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

Abstract

Methods for modulating MRGPR X4 in general or for treating MRGPR X4-dependent conditions in particular are provided by contacting MRGPR X4 with an effective amount of a compound having a structure of formula (I) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof, or administering to a subject in need thereof an effective amount of a compound having a structure of formula (I) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof, wherein m, n, p, t, A, B, Z, R 1 , R 2 and R 3 As defined herein. Also provided are pharmaceutical compositions comprising such compounds as well as the compounds themselves. Mas-related G protein (MRGPR) X4 modulators are particularly isoindolinones and isoquinolinones substituted on the carbocyclic ring. The compounds are useful for treating itch-related conditions, pain-related conditions or autoimmune disorders.

Description

background Technical Field

[0002] The present invention relates to a modulator of Mas-related G protein coupled receptor X4, a product containing the modulator, and a method for using and preparing the modulator.

[0003] Related technical description

[0004] Mas-related G protein receptors (MRGPRs) are a group of orphan receptors with limited expression in very specialized tissues. Little is known about the functions of most of these receptors. There are eight such related receptors expressed in humans, of which only four have easily identifiable orthologs in other species (i.e., MRGPR D, MRGPR E, MRGPR F, and MRGPR G). Based on homology, the other four receptors (MRGPR X1, MRGPR X2, MRGPR X3, and MRGPR X4) have no counterparts in species other than humans.

[0005] Brief Overview

[0006] The present invention is based in part on the identification that MRGPR A1 in mice corresponds functionally, at least in part, to human MRGPR X4. These receptors mediate disorders including chronic itch (e.g., pruritus), inflammatory disorders, autoimmunity, skin disorders, cardiovascular disease, 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 that circulate bilirubin and its metabolites (or are sensitive to activation by circulatory bilirubin and its metabolites), and are therefore important for itch sensation in conditions of elevated bilirubin such as cholestatic pruritus. In addition, MRGPR X4 is activated by 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 (and urobilin is a potent mediator of itch induction in mouse models), and thus may be important for pruritus sensation in conditions where urobilin is elevated, such as uremic pruritus. Furthermore, MRGPR X4 is a receptor for urobilin (urobilin is a potent mediator of itch induction in mouse models), and thus may be important for pruritus 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 itch conditions, as explained in more detail below.

[0007] Thus, in an embodiment, a method is provided for modulating MRGPR X4 by contacting the MRGPR X4 with an effective amount of a compound having a structure of Formula (I) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof:

[0008]

[0009] Among them n, m, p, t, A, B, Z, R 1 , R 2 and R 3 As defined below.

[0010] In another embodiment, a method for treating MRGPR X4-dependent conditions is provided 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.

[0011] In more specific embodiments, the MRGPR X4-dependent condition is one or more of an itch-associated condition, a pain-associated condition, an inflammation-associated condition, or an autoimmune disorder.

[0012] In another embodiment, a pharmaceutical composition is provided, which comprises a compound having a structure of Formula (I) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof in combination with a pharmaceutically acceptable excipient.

[0013] In another embodiment, a pharmaceutical composition is provided comprising a compound having one or more of the structures disclosed herein, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof.

[0014] In yet more specific embodiments, a pharmaceutical composition is provided, which further comprises a second therapeutic agent, 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, farnesoid X-receptor (FXR) agonist, peroxisome proliferator-activated receptor (PPAR) agonist, thyroid hormone receptor β (TRβ) agonist, or any combination thereof.

[0015] In another embodiment, a compound having the structure of Formula (IX) is provided:

[0016]

[0017] or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof, wherein p, R 2a , R 2c and R 3 As defined below.

[0018] In yet another embodiment, provided is a compound having the structure of Formula (X):

[0019]

[0020] or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof, wherein p, R 2a , R 2c and R 3 As defined below.

[0021] In yet another embodiment, provided is a compound having the structure of Formula (XII):

[0022]

[0023] or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof, wherein p, R 2a , R 2c and R 3 As defined below.

[0024] In another embodiment, a compound having the structure of Formula (XIII) is provided:

[0025]

[0026] or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof, wherein R 2a , R 2c and R 3 As defined below.

[0027] In another embodiment, provided is a compound having one or more of the structures disclosed herein, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof.

[0028] Detailed Description

[0029] As mentioned above, the present invention relates to modulators of MRGPR X4, products comprising said modulators, and methods of use and preparation thereof. The present invention is based, in part, on the identification that in mice MRGPR A1 corresponds functionally to human MRGPRX4. These receptors mediate disorders including chronic and intermittent itching (e.g., pruritus), inflammatory disorders, autoimmunity, skin disorders, and adverse skin reactions to drugs, and infectious diseases. More specifically, both MRGPR A1 and MRGPR X4 are expressed in sensory neurons and dorsal root ganglia. It has now been identified that both MRGPR A1 and MRGPR X4 are receptors that circulate bilirubin and its metabolites (or are sensitive to activation by circulating bilirubin and its metabolites), and are therefore important for the sensation of itch in conditions of elevated bilirubin such as cholestatic pruritus and end-stage renal failure. In addition, MRGPR X4 is also activated by bile acids, 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 MRGPR X4 and pruritogen, and thus may be important for itch sensation in conditions of elevated urobilin 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 disorders such as atopic dermatitis, and other chronic itch conditions, as explained in more detail below.

[0030] 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 acting as competitive antagonists that can specifically block individual ligands. In one embodiment, such modulation is selective for other MRGPRs such as MRGPR X1, MRGPR X2, and / or MRGPR X3.

[0031] Thus, in one embodiment, a method for modulating MRGPR X4 is provided, the method comprising contacting MRGPR X4 with an effective amount of a compound having a structure of Formula (I) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof:

[0032]

[0033] in:

[0034] A is a 5-membered or 6-membered carbocyclic ring or a 5-membered or 6-membered heterocyclic ring;

[0035] B is a carbocyclic ring or a heterocyclic ring;

[0036] Z is -O-, -CH2-O-, -S-, -N(R')-, -N(R')S(O)2-, -S(O)2N(R')-, -N(R')C(O)-, or -C(O)N(R')-;

[0037] Each R 1 are independently H or a hydrocarbon group;

[0038] Each R 2 are independently halogen, hydrocarbon, halogenated hydrocarbon or aromatic hydrocarbon, or two R 2 Together they form =O or =S;

[0039] Each R 3 are independently halogen, hydrocarbon, halogenated hydrocarbon, hydrocarbonoxy, halogenated hydrocarbonoxy, carbocyclic or heterocyclic, -CN, -(CH2) q C(O)OR 4 、-(CH2) q NHR 5 、-(CH2) q OR 6 、-C(O)NR 7 R 8 or carboxylic acid isosteres;

[0040] Each R 4 , R 5 , R 6 and R 7 are independently H or a hydrocarbon group;

[0041] Each R 8 are independently H, -SO2CH3, carbocyclic, heterocyclic or hydrocarbon, wherein each R 8 Independently by 0, 1, 2 or 3 R 9 replace;

[0042] Each R 9 is -OH, -CN, -NR'R", -C(O)OH, -C(O)NR'R", -SO2OH, alkoxy, carbocyclic or heterocyclic;

[0043] Each R' is independently H or a hydrocarbyl group;

[0044] Each R" is independently H or a hydrocarbon group;

[0045] m is 0-2;

[0046] n is 0-3;

[0047] p is 0-3;

[0048] q is 0-6; and

[0049] t is 0-6.

[0050] "Modulating" MRGPR X4 means that a compound interacts with MRGPR X4 in a manner such that the compound 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, MRGPR X2 and / or MRGPR X3.

[0051] "MRGPR" refers to one or more of the 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 such related receptors expressed in humans, of which only four have readily identifiable orthologs in other species (i.e., MRGPR D, MRGPR E, MRGPR F, and MRGPR G). Based on homology, the other four receptors (MRGPR X1, MRGPRX2, MRGPR X3, and MRGPR X4) have no counterparts in non-human species.

[0052] "Effective amount" refers to the amount of a specified agent that is sufficient to achieve a desired effect in a subject treated with the specified agent. Ideally, the 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. Based on this disclosure, those skilled in the art will appreciate methods for determining an effective amount of a disclosed compound that is sufficient to achieve a desired effect in a subject.

[0053] "Hydrocarbyl" means a saturated or unsaturated, straight or branched hydrocarbon group having from 1 to 8 carbon atoms, in some embodiments from 1 to 6 carbon atoms, in some embodiments from 1 to 4 carbon atoms, and in some embodiments from 1 to 3 carbon atoms. Examples of saturated straight chain hydrocarbon groups include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl groups. Examples of branched hydrocarbon groups include, but are not limited to, isopropyl, isobutyl, sec-butyl, tert-butyl, neopentyl, isopentyl, and 2,2-dimethylpropyl groups. Unsaturated hydrocarbon groups include alkenyl and alkynyl groups as defined below.

[0054] "Alkenyl" means a straight or branched alkenyl group having from 2 to 8 carbon atoms, in some embodiments from 2 to 6 carbon atoms, in some embodiments from 2 to 4 carbon atoms, and in some embodiments from 2 to 3 carbon atoms. An alkenyl group is an unsaturated hydrocarbon containing at least one carbon-carbon double bond. Examples of lower alkenyl groups include, but are not limited to, vinyl, propenyl, butenyl, pentenyl, and hexenyl.

[0055] "Alkynyl" means a straight or branched alkynyl group having from 2 to 8 carbon atoms, in some embodiments from 2 to 6 carbon atoms, in some embodiments from 2 to 4 carbon atoms, and in some embodiments from 2 to 3 carbon atoms. An alkynyl group is an unsaturated hydrocarbon containing at least one carbon-carbon triple bond. Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, and hexynyl.

[0056] "Halo" or "halogen" refers to fluorine, chlorine, bromine and iodine.

[0057] "Hydroxyl" refers to -OH.

[0058] "Cyano" refers to -CN.

[0059] Amino refers to -NH2, -NHalkyl or N(alkyl)2, wherein alkyl is as defined above. Examples of amino include, but are not limited to, -NH2, -NHCH3, -N(CH3)2, and the like.

[0060] "Haloalkyl" refers to a hydrocarbon group as defined above in which one or more hydrogen atoms are replaced by halogen. Examples of lower haloalkyl groups include, but are not limited to, -CF3, -CHF2, and the like.

[0061] "Alkyloxy" refers to an alkyl group as defined above attached through an oxygen atom (ie, -O-alkyl). Examples of alkyloxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, n-butoxy, isopropoxy, sec-butoxy, tert-butoxy, and the like.

[0062] "Haloalkyloxy" refers to a haloalkyl group as defined above attached through an oxygen atom (ie, -O-haloalkyl). Examples of lower haloalkyloxy groups include, but are not limited to, -OCF3 and the like.

[0063] "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 groups. 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 from 3 to 5, 3 to 6 or 3 to 7. Cycloalkyl groups also include polycyclic cycloalkyl groups such as, but not limited to, norbornyl, adamantyl, bornyl, camphenyl, isocamphenyl and carenyl groups and fused rings such as, but not limited to, decahydronaphthyl, etc.

[0064] The aryl group is a cyclic aromatic hydrocarbon that does not contain heteroatoms. Representative aryl groups include, but are not limited to, phenyl, azulenyl, heptalenyl, biphenyl, indacenyl, fluorenyl, phenanthrenyl, triphenylenyl, pyrenyl, naphthacenyl, In some embodiments, the aryl group comprises 6 to 14 carbons in the ring portion of the group. The terms "aryl" and "aryl group" include fused rings in which at least one ring but not necessarily all rings are aromatic, such as fused aromatic-aliphatic ring systems (e.g., indanyl, tetrahydronaphthyl, etc.). In one embodiment, the aryl group is phenyl or naphthyl, and in another embodiment, the aryl group is phenyl.

[0065] "Carbocycle" refers to a hydrocarbon 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, the conjugation of the π electrons in the ring may produce aromaticity. In one embodiment, the carbocycle includes a cycloalkyl as defined above. In another embodiment, the carbocycle includes an aryl as defined above.

[0066] "Heterocycle" refers to aromatic and non-aromatic ring moieties containing 3 or more ring members, one or more of which is a heteroatom, such as, but not limited to, N, O, S, or P. In some embodiments, heterocyclyl groups contain 3 to 20 ring members, while other such groups have 3 to 15 ring members. At least one ring contains heteroatoms, but it is not necessary for each ring in a polycyclic system to contain heteroatoms. For example, both dioxolanyl rings and benzodioxolanyl ring systems (methylenedioxyphenyl ring systems) are heterocyclyl groups within the meaning of this article.

[0067] Heterocyclyl groups also include fused ring materials, including those with fused aromatic groups and non-aromatic groups. Heterocyclyl groups also include polycyclic systems including heteroatoms such as, but not limited to, quinuclidine (quinuclidyl), and also include heterocyclyl groups with substituents combined with one of the ring members, including, but not limited to, alkyl, halogen, amino, hydroxyl, cyano, carboxyl, nitro, thio or oxyalkyl groups. Heterocyclyl groups as defined herein can be heteroaryl groups or partially or completely saturated cyclic groups including at least one ring heteroatom. Heterocyclyl groups include, but are not limited to, pyrrolidinyl, furanyl, tetrahydrofuranyl, dioxolanyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, thienyl, benzothienyl, benzofuranyl, dihydrobenzofuranyl, indolyl, indolinyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups.

[0068] "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 groups include, but are not limited to, groups such as pyrrolyl, pyrazolyl, pyridinyl, pyridazinyl, pyrimidyl, pyrazyl, pyrazinyl, pyrimidinyl, thienyl, triazolyl, tetrazolyl, triazinyl, thiazolyl, thiophenyl, oxazolyl, isoxazolyl, benzothiophenyl, benzofuranyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridyl, isoxazolopyridyl, thienazinyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolyl, isoquinolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, quinoxalinyl, and quinazolinyl groups. The terms "heteroaryl" and "heteroaryl group" 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-dihydroindolyl.

[0069] "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 optical isomers enriched or split at any or all asymmetric atoms to any degree of enrichment, as apparent from the description. Both racemic mixtures and diastereomeric mixtures and individual optical isomers can be synthesized so as to be substantially free of their enantiomeric partner or diastereomeric partner, 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". The single enantiomer of a pure compound is optically active (i.e., it can rotate the plane of plane polarized light and is designated as R or S).

[0070] "Isolated optical isomer" means a compound that has been substantially purified from the corresponding optical isomer of the same formula. For example, the isolated isomer can be at least about 80% pure, at least 80% pure, or at least 85% pure by weight. In other embodiments, the isolated isomer is at least 90% pure, or at least 98% pure, or at least 99% pure by weight.

[0071] "Substantially enantiomerically or diastereomerically pure" means that the level of enantiomeric or diastereomeric enrichment of one enantiomer relative to the other enantiomer or diastereomer is at least about 80%, and more specifically greater than 80%, 85%, 90%, 95%, 98%, 99%, 99.5% or 99.9%.

[0072] The terms "racemate" and "racemic mixture" refer to an equal mixture of two enantiomers. A racemate is labeled "(±)" because it is not optically active (i.e., will not rotate plane-polarized light in either direction because its constituent enantiomers cancel each other out). All compounds bearing an asterisk (*) adjacent to a tertiary or quaternary carbon are optically active isomers that can be purified from the corresponding racemate and / or synthesized by appropriate chiral synthesis.

[0073] A "hydrate" is a compound that exists in combination with water molecules. The combination may contain a stoichiometric amount of water, such as a monohydrate or a dihydrate, or may contain a random amount of water. The term "hydrate" as used herein refers to the solid form; in other words, a compound in aqueous solution may be hydrated but is not a hydrate as the term is used herein.

[0074] "Solvates" are similar to hydrates, except that a solvent other than water is present. For example, methanol or ethanol can form "alcoholates," which again can be stoichiometric or non-stoichiometric. The term "solvate" as used herein refers to a solid form; in other words, a compound in a solvent solution, while solvated, is not a solvate as that term is used herein.

[0075] "Isotope" refers to an atom with the same number of protons but different numbers of neutrons, and the isotopes of a compound of formula (I) include any such compound in which one or more atoms are replaced by an isotope of the atom. For example, carbon 12 is the most common form of carbon, with 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 a variety of isotopes, fluorine 19 has the longest lifespan. Therefore, the isotopes of a compound with a structure of formula (I) include, but are not limited to, compounds of formula (I) below: one or more carbon 12 atoms are replaced by carbon 13 and / or carbon 14 atoms, one or more hydrogen atoms are replaced by deuterium and / or tritium, and / or one or more fluorine atoms are replaced by fluorine 19.

[0076] "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 its anionic form and a cation is called an "acid addition salt." In contrast, a salt formed between a base in its cationic form and an anion is called a "base addition salt."

[0077] The term "pharmaceutically acceptable" refers to 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).

[0078] 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, for example, 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, for example, N, N'dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine.

[0079] 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 acid, acetic acid, propionic acid, succinic acid, glycolic acid, gluconic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, glucuronic acid, maleic acid, fumaric acid, pyruvic acid, aspartic acid, glutamic acid, benzoic acid, anthranilic acid, 4-hydroxybenzoic acid, phenylacetic acid, mandelic acid, hippuric acid, malonic acid, oxalic acid, pamoic acid (pamoic acid), methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, pantothenic acid, trifluoromethanesulfonic acid, 2-hydroxyethanesulfonic acid, p-toluenesulfonic acid, sulfanilic acid, cyclohexylaminosulfonic acid, stearic acid, alginic acid, β-hydroxybutyric acid, salicylic acid, galactaric acid and galacturonic acid.

[0080] Although pharmaceutically unacceptable salts are generally not useful as pharmaceuticals, such salts may be useful, for example, as intermediates in the synthesis of compounds having the structure of Formula I, for example, in the purification of such compounds by recrystallization.

[0081] In another embodiment, a method of treating a subject suffering from a MRGPR X4-dependent condition is provided, the method comprising administering to the subject a pharmaceutically effective amount of a compound having a structure of Formula (I) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof:

[0082]

[0083] in:

[0084] A is a 5-membered or 6-membered carbocyclic ring or a 5-membered or 6-membered heterocyclic ring;

[0085] B is a carbocyclic ring or a heterocyclic ring;

[0086] Z is -O-, -CH2-O-, -S-, -N(R')-, -N(R')S(O)2-, -S(O)2N(R')-, -N(R')C(O)-, or -C(O)N(R')-;

[0087] Each R 1 are independently H or a hydrocarbon group;

[0088] Each R 2 are independently halogen, hydrocarbon, halogenated hydrocarbon or aromatic hydrocarbon, or two R 2 Together they form =O or =S;

[0089] Each R 3are independently halogen, hydrocarbon, halogenated hydrocarbon, hydrocarbonoxy, halogenated hydrocarbonoxy, carbocyclic or heterocyclic, -CN, -(CH2) q C(O)OR 4 、-(CH2) q NHR 5 、-(CH2) q OR 6 、-C(O)NR 7 R 8 or carboxylic acid isosteres;

[0090] Each R 4 , R 5 , R 6 and R 7 are independently H or a hydrocarbon group;

[0091] Each R 8 are independently H, -SO2CH3, carbocyclic, heterocyclic or hydrocarbon, wherein each R 8 Independently by 0, 1, 2 or 3 R 9 replace;

[0092] Each R 9 is -OH, -CN, -NR'R", -C(O)OH, -C(O)NR'R", -SO2OH, alkoxy, carbocyclic or heterocyclic;

[0093] Each R' is independently H or a hydrocarbyl group;

[0094] Each R" is independently H or a hydrocarbon group;

[0095] m is 0-2;

[0096] n is 0-3;

[0097] p is 0-3;

[0098] q is 0-6; and

[0099] t is 0-6.

[0100] As used herein, the phrase "MRGPR X4-dependent condition" means a condition in which a pathological condition is initiated, mediated, maintained or enhanced by activation, oversensitization 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.

[0101] 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 that are caused by the activation of MRGPR X4 by bile acids and that would benefit from modulation of MRGPR X4.

[0102] In some embodiments, the MRGPR X4-dependent condition is an itch-related condition, a pain-related condition, an autoimmune condition, or an autoimmune or inflammatory disorder.

[0103] As used herein, the phrase "itch-related condition" means pruritus associated with any condition (including acute pruritus and chronic pruritus). The itch sensation may originate, for example, from the peripheral nervous system (e.g., cutaneous pruritus or neuropathic pruritus) or from the central nervous system (e.g., neuropathic pruritus, neurogenic pruritus or psychogenic pruritus). Thus, in one embodiment, the methods of the invention are provided for treating itch-related conditions such as chronic itch; 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; cutaneous amyloidosis; acne; wound healing; ocular pruritus; and urticaria.

[0104] As used herein, the phrase "pain-related condition" means any pain caused by a medical condition. Thus, in one embodiment, the methods of the present 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 (syndrome), burning mouth syndrome, bursitis, cancer pain, carpal tunnel pain, cauda equina syndrome, central pain syndrome, cerebral palsy, cervical stenosis, Charcot-Marie-Tooth (CMT) disease, chronic fatigue syndrome (CFS), chronic functional abdominal pain (CFAP), chronic pain, chronic pancreatitis, collapsed lung (pneumothorax), complex regional pain syndrome (RSD), corneal neuropathic pain, Crohn's disease (Crohn's disease), degenerative disc disease, Dercum's disease, dermatomyositis, diabetic peripheral neuropathy (DPN), dystonia, Ehlers-Danlos Syndrome,EDS), endometriosis, eosinophilia-myalgia syndrome (EMS), erythromelalgia, fibromyalgia, gout, headache, herniated disc, hydrocephalus, intercostal neuralgia, interstitial cystitis, irritable bowel syndrome (IBS), juvenile dermatositis (dermatomyositis), knee injury, leg pain, low back pain-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, hernia repair pain syndrome, 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 Oddi dysfunction dysfunction), spinocerebellar ataxia (SCA ataxia), spinal cord injury, spinal stenosis, syringomyelia, sacral cysts (Tarlov cysts), transverse myelitis, trigeminal neuralgia, neuropathic pain, ulcerative colitis, vascular pain, and vulvar pain.

[0105] 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-segregate or manifestation thereof, or a condition resulting therefrom. Typically, there may be a variety of clinical and laboratory markers of autoimmune diseases, 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, Stevens Johnson syndrome, appendicitis, bursitis, colitis, cystitis, dermatitis, phlebitis, reflex sympathetic dystrophy / complex regional pain syndrome (rsd / crps), rhinitis, tendinitis, tonsillitis, acne vulgaris, reactive airway disorder, asthma, airway infection, autoinflammatory disease, celiac disease, chronic prostatitis, diverticulitis, glomerulonephritis, hidradenitis suppurativa, allergies, intestinal disorders, epithelial intestinal disorders, inflammatory bowel disease, irritable bowel syndrome, 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.

[0106] 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 it can be self-administered by the subject. Non-limiting examples of routes of administration are oral, parenteral (e.g., intravenous), or topical.

[0107] As used herein, the term "treatment" refers to an intervention that improves the signs or symptoms of a disease or pathological condition. As used herein, the terms "treatment", "treat" and "treating" with respect to a disease, pathological condition or symptom also refer to any observable beneficial effect of treatment. The beneficial effect can be demonstrated, for example, by the delayed onset of clinical symptoms of the disease in susceptible subjects, a reduction in the severity of some or all clinical symptoms of the disease, a slower progression of the disease, a reduction in the number of relapses of the disease, an improvement in the overall health or well-being of the subject, or by other parameters that are well known in the art and are specific to a particular disease. Preventive treatment is a treatment administered to a subject who does not show signs of the disease or only shows early signs, with the aim of reducing the risk of developing pathology. Therapeutic treatment is a treatment administered to a subject after the signs and symptoms of the disease develop.

[0108] 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 may 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 may 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 been subjected to standard testing, or may have been identified, without examination, as a subject at risk due to the presence of one or more risk factors associated with a disease or condition.

[0109] In another embodiment, the method described herein for treating a subject with a MRGPR X4-dependent condition (e.g., an itch-related condition, a pain-related condition, an autoimmune condition, or an autoimmune disorder) further comprises administering to the subject a pharmaceutically effective amount of a second therapeutic agent. In one embodiment, the itch-related condition is a liver disease. In one embodiment, the second therapeutic agent is a liver disease therapeutic agent. In one embodiment, the 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, farnesoid X-receptor (FXR) agonist, peroxisome proliferator-activated receptor (PPAR) agonist, thyroid hormone receptor β (TRβ) agonist, or any combination thereof.

[0110] 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, silybin, hedragon 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, tophenytoin (WAY-362450), BAR502, herzognic acid, or BAR704) or a non-bile acid agonist (e.g., EDP-305, tropifexor, nidufexor, cilofexor, GW4064, tophenytoin, fexaramine, 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). In one embodiment, the PPAR agonist is a PPAR-alpha agonist, a PPAR-gamma agonist, a PPAR-delta agonist, a PPAR-alpha / gamma dual agonist, a PPARalpha / delta dual agonist, a PPARgamma / delta dual agonist, or a PPARalpha / gamma / delta pan agonist.

[0111] 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.

[0112] 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.

[0113] 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.

[0114] Examples of PPAR alpha / gamma agonists that can be used in the methods described herein include saroglitazar, aleglitazar, muraglitazar, tesaglitazar, and DSP-8658.

[0115] Examples of PPAR alpha / delta agonists that can be used in the methods described herein include elafibranor and T913659.

[0116] Examples of PPAR gamma / delta agonists that can be used in the methods described herein include conjugated linoleic acid (CLA) and T3D-959.

[0117] 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.

[0118] 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).

[0119] The second therapeutic agent can be administered simultaneously, separately, or sequentially with the compound of the disclosure. If administered simultaneously, the second therapeutic agent and the compound of the disclosure can be administered in separate dosage forms or in the same dosage form.

[0120] In another embodiment, a method of 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 having a structure of Formula (I) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof, or a pharmaceutical composition thereof. In one embodiment, the itch-related condition is cholestatic pruritus, uremic pruritus, atopic dermatitis, dry skin, psoriasis, contact dermatitis or eczema.

[0121] In one embodiment of Formula (I), the compound has the structure of Formula (II):

[0122]

[0123] or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof, wherein m, n, p, A, B, Z, R 1 , R 2 and R3 As defined above.

[0124] In one embodiment of formula (I), A is a 5- or 6-membered carbocyclic ring.

[0125] In yet another embodiment of formula (I), A is a 5- or 6-membered heterocyclic ring.

[0126] In one embodiment of formula (I), A is a 5-membered heterocycle and the compound has the structure of formula (III):

[0127]

[0128] or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof, wherein m, p, B, Z, R 1 and R 3 As defined above, and wherein:

[0129] R 2a , R 2b , R 2c and R 2d Each is independently H, halogen, hydrocarbon group, halogenated hydrocarbon group or aromatic hydrocarbon group.

[0130] In one embodiment of formula (I), A is a 6-membered heterocycle and the compound has the structure of formula (IV):

[0131]

[0132] or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof, wherein m, p, B, Z, R 1 , R 2a , R 2b , R 2c , R 2d and R 3 As defined above.

[0133] In one embodiment of Formula (I), B is a heterocycle.

[0134] In one embodiment of formula (I), B is pyridine, pyrimidine, pyrazole, furan, oxazole, isoxazole, oxadiazole, thiophene, thiazole, thiadiazole, tetrahydro-2H-pyran, benzoxadiazole, benzothiazole, benzotriazole or 2,3-dihydrobenzo[b][1,4]dioxin.

[0135] In another embodiment of Formula (I), B is carbocyclic.

[0136] In another embodiment of formula (I), B is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthalene or tetralin.

[0137] In another embodiment of Formula (I), B is phenyl.

[0138] In one embodiment of formula (I), A is a 5-membered heterocycle, B is phenyl, and the compound has the structure of formula (V):

[0139]

[0140] or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof, wherein m, p, B, Z, R 1 , R 2a , R 2b , R 2c , R 2d and R 3 As defined above.

[0141] In one embodiment of formula (1), A is a 6-membered heterocycle, B is phenyl and the compound has the structure of formula (VI):

[0142]

[0143] or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof, wherein m, p, B, Z, R 1 , R 2a , R 2b , R 2c , R 2d and R 3 As defined above.

[0144] In one embodiment of Formula (I), Z is -O-.

[0145] In one embodiment of Formula (I), m is 1, R 1 is H, A is a 5-membered heterocycle, B is phenyl, Z is -O-, and the compound has the structure of formula (VII):

[0146]

[0147] or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof, wherein p, R 2a , R 2c and R 3 As defined above.

[0148] In one embodiment of Formula (I), m is 1, R 1 is H, A is a 6-membered heterocycle, B is phenyl, Z is -O-, and the compound has the structure of formula (VIII):

[0149]

[0150] or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof, wherein p, R 2a , R 2c and R 3 As defined above.

[0151] In one embodiment of Formula (I), Z is -N(R')-.

[0152] In one embodiment of Formula (I), m is 1, R 1 is H, A is a 6-membered heterocycle, B is phenyl, Z is -N(R')-, wherein R' is H, and the compound has the structure of formula (IX):

[0153]

[0154] or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof, wherein p, R 2a , R 2c and R 3 As defined above.

[0155] In one embodiment of formula (I), Z is -N(R')SO2-.

[0156] In one embodiment of Formula (I), m is 1, R 1 is H, A is a 6-membered heterocycle, B is phenyl, Z is -N(R')SO2-, wherein R' is H, and the compound has the structure of formula (X):

[0157]

[0158] or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof, wherein p, R 2a , R 2c and R 3 As defined above.

[0159] In one embodiment of Formula (I), Z is -N(R')C(O)-.

[0160] In one embodiment of Formula (I), m is 1, R 1 is H, A is a 6-membered heterocycle, B is phenyl, Z is -N(R')C(O)-, wherein R' is H, and the compound has the structure of formula (XI):

[0161]

[0162] or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof, wherein p, R 2a , R 2c and R 3 As defined above.

[0163] In one embodiment of formula (I), Z is -SO2N(R')-.

[0164] In one embodiment of Formula (I), m is 1, R 1 is H, A is a 6-membered heterocycle, B is phenyl, Z is -SO2N(R')-, wherein R' is H, and the compound has the structure of formula (XII):

[0165]

[0166] or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof, wherein p, R 2a , R 2c and R 3 As defined above.

[0167] In one embodiment of Formula (I), Z is -C(O)N(R')-.

[0168] In one embodiment of Formula (I), m is 1, R 1 is H, A is a 6-membered heterocycle, B is phenyl, Z is -C(O)N(R')-, wherein R' is H, and the compound has the structure of formula (XIII):

[0169]

[0170] or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof, wherein p, R 2a , R 2c and R 3 As defined above.

[0171] Where applicable, representative compounds of formula (I) and formula (II) to formula (XIII) include any of the compounds listed in Table A below, and pharmaceutically acceptable isomers, racemates, hydrates, solvates, isotopes or salts thereof. For this purpose, representative compounds are identified herein by their corresponding "Compound Number", which is sometimes abbreviated as "Compound No." or "Cpd. No.".

[0172] Table A

[0173] Representative compounds

[0174]

[0175]

[0176]

[0177]

[0178]

[0179]

[0180]

[0181]

[0182] In other embodiments, prodrugs and / or metabolites of compounds of Formula (I) and Formula (II) to Formula (XIII) are provided.

[0183] Therefore, in one embodiment, there is provided a prodrug of a compound of the present invention, which, after being administered to a subject, undergoes chemical transformation to become an active pharmacological substance by metabolic processes or other physiological processes. The transformation by metabolic processes or other physiological processes includes but is not limited to the chemical transformation of prodrugs to active pharmacological substances enzymatic (e.g., specific enzymatic catalysis) and non-enzymatic (e.g., general or specific acid or base induction) chemical transformation. Typically, such a prodrug will be a functional derivative of a compound of the present invention, which is easily converted into a compound of the present invention in vivo. Conventional procedures for selecting and preparing suitable prodrug derivatives are described in, for example, Design of Prodrugs, editor H.Bundgaard, Elsevier, 1985.

[0184] 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's body. Examples of prodrugs include esters of carboxylic acid groups, which can be hydrolyzed by endogenous esterases, such as those found in the bloodstream of humans and other mammals. In one embodiment, a substance is provided that can be administered to a subject and then converted in the subject's body to provide a compound having a structure of formula (I) or a structure of any one of formulas (II) to (XIII).

[0185] As used herein, "metabolites" are compounds that are transformed in the subject's body to produce active substances after administration to the subject. Such transformations often involve hydrolysis, phosphorylation, and / or oxidation / reduction processes and can be mediated by any number of enzymes (e.g., esterases, phosphatases, cytochrome P450 and similar enzymes) and by different environments in the body (e.g., changes in pH).

[0186] In certain embodiments, the present invention provides a pharmaceutical composition comprising a compound of any one of formula (I) to formula (XIV) together with at least one pharmaceutically acceptable carrier, diluent or excipient. For example, the active compound will generally be mixed with a carrier, or diluted by a carrier, or encapsulated in a carrier, which may be in the form of an ampoule, capsule, sachet, paper or other container. When the active compound is mixed with a carrier, or when the carrier is used as a diluent, the carrier may be a solid, semisolid or liquid material serving 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, agar, pectin, gum arabic, stearic acid, or the lower alkyl ethers of cellulose, silicic acid, fatty acid, fatty acid amine, fatty acid monoglyceride and fatty acid 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 a wax.

[0187] As used herein, the term "pharmaceutical composition" refers to a composition comprising 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, may also contain other additives, and is manufactured or sold as part of a therapeutic regimen for treating a disease in a mammal approved by a governmental regulatory agency. The pharmaceutical composition may be formulated, for example, for oral administration in a unit dosage form (e.g., tablets, capsules, caplets, gelcaps or syrups); for topical administration (e.g., as a cream, gel, lotion or ointment); for intravenous administration (e.g., as a sterile solution free of particulate plugs and in 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 in The United States Pharmacopeia: The National Formulary (USP 36NF31), published in 2013.

[0188] In some embodiments, the pharmaceutical composition comprising any one of the compounds of formula (I) to formula (XIII) and at least one pharmaceutically acceptable carrier, diluent or excipient 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, farnesoid X-receptor (FXR) agonist, peroxisome proliferator-activated receptor (PPAR) agonist, thyroid hormone receptor β (TRβ) agonist or any combination thereof.

[0189] Examples of FXR agonists that can be used in the pharmaceutical compositions described herein include obeticholic acid, tophenoxy isopropyl ester (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, tropifexor (LJN452), nidufexor ... Fenisopropyl ester, fexaramine, silymarin, silybin, herzognic 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, tophenytoin (WAY-362450), BAR502, herzognic acid, or BAR704) or a non-bile acid agonist (e.g., EDP-305, tropifexor, nidufexor, cilofexor, GW4064, tophenytoin, fexaramine, 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). 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.

[0190] Examples of PPARα agonists that can be used in the pharmaceutical compositions described herein include fenofibrate, ciprofibrate, pemafibrate, gemfibrozil, clofibrate, binifibrate, clinofibrate, clofibric acid, nicofibrate, pirfibrate, prafibride, ronifibrate, edoxaborate, tocofibrate, or SRI 0171.

[0191] 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.

[0192] Examples of PPARδ agonists that can be used in the pharmaceutical compositions described herein include GW501516 (endurabol or ({4-[({4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}acetic acid)), MBX8025 (Ceradilpa 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.

[0193] Examples of PPAR alpha / gamma agonists that can be used in the pharmaceutical compositions described herein include saroglitazar, aleglitazar, muraglitazar, tesaglitazar, and DSP-8658.

[0194] Examples of PPAR alpha / delta agonists that can be used in the pharmaceutical compositions described herein include elafibranor and T913659.

[0195] Examples of PPAR gamma / delta agonists that can be used in the pharmaceutical compositions described herein include conjugated linoleic acid (CLA) and T3D-959.

[0196] Examples of PPARα / γ / δ agonists that can be used in the pharmaceutical compositions described herein include IVA337 (lanifibranor), 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.

[0197] 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).

[0198] 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 and having the property of being non-toxic and non-inflammatory in a patient (e.g., a carrier capable of suspending or dissolving an active compound). Excipients may include, for example, anti-adherents, antioxidants, binders, coatings, compression aids, disintegrants, dyes (colorants), softeners, emulsifiers, fillers (diluents), film formers or coatings, flavoring agents, 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 (dicalcium phosphate), 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, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, and xylitol.

[0199] The preparation may be mixed with adjuvants that do not react harmfully with the active compound. Such additives may include wetting agents, emulsifying agents and suspending agents, salts for affecting osmotic pressure, buffers and / or coloring substances, preservatives, sweeteners or flavoring agents. If desired, the composition may also be sterilized.

[0200] 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, 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.

[0201] 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 it is considered desirable by the prescribing physician or the prescription information of the drug, the dosage form can be administered less frequently than every day, such as every other day or every week. The dosage regimen includes, for example, dose titration to a necessary or useful degree for the indication to be treated, thereby allowing the patient's body to adapt to the treatment, to minimize or avoid unwanted side effects associated with the treatment, and / or to maximize the therapeutic effect of the compounds of the invention. Other dosage forms include delayed release forms or controlled release forms. Suitable dosage regimens and / or forms include, for example, those stated in the latest version of the Physicians' Desk Reference, which is incorporated herein by reference.

[0202] In one embodiment, the present invention provides an oral pharmaceutical composition comprising a compound of any one of Formula (I) to Formula (XIII) together with 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 Formula (XIII) together with at least one pharmaceutically acceptable topical carrier, diluent or excipient. For example, an oral pharmaceutical composition is provided to treat cholestatic pruritus, wherein the dosage regimen is, for example, once a day. In one embodiment, a topical pharmaceutical composition is provided to treat atopic dermatitis.

[0203] In another embodiment, a method for preparing a composition of a compound described herein is provided, the method comprising formulating a compound of the present invention with a pharmaceutically acceptable carrier or diluent. In some embodiments, the pharmaceutically acceptable carrier or diluent is suitable for oral administration. In some such embodiments, the method may also include 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 also includes the step of freeze-drying the composition to form a freeze-dried preparation.

[0204] In certain embodiments, the present invention provides compounds having the structure of any one of formula (I) to formula (XIII). Such compounds can be synthesized using standard synthesis techniques known to those skilled in the art. For example, compounds of the present invention can be synthesized using the synthetic procedures of the appropriate modifications set forth in the following examples and reaction schemes.

[0205] For this purpose, the reactions described herein, processes and synthetic methods are not limited to the specific conditions described in the following experimental section, but are intended as guidance to a suitable technician in the field. For example, the reaction can be carried out with any suitable solvent or other reagent to carry out the necessary transformation. Generally, suitable solvents are protic solvents or aprotic solvents, which are generally not reacted with reactants, intermediates or products at the temperature (that is, the temperature in the range from freezing temperature to boiling temperature) of 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 a specific post-treatment after the reaction can be used.

[0206] All reagents for the synthesis not described in the experimental part are commercially available, or are known compounds, or can be formed by known compounds by known methods by those skilled in the art. Compounds and intermediates produced according to the method of the present invention may need purification. The purification of organic compounds is well known to those skilled in the art, and there may be several ways 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, especially flash column chromatography, using a special or pre-loaded silica gel column and an eluent such as a gradient solvent, such as heptane, ether, ethyl acetate, acetonitrile, ethanol and similar solvents. In some cases, the method as described can be used to purify the compound by preparative HPLC.

[0207] The purification methods as described herein can provide the compounds of the invention with sufficient basic or acidic functionality in the form of salts, such as trifluoroacetate or formate 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 form or free acid form, respectively, by a variety of 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.

[0208] 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. Example

[0209] General approach

[0210] 1 H NMR (400 MHz) spectra were obtained in solutions of deuterated chloroform (CDCl3), deuterated methanol (CD3OD) or dimethyl sulfoxide-D6 (DMSO). HPLC retention time, purity and mass spectra (LCMS) were obtained using one of the following methods:

[0211] Method 1 : Agilent 1260 Infinity II system, equipped with Agilent Poroshell 120EC-18, 2.7 μm, 4.6×100 mm column, using H2O with 0.1% formic acid as mobile phase A, and using MeCN with 0.1% formic acid as mobile phase B. Use ESI detector in positive mode. Gradient is 20%-95% mobile phase B in 5 min, then keep at 95% for 3.8 min, then return to 20% mobile phase B in 0.2 min. Flow rate is 1 mL / min.

[0212] Method 2 : Agilent 1260 Infinity II system, equipped with Agilent Poroshell 120EC-18, 2.7 μm, 4.6×100 mm column, using H2O with 0.1% formic acid as mobile phase A, and using MeCN with 0.1% formic acid as mobile phase B. Use ESI detector in positive mode. Gradient is 10%-95% mobile phase B in 12 min, then keep at 95% for 2 min, then return to 10% mobile phase B in 1 min. Flow rate is 1 mL / min.

[0213] Method 3: Shimadzu SCL-10A system, equipped with Agilent Eclipse XDB-C18, 3.5μm, 4.6×150mm column and PE Sciex API 150EX, using H2O with 0.1% trifluoroacetic acid as mobile phase A, and using methanol with 0.1% trifluoroacetic acid as mobile phase B. The gradient was 5%-95% mobile phase B in 12 min, then kept at 95% mobile phase B for 3 min, and then returned to 5% mobile phase B for 1 min. The flow rate was 1 mL / min.

[0214] Method 4 : Waters Acquity system equipped with an Acquity UPLC BEH C18 1.7 μm, 2.1×50 mm column using H 2 O with 0.1% ammonium formate 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 and then held at 100% mobile phase B for 1 minute. The flow rate was 0.7 mL / min.

[0215] Method 5 : Waters Acquity system equipped with EVO C18 (5 μm, 3.0×50 mm) using a low pH buffer gradient of 5% to 100% MeCN (0.1% HCOOH) in H 2 O at 2.2 mL / min in 2.5 min and held at 100% for a total time of 3.5 min.

[0216] The pyridine, dichloromethane (DCM), tetrahydrofuran (THF) and toluene used in the procedure were from Aldrich Sure-Seal bottles stored under nitrogen (N2). All reactions were stirred magnetically, and the temperature was the external reaction temperature. Chromatography was typically performed using a Combiflash Rf rapid purification system (Teledyne Isco) equipped with Redisep (Teledyne Isco) Rf Gold normal phase silica gel (SiO2) column or by using a similar system.

[0217] 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 30×150 mm column, and eluted with various gradients of H2O / MeCN (0.1% formic acid) at a flow rate of 30 mL / min, 2) a Teledyne Isco HP150 UV system, equipped with a Waters xBridge Prep C18 5μm OBD 30×150mm column and eluted with various gradients of H2O / MeCN (0.1% formic acid) at a flow rate of 42.5mL / min, or 3) column: Phenomenex Synergi C18 150×30mm-4μm; mobile phase: [H2O(0.225% formic acid)-MeCN]; B%: 55%-85%, 12min), and usually concentrated using Genevac EZ-2.

[0218] The following additional abbreviations are used: ethyl acetate (EA), triethylamine (TEA), dimethyl sulfoxide (DMSO), silica gel (SiO2), azobisisobutyronitrile (AIBN), diisobutylaluminum hydride (DIBAL), trifluoroacetic acid (TFA), 4-dimethylaminopyridine (DMAP), diphenylphosphoryl azide (DPPA), benzoyl peroxide (BPO), 1,1'-bis(diphenylphosphino)ferrocene (dppf), bis(pinacolato)diboron (B2pin2), tetrahydrofuran (THF), 1,4-diazabicyclo[2.2.2]octane bis(sulfur dioxide) adduct (DABSO), azabenzotriazole tetramethyl urea hexafluorophosphate (HATU), hydroxybenzotriazole (HOBt), N-methylmorpholine (NMM), N-bromosuccinimide Amine (NBS), diisopropylethylamine (DIPEA), diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), 2-[2-(dicyclohexylphosphino)phenyl]-N-methylindole (CM-Phos), trifluoromethanesulfonic acid (TfOH), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC), isopropyl alcohol (IPA), dimethylformamide (DMF), dimethylacetamide (DMA), dichloromethane (DCM), 1,2-dichloroethane (DCE), 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).

[0219] Example 1

[0220] Synthesis of Compound 1-1, Compound 1-5 and other representative compounds

[0221]

[0222] Solution 1

[0223]

[0224] Reagents: (i) K2CO3, solvent (MeCN or DMF); ii. NaH or KO t Bu, solvent (THF or DMF)

[0225] Step 1-1. Synthesis of 7-((4-chlorobenzyl)oxy)isoindolin-1-one (Compound 1-1)

[0226]

[0227] To a stirred solution of 4-chlorobenzyl chloride (108 mg, 1.0 eq., 670 μmol) and 7-hydroxyisoindolin-1-one (100 mg, 1.0 eq., 670 μmol) in DMF (4 mL) was charged KCO (120 mg, 1.3 eq., 872 μmol). The resulting yellow suspension was heated at 80 °C and stirred for 14 hours. The reaction mixture was cooled to room temperature and filtered. The filtrate was purified by preparative HPLC to give 63.4 mg (34.5%) of 7-((4-chlorobenzyl)oxy)isoindolin-1-one (Compound 1-1) as white needles. LCMS-ESI (m / z) for C 15 H 12 Calculated value for ClNO2: 273.06; Found 274.1 [M+H] + , t R =7.86min (Method 2). 1 H NMR (400MHz, DMSO-d6) δ8.26(s,1H),7.56–7.43(m,5H),7.10(d,J=7.6Hz,1H),7.04(d,J=8.3Hz,1H),5.24(s,2H),4.29(s,2H).

[0228] The compounds listed in Table 1A were prepared using the procedure of Scheme 1.

[0229] Table 1A

[0230]

[0231]

[0232] Step 1-2. Synthesis of 7-((4-chlorobenzyl)oxy)-2-methylisoindolin-1-one (Compound 1-5)

[0233]

[0234] To a stirred solution of compound 1-1 (57.7 mg, 1.0 eq., 211 μmol) in DMF (2 mL) was charged with NaH (60% dispersion in mineral oil, 8.4 mg, 1.0 eq., 211 μmol) in one portion. The suspension was stirred at room temperature for 15 minutes and then charged with iodomethane (29.9 mg, 13.1 μL, 1.0 eq., 211 μmol). The resulting mixture was stirred at room temperature for 14 hours. The reaction mixture was filtered and the filtrate was purified by preparative HPLC to give 23.3 mg (38.4%) of 7-((4-chlorobenzyl)oxy)-2-methylisoindolin-1-one (compound 1-5) as a white solid. LCMS-ESI (m / z) for C 16 H 14 Calculated value for ClNO2: 287.07; Found: 288.1 [M+H] + , t R =8.66min (Method 2). 1 H NMR (400MHz, DMSO-d6) δ7.57–7.43(m,5H),7.11(d,J=7.4Hz,1H),7.05(d,J=8.2Hz,1H),5.25(s,2H),4.38(s,2H),3.01(s,3H).

[0235] The compounds listed in Table 1B were prepared using the procedure of Scheme 1.

[0236] Table 1B:

[0237]

[0238] Example 2

[0239] Synthesis of compound 2-1 and other representative compounds

[0240]

[0241] Solution 2

[0242]

[0243] Reagents: (i) 4-nitrophenyl chloroformate, Et3N, DMF; (ii) TfOH, DCE; (iii) BBr3, DCM; (iv) K2CO3, solvent (MeCN or DMF)

[0244] Step 2-1. Synthesis of 4-nitrophenyl (2-methoxyphenylethyl) (methyl) carbamate (INT 2-A)

[0245]

[0246] To the stirring solution of 2-(2-methoxyphenyl)-N-methyl second-1-amine (302mg, 1.0 equivalent, 1.83mmol) in DMF (6mL), triethylamine (580mg, 0.80mL, 3.2 equivalents, 5.80mmol) is added, and the mixture is stirred at room temperature for 10 minutes. Then the reaction mixture is loaded with solid 4-nitrophenyl chloroformate (450mg, 1.2 equivalents, 2.23mmol) in one portion, and the resulting orange suspension is stirred at room temperature for 3 hours. The reaction mixture is then distributed between EA and water, and the organic layer is collected. The water-bearing layer is stripped 2× with EA, and the combined organic layer is washed with salt water, through Na2SO4, dried and concentrated in vacuo. The residue was purified by flash SiO2 chromatography (0%-50% EA / hexanes) to provide 363 mg (60.1%) of 4-nitrophenyl(2-methoxyphenethyl)(methyl)carbamate (INT 2-A) as a light yellow syrup, which was used directly in the next step. LCMS-ESI (m / z) for C 17 H 18 Calculated value for N2O5: 330.12; Found 331.2 [M+H] + , t R =5.88min (Method 1).

[0247] Step 2-2. Synthesis of 5-methoxy-2-methyl-3,4-dihydroisoquinolin-1(2H)-one (INT 2-B)

[0248]

[0249] Trifluoromethanesulfonic acid (1.67 g, 986 μL, 10.3 eq., 11.10 mmol) was added to an ice-cold solution of INT-2A (356 mg, 1.0 eq., 1.08 mmol) in DCE (5 mL). The reaction mixture was stirred at 0 ° C for 30 minutes and then at 70 ° C for 3 hours. After cooling to room temperature, the reaction was carefully poured into ice water and stirred for several minutes. The biphasic mixture was extracted twice with DCM. The combined organic extracts were washed with 2M Na2CO3 and the aqueous phase was back extracted with DCM. The DCM layers were combined, dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified by flash SiO2 chromatography (10%-100% EA / hexanes) to provide 136 mg (66%) of 5-methoxy-2-methyl-3,4-dihydroisoquinolin-1(2H)-one (INT 2-B) as a pale yellow oil. LCMS-ESI (m / z) for C 11 H 13 Calculated value of NO2: 191.09; Found: 192.2 [M+H] + , t R=5.86min (Method 2). 1 H NMR (400MHz, DMSO-d6) δ7.48(d,J=7.8Hz,1H),7.30(t,J=8.0Hz,1H),7.13(d,J=8 .2Hz,1H),3.82(s,3H),3.50(t,J=6.8Hz,2H),3.00(s,3H),2.87(t,J=6.8Hz,2H).

[0250] Step 2-3. Synthesis of 5-hydroxy-2-methyl-3,4-dihydroisoquinolin-1(2H)-one (INT 2-C)

[0251]

[0252] To an ice-cold solution of INT 2-B (116 mg, 1.0 eq., 607 μmol) in DCM (3 mL) was added 1 M boron tribromide (456 mg, 1.8 mL, 3.0 eq., 1.82 mmol) in DCM. After stirring at 0 °C for a few minutes, the reaction was stirred at room temperature for 3 hours. The reaction was then poured into ice water and extracted 3× with EA. The organic extracts were combined, washed with saturated NaHCO3 and brine, dried over Na2SO4 and concentrated in vacuo to provide 88 mg (82%) of 5-hydroxy-2-methyl-3,4-dihydroisoquinolin-1(2H)-one (INT2-C) as a tan solid. LCMS-ESI (m / z) for C 10 H 11 Calculated value of NO2: 177.08; Found: 178.1 [M+H] + , t R =2.18min (Method 1). 1 H NMR (400MHz, DMSO-d6) δ9.69 (s, 1H), 7.34 (d, J = 7.8Hz, 1H), 7.12 (t, J = 7.8Hz, 1H), 6. 95(dd,J=8.0,1.3Hz,1H),3.49(t,J=6.8Hz,2H),3.00(s,3H),2.83(t,J=6.8Hz,2H).

[0253] Step 2-4. 5-((2-chloro-4-(trifluoromethyl)benzyl)oxy)-2-methyl-3,4-dihydroisoquinoline-1(2H)- Synthesis of ketone (compound 2-1)

[0254]

[0255] A solution of INT 2-C (34 mg, 1.0 eq., 0.19 mmol) in DMF (2 mL) was added to a vial containing 2-chloro-1-(chloromethyl)-4-(trifluoromethyl)benzene (44 mg, 1.0 eq., 0.19 mmol), followed by potassium carbonate (34 mg, 1.3 eq., 0.25 mmol). The resulting yellow suspension was stirred at 80 °C for 4 hours. The reaction was cooled to room temperature, filtered, and purified by preparative HPLC to provide 36.8 mg (52%) of 5-((2-chloro-4-(trifluoromethyl)benzyl)oxy)-2-methyl-3,4-dihydroisoquinolin-1(2H)-one (Compound 2-1) as a white solid. LCMS-ESI (m / z) for C 18 H 15 Calculated value of ClF3NO2: 369.07; Found 369.8, 371.8 [M+H] + , t R =11.08min (Method 2). 1 H NMR (400MHz, DMSO-d6) δ7.96(s,1H),7.87(d,J=8.1Hz,1H),7.80(d,J=8.1Hz,1H),7.54(d,J=7.6Hz,1H),7.32( t,J=7.9Hz,1H),7.26(d,J=8.3Hz,1H),5.31(s,2H),3.53(t,J=6.8Hz,2H),3.02(s,3H),2.96(t,J=6.8Hz,2H). 19 F NMR(376MHz,DMSO-d6)δ-61.15.

[0256] The compounds listed in Table 2 were prepared using the procedure of Scheme 2.

[0257] Table 2

[0258]

[0259]

[0260]

[0261]

[0262]

[0263]

[0264]

[0265]

[0266]

[0267] Example 3

[0268] Synthesis of compound 3-1 and other representative compounds

[0269]

[0270] Solution 3

[0271]

[0272] Reagents: (i) NaH, DMF; (ii) BBr3, DCM; (iii) K2CO3, solvent (MeCN or DMF)

[0273] Step 3-1. Synthesis of 4-methoxy-2-methylisoindolin-1-one (INT 3-A)

[0274]

[0275] To an ice-cold solution of 4-methoxyisoindolin-1-one (300 mg, 1.0 eq., 1.84 mmol) in DMF (5 mL) was added NaH (60% dispersion in mineral oil, 81 mg, 1.1 eq., 2.02 mmol) in one portion. The suspension was stirred at 0 °C for 15 min and then charged with iodomethane (313 mg, 137 μL, 1.2 eq., 2.21 mmol). The resulting mixture was stirred at room temperature for 16 h. The reaction was poured into ice water and extracted 4× with EA. The organic extracts were combined, washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash SiO2 chromatography (20%-100% EA / hexanes) to provide 178 mg (54.6%) of 4-methoxy-2-methylisoindolin-1-one (INT 3-A) as a white solid. LCMS-ESI (m / z) for C 10 H 11 Calculated value of NO2: 177.08; Found: 178.2 [M+H] + , t R =2.81min (Method 1).

[0276] Step 3-2. Synthesis of 4-hydroxy-2-methylisoindolin-1-one (INT 3-B)

[0277]

[0278] To an ice-cold solution of INT 3-A (168 mg, 1.0 eq., 948 μmol) in DCM (4 mL) was added 1.0 M boron tribromide (2.84 mL, 3.0 eq., 2.84 mmol) in DCM dropwise. After stirring at 0 °C for 5 min, the reaction mixture was stirred at room temperature for 5 h. The reaction was then poured into ice water and extracted 3× with EA. The organic extracts were combined, washed with saturated NaHCO and brine, dried over NaSO and concentrated in vacuo to provide 92 mg (59%) of 4-hydroxy-2-methylisoindolin-1-one (INT 3-B) as an off-white solid. LCMS-ESI (m / z) calculated for C9H9NO2: 163.06; found 164.2 [M+H] + , t R =1.70min (Method 1).

[0279] Step 3-3. 4-((2-chloro-4-(trifluoromethyl)benzyl)oxy)-2-methylisoindolin-1-one (Compound 3- 1) Synthesis

[0280]

[0281] A 1-dram vial containing 2-chloro-1-(chloromethyl)-4-(trifluoromethyl)benzene (53 mg, 1.0 eq., 0.23 mmol) was charged with a solution of INT 3-B (38 mg, 1.0 eq., 0.23 mmol) in DMF (2 mL) followed by potassium carbonate (42 mg, 1.3 eq., 0.30 mmol). The resulting yellow suspension was stirred at 80 °C for 13 hours. The reaction was cooled to room temperature and filtered. The filtrate was purified by preparative HPLC to provide 37.2 mg (45%) of 4-((2-chloro-4-(trifluoromethyl)benzyl)oxy)-2-methylisoindolin-1-one (Compound 3-1) as a white solid. LCMS-ESI (m / z) for C 17 H 13 Calculated value for ClF3NO2: 355.06; Found 355.8 [M+H] + , t R =10.43min (Method 2). 1 H NMR (400MHz, DMSO-d6) δ7.97(s,1H),7.86(d,J=8.1Hz,1H),7.79(d,J=8.1Hz,1H) ,7.46(t,J=7.8Hz,1H),7.32–7.27(m,2H),5.40(s,2H),4.45(s,2H),3.07(s,3H). 19 F NMR(376MHz,DMSO-d6)δ-61.16.

[0282] The compounds listed in Table 3 were prepared using the procedure of Scheme 3.

[0283] Table 3

[0284]

[0285] Example 4

[0286] Synthesis of compound 4-1 and other representative compounds

[0287]

[0288] Solution 4

[0289]

[0290] Reagents: (i) CH3I, K2CO3, DMF; (ii) NBS, AIBN, CCl4; (iii) R 2c NH2, THF; (iv) K2CO3, solvent (DMF or MeCN)

[0291] Step 4-1. Synthesis of methyl 3-acetoxy-2-methylbenzoate (INT 4-A)

[0292]

[0293] Potassium carbonate (3.35 g, 1.1 eq., 24.22 mmol) was added to a 250RBF containing a stirred solution of 3-acetoxy-2-methylbenzoic acid (4.28 g, 1.0 eq., 22.02 mmol) in DMF (42 mL), followed by iodomethane (1.64 mL, 1.2 eq., 26.42 mmol). The resulting mixture was stirred at room temperature for 40 minutes. The reaction mixture was then treated with water and extracted 3× with ether. The organic layers were combined, washed with brine, dried over Na2SO4 and dry-loaded onto Celite. The residue was purified by flash SiO2 chromatography (0%-40% EA / hexanes) to provide 2.34 g (50.9%) of 3-acetoxy-2-methylbenzoic acid methyl ester (INT4-A) as a colorless oil. LCMS-ESI (m / z) for C 11 H 12 Calculated value for O4: 208.07; Found: 209.2 [M+H] + , t R =4.86min (Method 1). 1H NMR (400MHz, CDCl3) δ7.77(d,J=7.8Hz,1H),7.29–7.23(m,1H),7.17(d,J=8.0Hz,1H),3.89(s,3H),2.40(s,3H),2.35(s,3H).

[0294] Step 4-2. Synthesis of methyl 3-acetoxy-2-(bromomethyl)benzoate (INT 4-B)

[0295]

[0296] To a stirred solution of INT 4-A (2.33 g, 1.0 eq., 11.19 mmol) in CCl4 (55 mL) was added NBS (2.39 g, 1.1 eq., 24.22 mmol) and AIBN (183.7 mg, 0.1 eq., 1.12 mmol). The flask was equipped with a reflux condenser and stirred at 100°C for 20 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was partitioned between EA and water. The organic layer was collected and the aqueous layer was extracted twice more with EA. The organic layers were combined, dried over Na2SO4 and dry loaded onto diatomaceous earth. The residue was purified by flash SiO2 chromatography (0%-40% EA / hexanes) to provide 2.88 g (89.5%) of methyl 3-acetoxy-2-(bromomethyl)benzoate (INT 4-B) as a colorless oil. LCMS-ESI (m / z) for C 11 H 11 Calculated value of BrO4: 285.98; Found 286.8, 288.8 [M+H] + , t R =5.12min (Method 1). 1 HNMR (400MHz, CDCl3) δ7.86 (d, J = 7.8 Hz, 1H), 7.41 (t, J = 8.0 Hz, 1H), 7.31 (d, J = 8.2 Hz, 1H), 4.94 (s, 2H), 3.95 (s, 3H), 2.41 (s, 3H).

[0297] Step 4-3. Synthesis of 4-hydroxy-2-methylisoindolin-1-one (INT 4-C)

[0298]

[0299] To a stirred solution of INT 4-B (2.87 g, 1.0 eq., 11.19 mmol) in THF (28 mL) was added 2.0 M methylamine (25 mL, 5.0 eq., 49.95 mmol) in THF. The resulting white slurry was stirred at room temperature for 15 hours. The reaction mixture was then concentrated in vacuo, and the residue was suspended in ether and filtered. The filter cake was washed with ether, dried to give a white solid, which was dissolved in DMSO and purified by reverse phase flash column chromatography to provide 540 mg (33.1%) of 4-hydroxy-2-methylisoindolin-1-one (INT 4-C) as a bright white powder. LCMS-ESI (m / z) calculated for C9H9NO2: 163.06; found 164.0 [M+H] + , t R =2.19min (Method 1). 1 H NMR (400MHz, DMSO-d6) δ10.02(s,1H),7.28(t,J=7.7Hz,1H),7.11(d,J=7.3Hz,1H),6.96(d,J=7.9Hz,1H),4.32(s,2H),3.05(s,3H).

[0300] Step 4-4. Synthesis of 4-((2,4-dichlorobenzyl)oxy)-2-methylisoindolin-1-one (Compound 4-1)

[0301]

[0302] To a stirred solution of INT 4-C (50 mg, 1.0 eq., 0.31 mmol) in DMF (2 mL) was added 3,4-dichlorobenzyl bromide (74 mg, 1.0 eq., 0.31 mmol) and potassium carbonate (55 mg, 1.3 eq., 0.40 mmol). The resulting white suspension was stirred at 80 °C for 20 hours. The reaction mixture was cooled to room temperature and filtered. The filtrate was purified by preparative HPLC to provide 40.3 mg (41%) of 4-((2,4-dichlorobenzyl)oxy)-2-methylisoindolin-1-one (Compound 4-1) as a white solid. LCMS-ESI (m / z) for C 16 H 13 Calculated value of Cl2O2: 321.03; Found 322.0, 324.0 [M+H] + , t R =9.99min (Method 2). 1H NMR (400MHz, DMSO-d6) δ7.76(s,1H),7.67(d,J=8.3Hz,1H),7.50–7.41(m,2H),7.29–7.21(m,2H),5.27(s,2H),4.45(s,2H),3.06(s,3H).

[0303] The compounds listed in Table 4 were prepared using the procedure of Scheme 4.

[0304] Table 4

[0305]

[0306]

[0307] Example 5

[0308] Synthesis of compound 5-1 and other representative compounds

[0309]

[0310] Solution 5

[0311]

[0312] Reagents: (i) NaBH(OAc)3, HCl, DCE, MeOH

[0313] Step 5-1. 5-((2,4-dichlorobenzyl)amino)-2-methyl-3,4-dihydroisoquinolin-1(2H)-one (Compound 5-1) Synthesis

[0314]

[0315] To a stirred solution of 5-amino-2-methyl-3,4-dihydroisoquinolin-1(2H)-one (80 mg, 1.0 eq., 0.45 mmol) in DCE (10 mL) was added 2,4-dichlorobenzaldehyde (79 mg, 1.0 eq., 0.45 mmol) followed by NaBH(OAc)3 (289 mg, 3.0 eq., 1.36 mmol). The resulting mixture was stirred at room temperature for 16 minutes. Additional NaBH(OAc)3 (1.60 g, 20 eq., 9.00 mmol) was added in one portion and the reaction was stirred at room temperature for 6 hours. The reaction mixture was then charged with 2 drops of HCl (1.25 M in MeOH) followed by 2,4-dichlorobenzaldehyde (1.0 eq.) and the reaction was stirred at room temperature for 16 hours. An additional 3 equivalents of NaBH(OAc)3 were added, and after stirring for 3 hours, LCMS indicated consumption of most of the starting material. The reaction mixture was adjusted to pH 10 using 1M aqueous NaOH and extracted with EA. The organic phase was washed with saturated NaHCO3 and brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash SiO2 chromatography (EA / hexanes) to provide 131 mg (86.3%) of 5-((2,4-dichlorobenzyl)amino)-2-methyl-3,4-dihydroisoquinolin-1(2H)-one (Compound 5-1) as a solid. LCMS-ESI (m / z) for C 17 H 16 Calculated value for Cl2N2O: 334.06; found 335.3 [M+H] + , t R =13.88min (Method 3). 1 H NMR (400MHz, CDCl3) δ7.56(d,J=7.7Hz,1H),7.42(s,1H),7.28(t,J=7.4Hz,1H),7.23–7.13(m,2H),6.63(d,J=8.0Hz,1H),4.44(s,2H),4.02(br s, 1H), 3.58 (t, J = 6.8Hz, 2H), 3.14 (s, 3H), 2.79 (t, J = 6.6Hz, 2H).

[0316] The compounds listed in Table 5 were prepared using the procedure of Scheme 5.

[0317] Table 5

[0318]

[0319] Example 6

[0320] Synthesis of Compound 6-1, Compound 6-2 and other representative compounds

[0321]

[0322] Solution 6

[0323]

[0324] Reagents: (i) CO, Pd(dppf)Cl2.CH2Cl2, solvent (DMF, MeOH); (ii) reducing agent (LiBH4 or NaBH4), THF; (iii) DEAD or DIAD, PPh3, THF; (iv) NaH or KO t Bu, solvent (THF or DMF)

[0325] Step 6-1. Synthesis of 1-oxo-1,2,3,4-tetrahydroisoquinoline-5-carboxylic acid methyl ester (INT 6-A)

[0326]

[0327] To a stirred solution of 5-bromo-3,4-dihydro-2H-isoquinolin-1-one (395 mg, 1.0 eq., 1.75 mmol) and Et3N (1.22 mL, 5.0 eq., 8.74 mmol) in DMF (6 mL) was added Pd(dppf)Cl2.DCM (285 mg, 0.2 eq., 0.35 mmol). The mixture was evacuated and refilled with CO for 3 cycles. MeOH (3.08 mL, 43.42 eq., 76.00 mmol) was added and the mixture was heated to 85 °C for 16 h under a CO atmosphere (1 atm). The mixture was diluted with EA (25 mL) and filtered through a pad of celite. The filtrate was concentrated under reduced pressure. The residue was diluted with EA (100 mL) and water (100 mL). The aqueous phase was extracted with EA (3×25 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash SiO2 chromatography (0%-100% EA / hexanes) to provide 285 mg (80%) of 1-oxo-1,2,3,4-tetrahydroisoquinoline-5-carboxylic acid methyl ester (INT 6-A). MS-ESI for C 11 H 11 Calculated value of NO3: 205.07; Measured value: 205.74[M] + , t R =1.82min (Method 5). 1H NMR (400MHz, CDCl3) δ8.30 (dd, J=7.7, 1.5Hz, 1H), 8.09 (dd, J=7.8, 1.5Hz, 1H), 7.42 (dd,J=7.8Hz,1H),5.95(s,1H),3.92(s,3H),3.58–3.52(m,2H),3.49–3.40(m,2H).

[0328] Step 6-2. Synthesis of 5-(hydroxymethyl)-3,4-dihydroisoquinolin-1(2H)-one (INT 6-B)

[0329]

[0330] To a stirred solution of INT 6-A (182 mg, 1.0 eq., 0.89 mmol) in THF (5 mL) was added LiBH4 (2 M in THF, 2.66 mL, 6.0 eq., 5.32 mmol) at room temperature under nitrogen. The resulting mixture was stirred at room temperature for 20 hours. The mixture was diluted with saturated aqueous NH4Cl solution (10 mL). The aqueous phase was extracted with EA (3×20 mL), and the combined organic phases were washed with brine (50 mL), dried over Na2SO4, and concentrated in vacuo to provide 88 mg (56%) of 5-(hydroxymethyl)-3,4-dihydroisoquinolin-1(2H)-one (INT 6-B). MS-ESI (m / z) for C 10 H 11 Calculated value of NO2: 177.08; Found: 178.13 [M+H] + , t R =1.39min (Method 5). 1 H NMR (500MHz, CDCl3) δ8.07 (dd, J=7.8, 1.4Hz, 1H), 7.52 (dd, J=7.6, 1.4Hz, 1H), 7.36 (t, J=7.7Hz ,1H),5.95(s,1H),4.75(s,2H),3.57(td,J=6.7,2.9Hz,2H),3.07(t,J=6.6Hz,2H),1.72(s,1H).

[0331] Step 6-3. 5-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-3,4-dihydroisoquinolin-1(2H)-one (Chemical Synthesis of Compound 6-1)

[0332]

[0333] To an ice-cold mixture of INT 6-B (88 mg, 1.0 eq., 0.50 mmol), 2-chloro-4-(trifluoromethyl)phenol (69.7 μL, 1.04 eq., 0.52 mmol) and PPh3 (143 mg, 1.1 eq., 0.55 mmol) in THF (5 mL) was added DIAD (108 μL, 1.1 eq., 0.55 mmol). The resulting mixture was stirred at room temperature for 18 hours and then concentrated in vacuo. Some of this material was used in the next step without further purification. The remainder of the material was further purified by reverse phase chromatography (MeCN / H2O, containing 0.1% formic acid) to provide 32.7 mg (19%) of 5-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-3,4-dihydroisoquinolin-1(2H)-one (Compound 6-1) as a solid. MS-ESI (m / z) for C 17 H 13 Calculated for ClF3NO: 355.06; Found: 356.07 [M+H] + , t R =4.69min (Method 4). 1 HNMR(500MHz,DMSO-d6)δ8.00(s,1H),7.90(dd,J=7.8,1.4Hz,1H),7.88–7.85(m,1H),7.73(ddd,J=8.7,2.3,0.9Hz,1H),7.68(dd, J=7.6,1.4Hz,1H),7.52(d,J=8.6Hz,1H),7.40(dd,J=7.6Hz,1H),5.38(s,2H),3.38(td,J=6.6,2.8Hz,2H),2.96(t,J=6.6Hz,2H).

[0334] Step 6-4. 5-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-2-methyl-3,4-dihydroisoquinoline-1 Synthesis of (2H)-ketone (Compound 6-2)

[0335]

[0336] To an ice-cold solution of compound 6-1 (154 mg, 50% purity, 1.0 eq., 0.22 mmol) in THF (5 mL) was added NaH (24.9 mg, 5.0 eq., 1.08 mmol). The resulting mixture was stirred at room temperature for 30 minutes. Iodomethane (67.4 μL, 5.0 eq., 1.08 mmol) was added and the mixture was stirred at 70 °C for 1 hour. The mixture was diluted with MeOH (10 mL) and concentrated in vacuo. The residue was purified by reverse phase chromatography (CH3CN / H2O, containing 0.1% formic acid) to provide 60.4 mg (76%) of 5-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-2-methyl-3,4-dihydroisoquinolin-1(2H)-one (compound 6-2) as a solid. MS-ESI (m / z) for C 18 H 15 Calculated value for ClF3NO2: 369.07; Found 370.08 [M+H] + , t R =5.08min (Method 4). 1 H NMR (400MHz, DMSO-d6) δ7.92(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(d d,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,5H).

[0337] The compounds listed in Table 6 were prepared using the procedure of Scheme 6.

[0338] Table 6

[0339]

[0340] Example 7

[0341] Synthesis of compound 7-1 and other representative compounds

[0342]

[0343] Solution 7

[0344]

[0345] Reagents: (i) NBS, H2SO4; (ii) NaH, THF; (iii) (Bpin)2, Pd(dppf)Cl2.CH2Cl2, KOAc, THF; (iv) Acetone, H2O; (v) K2CO3, solvent (DMF or THF)

[0346] Step 7-1. Synthesis of 5-bromo-7-fluoro-3,4-dihydroisoquinolin-1(2H)-one (INT7-A)

[0347]

[0348] To a stirred solution of 7-fluoro-3,4-dihydro-2H-isoquinolin-1-one (550 mg, 1.0 eq., 3.33 mmol) in H2SO4 (20 mL) at room temperature under nitrogen was added NBS (711 mg, 1.2 eq., 4.00 mmol). The mixture was stirred at room temperature for 22 hours. The reaction was diluted with ice water (40 mL), filtered, washed with water (40 mL) and dried to provide 5-bromo-7-fluoro-3,4-dihydroisoquinolin-1(2H)-one (INT 7-A), which was used immediately in the next step.

[0349] Step 7-2. 5-Bromo-7-fluoro-2-methyl-3,4-dihydroisoquinolin-1(2H)-one (INT 7-B)

[0350]

[0351] To a mixture of INT 7-A and NaH (60% dispersion in mineral oil, 319 mg, 2.5 eq., 8.33 mmol) in THF (40 mL) was added iodomethane (415 μL, 2.0 eq., 6.66 mmol) at room temperature under nitrogen. The resulting mixture was stirred at room temperature for 18 hours. The reaction was diluted with 1M HCl (40 mL), and the aqueous phase was extracted with EA (3×50 mL). The combined organic phases were washed with brine (100 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash SiO2 chromatography (0%-50% EA / hexanes) to provide 585 mg (55% over two steps) of 5-bromo-7-fluoro-2-methyl-3,4-dihydroisoquinolin-1(2H)-one (INT7-B) as a solid. MS (ESI) [M] + For C 10 Calculated for H9BrFNO: 256.99; found 258.13 [M+H] + , t R =2.34min (Method 5). 1H NMR (400MHz, CDCl3) δ7.80 (dd, J=8.8, 2.7Hz, 1H), 7.41 (dd, J=7.8, 2.7Hz, 1H), 3.57 (t, J=6.8Hz, 2H), 3.16 (s, 3H), 3.08–3.02 (m, 2H).

[0352] Step 7-3. 7-Fluoro-2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- Synthesis of 3,4-Dihydroisoquinolin-1(2H)-one (INT 7-C)

[0353]

[0354] A mixture of INT 7-B (585 mg, 1.0 eq., 2.27 mmol), B2pin2 (1.44 g, 2.5 eq., 5.67 mmol), KOAc (667 mg, 3.0 eq., 6.80 mmol) and Pd(dppf)Cl2 (332 mg, 0.2 eq., 0.45 mmol) in THF (30 mL) was stirred at 70 °C for 18 h. The mixture was diluted with EA (20 mL) and filtered through diatomaceous earth. The filter cake was washed with EA (100 mL), and the filtrate was concentrated in vacuo. The residue was purified by flash SiO2 chromatography (0%-75% EA / hexanes) to afford 7-fluoro-2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinolin-1(2H)-one (INT 7-C), which was used immediately in the next step.

[0355] Step 7-4. Synthesis of 7-fluoro-5-hydroxy-2-methyl-3,4-dihydroisoquinolin-1(2H)-one (INT 7-D)

[0356]

[0357] To a mixture of INT 7-C in acetone (50 mL) was added (1.53 g, 1.1 eq., 2.49 mmol). The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with aqueous NaHSO3 (60 mL). The aqueous phase was extracted with EA (3×50 mL). The combined organic phases were washed with brine (100 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash SiO2 chromatography (0%-100% EA / hexanes) to provide 218 mg (47% over two steps) of 7-fluoro-5-hydroxy-2-methyl-3,4-dihydroisoquinolin-1(2H)-one (INT 7-D) as a solid. MS-ESI (m / z) for C 10 H 10 Calculated value of FNO2: 195.07; Measured value: 194.20 [MH]- , t R =1.92min (Method 5). 1 H NMR(400MHz,DMSO-d6)δ10.26(s,1H),7.04(dd,J=9.4,2.7Hz,1H),6.74(dd,J =10.5, 2.7Hz, 1H), 3.50 (t, J = 6.8Hz, 2H), 3.00 (s, 3H), 2.79 (t, J = 6.5Hz, 2H).

[0358] Step 7-5. 5-((4-chlorobenzyl)oxy)-7-fluoro-2-methyl-3,4-dihydroisoquinolin-1(2H)-one (compound Synthesis of Compound 7-1)

[0359]

[0360] A mixture of INT 7-D (46 mg, 1.0 eq., 0.24 mmol), 1-(bromomethyl)-4-chloro-benzene (53.3 mg, 1.1 eq., 0.26 mmol) and K2CO3 (97.7 mg, 3.0 eq., 0.71 mmol) in DMF (2 mL) was stirred at 70°C for 5 hours. The mixture was cooled to room temperature and concentrated. The residue was purified by preparative HPLC (5%-100% ACN / NH4OAc 10 mM, pH 4) to provide 49 mg (58%) of 5-((4-chlorobenzyl)oxy)-7-fluoro-2-methyl-3,4-dihydroisoquinolin-1(2H)-one (Compound 7-1) as a solid. MS-ESI (m / z) for C 17 H 15 Calculated value of ClFNO2: 319.08; Found: 319.08[M] + , t R =4.90min (Method 4). 1 H NMR (400MHz, DMSO-d6) δ7.52–7.46(m,4H),7.21–7.15(m,2H),5.18(s,2H),3.52(t,J=6.8Hz,2H),3.01(s,3H),2.87(t,J=7.3Hz,2H). 19 FNMR (376MHz, DMSO-d6) δ-113.00 (dd, J=10.6, 9.5Hz).

[0361] The compounds listed in Table 7 were prepared using the procedure of Scheme 7.

[0362] Table 7

[0363]

[0364] Example 8

[0365] Synthesis of compound 8-1 and other representative compounds

[0366]

[0367] Solution 8

[0368]

[0369] Reagents: (i) NaH, CH3I, THF; (ii) (Bpin)2, Pd(dppf)Cl2.CH2Cl2, KOAc, THF; (iii) Acetone, H2O; (iv) K2CO3, solvent (DMF or THF)

[0370] Step 8-1. Synthesis of 5-bromo-2,7-dimethyl-3,4-dihydroisoquinolin-1(2H)-one (INT 8-A)

[0371]

[0372] To an ice-cold solution of 5-bromo-7-methyl-3,4-dihydro-2H-isoquinolin-1-one (100 mg, 1.0 eq., 0.42 mmol) in THF (4 mL) was added NaH (60% in oil, 31.9 mg, 2.0 eq., 0.84 mmol) under nitrogen, and the resulting mixture was stirred at 0 ° C for 30 minutes. Iodomethane (38.9 μL, 1.5 eq., 0.625 mmol) was added, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with water (5 mL) and stirred at room temperature for 30 minutes. The aqueous phase was extracted with EA (3×25 mL). The combined organic phases were washed with saturated aqueous Na2S2O3 (5 mL) and brine (25 mL), dried over Na2SO4, and concentrated in vacuo to provide 106 mg (99%) of 5-bromo-2,7-dimethyl-3,4-dihydroisoquinolin-1(2H)-one (INT 8-A) as a solid. MS-ESI (m / z) for C 11 H 12 Calculated for BrNO: 253.01; found 255.35 [M+H] + , t R =2.27min (Method 5). 1 H NMR (400MHz, CDCl3) δ7.92–7.82(m,1H),7.48(dd,J=1.8,0.8Hz,1H),3.55(dd ,J=7.1,6.5Hz,2H),3.15(s,3H),3.05(t,J=6.8Hz,2H),2.35(t,J=0.7Hz,3H).

[0373] Step 8-2. 2,7-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3, 4-Dihydroisoquinolin-1(2H)-one (INT 8-B)

[0374]

[0375] A mixture of INT 8-A (106 mg, 1.0 eq., 0.42 mmol), bis(pinacolato)diboron (127 mg, 1.2 eq., 0.50 mmol), KOAc (123 mg, 3.0 eq., 1.25 mmol) and Pd(dppf)Cl (15.3 mg, 0.05 eq., 0.021 mmol) in THF (4 mL) was stirred at 70° C. for 72 h. The mixture was diluted with EA (20 mL), filtered through a pad of celite with EtOAc (40 mL), and concentrated in vacuo. The residue was purified by flash SiO2 chromatography (0%-60% EA / hexanes) to afford 2,7-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinolin-1(2H)-one (INT 8-B) as a solid, which was used in the next step without further purification.

[0376] Step 8-3. Synthesis of 5-hydroxy-2,7-dimethyl-3,4-dihydroisoquinolin-1(2H)-one (INT 8-C)

[0377]

[0378] Will (282 mg, 0.459 mmol, in 4 mL of water) was added to a mixture of INT8-B in acetone (20 mL), and the mixture was stirred at room temperature for 2 hours. The mixture was then diluted with saturated NaHSO3 aqueous solution (40 mL) and acidified with HCl aqueous solution (pH 4). The aqueous phase was extracted with EA (3×50 mL). The combined organic phases were washed with brine (100 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash SiO2 chromatography (0%-10% CH2Cl2 / MeOH) to provide 52 mg (47% over two steps) of 5-hydroxy-2,7-dimethyl-3,4-dihydroisoquinolin-1(2H)-one (INT 8-C) as a solid. MS-ESI (m / z) for C 11 H 13 Calculated value of NO2: 191.09; Measured value: 190.46 [MH] - ;t R =1.76min (Method 5). 1H NMR (500MHz, CDCl3) δ7.52 (d, J=1.6Hz, 1H), 6.73 (dd, J=1.6, 0.8Hz, 1H), 5.08 (s, 1H ), 3.54 (t, J = 6.9 Hz, 2H), 3.14 (s, 3H), 2.93 (t, J = 6.8 Hz, 2H), 2.31 (t, J = 0.7 Hz, 3H).

[0379] Step 8-4. 5-((4-chlorobenzyl)oxy)-2,7-dimethyl-3,4-dihydroisoquinolin-1(2H)-one (Compound 8-1) Synthesis

[0380]

[0381] A mixture of INT 8-C (50 mg, 1.0 eq., 0.26 mmol), 1-(bromomethyl)-4-chloro-benzene (80.6 mg, 1.5 eq., 0.39 mmol) and KCO (108 mg, 3.0 eq., 0.78 mmol) in DMF (2 mL) was stirred at 70 ° C for 24 hours. The mixture was diluted with water (25 mL) and DCM (25 mL). The aqueous phase was extracted with DCM (3 × 25 mL). The combined organic phases were washed with brine (25 mL), dried over NaSO, and concentrated in vacuo. The residue was purified by reverse phase chromatography with water (+10 mM NH4OAc) and MeCN (0%-80%) to provide 51.8 mg (63%) of 5-((4-chlorobenzyl)oxy)-2,7-dimethyl-3,4-dihydroisoquinolin-1(2H)-one (Compound 8-1) as a solid. MS-ESI (m / z) for C 18 H 18 Calculated value of ClNO2: 315.10; Measured value: 315.10 [M] + ;t R =4.98min (Method 4). 1 H NMR (400MHz, DMSO-d6) δ7.53–7.44(m,4H),7.33(dd,J=1.6,0.8Hz,1H),7.07(d,J=1.6Hz, 1H), 5.13 (s, 2H), 3.49 (t, J = 6.8Hz, 2H), 3.00 (s, 3H), 2.86 (t, J = 6.8Hz, 2H), 2.32 (s, 3H).

[0382] The compounds listed in Table 8 were prepared using the procedure of Scheme 8.

[0383] Table 8

[0384]

[0385] Example 9

[0386] MRGPR X4 activity

[0387] HEK cells stably transfected to express human MRGPR X4 were maintained in an incubator at 37°C with 5% CO2 and grown in DMEM medium with 10% fetal bovine serum (FBS) and 1% each of sodium pyruvate, Glutamax, penicillin / streptomycin, and geneticin. HEK cells stably transfected to express mouse MRGPR A1 were maintained in the same incubator and grown in DMEM medium with 10% FBS, 1% each of sodium pyruvate, Glutamax, penicillin / streptomycin, geneticin, and 2.2 mg / mL hygromycin.

[0388] Cells were plated in Opti-MEM of 12 μL in 384-well assay plates with 20,000 cells per well, and kept in an incubator overnight. On the day of determination, the compound dissolved in DMSO at 10 mM was added as a 10-point curve (10 μM final maximum concentration, with 1:3 serial dilution) using a Tecan D300E digital distributor. Agonists were diluted in assay buffer (final concentration of 5.7 mM Tris-HCl, 43 mM NaCl, 50 mM LiCl, pH=8), and 2 μL of suitable agonists were added to each well. The final concentration of agonists 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. Plates were incubated in the dark at 37 ° C for 1 h, 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 at room temperature in the dark for 1 h. Plates were read on a Molecular Devices SpectraMax iD5 plate reader. HTRF ratios were calculated from the raw data and graphed using GraphPad Prism to calculate the IC of each compound. 50 value.

[0389] Activity data for selected MRGPR X4 antagonists (relative to 20 μM deoxycholic acid agonist) are shown in Table 9. The activity range is indicated as follows: "++++++" indicates antagonist activity <100 nM; "++++" indicates antagonist activity between 100 nM and 500 nM; "+++" indicates activity between 501 nM and 1000 nM; "++" indicates activity between 1001 nM and 2500 nM; and "+" indicates activity >2500 nM.

[0390] Table 9

[0391]

[0392] The various embodiments described above can be combined to provide additional embodiments. All U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications, and non-patent publications mentioned in this specification and / or listed in the application data sheet are incorporated herein by reference in their entirety. Aspects of the embodiments can be modified, and if necessary, the concepts of various patents, applications, and publications are adopted to provide yet other embodiments.

[0393] This application claims the benefit of priority to U.S. Provisional Application No. 63 / 011,964, filed on April 17, 2020, which is hereby incorporated by reference in its entirety.

[0394] These and other changes can be made to the embodiments in light of the above detailed description. Generally, in the accompanying claims, the terms used should not be interpreted as limiting the claims to the specific embodiments disclosed in the specification and claims, but should be interpreted to include all possible embodiments along with the full range of equivalents to which such claims are entitled. Therefore, the claims are not limited by the present disclosure.

Claims

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

2. A pharmaceutical composition comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

3. Use of the compound according to claim 1 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 2 in the preparation of a medicament for treating cholestatic pruritus in a subject in need thereof.

Images