Production of P2X3 antagonist

Abstract

Described herein are two stepwise methods for the preparation of methyl (S)-2-((2-(2,6-difluoro-4-(methylcarbamoyl)phenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl)morpholine-4-carboxylate (a P2X3 antagonist), as well as chemical intermediates used in the synthetic methods.

Description

Technical Field

[0001] Cross-reference This application claims the benefit of U.S. Provisional Application No. 62 / 977,004, filed Feb. 14, 2020; and U.S. Provisional Application No. 63 / 144,902, filed Feb. 2, 2021, both of which are hereby incorporated by reference in their entirety.

Background Art

[0002] P2X purinoreceptors are a family of ion channels activated by extracellular adenosine triphosphate (ATP). Purinoreceptors are associated with various biological functions. The P2X3 receptor subunit is a member of this family. It was first cloned from rat dorsal root ganglia. Non-Patent Document 1. The nucleotide and amino acid sequences of both rat and human P2X3 are now known. Non-Patent Document 2; and Non-Patent Document 3.

Prior Art Documents

Non-Patent Documents

[0003]

Non-Patent Document 1

Non-Patent Document 2

Non-Patent Document 3

Summary of the Invention

Means for Solving the Problems

[0004] Disclosed herein is a method for the synthesis of a P2X3 antagonist, wherein the P2X3 antagonist is methyl (S)-2-((2-(2,6-difluoro-4-(methylcarbamoyl)phenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl)morpholine-4-carboxylate (Compound 1), or a pharmaceutically acceptable salt thereof.

[0005] One embodiment is a method for the production of methyl (S)-2-((2-(2,6-difluoro-4-(methylcarbamoyl)phenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl)morpholine-4-carboxylate (Compound 1):

Chemical formula

Chemical formula

[0006] In some embodiments of the method for the production of methyl (S)-2-((2-(2,6-difluoro-4-(methylcarbamoyl)phenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl)morpholine-4-carboxylate (Compound 1), the compound having the structure:

Chemical formula

Chemical formula

[0007] In some embodiments of a method for the preparation of methyl (S)-2-((2-(2,6-difluoro-4-(methylcarbamoyl)phenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl)morpholine-4-carboxylate (Compound 1), the structure:

Chem.

Chem.

[0008] In some embodiments of a method for the preparation of methyl (S)-2-((2-(2,6-difluoro-4-(methylcarbamoyl)phenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl)morpholine-4-carboxylate (Compound 1), the structure:

Chem.

Chem.

[0009] In some embodiments of a method for the preparation of methyl (S)-2-((2-(2,6-difluoro-4-(methylcarbamoyl)phenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl)morpholine-4-carboxylate (Compound 1), the structure:

Chem.

[0010] In some embodiments of the method for the production of methyl (S)-2-((2-(2,6-difluoro-4-(methylcarbamoyl)phenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl)morpholine-4-carboxylate (Compound 1), structure: [Chemical formula] The compound having [chemical formula] has the structure: [Chemical formula] It is produced by a method that includes contacting a compound having [chemical formula] with a hydrogenation catalyst and hydrogen. In some embodiments, the hydrogenation catalyst is palladium on carbon, palladium hydroxide, rhodium on carbon, rhodium on alumina, platinum oxide, or platinum on carbon. In some embodiments, the hydrogenation catalyst is palladium on carbon.

[0011] In some embodiments of the method for the production of methyl (S)-2-((2-(2,6-difluoro-4-(methylcarbamoyl)phenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl)morpholine-4-carboxylate (Compound 1), structure: [Chemical formula] The compound having [chemical formula] has the structure: [Chemical formula] a compound having [chemical formula] and structure: [Chemical formula] It is produced by a method comprising contacting a compound having with a base. In some embodiments, the base is a mixture of potassium bicarbonate and potassium carbonate

[0012] In some embodiments of the method for the production of methyl (S)-2-((2-(2,6-difluoro-4-(methylcarbamoyl)phenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl)morpholine-4-carboxylate (Compound 1), structure:

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0013] In some embodiments of a method for the production of methyl (S)-2-((2-(2,6-difluoro-4-(methylcarbamoyl)phenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl)morpholine-4-carboxylate (Compound 1), the structure: [Chemical formula] The compound having is produced by a method comprising contacting a compound having the structure: [Chemical formula] with a base and optionally sodium borohydride in the presence of a solvent. In some embodiments, the solvent is aqueous tetrahydrofuran, dioxane, 2-methyltetrahydrofuran, aqueous methanol, aqueous ethanol, or aqueous acetonitrile. In some embodiments, the solvent is aqueous tetrahydrofuran. In some embodiments, the base is lithium hydroxide.

[0014] In some embodiments of a method for the production of methyl (S)-2-((2-(2,6-difluoro-4-(methylcarbamoyl)phenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl)morpholine-4-carboxylate (Compound 1), the structure: [Chemical formula] The compound having is produced by a method comprising contacting a compound having the structure: [Chemical formula] with 2-amino-4-methylpyridine.

[0015] In some embodiments of a method for the production of methyl (S)-2-((2-(2,6-difluoro-4-(methylcarbamoyl)phenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl)morpholine-4-carboxylate (Compound 1), the structure: [Chemistry] The compound having is of the structure: [Chemistry] It is produced by a method comprising contacting a compound having with a brominating agent. In some embodiments, the brominating agent is copper(II) bromide. In some embodiments, the brominating agent is liquid bromine.

[0016] In some embodiments of the method for the production of methyl (S)-2-((2-(2,6-difluoro-4-(methylcarbamoyl)phenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl)morpholine-4-carboxylate (Compound 1), of the structure: [Chemistry] The compound having is of the structure: [Chemistry] It is produced by a method comprising contacting a compound having with methyl chloroformate and a base. In some embodiments, the base is sodium bicarbonate.

[0017] In some embodiments of the method for the production of methyl (S)-2-((2-(2,6-difluoro-4-(methylcarbamoyl)phenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl)morpholine-4-carboxylate (Compound 1), of the structure: [Chemistry] The compound having is of the structure: [Chemistry] It is produced by a method comprising contacting a compound having with hydrogen chloride and methanol.

[0018] In some embodiments of the method for the production of methyl (S)-2-((2-(2,6-difluoro-4-(methylcarbamoyl)phenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl)morpholine-4-carboxylate (Compound 1), the structure:

Chem.

Chem.

[0019] In some embodiments of the method for the production of methyl (S)-2-((2-(2,6-difluoro-4-(methylcarbamoyl)phenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl)morpholine-4-carboxylate (Compound 1), the structure:

Chem.

Chem.

[0020] In some embodiments of the method for the production of methyl (S)-2-((2-(2,6-difluoro-4-(methylcarbamoyl)phenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl)morpholine-4-carboxylate (Compound 1), the structure:

Chem.

[0021] In some embodiments of the method for the production of methyl (S)-2-((2-(2,6-difluoro-4-(methylcarbamoyl)phenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl)morpholine-4-carboxylate (Compound 1), the structure: [Chemical formula] The compound having [chemical formula] has the structure: [Chemical formula] It is produced by a method that includes contacting a compound having [chemical formula] with a hydrogenation catalyst and hydrogen. In some embodiments, the hydrogenation catalyst is palladium on carbon, palladium hydroxide, rhodium on carbon, rhodium on alumina, platinum oxide, or platinum on carbon. In some embodiments, the hydrogenation catalyst is palladium on carbon.

[0022] In some embodiments of the method for the production of methyl (S)-2-((2-(2,6-difluoro-4-(methylcarbamoyl)phenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl)morpholine-4-carboxylate (Compound 1), the structure: [Chemical formula] The compound having [chemical formula] has the structure: [Chemical formula] It is produced by a method comprising contacting a compound having [the relevant structure] with a base in aqueous tetrahydrofuran. In some embodiments, the base is sodium hydroxide.

[0023] In some embodiments of the method for the preparation of methyl (S)-2-((2-(2,6-difluoro-4-(methylcarbamoyl)phenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl)morpholine-4-carboxylate (Compound 1), the structure:

Chemical formula

Chemical formula

[0024] In some embodiments of the method for the preparation of methyl (S)-2-((2-(2,6-difluoro-4-(methylcarbamoyl)phenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl)morpholine-4-carboxylate (Compound 1), the structure:

Chemical formula

Chemical formula

[0025] Further disclosed herein is a method for the preparation of methyl (S)-2-((2-(2,6-difluoro-4-(methylcarbamoyl)phenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl)morpholine-4-carboxylate (Compound 1) which:

[0026] A) Structure:

Chem.

Chem.

[0027] B) Subsequently, the structure:

Chem.

Chem.

[0028] C) Subsequently, the structure:

Chem.

Chem.

[0029] D) Subsequently, the structure:

Chem.

Chem.

[0030] E) Subsequently, the structure:

Chem.

Chem.

[0031] F) Subsequently, the structure:

Chem.

Chem.

[0032] G) Subsequently, the structure:

Chem.

Chem.

[0033] H) Subsequently, the structure:

Chem.

Chem.

[0034] Further disclosed herein is a method for the production of methyl (S)-2-((2-(2,6-difluoro-4-(methylcarbamoyl)phenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl)morpholine-4-carboxylate (Compound 1), comprising:

[0035] A) The reaction of a compound having the structure:

Chemical formula

Chemical formula

[0036] B) Subsequently, the reaction of a compound having the structure:

Chemical formula

Chemical formula

[0037] C) Subsequently, the reaction of a compound having the structure:

Chemical formula

Chemical formula

[0038] D) Subsequently, the reaction of a compound having the structure:

Chemical formula

[0039] E) Subsequently, the structure: [Chemical formula] Structure of N,O-dimethylhydroxylamine, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, and 1-hydroxybenzotriazole for generating a compound having: [Chemical formula] Reaction of a compound having;

[0040] F) Subsequently, the structure: [Chemical formula] Structure of tert-butyl 3,5-difluorobenzoate and lithium diisopropylamide for generating a compound having: [Chemical formula] Reaction of a compound having;

[0041] G) Subsequently, the structure: [Chemical formula] Structure of hydrogen chloride in ethyl acetate for generating a compound having: [Chemical formula] Reaction of a compound having;

[0042] H) Subsequently, the structure: [Chemical formula] Structure of hydrogen chloride and methanol for generating a compound having: [Chemical formula] Reaction of a compound having;

[0043] I) Subsequently, the structure:

Chem.

Chem.

[0044] J) Subsequently, the structure:

Chem.

Chem.

[0045] K) Subsequently, the structure:

Chem.

Chem.

[0046] L) Subsequently, the structure:

Chem.

Chem.

[0047] M) Subsequently, the structure:

Chem.

Chem.

[0048] Further disclosed herein is a structure:

Chem.

[0049] Further disclosed herein is a structure:

Chem.

[0050] Further disclosed herein is a structure:

Chem.

[0051] Further disclosed herein is a structure:

Chem.

[0052] Further disclosed herein is a structure:

Chem.

[0053] Further disclosed herein is a structure: [Chemical formula] A compound having the same; or a pharmaceutically acceptable salt thereof.

[0054] Further disclosed herein is a structure: [Chemical formula] A compound having the same; or a pharmaceutically acceptable salt thereof.

[0055] Further disclosed herein is a structure: [Chemical formula] A compound having the same; or a pharmaceutically acceptable salt thereof.

[0056] Further disclosed herein is a structure: [Chemical formula] A compound having the same; or a pharmaceutically acceptable salt thereof.

[0057] Further disclosed herein is a structure: [Chemical formula] A compound having the same; or a pharmaceutically acceptable salt thereof.

[0058] Incorporation by reference All publications, patents, and patent applications mentioned herein are hereby incorporated by reference into this specification to the same extent as if each individual publication, patent, or patent application were specifically and individually indicated as being incorporated by reference. [Modes for Carrying Out the Invention]

[0059] Good manufacturing practices are normally required for the large-scale manufacture of clinically useful drug candidates. Provided herein are specific processes and methods for the manufacture of methyl (S)-2-((2-(2,6-difluoro-4-(methylcarbamoyl)phenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl)morpholine-4-carboxylate (Compound 1), or a pharmaceutically acceptable salt thereof.

[0060] Definitions As used herein and in the appended claims, unless the contrary is specified, the following terms have the meanings set forth below.

[0061] As used herein and in the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “an agent” includes reference to one or more such agents, and reference to “a cell” includes reference to one or more cells (or a plurality of cells) and equivalents thereof.

[0062] When ranges of physical properties such as molecular weight, or chemical properties such as chemical formula, are used herein, all combinations and sub-combinations of ranges therein and specific embodiments are intended to be included.

[0063] The term “about” when referring to a numerical value or range of numerical values means that the recited numerical value or range of numerical values is an approximation within experimental variability (or within statistical experimental error), and thus the numerical value or range of numerical values may vary between 1% and 15% of the recited numerical value or range of numerical values.

[0064] The term "comprising" (and related terms such as "comprise", "comprises", "having", or "including") is not intended in other certain embodiments to exclude, for example, embodiments of any substance composition, composition, method, or process described herein, or of the same kind, that "consist of" or "consist essentially of" the recited configuration.

[0065] The terms "subject" or "patient" include mammals and non-mammals. Examples of mammals include, but are not limited to, any member of the following classes of mammals: humans, non-human primates such as chimpanzees, as well as other ape and monkey species; domestic animals such as cows, horses, sheep, goats, pigs; companion animals such as rabbits, dogs, and cats; laboratory animals including rodents such as rats, mice, and guinea pigs, as well as the like. Examples of non-mammals include, but are not limited to, birds, fish, and the like. In one embodiment of the methods and compositions provided herein, the mammal is a human.

[0066] As used herein, the terms "treatment", "treating", "palliating", or "ameliorating" are used interchangeably herein. These terms refer to an approach for obtaining beneficial or desired results including, but not limited to, therapeutic and / or prophylactic benefits. By "therapeutic benefit" is meant eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit is achieved by eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that improvement is observed in the patient, even though the patient may still be afflicted with the underlying disorder. With regard to prophylactic benefits, the compositions are administered to a patient at risk of developing a particular disease or to a patient reporting one or more of the physiological symptoms of a disease even if the disease has not been diagnosed.

[0067] "Pharmaceutically acceptable salts" include both acid addition salts and base addition salts. Any pharmaceutically acceptable salt of any one of the compounds described herein is intended to encompass all pharmaceutically suitable salt forms. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0068] "Pharmaceutically acceptable acid addition salts" refer to salts that retain the biological effects and properties of the free base, which are not biologically or otherwise undesirable, and are formed using inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like. Also included are salts formed using organic acids such as aliphatic monocarboxylic and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Thus, exemplary salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, and the like. Also contemplated are salts of amino acids such as alginates, gluconates, and galacturonates (see, for example, Berge S.M. et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science, 66:1-19 (1997)). Acid addition salts of basic compounds are prepared by contacting the free base form with a sufficient amount of the desired acid to form the salt.

[0069] "Pharmaceutically acceptable basic addition salts" refers to salts that retain the biological effects and properties of the free acid, which are not biologically or otherwise undesirable. These salts are produced by the addition of an inorganic or organic base to the free acid. In some embodiments, the pharmaceutically acceptable basic addition salts are produced using a metal or amine such as an alkali metal and alkaline earth metal or an organic amine. Salts derived from inorganic bases include, but are not limited to, sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts, aluminum salts and the like. Salts derived from organic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines as well as basic ion exchange resins, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N,N-dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, N-methylglucamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. See Berge et al., supra.

[0070] As used herein, the term "combination medicament" means a product resulting from the mixing or combination of more than one active ingredient and including both fixed and non-fixed combinations of the active ingredients. The term "fixed combination" means that the active ingredients are administered to the patient simultaneously as a single entity or dosage form. The term "non-fixed combination" means that the active ingredients are administered to the patient as separate entities simultaneously, concurrently, or sequentially without a specific intervening time limit, where such administration results in effective levels of the two compounds in the patient's body. The latter also applies to cocktail therapies, for example, the administration of three or more active ingredients.

[0071] As used herein, the term "co-administration" or the like is intended to encompass the administration of a selected therapeutic agent to a single patient and is intended to include treatment regimens in which the agent is administered by the same or different routes of administration, or at the same or different times.

[0072] As used herein, the term "activator" is used to represent any molecular species that leads to the activation of the indicated receptor, whether the molecular species itself binds to the receptor or a metabolite of the molecular species binds to the receptor, when the molecular species is administered locally. Thus, an activator can be a ligand of the receptor, or it can be an activator that is a ligand of the receptor, i.e., is generated in the tissue and is metabolized to the actual ligand, the metabolite.

[0073] As used herein, the term "antagonist" refers to a small molecule drug that binds to a nuclear hormone receptor and subsequently reduces the agonist-induced transcriptional activity of the nuclear hormone receptor.

[0074] As used herein, the term "agonist" refers to a small molecule drug that binds to a nuclear hormone receptor and subsequently enhances the transcriptional activity of the nuclear hormone receptor in the absence of a known agonist.

[0075] As used herein, the term "inverse agonist" refers to a small molecule drug that binds to a nuclear hormone receptor and subsequently reduces the basal level of nuclear hormone receptor transcriptional activity that exists in the absence of a known agonist.

[0076] As used herein, the term "modulate", when used herein, means to interact directly or indirectly with a target protein to change the activity of the target protein, including, by way of example only, inhibiting the activity of the target, or restricting or reducing the activity of the target.

[0077] As used herein, the term "modulator" refers to a compound that changes the activity of a target. For example, a modulator can increase or decrease the magnitude of a certain activity of a target compared to the magnitude of the activity in the absence of the modulator. In certain embodiments, the modulator is an inhibitor, which decreases the magnitude of one or more activities of the target. In certain embodiments, the inhibitor completely blocks one or more activities of the target.

[0078] Compound In some embodiments, the P2X3 antagonist described herein is methyl (S)-2-((2-(2,6-difluoro-4-(methylcarbamoyl)phenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl)morpholine-4-carboxylate (Compound 1), or a pharmaceutically acceptable salt thereof. Compound 1 has the structure:

Chemical formula

Chemical formula

Chemical formula

[0079] In some embodiments, the P2X3 antagonist described herein is methyl (S)-2-((2-(2,6-difluoro-4-(methylcarbamoyl)phenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl)morpholine-4-carboxylate (Compound 1), or a pharmaceutically acceptable salt thereof. Compound 1 has the structure: [Chemical formula] has.

[0080] In some embodiments, the starting material for the synthesis of Compound 1 is [Chemical formula] That is. In some embodiments, the intermediate in the synthesis of Compound 1 is

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0081] Further forms of the compound The compounds described herein can, in some cases, exist as diastereomers, enantiomers, or other stereoisomeric forms. The compounds presented herein include all diastereomeric forms, enantiomeric forms, and epimeric forms, as well as suitable mixtures thereof. Separation of stereoisomers can be carried out by chromatography, or by formation of diastereomers and recrystallization, or separation by chromatography, or any combination thereof. (Jean Jacques, Andre Collet, Samuel H. Wilen, "Enantiomers, Racemates and Resolutions", John Wiley And Sons, Inc., 1981, which is incorporated herein by reference for the purposes of this disclosure). Stereoisomers can also be obtained by stereoselective synthesis.

[0082] In some situations, the compound can exist as a tautomer. All tautomers are included in the formulas described herein.

[0083] Pharmaceutically acceptable salts In some embodiments, the compounds described herein exist as their pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such pharmaceutically acceptable salts as pharmaceutical compositions.

[0084] In some embodiments, the compounds described herein have acidic or basic groups and thus react with any of several inorganic or organic bases, and inorganic and organic acids to produce pharmaceutically acceptable salts. In some embodiments, these salts are produced in situ during the final isolation and purification of the compounds of the invention or by reacting the purified compound in its free form separately with a suitable acid or base and isolating the thus-produced salt.

[0085] In some embodiments, the pharmaceutically acceptable salts of Compound 1 are acetate, benzoate, besylate, bitartrate, carbonate, citrate, fumarate, gluconate, hydrobromide, hydrochloride, maleate, mesylate, nitrate, phosphate, salicylate, succinate, sulfate, or tartrate. In some embodiments, the pharmaceutically acceptable salt of Compound 1 is hydrochloride monohydrate. In further embodiments, the pharmaceutically acceptable salt of Compound 1 is hydrochloride monohydrate.

[0086] Solvates In some embodiments, the compounds described herein exist as solvates. The present invention provides methods of treating a disease by administering such solvates. The present invention further provides methods of treating a disease by administering such solvates as pharmaceutical compositions.

[0087] Solvates contain a stoichiometric or non-stoichiometric amount of a solvent and, in some embodiments, are produced during a crystallization process using a pharmaceutically acceptable solvent such as water, ethanol, and the like. When the solvent is water, a hydrate is formed, or when the solvent is an alcohol, an alcoholate is formed. Solvates of the compounds described herein are conveniently prepared or generated during the methods described herein. By way of mere example, hydrates of the compounds described herein are conveniently prepared by recrystallization from an aqueous / organic solvent mixture using an organic solvent including, but not limited to, dioxane, tetrahydrofuran, or methanol. In addition, the compounds provided herein exist in both unsolvated and solvated forms. Generally, the solvated forms are considered equivalent to the unsolvated forms in the compounds and methods provided herein.

[0088] Labeled compound In some embodiments, the compounds described herein exist in their isotopically labeled forms. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such an isotopically labeled compound. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such an isotopically labeled compound as a pharmaceutical composition. Thus, in some embodiments, the compounds disclosed herein include isotopically labeled compounds, which are identical to those described herein except that one or more atoms have been replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number normally found in nature. Examples of isotopes incorporated into the compounds of the invention include, respectively 2 H, 3 H, 13 C, 14 C, l5 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, and 36It includes isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as Cl. Compounds described herein that contain the aforementioned isotopes and / or other isotopes of other atoms, and their pharmaceutically acceptable salts, esters, solvates, hydrates or derivatives are within the scope of the present invention. Certain isotope-labeled compounds, for example 3 H and 14 those incorporating radioactive isotopes such as 3 C are useful in drug and / or substrate tissue distribution assays. Tritium labeling, i.e., 14 H isotope and carbon-14, i.e., 2 C isotope are particularly preferred due to their ease of preparation and detectability. Furthermore, substitution with heavy isotopes such as deuterium, i.e.,

[0089] H results in certain therapeutic advantages such as increased in vivo half-life or reduced dosing requirements due to greater metabolic stability. An increase in the deuterium incorporation level produces a detectable kinetic isotope effect (KIE) that can affect the pharmacokinetic, pharmacological and / or toxicological parameters of Compound 1 compared to Compound 1 having natural levels of deuterium. In some embodiments, the isotope-labeled compound, or its pharmaceutically acceptable salt, is produced by any suitable method.

[0090] In some embodiments, the compounds described herein are labeled by other means including, but not limited to, the use of a chromophore or fluorescent moiety, a bioluminescent label, or a chemiluminescent label.

[0091] Methods for manufacture In some embodiments, the synthesis of the compounds described herein is achieved using means described in the chemical literature, using the methods described herein, or a combination thereof. Additionally, the solvents, temperatures and other reaction conditions presented herein may vary.

[0092] In other embodiments, the starting materials and reagents used for the synthesis of the compounds described herein are obtained from commercial sources such as, but not limited to, Sigma-Aldrich, Fischer Scientific (Fischer Chemicals), and Acros Organics. In further embodiments, the compounds described herein, and other related compounds having different substituents, are synthesized using techniques and materials described herein, and those recognized in the art such as, for example, Fieser and Fieser’s Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd’s Chemistry of Carbon Compounds, Volumes 1-5 and Supplements (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), Larock’s Comprehensive Organic Transformations (VCH Publishers Inc., 1989), March, Advanced Organic Chemistry, 4th Edition, (Wiley 1992); Carey and Sundberg, Advanced Organic Chemistry, 4th Edition, Volumes A and B (Plenum 2000, 2001), and Greene and Wuts, Protective Groups in Organic Synthesis, 3rd Edition, (Wiley 1999) (all of which are incorporated by reference for such disclosure). General methods for the preparation of compounds as disclosed herein can be derived from the reactions, which can be modified by the use of appropriate reagents and conditions for the introduction of the various moieties found in the formulas as provided herein.

[0093] In some embodiments, methyl (S)-2-((2-(2,6-difluoro-4-(methylcarbamoyl)phenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl)morpholine-4-carboxylate (Compound 1):

Chemical formula

Chemical formula

[0094] In some embodiments of a method for the production of methyl (S)-2-((2-(2,6-difluoro-4-(methylcarbamoyl)phenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl)morpholine-4-carboxylate (Compound 1), having the structure:

Chemical formula

Chemical formula

Chemical formula

[0095] In some embodiments of the process for the preparation of methyl (S)-2-((2-(2,6-difluoro-4-(methylcarbamoyl)phenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl)morpholine-4-carboxylate (Compound 1), the compound has the structure: [ka] A compound having the structure: [ka] with a brominating agent. In some embodiments, the brominating agent is N-bromosuccinimide. In some embodiments, the brominating agent is copper(II) bromide. In some embodiments, the brominating agent is liquid bromine.

[0096] In some embodiments of the process for the preparation of methyl (S)-2-((2-(2,6-difluoro-4-(methylcarbamoyl)phenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl)morpholine-4-carboxylate (Compound 1), the compound has the structure: [ka] A compound having the structure: [ka] It is produced by a method comprising contacting a compound having [the relevant structure] with methyl chloroformate and a base. In some embodiments, the base is sodium bicarbonate.

[0097] In some embodiments of the method for the production of methyl (S)-2-((2-(2,6-difluoro-4-(methylcarbamoyl)phenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl)morpholine-4-carboxylate (Compound 1), the structure:

Chemical formula

Chemical formula

[0098] In some embodiments of the method for the production of methyl (S)-2-((2-(2,6-difluoro-4-(methylcarbamoyl)phenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl)morpholine-4-carboxylate (Compound 1), the structure:

Chemical formula

Chemical formula

[0099] In some embodiments of the method for the preparation of methyl (S)-2-((2-(2,6-difluoro-4-(methylcarbamoyl)phenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl)morpholine-4-carboxylate (Compound 1), the structure:

Chemical formula

Chemical formula

Chemical formula

[0100] In some embodiments of the method for the preparation of methyl (S)-2-((2-(2,6-difluoro-4-(methylcarbamoyl)phenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl)morpholine-4-carboxylate (Compound 1), the structure:

Chemical formula

Chemical formula

[0101] Further disclosed herein is a method for the preparation of methyl (S)-2-((2-(2,6-difluoro-4-(methylcarbamoyl)phenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl)morpholine-4-carboxylate (Compound 1) comprising:

[0102] A) Structure:

Chem.

Chem.

[0103] B) Subsequently, the structure:

Chem.

Chem.

Chem.

[0104] C) Subsequently, the structure:

Chem.

Chem.

[0105] D) Subsequently, the structure:

Chem.

Chem.

[0106] E) Subsequent structure:

Chem.

Chem.

[0107] F) Subsequent structure:

Chem.

Chem.

[0108] G) Subsequent structure:

Chem.

Chem.

[0109] H) Subsequent structure:

Chem.

Chem.

[0110] In some embodiments of the method for the production of methyl (S)-2-((2-(2,6-difluoro-4-(methylcarbamoyl)phenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl)morpholine-4-carboxylate (Compound 1), the structure:

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0111] In some embodiments of the method for the production of methyl (S)-2-((2-(2,6-difluoro-4-(methylcarbamoyl)phenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl)morpholine-4-carboxylate (Compound 1), the structure:

Chemical formula

[0112] In some embodiments of the method for the production of methyl (S)-2-((2-(2,6-difluoro-4-(methylcarbamoyl)phenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl)morpholine-4-carboxylate (Compound 1), the structure: [Chemical formula] The compound having is of the structure: [Chemical formula] It is produced by a method comprising contacting the compound having with a brominating agent. In some embodiments, the brominating agent is copper(II) bromide. In some embodiments, the brominating agent is liquid bromine.

[0113] In some embodiments of the method for the production of methyl (S)-2-((2-(2,6-difluoro-4-(methylcarbamoyl)phenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl)morpholine-4-carboxylate (Compound 1), the structure: [Chemical formula] The compound having is of the structure: [Chemical formula] It is produced by a method comprising contacting the compound having with methyl chloroformate and a base. In some embodiments, the base is sodium bicarbonate.

[0114] In some embodiments of the method for the production of methyl (S)-2-((2-(2,6-difluoro-4-(methylcarbamoyl)phenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl)morpholine-4-carboxylate (Compound 1), the structure:

Chemical formula

Chemical formula

[0115] In some embodiments of the method for the production of methyl (S)-2-((2-(2,6-difluoro-4-(methylcarbamoyl)phenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl)morpholine-4-carboxylate (Compound 1), the structure:

Chemical formula

Chemical formula

[0116] In some embodiments of the method for the production of methyl (S)-2-((2-(2,6-difluoro-4-(methylcarbamoyl)phenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl)morpholine-4-carboxylate (Compound 1), the structure:

Chemical formula

Chemical formula

[0117] In some embodiments of the method for the production of methyl (S)-2-((2-(2,6-difluoro-4-(methylcarbamoyl)phenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl)morpholine-4-carboxylate (Compound 1), the structure:

Chemical formula

Chemical formula

[0118] In some embodiments of the method for the production of methyl (S)-2-((2-(2,6-difluoro-4-(methylcarbamoyl)phenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl)morpholine-4-carboxylate (Compound 1), the structure:

Chemical formula

Chemical formula

[0119] In some embodiments of a method for the preparation of methyl (S)-2-((2-(2,6-difluoro-4-(methylcarbamoyl)phenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl)morpholine-4-carboxylate (Compound 1), the structure:

Chemical formula

Chemical formula

[0120] In some embodiments of a method for the preparation of methyl (S)-2-((2-(2,6-difluoro-4-(methylcarbamoyl)phenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl)morpholine-4-carboxylate (Compound 1), the structure:

Chemical formula

Chemical formula

[0121] In some embodiments of a method for the preparation of methyl (S)-2-((2-(2,6-difluoro-4-(methylcarbamoyl)phenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl)morpholine-4-carboxylate (Compound 1), the structure:

Chemical formula

[0122] Further disclosed herein is a method for the production of methyl (S)-2-((2-(2,6 - difluoro - 4-(methylcarbamoyl)phenyl)-7 - methylimidazo[1,2 - a]pyridin - 3 - yl)methyl)morpholine - 4 - carboxylate (Compound 1), which comprises:

[0123] A) A reaction of 2,2,6,6 - tetramethylpiperidine 1 - oxyl with a compound having the structure: [Chemical formula] to produce a compound having the structure: [Chemical formula] ;

[0124] B) Subsequently, a reaction of (carbethoxymethylene)triphenylphosphorane with a compound having the structure: [Chemical formula] to produce a compound having the structure: [Chemical formula] ;

[0125] C) Subsequently, a reaction of sodium hydroxide in aqueous tetrahydrofuran with a compound having the structure: [Chemical formula] to produce a compound having the structure: [Chemical formula] ;

[0126] D) Subsequently, the structure: [Chemical formula] The structure of palladium on carbon with hydrogen for generating a compound having; [Chemical formula] The reaction of a compound having;

[0127] E) Subsequently, the structure: [Chemical formula] The structure of N,O-dimethylhydroxylamine, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, and 1-hydroxybenzotriazole for generating a compound having; [Chemical formula] The reaction of a compound having;

[0128] F) Subsequently, the structure: [Chemical formula] The structure of tert-butyl 3,5-difluorobenzoate and lithium diisopropylamide for generating a compound having; [Chemical formula] The reaction of a compound having;

[0129] G) Subsequently, the structure: [Chemical formula] The structure of hydrogen chloride and ethyl acetate for generating a compound having; [Chemical formula] The reaction of a compound having;

[0130] H) Subsequent structure:

Chem.

Chem.

[0131] I) Subsequent structure:

Chem.

Chem.

[0132] J) Subsequent structure:

Chem.

Chem.

[0133] K) Subsequent structure:

Chem.

Chem.

[0134] L) Subsequent structure:

Chem.

[0135] M) Subsequently, the structure: [Chemical formula] the structure of carbonyldiimidazole and methylamine for generating a compound having [Chemical formula] a method including the reaction of a compound having

[0136] Pharmaceutical compositions and methods of administration Administration of a P2X3 antagonist as described herein can be in any pharmacological form comprising a therapeutically effective amount of the P2X3 antagonist, alone or in combination with a pharmaceutically acceptable carrier.

[0137] The pharmaceutical composition can be formulated in a conventional manner using one or more physiologically acceptable carriers including excipients and auxiliaries that facilitate the processing of the active compound into a preparation that can be used pharmaceutically. The appropriate formulation depends on the chosen route of administration. Further details regarding excipients suitable for the pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, 19th Edition (Easton, Pa.: Mack Publishing Company, 1995), which is incorporated herein by reference for such disclosure; Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th Edition (Lippincott Williams & Wilkins 1999).

[0138] As used herein, a pharmaceutical composition refers to a mixture of Compound 1 described herein with other chemical components such as carriers, stabilizers, diluents, dispersants, suspending agents, thickening agents, and / or excipients. The pharmaceutical composition facilitates the administration of the compound to a living being. In the practice of the methods of treatment or use provided herein, a therapeutically effective amount of the compound described herein is administered to a mammal having a disease, disorder, or condition to be treated in a pharmaceutical composition. In some embodiments, the mammal is a human. The therapeutically effective amount can vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used, as well as other factors. Compound 1 can be used alone or in combination with one or more therapeutic agents as a component of a mixture (as in combination therapy).

[0139] The pharmaceutical formulations described herein can be administered to a subject by multiple routes of administration including, but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular), intranasal, buccal, topical, rectal, or transdermal routes. Further, the pharmaceutical compositions described herein that contain Compound 1 can be formulated into any suitable dosage form including, but not limited to, aqueous oral dispersions, solutions, gels, syrups, elixirs, slurries, suspensions, aerosols, controlled release formulations, rapid dissolution formulations, effervescent formulations, lyophilized formulations, tablets, powders, pills, dragees, capsules, delayed release formulations, sustained release formulations, pulsatile release formulations, multiparticulate formulations, and immediate and controlled release combination formulations.

[0140] In some embodiments, Compound 1 is formulated in a tablet dosage form. In some embodiments, Compound 1 is formulated in a capsule dosage form. In some embodiments, Compound 1 is formulated in a suspension dosage form. In some embodiments, Compound 1 is formulated as a powder in capsule dosage form. In some embodiments, Compound 1 is formulated as a powder in a bottle for reconstitution as a suspension.

[0141] The pharmaceutical compositions containing the compounds described herein can be manufactured in a conventional manner, such as, by way of example only, conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or compression processes.

[0142] Dosage administration can be repeated depending on the pharmacokinetic parameters of the dosage formulation and the route of administration used.

[0143] It is particularly advantageous to formulate the composition in dosage unit form for ease of administration and uniformity of dosage. As used herein, a dosage unit form refers to a physically discrete unit suitable as a unit dosage for a mammalian subject to be treated; each unit contains a predetermined quantity of the active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification of the dosage unit form is determined by and directly depends on (a) the particular characteristics of compound 1 and the specific therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding such active compounds for the treatment of sensitivity in an individual. A particular dosage can be readily calculated by one skilled in the art, for example, according to the approximate weight or body surface area of the patient or the volume of body space to be occupied. The dosage will also be calculated according to the particular route of administration selected. Further refinement of the calculations necessary to determine the appropriate dosage for treatment is routinely carried out by one skilled in the art. The exact dosage is determined in relation to standard dose-response studies. It will be understood that the amount of the composition actually administered will be determined by the physician in view of the relevant circumstances including the (one or more) condition(s) to be treated, the choice of composition to be administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the selected route of administration.

[0144] Methods of dosing and treatment regimens The compounds described herein can be used in the preparation of a medicament for the modulation of P2X3, which will at least in part obtain the benefits of modulation of P2X3, or for the treatment of a disease or condition. In addition, a method for treating any of the diseases or conditions described herein in a subject in need thereof involves administration to the subject of a pharmaceutical composition comprising a therapeutically effective amount of at least one compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate or hydrate thereof.

[0145] Compositions comprising the (one or more) compounds described herein can be administered for prophylactic and / or therapeutic treatment. In therapeutic use, the composition is administered to a patient already suffering from a disease or condition in an amount sufficient to cure or at least partially arrest the symptoms of the disease or condition. The amount effective for this use will depend on the severity and course of the disease or condition, pre-therapy, the health state of the patient, weight, and response to the drug, as well as the judgment of the physician administering the treatment.

[0146] In prophylactic use, the composition comprising the compounds described herein is administered to a patient who is at risk of or otherwise likely to develop a particular disease, disorder or condition. Such an amount is defined as a "prophylactically effective amount or dose". In this use, the exact amount also depends on the health state, weight, and the like of the patient. When used in a patient, the amount effective for this use will depend on the severity and course of the disease, disorder or condition, pre-therapy, the health state of the patient and response to the drug, as well as the judgment of the physician administering the treatment.

[0147] If the condition of the patient does not improve, at the discretion of the physician, administration of the compound can be chronic, i.e., over an extended period, including for the entire duration of the patient's life, to alleviate or otherwise control or limit the symptoms of the patient's disease or condition.

[0148] If the patient's condition does not improve, the administration of the compound can be continued at the discretion of the physician; alternatively, the dose of the administered drug can be temporarily reduced or the administration can be interrupted for a certain period (i.e., the "drug holiday"). The length of the drug holiday can vary between 2 days and 1 year, including, by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, or 365 days. The dose reduction during the drug holiday can be, by way of example only, from about 10% to about 100%, including about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%.

[0149] If the patient's condition improves, a maintenance dose is administered if necessary. Subsequently, the dosage or dosing frequency, or both, can be reduced according to the symptoms to a level at which the improvement of the disease, disorder or condition is maintained. However, the patient may require long-term intermittent treatment upon recurrence of any symptoms.

[0150] The amount of a given agent that will correspond to such amounts will vary depending on factors such as the particular compound, disease or condition and its severity, the identity (e.g., weight) of the subject or host in need of treatment, but can still be determined in a manner recognized in the art according to the particular circumstances surrounding the case, including, for example, the particular agent being administered, the route of administration, the condition being treated, and the subject or host being treated. However, generally, the dosage used for the treatment of adults will typically be in the range of about 0.01 mg per day to about 5000 mg per day, and in some embodiments, about 1 mg per day to about 1500 mg per day. The desired dosage can be conveniently presented as a single dosage administered at one time (or over a short period of time), or as a divided dosage administered at appropriate intervals, such as two, three, four or more sub-dosages per day.

[0151] The pharmaceutical compositions described herein can be in unit dosage forms suitable for the administration of exact dosages. In a unit dosage form, the formulation is divided into unit dosages containing appropriate amounts of one or more compounds. A unit dosage can be in the form of a package containing an individual amount of the formulation. Non-limiting examples are packaged tablets or capsules, and powders within vials, capsules, bottles, or ampoules. An aqueous suspension composition can be packaged in a single-dose non-refillable container. Alternatively, a multi-dose refillable container can be used, in which case it is typical to include a preservative in the composition. By way of example only, parenteral infusion formulations can be presented in unit dosage forms including, but not limited to, ampoules, or in multi-dose containers with added preservatives.

[0152] Examples All chemicals, reagents, and solvents were purchased from commercial sources when available and used without further purification.

Examples

[0153] Synthesis of Methyl (S)-2-(3-(2,6-difluoro-4-(methoxycarbonyl)phenyl)-3-oxopropyl)morpholine-4-carboxylate (Compound J) [Chemical formula]

[0154] Step 1: The hydroxymethyl group of A (106 kg, 487.9 mol) was oxidized to the corresponding aldehyde B under biphasic conditions (dichloromethane - water) at a temperature of -3°C to 1.5°C by reaction with sodium bromide, sodium bicarbonate, the catalyst TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy, a free radical), and sodium hypochlorite (added dropwise over about 10 hours while maintaining the temperature at -3°C to 1.5°C). After stirring for an additional 2 hours, the reaction was quenched with sodium thiosulfate at -5°C to 0°C and stirred for 30 minutes.

[0155] Step 2: The biphasic system from the above containing aldehyde B was treated portionwise at 5°C to 10°C with commercially available (carbethoxymethylene)triphenylphosphorane. After stirring at 8°C to 15°C for 1 hour, water was added, the mixture was stirred for 30 minutes, the layers were separated, and the aqueous layer was extracted with additional dichloromethane. The combined organic layers containing the unsaturated ester C were washed with brine and concentrated to remove most of the dichloromethane. A mixture of petroleum ether / THF was added, and the resulting mixture was stirred at 20°C for 1 hour. The mixture was then filtered to remove triphenylphosphine oxide, and the filter cake was washed with additional petroleum ether / THF. The filtrate containing C was concentrated, and THF was added. The mixture was concentrated again, and fresh THF was added. This solution of C was used "as is" in the following step. The assay yield of C was 58.2 kg.

[0156] Step 3: A solution of C in THF was droplet-treated with a solution of 3 M NaOH at 15 °C to 25 °C over 2 hours. The mixture was then warmed to 25 °C to 35 °C and stirred for 8 hours. The mixture was cooled to 20 °C to 25 °C, MTBE was added, and the layers were separated. The organic layer was extracted with water, and while maintaining the temperature below 15 °C, the combined aqueous layer containing the sodium salt of D was slowly acidified with 3 N HCl until the pH was 10 to 11. The aqueous mixture was then washed with dichloromethane to remove any residual triphenylphosphine oxide, and then slowly acidified to pH 5 using 3 N HCl while maintaining the temperature below 15 °C. The resulting mixture was extracted with dichloromethane, and the organic extract containing D was concentrated. THF was then added and evaporated. The crude product D was dissolved in THF and used directly in the following step.

[0157] Step 4: A solution of D in THF (43.7 kg per assay) was placed in a hydrogenation reactor. A Pd / C THF slurry (2.90 kg) was added, and the resulting mixture was stirred at 25 °C to 49 °C under hydrogen (about 145 psi) for 12 hours. The mixture was filtered under nitrogen, the filter cake was washed with THF, and the filtrate was concentrated. Dichloromethane was added and concentrated to remove THF, and the operation was repeated. Fresh dichloromethane was added to the mixture, and the resulting solution of E (43.5 kg based on the assay) was used directly in the following step.

[0158] Step 5: A solution of E in dichloromethane at 10 °C to 15 °C was treated with N-hydroxybenzotriazole (HOBT), N,O-dimethylhydroxylamine hydrochloride, and triethylamine. Then, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) was added little by little. The mixture was stirred at 15 °C to 25 °C for 12 hours. Water was added, the resulting mixture was stirred for 12 hours, and the layers were separated. The aqueous layer was separated and extracted with fresh dichloromethane. The combined organic layers were washed with sodium bicarbonate solution to remove HOBT, and dried. Dichloromethane was concentrated, n-heptane was added, the mixture was concentrated to remove dichloromethane. Fresh n-heptane was added, and the mixture was stirred at 15 °C for 10 hours. The solid was filtered and dried to obtain 38.6 kg of F.

[0159] Step 6: A solution of tert-butyl 3,5-difluorobenzoate in THF was cooled to -65 °C under nitrogen and treated dropwise with 1.5 equivalents of LDA solution. The mixture was stirred at -60 °C to -65 °C for 1 hour, then treated dropwise with a solution of compound F (37 kg) in THF. The reaction was stirred between -65 °C and -60 °C for 6 hours, then quenched at -65 °C with a solution of acetic acid in THF. The temperature was raised to -33 °C and the mixture was stirred for 30 minutes. Ethyl acetate was added and the mixture was diluted with brine. The layers were separated, the organic layer was washed with brine, and then concentrated to produce a solution of compound G in ethyl acetate, which was used directly in the next step.

[0160] Step 7: HCl gas (60.4 kg) was bubbled into ethyl acetate (360 kg) between -6 °C and 0 °C. Compound G was added to the mixture at 20 °C to 25 °C over 2 hours. Then, the reaction was stirred for 16 hours, filtered, and the product was washed with ethyl acetate and MTBE and dried under vacuum to obtain H.

[0161] Step 8: Methanol was charged into the reactor at 26 °C and cooled to -7 °C. Then, HCl was bubbled into the methanol at -7 °C to 0 °C over 8 hours. Compound H (28.8 kg) was added at 2 °C, and the mixture was heated to 40 °C to 50 °C and then stirred for 6 hours. Then, the reaction mixture was concentrated, and the residual dichloromethane solvent was first exchanged with heptane (addition of heptane followed by concentration), and then with THF (addition of THF followed by concentration). The resulting solution of Compound I was used directly in the next step.

[0162] Step 9: A solution of Compound I (about 24.6 kg) in THF was diluted with water, and the mixture was cooled to -5 °C to 0 °C. The pH was adjusted to 7 - 8 using sodium bicarbonate solution (2.5 equivalents of bicarbonate). An additional 2 equivalents of sodium bicarbonate were added, and methyl chloroformate (1.2 equivalents) was added dropwise over 1.5 hours, and the reaction mixture was stirred at -5 °C to 0 °C for 1.5 hours. Water, ethyl acetate, and 2N HCl were added, the layers were separated, the organic layer was washed with brine and then concentrated. Additional ethyl acetate was added and evaporated to give an ethyl acetate solution of J. Heptane (4 times the volume) was added with stirring at 55 °C, the mixture was cooled to 10 °C, and stirred for 6 hours. The product was filtered, washed with ethyl acetate:heptane (1:4), and dried to give J (20.6 kg).

[0163] J (20.6 kg) was dissolved in ethyl acetate at 28 °C, and the product was further purified by filtration through a pad of silica gel (25 kg). The filtrate was concentrated to about 50 liters at 40 °C to 50 °C, and 50 kg of ethyl acetate:heptane (1:3) was added at 55 °C. After stirring for 1 hour, the mixture was cooled to 10 °C and stirred for 6 hours. The product was filtered, washed with ethyl acetate:heptane (1:3), and dried to give J (18.5 kg).

[0164] Synthesis of tert-Butyl 3,5-Difluorobenzoate A solution of 3,5-difluorobenzoic acid (75 kg) in tert-butanol was treated with DMAP (5.8 kg) and triethylamine (67.2 kg) and cooled to 5 °C. Di-tert-butyl dicarbonate (124 kg, 1.2 eq) was added portionwise over 3 h, and then the mixture was stirred at 20 °C - 25 °C for 12 h. The mixture was diluted with MTBE and water and stirred for 30 min. The organic layer was cooled to 0 °C, acidified with 1.5 M HCl (470 kg), and the mixture was stirred for 30 min. The organic layer was then washed with brine, concentrated to about 150 L, then THF (90 kg) was added and the mixture was concentrated. This procedure was repeated (90 kg of THF was added and evaporated) to give a solution of 3,5-difluorobenzoic acid, tert-butyl ester in THF which was used directly in Step 6 (above) to produce Compound G.

Example

[0165] Synthesis of methyl (S)-2-((2-(2,6-difluoro-4-(methylcarbamoyl)phenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl)morpholine-4-carboxylate (Compound 1)

Chem.

[0166] Ethyl acetate was charged to a reactor and degassed. Compound J (80 g) was added followed by CuBr2 (101 g). The resulting mixture was stirred at 65 °C - 75 °C for 15 - 24 h and, if HPLC indicated that the reaction was incomplete, treated with additional CuBr2. The reaction was stirred at 65 °C for an additional 3 - 5 h and up to 75 °C for a further 3 - 5 h, cooled to 20 °C - 30 °C, and water followed by sodium bicarbonate were added. The resulting mixture was filtered through Celite and the filter cake was washed with ethyl acetate. The organic layer was washed with 5% EDTA disodium salt solution to remove copper residues and then with 1% sodium bicarbonate solution followed by water to give Compound K which was used directly in the following step (「as is」).

[0167] The ethyl acetate solution from the above was exchanged with acetonitrile to produce a solution of K (100 g) in acetonitrile. 2-Amino-4-methylpyridine (72.06 g) was added to the solution, and then it was stirred at 75 °C to 85 °C for 30 hours to 40 hours under nitrogen. The mixture was concentrated to less than 40 °C to 1 to 2 times the volume and diluted with dichloromethane. Water was added, the mixture was cooled to 0 °C to 10 °C, and acidified with 2N HCl to pH 4 to 5. The layers were separated, and the aqueous layer was extracted with additional dichloromethane. The combined organic layers were washed with water at 0 °C to 10 °C, 7% sodium bicarbonate solution at 0 °C to 10 °C, and then with water. The organic layer was treated with silica gel, and the mixture was concentrated to dryness at less than 35 °C. The residue was transferred to a silica pad, eluted with dichloromethane-ethyl acetate (1V / 9V), the fraction containing compound L was concentrated, and diluted with THF. This was repeated until the residual ethyl acetate was 1% or less.

[0168] The THF solution of L was cooled to 15 °C to 25 °C, treated with 10% LiOH solution, and the mixture was stirred for 2 hours to 5 hours. Then, NaBH4 (2.11 g) was added to the mixture little by little at 15 °C to 25 °C, and the reaction was stirred for 2 hours to 4 hours. Water was added dropwise at 0 °C to 10 °C, and the mixture was diluted with MTBE. The layers were separated, and the aqueous layer was washed with fresh MTBE. The aqueous layer was cooled to 0 °C to 10 °C, treated with dichloromethane-methanol (about 6-1), and the pH was adjusted to 4 to 5 using 2N HCl. The mixture was filtered through celite, and the aqueous layer was extracted with fresh dichloromethane-methanol (6-1). The combined organic layers were concentrated to 1 to 2V at less than 35 °C, and ethanol (2 to 3V) was added. This solution was concentrated to 1 to 2V, treated with ethyl acetate, and the resulting mixture was concentrated to 1 to 2V. Additional ethanol-ethyl acetate was added, and the mixture was heated to 70 °C to 85 °C for 10 to 30 minutes. The mixture was cooled and stirred at -15 °C to 5 °C for 2 to 8 hours. The mixture was filtered to obtain compound M, which was washed with ethyl acetate. Compound M was slurried in ethyl acetate and stirred at -15 °C to 5 °C for 1 to 3 hours. The mixture was filtered, and compound M was washed with additional ethyl acetate and dried.

[0169] A solution of M (26 g) in THF (115 mL) was stirred at 20 °C to 30 °C, and 19 g of CDI (1,1-carbonyldiimidazole) was added. The mixture was stirred for 0.5 hour to 1 hour, then 7.9 g of methylamine hydrochloride was added portionwise, followed by dropwise addition of 18.9 g of diisopropylethylamine. The reaction mixture was stirred at 20 °C to 30 °C for 2 to 34 hours, then diluted dropwise with water while maintaining the temperature. Dichloromethane (173 g) was added, the mixture was stirred, and the layers were separated. The aqueous layer was extracted with fresh dichloromethane, and the combined organic layers were washed twice with 27% ammonium chloride solution and then twice with water. Using a CUNO filter, the organic layer containing Compound 1 was circulated through activated carbon for 1 to 3 hours. The filtrate was concentrated at a temperature below 35 °C to 1 to 2 V, and dichloromethane was exchanged with ethyl acetate through sequential addition / evaporation operations until the residual dichloromethane was 1% or less. Ethyl acetate (2 to 4 V) was added. The mixture of Compound 1 in ethyl acetate was stirred at 45 °C to 55 °C for 1 to 2 hours, cooled to 20 °C to 30 °C, and then stirred for 1 to 2 hours. Compound 1 was filtered, washed with ethyl acetate, and dried.

[0170] Recrystallization of Compound 1 Compound 1 was treated with water / methanol (1 V / 7 V; 6.5 to 7.9 kg) and stirred at 47 °C to 55 °C for 0.5 to 3 hours under nitrogen until a clear solution was obtained. The solution was polish filtered, and the original reactor was rinsed with methanol / water. The mixture was warmed to 47 °C to 55 °C and stirred for 10 minutes to 30 minutes to obtain a clear solution. While maintaining the temperature, water (8 kg) was added under nitrogen, and a seed crystal was added to the mixture. The mixture was stirred at 47 °C to 55 °C for 3 hours to 6 hours under nitrogen, then cooled to 22 °C to 27 °C over 5 hours. The mixture was stirred for 12 hours to 24 hours and filtered under nitrogen. Compound 1 was washed with water / methanol (2 / 1.8) and dried at 47 °C to 53 °C.

Example

[0171] Alternative synthesis of methyl (S)-2-((2-(2,6-difluoro-4-(methylcarbamoyl)phenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl)morpholine-4-carboxylate (Compound 1)

Chemical formula

[0172] A solution of starting material A (30 g, 0.138 mol) in ethyl acetate (100 mL) was treated with DMSO (129 g, 1.66 mol, 117 mL; 12 equivalents) while maintaining the temperature below 30 °C. The mixture was cooled to -10 °C under nitrogen, and a solution of propanephosphonic anhydride (T3P) (0.221 mol; 1.6 equivalents) in ethyl acetate was added dropwise. The resulting mixture was stirred at -10 °C to 0 °C for 1 hour and then treated dropwise with N,N-diisopropylethylamine (39.2 g, 0.304 mol; 2.2 equivalents). The resulting mixture was stirred at -10 °C to 0 °C for 18 hours.

[0173] A slurry of potassium bicarbonate (9 equivalents relative to Compound A) in water (8-fold volume) was cooled to -5 °C. While maintaining the temperature at -5 °C to 5 °C, the reaction mixture containing aldehyde B was quenched into the bicarbonate solution. To this were sequentially added intermediate V (48.7 g, 0.145 mol; 1.05 equivalents), THF (6V), and a solution of 2.5 equivalents (47.7 g, 0.345 mol) of K2CO3 in 3-fold volume of water at -5 °C to 5 °C. The reaction was stirred at -5 °C to 5 °C for 5 hours and then at 20 °C to 30 °C for 5 hours. The reaction was cooled to -5 °C to 5 °C and a 20% aqueous solution of oxone (1 equivalent) was added while maintaining the temperature. Then the mixture was stirred for 1 hour while maintaining the temperature at -5 °C to 5 °C. Then the pH was adjusted to 3 - 5 using 85% H3PO4. The reaction was filtered and the filter cake was washed with fresh ethyl acetate (10V). The layers were separated and the aqueous phase was extracted with ethyl acetate (2 × 20-fold volume). The organic layers were combined and washed with water (2 × 10-fold volume). The organic solution was concentrated to obtain Compound N, which was recrystallized from 2-fold volume of acetonitrile by cooling to -15 °C to 5 °C to obtain N (total yield over two steps from Compound A 64%).

[0174] A solution of recrystallized N (25 g) in THF (100 mL) was stirred under nitrogen. Wet Pd / C (1.25 g) was added and the resulting mixture was stirred at room temperature under H2 at 40 - 50 psi for 18 hours. The catalyst was filtered and washed with fresh THF. The filtrate was concentrated and the residual THF solvent was exchanged several times with acetonitrile. A solution of the reduced product P in acetonitrile (75 mL) was cooled to -15 °C to -5 °C and stirred. The crystallized product was filtered and washed with about 10 mL of acetonitrile to obtain P (21.1 g) in 84% yield).

[0175] Compound P (130 g) in ethyl acetate was treated with 4M HCl in ethyl acetate (HCl 5 equivalents). The reaction was stirred at 15 °C to 25 °C and monitored by HPLC to ensure completion (about 2 hours). The solid was filtered, washed with ethyl acetate, and dried at 50 °C for 10 hours to obtain Compound H (108.2 g).

[0176] A solution of compound H (20 g, 0.06 mol) was followed by adding THF (100 mL) and water (30 mL) to the flask. The mixture was cooled to -5 °C and sodium bicarbonate (22.5 g, 0.27 mol; 4.5 equivalents) was added. While maintaining the temperature at -5 °C to 0 °C, a solution of Moc-Cl (6.77 g, 0.072 mol; 1.2 equivalents) in THF (40 mL) was added dropwise to the mixture over 30 minutes. After the starting material 6 was consumed, the resulting solid was filtered, washed with water (about 40 mL), and then dried at 45 °C to 55 °C to obtain the sodium salt of Q (29.55 g). The sodium salt was converted to the carboxylic acid by adding it to water and the pH was adjusted to 3 using 3M HCl. The resulting mixture was extracted with ethyl acetate and the organic extract was concentrated. The product Q was recrystallized from ethyl acetate:methylcyclohexane (1.5V:10V).

[0177] A solution of compound Q (80 g, 0.224 mol based on the starting sodium salt) in dichloromethane (400 mL) was prepared. N-Bromosuccinimide (NBS; 39.6 g, 0.224 mol) was added at room temperature and the resulting mixture was cooled to -5 °C. Trifluoroacetic acid (1 equivalent) was added dropwise and the resulting mixture was stirred at 25 °C to 30 °C. Additional NBS (0.02 equivalent) was added and the mixture was stirred for an additional 1 hour. The reaction was cooled to -5 °C and poured into a cold 7% aqueous solution of sodium bicarbonate. The resulting pH was 5 - 6. Ascorbic acid (0.01 equivalent) was added, the layers were separated, and the aqueous layer was extracted with dichloromethane (2 × 250 mL). The combined organic layers were washed with water and the resulting solution of compound R (assay yield of 101% for the two diastereomers) was used directly in the following step.

[0178] The solution of R in DCM was concentrated to a small volume, and DCM was exchanged with acetonitrile (a total of 10V of acetonitrile). 2-Amino-4-methylpyridine (5 equivalents relative to R) was added, and the reaction mixture was stirred at 50 °C for 24 hours and then at 80 °C for 16 hours. The reaction mixture was concentrated to remove acetonitrile, and a mixture of dichloromethane (8 volumes) - water (3 volumes) was added. The mixture was cooled to 0 - 10 °C, and the pH was adjusted to 2.5 using 2N HCl. The aqueous layer was extracted with dichloromethane, the organic layer was concentrated, and the solvent was exchanged with THF. 10% aqueous NaOH (1.5 equivalents of NaOH) was added, followed by NaBH4 (0.45 equivalents), and the mixture was stirred at 20 °C for 2 - 5 hours. Water was added (4 volumes), and the mixture was washed with MTBE. Dichloromethane (5 volumes) was added to the aqueous layer containing the sodium salt of the product, and the pH was adjusted to 5.6 - 5.8 using 2N HCl. The aqueous layer was extracted with dichloromethane, concentrated, the solvent was exchanged with ethanol, and concentrated to about 0.4 times the volume. 2 volumes of ethyl acetate were added, the mixture was stirred at 0 °C, and filtered to obtain Compound M. Compound M was recrystallized by heating in methanol (5 volumes) at 55 - 60 °C, followed by adding seed crystals and then cooling to 0 - 5 °C over 1 hour. Water (10 volumes) was added dropwise at - 5 - 5 °C, the mixture was stirred for 15 hours, filtered, Compound M was washed with 1:2 methanol - water, and dried under vacuum at 55 - 60 °C.

[0179] Compound 1 was prepared from Compound M as described in Example 2.

[0180] Synthesis of Intermediate V

Chemical Structure

[0181] A solution of carboxylic acid S (100 g, 0.387 mol) in 2-methyltetrahydrofuran (400 mL) and DMF (1.61 g, 0.022 mol) was cooled to 10 °C to 20 °C. Then, the solution was treated dropwise with oxalyl chloride (61.45 g, 0.48 mol) so as to maintain the temperature at 10 °C to 20 °C, and the resulting mixture was stirred at 10 °C to 20 °C for 1 to 3 hours. The resulting solution of acid chloride T was used directly in the next step.

[0182] MgCl2 (46.46 g, 0.488 mol) was placed in a flask containing T, followed by 2-methyltetrahydrofuran (400 mL). Then, ethyl 2-diethoxyphosphorylacetate (101.06 g, 0.4686 mol) was added to the flask. While maintaining the temperature at 10 °C to 25 °C, triethylamine (196 g, 1.9365 mol) was added dropwise. Then, the reaction mixture was stirred at 10 °C to 25 °C for 1 to 3 hours. Then, the temperature was adjusted to 0 °C to 10 °C, and water (250 mL) was added dropwise while maintaining the temperature below 10 °C. Then, about 275 g of 18% sulfuric acid was used to adjust the pH to 2.0 to 4.0 (while maintaining the temperature below 10 °C). An additional 250 mL of water was added, and the organic layer was separated. The organic layer was washed with 7% sodium bicarbonate and then concentrated to 2 to 3 times the volume while maintaining the temperature below 40 °C. Toluene (170 mL) was added, and the resulting solution was concentrated to 2 to 3 times the volume while maintaining the temperature below 40 °C. Acetic acid (944 mL) was added, and the resulting solution containing U was used directly in the next step.

[0183] Trifluoroacetic acid (220.8 g, 1.937 mol) was added dropwise to the solution of U prepared in the previous step at a temperature below 40 °C. The resulting mixture was stirred at 85 °C to 95 °C for 12 to 24 hours. Subsequently, the mixture was concentrated to 2 to 3 times its volume at a temperature below 70 °C. While maintaining the temperature at 20 °C to 30 °C, water (1.44 L) was added dropwise, and the resulting mixture was stirred for 2 to 4 hours. The product was filtered and washed with water (about 140 mL). The product was treated with methyl tert-butyl ether (133 mL), and the resulting slurry was stirred at -20 °C to -5 °C for 1 to 2 hours. The product was filtered, washed with methyl tert-butyl ether, and then dried at 50 °C to 60 °C to obtain Intermediate V (115 g).

Example

[0184] Potency and selectivity of human P2X3 and P2X2 / 3 receptors The ability of Compound 1 described herein to act as an antagonist of P2X3 and P2X2 / P2X3 channels (encoded by the human P2RX2 and P2RX3 genes, stably expressed in HEK293 cells) was evaluated using a Fluo-8 calcium kit. Compound 1 was evaluated at 12 concentrations.

[0185] For the evaluation of antagonist action, cells were pre-incubated with Compound 1 for 20 minutes and then stimulated with the P2X3 and P2X2 / P2X3 agonists α,β-methylene ATP (meATP) at final concentrations of 3 μM and 30 μM. 4 minutes and 50 seconds after the addition of meATP, ionomycin at a final concentration of 5 μM was added to obtain the maximum calcium influx and the possible fluorescence signal from the cells. Fluorescence was recorded continuously for 10 minutes starting 10 seconds before the addition of meATP. The IC 50 indicates that Compound 1 is a selective P2X3 antagonist (P2X3 IC 50 = 11 nM; P2X2 / 3 IC 50 > 30 μM).

[0186] The examples and embodiments described in this specification are for illustrative purposes only, and in some embodiments, various modifications or changes should be included within the scope of the disclosure and within the scope of the appended claims.

Claims

1. Methyl (S)-2-((2-(2,6-difluoro-4-(methylcarbamoyl)phenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl)morpholine-4-carboxylate (Compound 1): 【Chemical Formula 1】 A method for the production of, having the structure: 【Chemical Formula 2】 The method comprising contacting a compound having with an amide coupling reagent and methylamine or a salt of methylamine.

2. The method according to claim 1, wherein the amide coupling reagent is carbonyldiimidazole or propane phosphonic anhydride (T3P).

3. Structure: 【Chemical Formula 3】 The compound having is produced by a method comprising contacting a compound having with 2-amino-4-methylpyridine or contacting 2-amino-4-methylpyridine and sodium borohydride, according to claim 1 or 2. 【Chemical Formula 4】

4. Structure: 【Chemical Formula 5】 The compound having is produced by a method comprising contacting a compound having with a bromination reagent, according to claim 3. 【Chemical Formula 6】

5. The method according to claim 4, wherein the brominating agent is N-bromosuccinimide in the presence of an acid.

6. Structure: 【Chemical Formula 7】 The compound having is 【Chemical Formula 8】 The method according to any one of claims 4 to 5, which is produced by a method comprising contacting a compound having

7. The method according to claim 6, wherein the base is sodium bicarbonate.

8. Structure: 【Chemical Formula 9】 The compound having is of the structure: 【Chemical Formula 10】 The method according to any one of claims 6 to 7, which is produced by a method comprising contacting a compound having with hydrogen chloride in the presence of a solvent.

9. The method according to claim 8, wherein the solvent is ethyl acetate.

10. Structure: 【Chemical Formula 11】 The compound having is of the structure: 【Chemical Formula 12】 The method according to any one of claims 8 to 9, which is produced by a method comprising contacting a compound having with a hydrogenation catalyst and hydrogen.

11. The method according to claim 10, wherein the hydrogenation catalyst is palladium on carbon, palladium hydroxide, rhodium on carbon, rhodium on alumina, platinum oxide, or platinum on carbon.

12. Structure: 【Chemical Formula 13】 The compound having is of the structure: 【Chemical Formula 14】 The compound having and the structure: 【Chemical Formula 15】 The method according to any one of claims 10 to 11, which is produced by a method comprising contacting the compound having with a base.

13. The method according to claim 12, wherein the base is a mixture of potassium bicarbonate and potassium carbonate.

14. Structure: 【Chemical Formula 16】 A compound having the structure: 【Chemical Formula 17】 The method according to any one of claims 12 to 13, which is produced by a method comprising contacting a compound having the structure:

15. Structure: 【Chemical Formula 86】 Structure: 【Chemical Formula 87】 Structure: 【Chemical Formula 88】 Structure: 【Chemical Formula 89】 Structure: 【Chemical Formula 90】 Structure: 【Chemical Formula 91】 Structure: 【Chemical Formula 92】 Structure: 【Chemical Formula 93】 A compound having the structure; or a pharmaceutically acceptable salt thereof.

Images