hexanes) gave a residue which was washed with MeOH / H 2 O to give 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 CIF 3 N 2 O 2 The LCMS-ESI (m / z) calculated value is: 368.05; the found value is: 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).

[1093] Example 50:

[1094] Synthesis of Compound 50-1

[1095]

[1096] Scheme 50

[1097]

[1098] Reagents: (i)Na 2 CO 3 ,DMF.

[1099] Step 50-1. Preparation of 2-chloro-1-((3-(difluoromethyl)benzyl)oxy)-4-(trifluoromethyl)benzene (Compound 50-1) synthesis:

[1100]

[1101] To a stirred solution of (3-(difluoromethyl)phenyl)methanol (500 mg, 2.26 mmol) in DMF (8 mL) was added 2-chloro-4-(trifluoromethyl)phenol (450 mg, 2.26 mmol) and Na 2 CO 3 (720 mg, 6.79 mmol). After stirring at 50 °C for 18 h, the reaction mixture was washed with H 2 O, extracted into EA, and washed with H 2 O and brine. The organic layer was passed through SiO 2 Chromatography (EA / hexane) and concentration afforded 165 mg (22%) of 2-chloro-1-((3-(difluoromethyl)benzyl)oxy)-4-(trifluoromethyl)benzene (Compound 50-1). 15 H 10 CIF 5 LCMS-ESI (m / z) calculated value of O: 336.03; found value: 359.2 (M+Na) + , t R =5.68 minutes (Method 11). 1 H NMR (300 MHz, CDCl 3 )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).

[1102] Example 52:

[1103] Synthesis of compound 52-1

[1104]

[1105] Scheme 52

[1106]

[1107] Reagents: (I) HATU, DIPEA, DMF.

[1108] Step 52-1. N-Benzyl-3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)benzamide (Compound 52-1) Synthesis

[1109]

[1110] To a stirred solution of compound 1-55 (113 mg, 0.34 mmol) in DMF (5 mL) was added HATU (137 mg, 0.36 mmol), DIPEA (126 mg, 0.98 mmol) and benzylamine (35 mg, 0.33 mmol). After stirring at room temperature for 16 h, the reaction mixture was diluted with EA and washed with 30 mL each of H 2 O, 1M HCl, 1M NaOH, NaHCO 3 The organic layer was dried (Na2O3) and washed with brine. 2 SO 4 ), concentrated and passed through SiO 2 Chromatography (EA / hexane) gave 62 mg (54%) of N-benzyl-3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)benzamide (Compound 52-1). 22 H 17 CIF 3 NO 2 The LCMS-ESI (m / z) calculated value is: 419.1; the measured value is: 420.3 (MH) + , t R = 12.98 minutes (Method 10). 1 HNMR(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).

[1111] The compounds listed in Table 52 were prepared using the procedure of Scheme 52.

[1112] Table 52

[1113]

[1114]

[1115]

[1116] Example 53:

[1117] Synthesis of compound 53-1

[1118]

[1119] Scheme 53

[1120]

[1121] Reagents: (i) TFA, DCM.

[1122] Step 53-1. 3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-N-(2-(methylamino)ethyl)benzoyl Synthesis of amine (Compound 53-1)

[1123]

[1124] A solution of tert-butyl (2-(3-((2-chloro-4-(trifluoromethyl)phenoxy)m)methyl)benzamido)ethyl)(methyl)carbamate (50 mg, 0.099 mmol) (prepared by Scheme 52 from compound 1-55 and tert-butyl (2-aminoethyl)(methyl)carbamate) in 1:1 DCM:TFA (5 mL) was stirred at room temperature for 16 hours. The reaction mixture was concentrated and dissolved in H 2 O / CH 3 CN and lyophilized to give 30 mg (60%) of 3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-N-(2-(methylamino)ethyl)benzamide (Compound 53-1). 18 H 18 CIF 3 N 2 O 2 The LCMS-ESI (m / z) calculated value is: 386.1; the measured value is: 387.4 (MH) + , t R = 12.98 minutes (Method 10).

[1125] The compounds listed in Table 53 were prepared using the procedure of Scheme 53.

[1126] Table 53

[1127]

[1128] Example 54:

[1129] Synthesis of compound 54-1

[1130]

[1131] Scheme 54

[1132]

[1133] Reagents: (i) NaOH, EtOH.

[1134] Step 54-1. (3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)benzoyl)-L-valine (Compound 54-1) Synthesis

[1135]

[1136] To a solution of (3-((2-chloro-4-(trifluoromethyl)phenoxy)-methyl)benzoyl)-L-valine methyl ester (250 mg, 0.56 mmol) (prepared by Scheme 52 from compound 1-55 and L-valine methyl ester) in EtOH (5 mL) was added 2M NaOH (1.12 g, 1.1 mmol). After stirring at room temperature for 16 h, the reaction mixture was diluted with EA and acidified with 1 M HCl. The organic layer was collected and washed with brine, dried (Na2O3) and purified by HPLC. 2 SO 4 ), concentrated and then treated with reversed phase SiO 2 Chromatography (MeOH / H 2 O, containing 0.1% formic acid) to give 36 mg (15%) of (3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)benzoyl)-L-valine (Compound 54-1). 20 H 19 CIF 3 NO 4 The LCMS-ESI (m / z) calculated value is: 429.1; the measured value is: 430.6 (M+H) + , t R =5.31 min (Method 11).

[1137] The compounds listed in Table 54 were prepared using the procedure of Scheme 54.

[1138] Table 54

[1139]

[1140]

[1141] Example 55:

[1142] Synthesis of compound 55-1

[1143]

[1144] Scheme 55

[1145]

[1146] Reagents: (i) TFA, DCM.

[1147] Step 55-1. (3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)benzoyl)-L-asparagine (compound Synthesis of Compound 55-1)

[1148]

[1149] A solution of (3-((2-chloro-4-(trifluoromethyl)phenoxy)-methyl)benzoyl)-L-asparagine tert-butyl ester (200 mg, 0.4 mmol) (prepared by Scheme 52 from compound 1-55 and L-asparagine tert-butyl ester) in 1:1 TFA:DCM (5 mL) was stirred at room temperature for 16 hours. The mixture was concentrated and washed with reverse phase SiO 2 Chromatography (MeOH / H 2 O, containing 0.1% formic acid) to give 107 mg (60%) of (3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)benzoyl)-L-asparagine (Compound 55-1). 19 H 16 CIF 3 N 2 O 5 LCMS-ESI (m / z) calculated value: 444.1; found value: 445.4 (M+H) + , t R = 4.70 min (Method 11).

[1150] The compounds listed in Table 55 were prepared using the procedure of Scheme 55.

[1151] Table 55

[1152]

[1153] Example 56:

[1154] Synthesis of compound 56-1

[1155]

[1156] Scheme 56

[1157]

[1158] Reagents: (i) Thionyl-Cl, EtOH, DCM.

[1159] Step 56-1. Ethyl 3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-2-fluorobenzoate (Compound 56- 1) Synthesis

[1160]

[1161] 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 hours, the reaction mixture was concentrated and dissolved in EtOH (1 mL). After 1 hour, the mixture was concentrated and purified by RP-HPLC chromatography to give 32 mg (31%) of ethyl 3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-2-fluorobenzoate (compound 56-1). 17 H 13 CIF 4 O 3 The LCMS-ESI (m / z) calculated value is: 376.7; the found value is: 378.1 (M+H) + , t R = 12.5 minutes (appropriate purity).

[1162] The compounds listed in Table 56 were prepared using the procedure of Scheme 56.

[1163] Table 56

[1164]

[1165] Example 57:

[1166] Synthesis of compound 57-1

[1167]

[1168] Scheme 57

[1169]

[1170] Reagents: (i) Pd(dppf)Cl 2 -CH 2 Cl 2 , TEA, DMF, MeOH, CO; (ii) NaBH 4 , MeOH, DCM; (iii) SOCl 2 , DCM; (iv) NaOH, DMF.

[1171] Step 57-1. Synthesis of dimethyl 4-methylpyridine-2,6-dicarboxylate (INT 57-1)

[1172]

[1173] 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 2 -CH2 Cl 2 (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, and washed with H 2 O (100 mL) and extracted with EA (2×100 mL). The organic layers were collected, dried, filtered, concentrated, and filtered through SiO 2 Chromatography (EA / petroleum ether) gave 6.7 g (76%) of dimethyl 4-methylpyridine-2,6-dicarboxylate (INT57-1) as a yellow solid. 10 H 11 NO 4 The LCMS-ESI (m / z) calculated value is: 209.07; the measured value is: 210.1 (MH) + , t R = 0.742 min (Method 6).

[1174] Step 57-2. Synthesis of methyl 6-(hydroxymethyl)-4-methylpicolinate (INT 57-2)

[1175]

[1176] To a solution of INT 57-1 (6.7 g, 31.39 mmol) in MeOH (400 mL) and DCM (100 mL) was added a small portion of NaBH 4 (1.78 g, 47.08 mmol). After stirring at 0°C for 12 hours, the mixture was concentrated by adding NH 4 The reaction mixture was quenched with aqueous Cl (200 mL) and extracted into EA (3×200 mL). The combined organic layers were dried (Na 2 SO 4 ), filtered, concentrated, and passed through SiO 2 Chromatographic purification gave 3.7 g (64%) of methyl 6-(hydroxymethyl)-4-methylpicolinate (INT57-2). 9 H 11 NO 3 The LCMS-ESI (m / z) calculated value is: 181.2; the measured value is: 182.7 (MH) + , t R = 0.323 min (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).

[1177] Step 57-3. Synthesis of methyl 6-(chloromethyl)-4-methylpicolinate (INT 57-3)

[1178]

[1179] To a solution of INT 57-2 (200 mg, 1.1 mmol) in DCM (7 mL) was added SOCl at 0 °C. 2 (1 mL, 13.8 mmol). After stirring at room temperature for 1.5 hours, the reaction mixture was concentrated to give 32 mg (31%) of methyl 6-(chloromethyl)-4-methylpicolinate (INT 57-3) as a white solid, which was used in the next step without any further purification. 9 H 10 ClNO 2 The LCMS-ESI (m / z) calculated value is: 199.04; the measured value is: 200.0 (MH) + , t R = 0.755 min (Method 6).

[1180] Step 57-4. 6-(((2-chloro-4-(trifluoromethyl)phenyl)amino)methyl)-4-methylpicolinic acid (Compound 57-1) Synthesis

[1181]

[1182] 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 washed with H 2 O (10 mL), adjusted to pH = 7 with HCl (36%), then filtered and concentrated to provide a residue which was purified by reverse phase preparative HPLC (0.225% FA in HCl). 2 O / CH 3 CN) 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 CIF 3 N 2 O 2 The LCMS-ESI (m / z) calculated value is: 344.05; the measured value is: 345.0 (MH) + , t R = 0.873 min (Method 6). 1H NMR (400 MHz, MeOD 4 )δppm 2.35-2.51(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).

[1183] Example 58:

[1184] Synthesis of Compounds 58-1 and 58-2

[1185]

[1186] Scheme 58

[1187]

[1188] Reagents: (i) Pd(dppf)Cl 2 DCM, TEA, DMF, CO; (ii) LiBH 4 , THF; (iii) DIAD, PPh 3 , THF; (iv) NaH, THF, Mel.

[1189] Step 58-1. Synthesis of 1-oxo-1,2,3,4-tetrahydroisoquinoline-5-carboxylic acid methyl ester (INT 58-1)

[1190]

[1191] Pd(dppf)Cl 2 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). The mixture was evacuated and refilled with CO for 3 cycles. MeOH (3.08 mL) was added, and the mixture was heated to 85 ° C for 16 hours under a CO atmosphere (1 atm). The mixture was diluted with EA (25 mL) and filtered through a celite pad. The filtrate was concentrated under reduced pressure. The residue was washed with EA (100 mL) and H 2 O (100 mL). The aqueous phase was extracted with EA (3×25.0 mL). The combined organic layers were washed with brine (50 mL), dried (Na 2 SO 4 ), filtered and concentrated. The residue was filtered through SiO 2Chromatography (hexane and EA) gave 285 mg (80%) of methyl 1-oxo-1,2,3,4-tetrahydroisoquinoline-5-carboxylate (INT 58-1). 11 H 11 NO 3 The LCMS-ESI (m / z) calculated value is: 205.07; the measured value is: 205.74 (MH) + , t R = 1.82 minutes (Method 13). 1 H NMR (400 MHz, CDCl 3 )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).

[1192] Step 58-2. Synthesis of 5-(hydroxymethyl)-3,4-dihydroisoquinolin-1(2H)-one (INT 58-2)

[1193]

[1194] In N 2 At 22 °C, LiBH 4 (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). The mixture was stirred at 22 °C for 20 h. The mixture was washed with saturated aqueous NH 4 The aqueous phase was extracted with EA (3 x 20 mL), and the combined organic phases were washed with brine (50 mL), dried (Na 2 SO 4 ), filtered and concentrated to provide 88 mg (56%) of 5-(hydroxymethyl)-3,4-dihydroisoquinolin-1(2H)-one (INT 58-2) as an oil. 10 H 11 NO 2 The LCMS-ESI (m / z) calculated value is: 177.08; the measured value is: 178.13 (MH) + , t R = 1.39 minutes (Method 13). 1 H NMR (500 MHz, CDCl 3)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),5.9 5(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).

[1195] Step 58-3. 5-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-3,4-dihydroisoquinolin-1(2H)-one (Chemical Synthesis of Compound 58-1)

[1196]

[1197] In N 2 DIAD (108 μL, 0.55 mmol) was added to INT 58-2 (88.0 mg, 0.497 mmol), 2-chloro-4-(trifluoromethyl)phenol (69.7 μL, 0.521 mmol) and PPh 3 (143 mg, 0.546 mmol) in THF (5.00 mL). The mixture was stirred at 22 °C for 18 hours. The mixture was concentrated and the residue was purified by reverse phase chromatography (H 2 O (+0.1% formic acid) and MeCN) to give 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 CIF 3 NO 2 The LCMS-ESI (m / z) calculated value is: 355.06; the measured value is: 356.07 (MH) + , t R =4.69 minutes (Method 12). 1 H NMR (500 MHz, CDCl 3 )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=7.6,1.4 Hz,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).

[1198] Step 58-4. 5-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-2-methyl-3,4-dihydroisoquinoline-1 Synthesis of (2H)-ketone (Compound 58-2)

[1199]

[1200] In N 2 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. The mixture was stirred at 22 ° C for 30 minutes, iodomethane (67.4 μL, 1.08 mmol) was added, and the mixture was stirred at 70 ° C for 1 hour. The mixture was diluted with MeOH (10.0 mL) and concentrated. The product was purified by reverse phase chromatography (H 2 O (+0.1% formic acid) and MeCN) to give 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 CIF 3 NO 2 The LCMS-ESI (m / z) calculated value is: 369.77; the measured value is: 370.08 (MH) + , t R =5.08 minutes (Method 12). 1 H NMR (500 MHz, CDCl 3 )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).

[1201] Example 59:

[1202] Synthesis of Compound 59-1

[1203]

[1204] Scheme 59

[1205]

[1206] Reagents: (i) NaBH 4 , MeOH; (ii) DIAD, PPh3 , THF; (iii) N-chlorosulfonyl isocyanate, THF.

[1207] Step 59-1. Synthesis of (3-vinylphenyl)methanol (INT 59-1)

[1208]

[1209] In N 2 At 22 °C, NaBH 4 (327 mg, 8.66 mmol) was slowly added to a solution of 3-vinylbenzaldehyde (1.00 mL, 7.87 mmol) in MeOH (20 mL). The mixture was stirred at 22 °C for 1 hour and concentrated under reduced pressure. The residue was filtered through SiO 2 Chromatography (EA / hexane) gave 1.05 g (99%) of (3-vinylphenyl)methanol (INT 59-1). No LCMS-ESI (m / z) observed, t R = 2.00 min (Method 13). 1 H NMR (400 MHz, CDCl 3 )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).

[1210] Step 59-2. Synthesis of 2-chloro-4-(trifluoromethyl)-1-((3-vinylbenzyl)oxy)benzene (INT 59-2)

[1211]

[1212] In N 2 DIAD (1.29 mL, 6.56 mmol) was added dropwise to INT 59-1 (800 mg, 5.96 mmol), 2-chloro-4-(trifluoromethyl)phenol (793 mL, 5.93 mmol) and PPh 3 (2.35 g, 8.94 mmol) in THF (15.0 mL). The mixture was stirred at 22 °C for 6 h and concentrated. The residue was filtered through SiO 2 Chromatography (EA / hexanes) gave 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 not observed, t R = 2.95 minutes (Method 13).1 H NMR (500 MHz, CDCl 3 )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).

[1213] Step 59-3. 4-(3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)phenyl)azetidin-2-one (Chem. Synthesis of Compound 59-1)

[1214]

[1215] In N 2 N-chlorosulfonyl isocyanate (578 μL, 6.64 mmol) was added to a solution of INT59-2 (1.73 g, 5.53 mmol) in THF (5.00 mL) at 22° C. over 10 minutes. The mixture was stirred at 22° C. for 16 hours. The mixture was added to H at 0° C. over 20 minutes. 2 O (10.0 mL), sodium carbonate (1.93 g, 18.3 mmol) and sodium sulfite (1.05 g, 8.30 mmol) were stirred vigorously. The mixture was stirred at 22 ° C for 2 hours. The mixture was acidified with 1M HCl aqueous solution (pH about 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 4 ), filtered and concentrated. The residue was purified by reverse phase chromatography (H 2 O (+0.1% formic acid) and MeCN (50-100%)) to give 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 CIF 3 NO 2 The LCMS-ESI (m / z) calculated value is: 355.06; the measured value is: 356.07 (MH) + , t R =4.93 minutes (Method 12). 1 H NMR (500 MHz, CDCl 3)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).

[1216] Example 60:

[1217] Synthesis of Compound 60-1

[1218]

[1219] Scheme 60

[1220]

[1221] Reagents: (i) HO 2 SO 4 、MeOH;(ii)Zn(CN) 2 、Pd(Ph 3 ) 4 ;DMF;(iii)PdCl 2 (PPh 3 ) 2 , CuI, Et 3 N, 1,4-dioxane; (iv) NaOH, THF.

[1222] Step 60-1. Synthesis of 3-bromo-5-iodo-benzoic acid methyl ester (INT 60-1)

[1223]

[1224] H 2 SO 4 (600 μL, 11.3 mmol) was added to a solution of 3-bromo-5-iodo-benzoic acid (10.0 g, 30.6 mmol) in MeOH (65 mL). The mixture was stirred at 75 ° C for 18 hours. The mixture was cooled to 22 ° C and concentrated. The residue was diluted in EA (100 mL) and washed with saturated NaHCO 3 The mixture was washed with aqueous solution (100 mL) and dried (Na 2 SO 4 ), filtered and concentrated to give 9.90 g (95%) of 3-bromo-5-iodo-benzoic acid methyl ester (INT 60-1) as a solid. 8 H6 BrIO 2 The LCMS-ESI (m / z) calculated value is: 339.86; the measured value is: 339.6 (MH) + , t R = 2.72 minutes (Method 13).

[1225] Step 60-2. Synthesis of methyl 3-bromo-5-cyanobenzoate (INT 60-2)

[1226]

[1227] Zinc cyanide (1.76 g, 15.0 mmol) and Pd(PPh 3 ) 4 (2.88 g, 2.49 mmol) was 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 hours. The mixture was cooled to 22 °C and concentrated. The residue was diluted with EA (100 mL). The organic layer was washed with H 2 O (3×50.0 mL) and brine (150 mL), dried (Na 2 SO 4 ), filtered and concentrated. The residue was filtered through SiO 2 Chromatography (EA / hexanes) gave 3.00 g (50%) of methyl 3-bromo-5-cyanobenzoate (INT 60-2) as a solid. Not observed LCMS-ESI (m / z): mass, t R = 2.38 minutes (Method 13).

[1228] Step 60-3. Methyl 3-((2-chloro-4-(trifluoromethyl)phenyl)ethynyl)-5-cyanobenzoate (INT 60- 3) Synthesis

[1229]

[1230] 2-Chloro-1-ethynyl-4-(trifluoromethyl)benzene (551 μL, 1.87 mmol), PdCl 2 (PPh 3 ) 2 (132 mg, 0.19 mmol) and CuI (17.9 mg, 0.094 mmol) were added to INT 60-2 (225 mg, 0.94 mmol) in 1,4-dioxane (2 mL) and Et 3 N (2.0 mL). The mixture was stirred at 80 °C for 24 h. The mixture was cooled to 22 °C and washed with saturated NH 4 The mixture was diluted with aqueous Cl solution (20 mL). The aqueous phase was extracted with EA (3×50 mL), and the combined organic layers were concentrated. The residue was filtered through SiO2 Chromatography (EA / hexanes) gave 250 mg (73%) of methyl 3-((2-chloro-4-(trifluoromethyl)phenyl)ethynyl)-5-cyanobenzoate (INT 60-3) as a solid. 18 H 9 CIF 3 NO 2 The LCMS-ESI (m / z) calculated value is: 363.03; the measured value is: 365.5 (MH) + , t R = 2.92 minutes (Method 13). 1 H NMR (400 MHz, CDCl 3 )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).

[1231] Step 60-4. 3-((2-chloro-4-(trifluoromethyl)phenyl)ethynyl)-5-cyanobenzoic acid (Compound 60-1) Synthesis

[1232]

[1233] 2M NaOH aqueous solution (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 purified by HPLC. 2 O (10.0 mL) and acidified with saturated 2M HCl (pH about 2). The aqueous phase was extracted with EA (3×20.0 mL) and the combined organic layers were dried (Na 2 SO 4 ), filtered and concentrated. The residue was filtered through SiO 2 Chromatography (MeOH / DCM) gave 55.0 mg (95%) of 3-((2-chloro-4-(trifluoromethyl)phenyl)ethynyl)-5-cyanobenzoic acid (Compound 60-1) as a solid. 17 H 7 CIF 3 NO 2 The LCMS-ESI (m / z) calculated value is: 349.01; the measured value is: 348.49 (MH) + , t R =4.55 minutes (Method 12). 1H 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).

[1234] Example 61:

[1235] Synthesis of compound 61-1

[1236]

[1237] Scheme 61

[1238]

[1239] Reagents: (i) Pd / C, H 2 ,EA.

[1240] Step 61-1. Methyl 3-(2-(2-chloro-4-(trifluoromethyl)phenyl)ethyl)-5-cyanobenzoate (INT 61- 1) Synthesis

[1241]

[1242] INT 60-3 (100 mg, 0.275 mmol) and Pd / C (100 mg, 0.0940 mmol) were stirred in EA (10.0 mL) at 22 °C under hydrogen (1 atm) for 4 h. The mixture was filtered through celite and washed with EA (100 mL), and the filtrate was concentrated. The residue was purified by SiO 2 Chromatography (EA / hexanes) gave 101 mg (100%) of 3-[2-[2-chloro-4-(trifluoromethyl)phenyl]ethyl]-5-cyano-benzoic acid methyl ester (INT 61-1) as a solid. 18 H 13 CIF 3 NO 2 The LCMS-ESI (m / z) calculated value is: 367.06; the measured value is: 367.3 (MH) + , t R = 2.85 minutes (Method 13).

[1243] Step 61-2. Synthesis of 3-(2-chloro-4-(trifluoromethyl)phenethyl)-5-cyanobenzoic acid (Compound 61-2)

[1244]

[1245] 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 h and concentrated. The residue was acidified with 2M HCl (pH about 2) and heated to 40 °C. 2 The aqueous phase was extracted with EA (3 x 20 mL), and the combined organic layers were dried (Na 2 SO 4 ), filtered and concentrated. The residue was purified by reverse phase chromatography (H 2 O (+0.1% formic acid) and ACN) to give 47.0 mg (85%) of 3-(2-chloro-4-(trifluoromethyl)phenethyl)-5-cyanobenzoic acid (Compound 61-2) as a solid. 17 H 11 CIF 3 NO 2 The LCMS-ESI (m / z) calculated value is: 353.04; the measured value is: 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).

[1246] Example 62:

[1247] Synthesis of compound 62-1

[1248]

[1249] Scheme 62

[1250]

[1251] Reagents: (I) NaBH 4 , EtOH; (ii) DIAD, PPh 3 , THF; (iii) NaOH, MeOH, THF.

[1252] Step 62-1. Synthesis of methyl 3-(1-hydroxyethyl)benzoate (INT 62-1)

[1253]

[1254] NaBH 4 (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). The mixture was stirred at 0°C for 30 minutes and at 22°C for 1 hour. The mixture was washed with saturated aqueous NH 4 The aqueous phase was extracted with EA (3 x 30.0 mL), and the combined organic layers were washed with Na 2 SO 4 Dry, filter and concentrate. The residue is passed through SiO 2 Chromatography (EA / hexanes) gave 830 mg (70%) of methyl 3-(1-hydroxyethyl)benzoate (INT 62-1) as a solid. LCMS-ESI (m / z) mass not observed, t R = 1.93 minutes (Method 12). 1 H NMR (400 MHz, CDCl 3 )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).

[1255] Step 62-2. Synthesis of 3-(1-(2-chloro-4-(trifluoromethyl)phenoxy)ethyl)benzoate (INT 62-2)

[1256]

[1257] DIAD (981 μL, 4.98 mmol) was added to INT 62-1 (816 mg, 4.53 mmol), 2-chloro-4-(trifluoromethyl)phenol (886 mg, 4.51 mmol) and PPh 3 (1.78 g, 6.79 mmol) in THF (25.0 mL). The mixture was stirred at 22 °C for 3 hours. The mixture was concentrated and the residue was filtered through SiO 2 Chromatography (EA / hexanes) gave 1.40 g (86%) of methyl 3-(1-(2-chloro-4-(trifluoromethyl)phenoxy)ethyl)benzoate (INT 62-2) as a solid. 17 H 14 CIF 3 O 3The LCMS-ESI (m / z) calculated value is: 358.06; the measured value is: 357.06 (MH) + , t R = 2.87 minutes (Method 13).

[1258] Step 62-3. Synthesis of 3-(1-(2-chloro-4-(trifluoromethyl)phenoxy)ethyl)benzoic acid (Compound 62-1)

[1259]

[1260] 2M NaOH (4.68 mmol, 2.34 mL) was added to a solution of INT 62-2 (1.40 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 purified by HPLC. 2 O (10.0 mL) and 2M HCl (pH about 4). The aqueous phase was extracted with EA (3×25.0 mL). The combined organic layers were dried (Na 2 SO 4 ), filtered and concentrated, and the residue was passed through SiO 2 Chromatography (MeOH / DCM) gave 1.34 g (99%) of 3-(1-(2-chloro-4-(trifluoromethyl)phenoxy)ethyl)benzoic acid (Compound 62-1) as a solid. 16 H 12 CIF 3 O 3 The LCMS-ESI (m / z) calculated value is: 344.04; the measured value is: 343.04 (MH) + , t R =5.17 minutes (Method 12). 1 HNMR(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).

[1261] Example 63:

[1262] Synthesis of compound 63-1

[1263]

[1264] Scheme 63

[1265]

[1266] Reagents: (i) K 2 CO 3 , DMF; (ii) NaH, Mel, DMF; (iii) TFA, DCM.

[1267] Step 63-1. tert-Butyl N-((3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)phenyl)methyl)carbamate Synthesis of ester (INT 63-1)

[1268]

[1269] In N 2 tert-Butyl N-((3-(bromomethyl)phenyl)methyl)carbamate (100 mg, 0.333 mmol) was added to 2-chloro-4-(trifluoromethyl)phenol (50.0 μL, 0.366 mmol) and K at 22°C. 2 CO 3 (51.0 mg, 0.366 mmol) in DMF (1 mL). The mixture was stirred at 40 °C for 16 h. 2 O (20 mL), and the aqueous layer was extracted with DCM (3×20 mL). The combined organic layers were dried (MgSO 4 ), filtered and concentrated. The residue was filtered through SiO 2 Chromatography (EA / hexanes) gave 122 mg (88%) of tert-butyl N-((3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)phenyl)methyl)carbamate (INT 63-1). 20 H 21 CIF 3 NO 3 LCMS-ESI (m / z) calculated value: 415.12; found value: 414.17 (MH) + , t R = 2.86 minutes (Method 13). 1 H NMR (400 MHz, CDCl 3 )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).

[1270] Step 63-2. N-((3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)phenyl)methyl)-N-methyl-amino Synthesis of tert-butyl formate (INT 63-2)

[1271]

[1272] In N 2 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) at 22 ° C. The mixture was stirred at 22 ° C for 15 minutes. Iodomethane (21.6 μL, 0.346 mmol) was added and the mixture was stirred at 50 ° C for 24 hours. The mixture was concentrated and the residue was filtered through SiO 2 Chromatography (EA / hexanes) gave 71.2 mg (57%) of tert-butyl N-((3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)phenyl)methyl)-N-methyl-carbamate (INT 63-2). 21 H 23 CIF 3 NO 3 The LCMS-ESI (m / z) calculated value is: 429.13; the measured value is: 428.17 (MH) + , t R = 3.29 minutes (Method 13). 1 H NMR (500 MHz, CDCl 3 )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),7.0 1(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).

[1273] Step 63-3. 1-(3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)phenyl)-N-methylmethanamine (Compound Synthesis of 63-1)

[1274]

[1275] TFA solution (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 hours. The mixture was alkalized with 1M NaOH aqueous solution (10 mL) and stirred at 22 ° C for 15 minutes. The aqueous phase was extracted with DCM (3 × 20 mL), and the combined organic layer was washed with brine (20 mL), dried (MgSO 4 ), filtered and concentrated. The residue was purified by reverse phase chromatography (H 2O (+0.03% ammonium carbonate) / MeCN) to afford an oil in free form. HCl (2M in Et 2 O, 121 μL, 0.121 mmol) was added to the free form (40.0 mg, 0.121 mmol) in Et 2 O (2 mL). After 10 minutes, the mixture was concentrated to give 42.2 mg (70%) of 1-(3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)phenyl)-N-methylmethanamine (Compound 63-1). 16 H 15 CIF 3 LCMS-ESI (m / z) calculated value of NO: 329.08; found value: 330.09 (M+H) + , t R = 3.87 minutes (Method 12). 1 H NMR (500 MHz, CDCl 3 )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).

[1276] Example 64:

[1277] Synthesis of compound 64-1

[1278]

[1279] Scheme 64

[1280]

[1281] Reagents: (i) NaBH 4 , DMF; (ii) DIAD, PPh 3 , THF; (iii) NaOH, heating.

[1282] Step 64-1. Synthesis of 2-(3-(hydroxymethyl)phenyl)acetonitrile (INT 64-1)

[1283]

[1284] To a solution of methyl 3-(cyanomethyl)benzoate (3 g, 17.1 mmol) in THF (150 ml) was added NaBH in 5 portions.4 (1.3 g, 34 mmol). The mixture was heated to 80°C and stirred for 30 minutes. After cooling to room temperature, MeOH was added dropwise and the mixture was stirred at 80°C for 30 minutes and at room temperature for 16 hours. The solution was washed with H 2 O (30 mL) and concentrated. 2 O and extracted with EA. The organic layer was washed with H 2 O was then washed with brine and dried (Na 2 SO 4 ), filtered and concentrated. The resulting crude residue was purified by SiO 2 Chromatography (EA / hexane) gave 1.0 g (40%) of 2-(3-(hydroxymethyl)phenyl)acetonitrile (INT 64-1). 9 H 9 The LCMS-ESI (m / z) calculated value of NO is: 147.07; the measured value is: 170.3 (M+H 2 O) + , t R = 2 minutes (Method 11).

[1285] Step 64-2. Synthesis of 2-(3-((2,4-dichlorophenoxy)methyl)phenyl)acetonitrile (INT 64-2)

[1286]

[1287] To a solution of DIAD (495 mg, 2.4 mmol) in THF (10 mL) was added PPh 3 (641 mg, 2.4 mmol) and stirred for 10 minutes. 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 room temperature for 16 hours, diluted with EA and continuously treated with saturated NaHCO 3 (aqueous solution) and brine, then (Na 2 SO 4 ) was dried, filtered and concentrated. The resulting crude residue was filtered through SiO 2 Chromatography (EA / hexane) was performed twice to give 0.21 g (35%) of 2-(3-((2,4-dichlorophenoxy)methyl)phenyl)acetonitrile (INT 64-2). 1 H NMR (400 MHz, CDCl 3 )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).

[1288] Step 64-3. Synthesis of 2-(3-((2,4-dichlorophenoxy)methyl)phenyl)acetic acid (Compound 64-1)

[1289]

[1290] INT 64-2 (100 mg, 0.34 mmol) was dissolved in NaOH solution (aqueous solution, 2 M, 5 mL) and heated to 130 ° C in a sealed tube for 24 hours. The reaction mixture was acidified with 1 M HCl and extracted with EA. The organic layer was dried, washed with brine, dried (Na 2 SO 4 ), filtered and concentrated in vacuo. 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). No LCMS-ESI (m / z) mass was 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).

[1291] Example 65:

[1292] Synthesis of compound 65-1

[1293]

[1294] Scheme 65

[1295]

[1296] Reagents: (I)Na 2 CO 3 , DMF; (ii) Fe, HCl, MeOH

[1297] Step 65-1. Synthesis of 2-chloro-1-((3-nitrobenzyl)oxy)-4-(trifluoromethyl)benzene (INT 65-1):

[1298]

[1299] To a 250 mL flask were added 1-(bromomethyl)-3-nitrobenzene (1.0 g, 4.37 mmol), 2-chloro-4-(trifluoromethyl)phenol (858 mg, 4.37 mmol), Na 2 CO 3 (1.39 g, 13 mmol) and DMF (50 mL). After stirring at 50 °C for 18 h, the reaction was washed with H 2 O quenched and extracted with EA. The organic layer was dried (Na2 SO 4 ), concentrated, and passed through SiO 2 Chromatography (EA / hexanes) gave 1.0 g (69%) of 2-chloro-1-((3-nitrobenzyl)oxy)-4-(trifluoromethyl)benzene (INT 65-1). LCMS-ESI mass not observed, t R =5.66 minutes (Method 11).

[1300] Step 65-2. Synthesis of 3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)aniline (Compound 65-1)

[1301]

[1302] 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 h, filtered through celite, concentrated, and filtered through SiO 2 The resulting material was purified by reverse phase chromatography (MeOH / H containing 0.1% formic acid). 2 O) was further purified to obtain 800 mg (60%) of 3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)aniline (Compound 65-1). 14 H 11 CIF 3 LCMS-ESI (m / z) calculated value of NO: 301.05; found value: 302.1 (MH) + , t R = 2 minutes (Method 11).

[1303] Example 66

[1304] MRGPRX4 activity

[1305] HEK cells stably transfected to express human MRGPR X4 were maintained at 37 °C with 5% CO. 2 HEK cells stably transfected to express mouse MRGPR A1 were maintained in the same incubator and grown in DMEM medium containing 10% FBS, 1% each of sodium pyruvate, glutamine, penicillin / streptomycin, and geneticin.

[1306] Cells were seeded in 384-well assay plates in 12 μL Opti-MEM with 20,000 cells per well, and incubated overnight. On the day of the assay, a Tecan D300E digital dispenser was used to add a 10-point curve (10uM final maximum concentration, 1:3 serial dilution) of a compound dissolved in DMSO at 10mM. Agonists were diluted in assay buffer (final concentration of 5.7mM Tris-HCl, 43mM NaCl, 50mM LiCl, pH=8), and 2 μL of suitable agonists were added to each well. The final concentration of the agonist was 10 μM bilirubin, 20 μM deoxycholic acid or 100 μM conjugated bilirubin (obtained from Lee Biosolutions, catalog number 910-12). The final concentration of DMSO was kept consistent throughout the plate. The plate was incubated in the dark for 1 hour at 37°C, and then incubated at room temperature for 30 minutes. IP-1 standards and HTRF detection reagents were added according to the IP-One-Gq kit purchased from Cisbio (Part No. 62IPAPEJ) and incubated for 1 hour at room temperature in the dark. Plates were read on a Molecular Devices SpectraMax iD5 plate reader. HTRF ratios were calculated from the raw data and plotted using GraphPad Prism to calculate the IC for each compound. 50 value.

[1307] Activity data for selected MRGPR X4 antagonists (relative to 10 μM bilirubin agonist) are shown in Table 66 A. The activity range is indicated as follows: "++++++" indicates antagonist activity <100 nM; "++++" indicates antagonist activity between 100 and 500 nM; "+++" indicates activity between 500 and 1000 nM; "++" indicates activity between 1000 and 2500 nM; and "+" indicates activity >2500 nM.

[1308] Table 66A

[1309]

[1310]

[1311]

[1312]

[1313] Activity data for selected MRGPR X4 antagonists (relative to 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.

[1314] Table 66B

[1315]

[1316] ND = Not Determined

[1317] Example 67

[1318] Pharmacokinetic studies in mice

[1319] Compound is prepared with the concentration of 5mg / mL in 5%DMSO, 5%Solutol and 90% phosphate buffered saline, and usually shows as fine uniform suspension.50mg / kg dosage each compound is applied to male C57BL / 6 mice (n=3 / compound) by oral gavage under non-fasting condition.At 0.25 hour, 0.5 hour, 1 hour, 2 hours, 4 hours, 8 hours and 24 hours after administration, blood sample is collected on K2-EDTA by saphenous vein, and blood plasma is prepared and stored at≤60°℃ until analysis.The preparation of blood plasma sample for analysis is to be completed by protein precipitation and then centrifugation using acetonitrile (comprising Celecoxib as internal standard).LC-MS / MS is used to measure the compound concentration in the extracted blood plasma relative to the 8-point standard curve covering the range of 1 to 3000ng / mL.Phoenix WinNonlin is used to carry out non-compartmental analysis to estimate pharmacokinetic parameters, including area under the curve, clearance rate and half-life. The applied dose was confirmed by UPLC-UV analysis of the residual dose material relative to a single point calibration sample. The results of these studies are presented in Table 67.

[1320] Table 67

[1321] Compound No. Cmax(μM) AUC (μMxhr) T-1 / 2(hour) 1-18 113 376 4.2 1-115 306 1206 3.0 4-1 231 1503 5.9 1-29 196 615 4.6 1-55 230 2150 11.2 1-56 162 880 3.2 1-65 220 1037 4.8 1-78 57 219 4.0 1-85 239 1069 4.7 4-10 260 974 4.6 4-11 257 572 3.6 1-101 230 1200 4.8 42-3 460 4700 5.4

[1322] Example 68:

[1323] Urobilin is a potent MRGPRX4 agonist and pruritogen

[1324] Plasma urobilinogen is an oxidation product of the heme metabolite urobilinogen. Urobilinogen is a byproduct of bilirubin reduction in the intestine. Some urobilinogen is retained in the large intestine, where it is converted into sterobilin. Some urobilinogen is reabsorbed into the blood and delivered to the kidneys, where it is oxidized to urobilinogen when exposed to air.

[1325] Analyze the MRGPRX4 in vitro activation of heme metabolites (bilirubin, biliverdin, urobilin, urobilinogen and stercobilin). The cells were seeded in 384-well assay plates in 12 μL Opti-MEM at 20,000 cells per well and incubated overnight in an incubator. On the day of the assay, different agonists dissolved in 0.1% NaOH at 10 mM were added as a 10-point curve (10 mM final maximum concentration, 1:3 serial dilutions) using a Tecan D300E digital dispenser. The agonist was diluted in assay buffer (final concentration 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. The plate was incubated in the dark for 1 hour at 37 ° C, and then incubated at room temperature for 30 minutes. IP-1 standards and HTRF detection reagents were added according to the IP-One-Gq kit purchased from Cisbio (Part No. 62IPAPEJ) and incubated for 1 hour at room temperature in the dark. The plate was read on a Molecular Devices SpectraMax iD5 plate reader. HTRF ratios were calculated from the raw data and plotted using GraphPad Prism to calculate the IC50 value for each compound.

[1326] The results of this study are shown in Figure 1 Urobilin was shown to be at least 10-fold more effective than bilirubin in activating MRGPRX4.

[1327] The ability of urobilin to induce pruritus in wild-type mice was also tested. Typical mouse pruritus studies occur as follows: C57B6J male mice are repeatedly raised in a normal light cycle (open at 6 am; close at 6 pm) under temperature and humidity controlled conditions. Before testing, mice are handled and accustomed to the test room and then placed in a separate SCLABA test room. After 20 minutes, mice are orally administered with a vehicle (saline, pH 7-8). After 30 minutes, the pruritogen (100 mL saline) or saline studied is subcutaneously administered (SC) at the midline behind the ear of the neck. A 30-minute video is recorded using the SCLABA system starting from the first injection of the pruritogen. Scratching episodes are scored from the SCLABA thumbnails using the 12 / 45 / 85 / 100 waveform standard. Group size is typically 9-10 animals per group.

[1328] like Figure 2A As shown, urobilin induces a scratching response in mice in a dose-dependent manner. The itch induction of urobilin was also compared with that of the deoxycholic acid agonist and the bilirubin agonist. Figure 2B As shown, urobilin is a potent inducer of the scratching response in mice.

[1329] Example 69:

[1330] Bilirubin and urobilin can be photodegraded, reducing their agonist activity towards MRGPRX4

[1331] Bilirubin and urobilin are agonists of MRGPRX4 and have been shown to be active pruritogens. Phototherapy has been shown to reduce itch in patients with cholestatic pruritus, which has been attributed to the photoinduced degradation or chemical modification of bilirubin. To further explore the contribution of photodegradation to the reduction of MRGPRX4 agonism, bilirubin and urobilin were pretreated with different illuminations and their activity was measured.

[1332] Stock solutions of both bilirubin and urobilin were prepared at 210 μM in 0.1N NaOH (aqueous solution). The samples were stored in the dark at room temperature, in a -20°C refrigerator in the dark, placed on a work surface under normal laboratory lighting conditions at room temperature, or under a 400nM blue light lamp (similar to a medical lamp used to treat jaundice) at room temperature. The samples were evaluated after 24 hours, and the remaining percentages of urobilin and bilirubin were determined by measuring the degradation of the analytes contained in the samples relative to the time zero standard, as determined by tandem mass spectrometry (LC MS / MS). The ability of the samples (at 24 hours) to excite MRGPRX4 was also evaluated.

[1333] After 24 hours, the refrigerator bank had the highest amount of bilirubin remaining (44% of time zero), while all other conditions (room dark, room temperature lab light, and room temperature blue light) did not have any detectable bilirubin remaining. Figure 3A All samples stored at room temperature (dark, room temperature, and blue light) showed significantly reduced agonist activity compared to frozen samples. Figure 3B )

[1334] Urobilin showed greater stability than bilirubin, but degradation was still observed under all conditions. After 24 hours, samples stored in the dark had the highest amount of urobilin remaining relative to the zero-time measurement (40%), while frozen samples in the dark had only 21% remaining. Room temperature samples under ambient light had 34% remaining, but room temperature samples under blue light had no detectable urobilin remaining, indicating a higher vulnerability to the wavelength of light. ( Figure 4A ) The blue light samples showed very little agonist activity relative to the other three groups (room dark, frozen dark, and room light), corresponding to the remaining urobilinogen measured in these samples. Figure 4B )

[1335] Example 70:

[1336] The agonistic effect of FXR agonists on MRGPRX4 can be blocked by representative MRGPRX4 antagonists

[1337] BAR502, a dual FXR and GPBAR1 agonist, also has agonist activity against MRGPRX4 (5700 nM).The activity data for selected MRGPRX4 antagonists in Table 70 relative to 10 μM BAR502 show a range of antagonism from 11 to 48 nM.

[1338] Table 70

[1339] Compound No. <![CDATA[IC 50 (10μM BAR502)nM]]> 1-18 48 1-55 16 1-56 16 1-65 13 1-78 20 32-2 17 42-3 17 I-31 11

[1340] All U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications, and non-patent publications cited in this specification and / or listed in the Application Data Sheet are incorporated herein by reference in their entirety. Additionally, the terms used in the following claims should not be construed as limited to the specific embodiments disclosed in this specification, but should be construed to encompass all possible embodiments along with the full scope of equivalents to which such claims are entitled.

Claims

1. A compound having one of the following structures, or a pharmaceutically acceptable salt thereof:

2. The compound according to claim 1, wherein the compound is compound No. 1-55 or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 1, wherein the compound is compound number 1-55.

4. The compound according to claim 1, wherein the compound is compound No. 1-78 or a pharmaceutically acceptable salt thereof.

5. The compound according to claim 1, wherein the compound is compound number 1-78. 6 . The compound according to claim 1 , wherein the compound is compound No. 5-1 or a pharmaceutically acceptable salt thereof.

7. The compound according to claim 1, wherein the compound is compound No. 5-1.

8. The compound according to claim 1, wherein the compound is compound No. 4-10 or a pharmaceutically acceptable salt thereof.

9. The compound according to claim 1, wherein the compound is compound No. 4-10.

10. The compound according to claim 1, wherein the compound is compound No. 1-65 or a pharmaceutically acceptable salt thereof.

11. The compound according to claim 1, wherein the compound is compound number 1-65.

12. The compound according to claim 1, wherein the compound is compound No. 4-11 or a pharmaceutically acceptable salt thereof.

13. The compound according to claim 1, wherein the compound is compound No. 4-11.

14. The compound according to claim 1, wherein the compound is compound No. 1-58 or a pharmaceutically acceptable salt thereof.

15. The compound according to claim 1, wherein the compound is compound number 1-58.

16. The compound according to claim 1, wherein the compound is compound No. 1-56 or a pharmaceutically acceptable salt thereof.

17. The compound according to claim 1, wherein the compound is compound number 1-56.

18. The compound according to claim 1, wherein the compound is compound No. 9-1 or a pharmaceutically acceptable salt thereof.

19. The compound according to claim 1, wherein the compound is compound No. 9-1.

20. The compound according to claim 1, wherein the compound is compound No. 1-82 or a pharmaceutically acceptable salt thereof.

21. The compound according to claim 1, wherein the compound is compound number 1-82.

22. The compound according to claim 1, wherein the compound is compound No. 1-85 or a pharmaceutically acceptable salt thereof.

23. The compound according to claim 1, wherein the compound is compound number 1-85.

24. The compound according to claim 1, wherein the compound is compound No. 1-29 or a pharmaceutically acceptable salt thereof.

25. The compound according to claim 1, wherein the compound is compound number 1-29.

26. The compound according to claim 1, wherein the compound is compound No. 1-101 or a pharmaceutically acceptable salt thereof.

27. The compound according to claim 1, wherein the compound is compound number 1-101.

28. The compound according to claim 1, wherein the compound is compound No. 2-3 or a pharmaceutically acceptable salt thereof.

29. The compound according to claim 1, wherein the compound is compound number 2-3.

30. The compound according to claim 1, wherein the compound is compound No. 1-103 or a pharmaceutically acceptable salt thereof.

31. The compound of claim 1, wherein the compound is compound number 1-103.

32. The compound according to claim 1, wherein the compound is compound No. 1-112 or a pharmaceutically acceptable salt thereof.

33. The compound of claim 1, wherein the compound is compound number 1-112.

34. The compound according to claim 1, wherein the compound is compound No. 4-7 or a pharmaceutically acceptable salt thereof.

35. The compound according to claim 1, wherein the compound is compound number 4-7.

36. The compound according to claim 1, wherein the compound is compound No. 11-1 or a pharmaceutically acceptable salt thereof.

37. The compound according to claim 1, wherein the compound is compound No. 11-1.

38. A pharmaceutical composition comprising a compound according to any one of claims 1, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34 and 36, or a compound according to any one of claims 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35 and 37; and a pharmaceutically acceptable excipient.

39. The pharmaceutical composition of claim 38, further comprising a second therapeutic agent.

40. The pharmaceutical composition of claim 39, wherein the second therapeutic agent is ursodeoxycholic acid (UDCA), norursodeoxycholic acid, cholestyramine, stanozolol, naltrexone, rifampicin, alismatol B 23-acetate (AB23A), curcumin, dihydroartemisinin, fenofibrate, bezafibrate, metronidazole, methotrexate, colchicine, metformin, betaine, glucagon, naltrexone, farnesoid X-receptor (FXR) agonist, peroxisome proliferator-activated receptor (PPAR) agonist, thyroid hormone receptor β (TRβ) agonist, or any combination thereof.

41. The pharmaceutical composition according to claim 40, wherein: (a) The FXR agonist is obeticholic acid, trofibride isopropyl (WAY-362450), 3-(2,6-dichlorophenyl)-4-(3'-carboxy-2-chlorostilbene-4-yl)oxymethyl-5-isopropylisoxazole (GW4064), PX20606 (PX-102), PX-101, INT-767, INT-787, TERN-101, tricholomacin, tropifil (LJN452), nidofil, tropifil deisopropyl, phenoxamine, silymarin, silybin, herzognic acid, cafestol, zlofil (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-α agonist, a PPAR-γ agonist, a PPAR-δ agonist, a PPAR-α / γ dual agonist, a PPARα / δ dual agonist, a PPARγ / δ dual agonist or a PPARα / γ / δ pan-agonist, wherein: The PPARα agonist is fenofibrate, ciprofibrate, pemafibrate, gemfibrozil, clofibrate, binifibrate, clinfibrate, clofibric acid, nicofibrate, pilifibrate, prafibride, ronifibrate, tefibrate, tocofibrate or SRI 0171; The PPARγ agonist is rosiglitazone, pioglitazone, deuterium-stabilized R-pioglitazone, ivaglitazone, ATx08-001, OMS-405, CHS-131, THR-0921, SER-150-DN, KDT-501, GED-0507-34-levorotatory, CLC-3001 or ALL-4; The PPARδ agonist is anthracene or {4-[({4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}acetic acid (GW501516), serradelpa or {2-methyl-4-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethylsulfanyl]-phenoxy}-acetic acid (MBX8025), [4-[[[2-[3-fluoro-4-(trifluoromethyl)phenyl]-4-methyl-5-thiazolyl]methyl]thio]-2-methylphenoxy]acetic acid (GW0742), L165041, HPP-593 or NCP-1046; The PPARα / γ agonist is sarolitazar, aleglitazar, moraglitazar, teglitazar or DSP-8658; The PPARα / δ agonist is elafilbrano or T913659; The PPARγ / δ agonist is conjugated linoleic acid (CLA) or T3D-959; and The PPARα / γ / δ agonist is lanifebrano (IVA337), tetradecylthioacetic acid (TTA), methyl psoralen, GW4148, GW9135, bezafibrate, lobeglitazone, 2-(4-(5,6-methylenedioxybenzo[d]thiazol-2-yl)-2-methylphenoxy)-2-methylpropanoic acid (MHY2013) or CS038; or (c) The TRβ agonist is subitero, ilotero, GC-24, MGL-3196, MGL-3745, VK-2809, 3,5-dichloro-4-(4-hydroxy-3-isopropylphenoxy)phenylacetic acid (KB141), (2R,4S)-4-(3-chlorophenyl)-2-[(3,5-dimethyl-4-(4'-hydroxy-3'-isopropylbenzyl)phenoxy)methyl]-2-oxido-[1,3,2]-dioxaphosphinane (MB07811) or any combination thereof.

42. Use of a compound according to any one of claims 1, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34 and 36, or a pharmaceutically acceptable salt thereof, or a compound according to any one of claims 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35 and 37, or a pharmaceutical composition according to any one of claims 38-41 in the manufacture of a medicament for treating cholestatic pruritus in a subject in need thereof.

43. The use according to claim 42, wherein the medicament further comprises a second therapeutic agent.

44. The use according to claim 43, wherein the second therapeutic agent is ursodeoxycholic acid (UDCA), norursodeoxycholic acid, cholestyramine, stanozolol, naltrexone, rifampicin, alismatol B 23-acetate (AB23A), curcumin, dihydroartemisinin, fenofibrate, bezafibrate, metronidazole, methotrexate, colchicine, metformin, betaine, glucagon, naltrexone, farnesoid X-receptor (FXR) agonist, peroxisome proliferator-activated receptor (PPAR) agonist, thyroid hormone receptor β (TRβ) agonist or any combination thereof.

45. The use according to claim 44, wherein the FXR agonist is obeticholic acid, trofibride isopropyl (WAY-362450), 3-(2,6-dichlorophenyl)-4-(3'-carboxy-2-chlorostilbene-4-yl)oxymethyl-5-isopropylisoxazole (GW4064), PX20606 (PX-102), PX-101, INT-767, INT-787, TERN-101, fine galactosidase, tropifil (LJN452), nicardipine (Citrin), thiabendazole ... Dofil, trofilide isopropyl, phenoxamine, silymarin, silybin, herzognic acid, cafestol, zrofil (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.

46. ​​The use according to claim 44, wherein the PPAR agonist is a PPAR-α agonist, a PPAR-γ agonist, a PPAR-δ agonist, a PPAR-α / γ dual agonist, a PPARα / δ dual agonist, a PPARγ / δ dual agonist or a PPARα / γ / δ pan agonist, wherein: The PPARα agonist is fenofibrate, ciprofibrate, pemafibrate, gemfibrozil, clofibrate, binifibrate, clinfibrate, clofibric acid, nicofibrate, pilifibrate, prafibride, ronifibrate, tefibrate, tocofibrate or SRI 0171; The PPARγ agonist is rosiglitazone, pioglitazone, deuterium-stabilized R-pioglitazone, ivaglitazone, ATx08-001, OMS-405, CHS-131, THR-0921, SER-150-DN, KDT-501, GED-0507-34-levorotatory, CLC-3001 or ALL-4; The PPARδ agonist is anthracene or {4-[({4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}acetic acid (GW501516), serradelpa or {2-methyl-4-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethylsulfanyl]-phenoxy}-acetic acid (MBX8025), [4-[[[2-[3-fluoro-4-(trifluoromethyl)phenyl]-4-methyl-5-thiazolyl]methyl]thio]-2-methylphenoxy]acetic acid (GW0742), L165041, HPP-593 or NCP-1046; The PPARα / γ agonist is sarolitazar, aleglitazar, moraglitazar, teglitazar or DSP-8658; The PPARα / δ agonist is elafilbrano or T913659; The PPARγ / δ agonist is conjugated linoleic acid (CLA) or T3D-959; and The PPARα / γ / δ agonist is lanifebrano (IVA337), tetradecylthioacetic acid (TTA), methyl psoralen, GW4148, GW9135, bezafibrate, lobeglitazone, 2-(4-(5,6-methylenedioxybenzo[d]thiazol-2-yl)-2-methylphenoxy)-2-methylpropanoic acid (MHY2013) or CS038.

47. The use according to claim 44, wherein the TRβ agonist is subitero, ilotero, GC-24, MGL-3196, MGL-3745, VK-2809, 3,5-dichloro-4-(4-hydroxy-3-isopropylphenoxy)phenylacetic acid (KB141), (2R,4S)-4-(3-chlorophenyl)-2-[(3,5-dimethyl-4-(4'-hydroxy-3'-isopropylbenzyl)phenoxy)methyl]-2-oxido-[1,3,2]-dioxaphosphinane (MB07811) or any combination thereof.

48. A unit dosage form comprising the pharmaceutical composition according to any one of claims 38-41.

49. The unit dosage form according to claim 48, wherein said compound is a compound according to claim 3.

50. The unit dosage form according to claim 48, wherein said compound is a compound according to claim 5.

51. The unit dosage form according to claim 48, wherein said compound is a compound according to claim 7.

52. The unit dosage form according to claim 48, wherein said compound is a compound according to claim 9.

53. The unit dosage form according to claim 48, wherein said compound is a compound according to claim 11.

54. The unit dosage form according to claim 48, wherein said compound is a compound according to claim 13.

55. The unit dosage form according to claim 48, wherein said compound is a compound according to claim 15.

56. The unit dosage form according to claim 48, wherein said compound is a compound according to claim 17.

57. The unit dosage form according to claim 48, wherein said compound is a compound according to claim 19.

58. The unit dosage form according to claim 48, wherein said compound is a compound according to claim 21.

59. The unit dosage form according to claim 48, wherein said compound is a compound according to claim 23.

60. The unit dosage form according to claim 48, wherein said compound is a compound according to claim 25.

61. The unit dosage form according to claim 48, wherein said compound is a compound according to claim 27.

62. The unit dosage form according to claim 48, wherein said compound is a compound according to claim 29.

63. The unit dosage form according to claim 48, wherein said compound is a compound according to claim 31.

64. The unit dosage form according to claim 48, wherein said compound is a compound according to claim 33.

65. The unit dosage form according to claim 48, wherein said compound is a compound according to claim 35.

66. The unit dosage form according to claim 48, wherein said compound is a compound according to claim 37.

67. The unit dosage form according to any one of claims 48-66, wherein the unit dosage form is a tablet or a capsule.

68. The unit dosage form according to any one of claims 48-66, wherein the unit dosage form is a caplet or a softgel capsule.

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