Preparation of S1P receptor modulators

Abstract

Described herein is the preparation of the S1P receptor modulator tamuzimod ((R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one) and chemical intermediates used in the synthetic process.

Description

[Technical Field]

[0001] cross reference This application claims the benefit of U.S. Provisional Patent Application No. 63 / 479,932, filed January 13, 2023, which is incorporated herein by reference in its entirety. [Background technology]

[0002] Sphingosine-1-phosphate (S1P) receptors are a class of G protein-coupled receptors that are targets of the lipid signaling molecule sphingosine-1-phosphate. Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid that has been demonstrated to induce many cellular processes, including platelet aggregation, cell proliferation, cell morphology, tumor cell invasion, endothelial cell chemotaxis, and cytoskeletal rearrangements in many cell types to control angiogenesis, immune cell migration, vascular homeostasis, and intercellular communication between the central nervous system (CNS) and peripheral organ systems. S1P can bind to members of the endothelial cell differentiation gene family (EDG receptors) of plasma membrane-localized G protein-coupled receptors. To date, five members of this family, S1P1 (EDG-1), S1P2 (EDG-5), S1P3 (EDG-3), S1P4 (EDG-6), and S1P5 (EDG-8), have been identified as S1P receptors in different cell types. S1P receptor modulators are compounds that signal as agonists or antagonists at one or more S1P receptors. Because S1P mediates a wide variety of cellular responses, S1P receptor modulators are promising targets for a variety of therapeutic indications. Summary of the Invention

[0003] Described herein is a process for synthesizing an S1P receptor modulator compound, the compound being (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one (Compound 1), or a pharmaceutically acceptable salt thereof.

[0004] In one aspect, there is a process for preparing (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one (Compound 1), the process comprising: A) The following structure

[0005] [ka] with HOBT and EDCI to give a compound having the following structure:

[0006] [ka] producing a compound having the formula: B) Next, the following structure

[0007] [ka] with cesium carbonate to give a compound having the following structure:

[0008] [ka] and producing (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one (compound 1), is.

[0009] In another aspect, there is a process for preparing (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one (Compound 1), the process comprising: A) The following structure

[0010] [ka] with potassium carbonate to give a compound having the following structure:

[0011] [ka] producing a compound having the formula: B) Next, the following structure

[0012] [ka] with hydroxylamine to give a compound having the structure

[0013] [ka] producing a compound having the formula: C) The following structure

[0014] [ka] with HATU and DIEA to give a compound having the following structure:

[0015] [ka] and producing (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one (compound 1), is.

[0016] In some embodiments, the process for preparing (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one (Compound 1) comprises reacting (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one with (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one. and further comprising reacting (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one acetate (Compound 1A) with acetic acid.

[0017] In another embodiment, (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one (Compound 1)

[0018] [ka] 1. A process for preparing a compound having the following structure:

[0019] [ka] with a base in the presence of a solvent. In some embodiments, the base is selected from cesium carbonate, potassium carbonate, potassium phosphate, DBU, sodium t-butoxide, potassium t-butoxide, LiHMDS, NaHMDS, KHMDS, and mixtures thereof. In some embodiments, the base is cesium carbonate. In some embodiments, the base is a mixture of cesium carbonate and potassium phosphate. In some embodiments, the solvent is selected from dimethylacetamide, cyclopentyl methyl ether, DMF, NMP, THF, MeTHF, acetonitrile, toluene, and mixtures thereof. In some embodiments, the solvent is a mixture of dimethylacetamide and cyclopentyl methyl ether.

[0020] In some embodiments of the process for preparing (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one (Compound 1), a compound having the following structure:

[0021] [ka] The compound having the following structure:

[0022] [ka] The compound having the formula (I) is prepared by contacting the compound having the formula (I) with a coupling agent in the presence of a solvent. In some embodiments, the coupling agent is selected from HOBT and EDCI, thionyl chloride, oxalyl chloride, COMU (1-[(1-(cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylaminomorpholino)]uronium hexafluorophosphate), HBTU (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate), HCTU (O-(1H-6-chlorobenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate), TCFH (chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate), phenylboronic acid, silicon tetrachloride, and tetraethyl orthosilicate. In some embodiments, the coupling agent is HOBT and EDCI. In some embodiments, the solvent is selected from N-methyl-2-pyrrolidone, DMF, DMAc, toluene, MeTHF, and acetonitrile, hi some embodiments, the solvent is N-methyl-2-pyrrolidone.

[0023] (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one (compound 1), the structure of which is shown below.

[0024] [ka] In some embodiments of the process for preparing a compound having the following structure:

[0025] [ka] The present invention includes contacting a compound having the formula: with a coupling agent and a base in the presence of a solvent. In some embodiments, the coupling agent is selected from HATU, thionyl chloride, oxalyl chloride, COMU (1-[(1-(cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylaminomorpholino)]uronium hexafluorophosphate), HBTU (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate), HCTU (O-(1H-6-chlorobenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate), TCFH (chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate), phenylboronic acid, silicon tetrachloride, and tetraethyl orthosilicate. In some embodiments, the coupling agent is HATU. In some embodiments, the base is selected from diisopropylethylamine, triethylamine, N-methylmorpholine, N-methylimidazole, and N-methylpiperidine. In some embodiments, the base is diisopropylethylamine. In some embodiments, the solvent is selected from dichloromethane, THF, MeTHF, acetonitrile, NMP, DMAc, DMF, and toluene. In some embodiments, the solvent is dichloromethane.

[0026] In some embodiments of the process for preparing (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one (Compound 1), a compound having the following structure:

[0027] [ka] The compound having the following structure:

[0028] [ka] The compound is prepared by a process comprising contacting a compound having the formula: with hydroxylamine in the presence of a solvent. In some embodiments, the solvent is selected from dimethyl sulfoxide, DMF, DMAc, NMP, MeOH, EtOH, and 2-PrOH. In some embodiments, the solvent is dimethyl sulfoxide.

[0029] The following structure

[0030] [ka] In some embodiments of the process for preparing the compound (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one (Compound 1), having the following structure:

[0031] [ka] The compound having the formula (I) is prepared by a process comprising contacting the compound having the formula (I) with a base in the presence of a solvent. In some embodiments, the base is selected from potassium carbonate, DBU, sodium t-butoxide, potassium t-butoxide, LiHMDS, NaHMDS, and KHMDS. In some embodiments, the base is potassium carbonate. In some embodiments, the solvent is selected from 2-butanone, DMF, DMAc, NMP, THF, and acetonitrile. In some embodiments, the solvent is 2-butanone.

[0032] Incorporation by Reference All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. DETAILED DESCRIPTION OF THE INVENTION

[0033] Good manufacturing practice is typically required for large-scale production of clinically useful drug candidates. Provided herein are certain processes and methods for producing (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one (Compound 1), or a pharmaceutically acceptable salt or co-crystal thereof.

[0034] definition As used in this specification and the appended claims, unless otherwise stated, the following terms have the meanings indicated below.

[0035] As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context dictates otherwise. Thus, for example, reference to "an agent" includes a plurality of such agents, and reference to "the cell" includes a reference to one or more cells (or to a plurality of cells) and equivalents thereof.

[0036] When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formula, all combinations and subcombinations of ranges, and specific embodiments therein, are intended to be encompassed.

[0037] The term "about" when referring to a numerical value or numerical range indicates that the referenced numerical value or numerical range is an approximation within experimental variability (or within statistical experimental error), such that the numerical value or numerical range varies from 1% to 15% of the stated numerical value or numerical range.

[0038] The term "comprising" (and the related terms "comprise" or "comprises" or "having" or "including") is not intended to exclude that in other specific embodiments, an embodiment, such as any arrangement, composition, method, or process of matter described herein, "consists of" or "consists essentially of" the recited features.

[0039] The term "subject" or "patient" includes mammals and non-mammals. Examples of mammals include, but are not limited to, any member of the mammalian class, including humans, non-human primates such as chimpanzees, and other apes, as well as monkeys, livestock such as cows, horses, sheep, goats, and pigs, domestic animals such as rabbits, dogs, and cats, and laboratory animals including rodents such as rats, mice, and guinea pigs. 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.

[0040] As used herein, "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, a therapeutic effect and / or a prophylactic effect. A "therapeutic effect" refers to the eradication or amelioration of the underlying disease being treated. A therapeutic effect is also achieved by the eradication or amelioration of one or more physiological symptoms associated with the underlying disease, such that an improvement is observed in the patient despite the patient still suffering from the underlying disease. For a prophylactic effect, the composition may be administered to a patient at risk of contracting a particular disease or to a patient who reports one or more physiological symptoms of the disease, even if a diagnosis of the disease has not been made.

[0041] " Pharmaceutically acceptable salt " includes both acid addition salt and base addition salt. The pharmaceutically acceptable salt of any one of the compounds described herein is intended to include all pharmaceutically suitable salt forms. The preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0042] "Pharmaceutically acceptable acid addition salts" refers to salts formed with inorganic acids, such as hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, hydroiodic, hydrofluoric, phosphorous, and the like, which salts retain the biological effectiveness and properties of the free base, and which are not biologically or otherwise undesirable. Also included are salts formed with organic acids, including aliphatic monocarboxylic and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic acids, and aromatic sulfonic acids, such as acetic acid, adipic 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 sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphates, dihydrogenphosphates, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, adipate, trifluoroacetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoates, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, malate, tartrate, methanesulfonate, and the like. Also contemplated are salts of amino acids such as arginate, gluconate, and galacturonate (see, e.g., Berge SM 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 with a sufficient amount of the desired acid to produce the salt.

[0043] "Pharmaceutically acceptable base addition salts" refer to salts that retain the biological effectiveness and properties of the free acid, and which are not biologically or otherwise undesirable. These salts are prepared by adding an inorganic or organic base to the free acid. In some embodiments, pharmaceutically acceptable base addition salts are formed from metals or amines, such as alkali, alkaline earth metals, or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, naturally occurring substituted amines, substituted amines including cyclic amines, and basic ion exchange resins, such as 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, etc. See Berge et al., supra.

[0044] As used herein, the term "pharmaceutical combination" refers to a product resulting from the mixing or combining of more than one active ingredient, and includes both fixed and non-fixed combinations of active ingredients. The term "fixed combination" means that both active ingredients are administered to a patient simultaneously in the form of a single entity or dosage. The term "non-fixed combination" means that the active ingredients are administered to a patient as separate entities simultaneously, in parallel, or sequentially, with no specific time limit between them, such administration providing the patient's body with effective levels of the two compounds. The latter term also applies to cocktail therapy, e.g., the administration of three or more active ingredients.

[0045] The term "co-administration" and the like, as used herein, is meant to encompass the administration of selected therapeutic agents to one patient, and is intended to include treatment regimens in which the agents are administered by the same or different routes, or at the same or different times.

[0046] The term "activator" is used herein to refer to any molecular species that results in activation of an indicated receptor, regardless of whether the species itself binds to the receptor when administered locally, or whether a metabolite of the species binds to the receptor. Thus, an activator can be a ligand of a receptor, or an activator that is metabolized to a ligand of a receptor, i.e., a metabolite formed in the tissue and the actual ligand.

[0047] The term "antagonist," as used herein, refers to a small molecule agent that binds to a nuclear hormone receptor and subsequently reduces agonist-induced transcriptional activity of the nuclear hormone receptor.

[0048] As used herein, the term "agonist" refers to a small molecule agent that binds to a nuclear hormone receptor and subsequently increases nuclear hormone receptor transcriptional activity in the absence of a known agonist.

[0049] As used herein, the term "inverse agonist" refers to a small molecule agent 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.

[0050] As used herein, the term "modulate" means to interact directly or indirectly with a target protein so as to alter the activity of the target protein, including, by way of example only, inhibiting the activity of the target or limiting or reducing the activity of the target.

[0051] As used herein, the term "modulator" refers to a compound that alters the activity of a target. For example, a modulator can cause an increase or decrease in the magnitude of a particular activity of a target compared to the magnitude of the activity in the absence of the modulator. In some embodiments, a modulator is an inhibitor, which reduces the amount of one or more activities of a target. In some embodiments, an inhibitor completely prevents one or more activities of a target.

[0052] compound In some embodiments, the S1P receptor modulator described herein is (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one (Compound 1), or a pharmaceutically acceptable salt or co-crystal thereof. Compound 1 has the following structure:

[0053] [ka] In some embodiments, the starting material for the synthesis of Compound 1 is

[0054] [ka] In some embodiments, an intermediate in the synthesis of Compound 1 is

[0055] [ka] In some embodiments, an intermediate in the synthesis of Compound 1 is

[0056] [ka] In some embodiments, an intermediate in the synthesis of Compound 1 is

[0057] [ka] In some embodiments, the starting material in the synthesis of Compound 1 is:

[0058] [ka] In some embodiments, the starting material in the synthesis of Compound 1 is:

[0059] [ka] In some embodiments, the starting material in the synthesis of Compound 1 is:

[0060] [ka] In some embodiments, an intermediate in the synthesis of Compound 1 is

[0061] [ka] is.

[0062] Further forms of the compound The compounds described herein may exist in diastereomers, enantiomers, or other stereoisomeric forms in some cases. The compounds presented herein include all diastereomeric, enantiomeric, and epimeric forms, and the appropriate mixtures thereof. Separation of stereoisomers can be carried out by chromatography, or diastereomeric formation and recrystallization or chromatographic separation, or any combination thereof (Jean Jacques, Andre Collet, Samuel H. Wilen, "Enantiomers, Racemates and Resolutions", John Wiley and Sons, Inc., 1981, incorporated herein by reference for this disclosure). Stereoisomers can also be obtained by stereoselective synthesis.

[0063] In some situations, compounds may exist as tautomers, all of which are included in the formulae given herein.

[0064] Pharmaceutically acceptable salts In some embodiments, the compounds described herein are present 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.

[0065] In some embodiments, the compounds described herein possess acidic or basic groups and thus react with any of a number of inorganic or organic bases, as well as inorganic and organic acids, to form pharmaceutically acceptable salts. In some embodiments, these salts are prepared during the final isolation and purification of the compounds of the invention, or in situ by separately reacting the purified compound in free form with the appropriate acid or base and isolating the salt thus formed.

[0066] In some embodiments, the pharmaceutically acceptable salt of Compound 1 is acetate, adipate, 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 a monohydrochloride salt. In further embodiments, the pharmaceutically acceptable salt of Compound 1 is a monohydrochloride salt. In some embodiments, the pharmaceutically acceptable salt of Compound 1 is an adipate salt.

[0067] solvate In some embodiments, the compounds described herein exist as solvates. The present invention provides methods of treating diseases by administering such solvates. The present invention further provides methods of treating diseases by administering such solvates as pharmaceutical compositions.

[0068] Solvates contain stoichiometric or non-stoichiometric amounts of solvent, and in some embodiments, are formed during the crystallization process using a pharmaceutically acceptable solvent, such as water or ethanol. Hydrates are formed when the solvent is water, and alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein are preferably prepared or formed during the processes described herein. By way of example only, hydrates of the compounds described herein are preferably prepared by recrystallization from aqueous / organic solvent mixtures using organic solvents, including but not limited to dioxane, tetrahydrofuran, or methanol. Furthermore, the compounds provided herein exist in both solvated and unsolvated forms. Generally, solvated forms are considered equivalent to unsolvated forms for the purposes of the compounds and methods provided herein.

[0069] labeled compound In some embodiments, the compounds described herein exist in isotopically labeled form. In some embodiments, the methods disclosed herein include methods of treating disease by administering such isotopically labeled compounds. In some embodiments, the methods disclosed herein include methods of treating disease by administering such isotopically labeled compounds as pharmaceutical compositions. Thus, in some embodiments, the compounds disclosed herein include isotopically labeled compounds, which are identical to those listed herein except for the fact that one or more atoms are 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 that may be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, and chloride, respectively. 2 H, 3 H, 13 C. 14 C. l5 N, 18 O. 17 O. 31 P, 32 P, 35 S, 18 F, and 36 Cl, etc. Compounds described herein and pharmaceutically acceptable salts, esters, solvates, hydrates, or derivatives thereof that contain the aforementioned isotopes and / or other isotopes of other atoms are within the scope of this invention. 3 H and 14 Certain isotopically labeled compounds, such as those incorporating C, are useful in drug and / or substrate tissue distribution assays. 3 H isotopes, and carbon-14, i.e., 14 C isotopes are particularly preferred for their ease of preparation and detectability. Additionally, deuterium, i.e., 2Substitution with heavy isotopes such as H offers certain therapeutic advantages due to greater metabolic stability, e.g., increased in vivo half-life or reduced dosage requirements. Increased levels of deuterium incorporation result in a detectable kinetic isotope effect (KIE), which can affect the pharmacokinetic, pharmacological, and / or toxicological parameters of Compound 1 compared to Compound 1 having naturally occurring deuterium levels. In some embodiments, the isotopically labeled compound or a pharmaceutically acceptable salt thereof is prepared by any suitable method.

[0070] In some embodiments, the compounds described herein are labeled by other means, including but not limited to, a chromophore or fluorescent moiety, a bioluminescent label, or a chemiluminescent label.

[0071] Process for preparation In some embodiments, synthesis of the compounds described herein is achieved using means described in the chemical literature, using methods described herein, or by a combination thereof. Additionally, solvents, temperatures, and other reaction conditions set forth herein may be varied.

[0072] In other embodiments, the starting materials and reagents used in the synthesis of the compounds described herein are obtained from or synthesized from commercial sources, such as, but not limited to, Sigma-Aldrich, Fischer Scientific (Fischer Chemicals), and AcrosOrganics. In further embodiments, the compounds described herein, and other related compounds with different substituents, can be synthesized using techniques and materials described herein, as well as other methods and methods described in, 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 Supplementals (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 4 th Ed.,(Wiley 1992);Carey and Sundberg,Advanced Organic Chemistry 4 th Ed.,Vols.A and B(Plenum 2000,2001), and Green and Wuts,Protective Groups in Organic Synthesis 3 rd Ed., (Wiley 1999), all of which are incorporated by reference for such disclosure. General methods for the preparation of compounds as disclosed herein may be derived from reactions, which may be modified by utilizing appropriate reagents and conditions to introduce the various moieties found in the formulae as provided herein.

[0073] In some embodiments, there is a process for preparing (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one (Compound 1), the process comprising: A) The following structure

[0074] [ka] with HOBT and EDCI to give a compound having the following structure:

[0075] [ka] producing a compound having the formula: B) Next, the following structure

[0076] [ka] with cesium carbonate to give a compound having the following structure:

[0077] [ka] and producing (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one (compound 1), is.

[0078] In some embodiments, the process further comprises reacting (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one (Compound 1) with acetic acid to produce (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one acetate (Compound 1A).

[0079] In some embodiments, (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one (Compound 1)

[0080] [ka] 1. A process for preparing a compound having the following structure:

[0081] [ka]

[0013] A process includes contacting a compound having the formula: with a base in the presence of a solvent. In some embodiments, the base is selected from cesium carbonate, potassium carbonate, potassium phosphate, DBU, sodium t-butoxide, potassium t-butoxide, LiHMDS, NaHMDS, KHMDS, and mixtures thereof. In some embodiments, the base is cesium carbonate. In some embodiments, the base is potassium carbonate. In some embodiments, the base is potassium phosphate. In some embodiments, the base is DBU. In some embodiments, the base is sodium t-butoxide. In some embodiments, the base is potassium t-butoxide. In some embodiments, the base is LiHMDS. In some embodiments, the base is NaHMDS. In some embodiments, the base is KHMDS. In some embodiments, the base is a mixture of cesium carbonate and potassium phosphate. In some embodiments, the solvent is selected from dimethylacetamide, cyclopentyl methyl ether, DMF, NMP, THF, MeTHF, acetonitrile, toluene, and mixtures thereof. In some embodiments, the solvent is dimethylacetamide. In some embodiments, the solvent is cyclopentyl methyl ether. In some embodiments, the solvent is DMF. In some embodiments, the solvent is NMP. In some embodiments, the solvent is THF. In some embodiments, the solvent is MeTHF. In some embodiments, the solvent is acetonitrile. In some embodiments, the solvent is toluene. In some embodiments, the solvent is a mixture of dimethylacetamide and cyclopentyl methyl ether.

[0082] In some embodiments of the process for preparing (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one (Compound 1), a compound having the following structure:

[0083] [ka] The compound having the following structure:

[0084] [ka] The compound having the formula: is prepared by contacting the compound having the formula: with a coupling agent in the presence of a solvent. In some embodiments, the coupling agent is selected from HOBT and EDCI, thionyl chloride, oxalyl chloride, COMU (1-[(1-(cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylaminomorpholino)]uronium hexafluorophosphate), HBTU (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate), HCTU (O-(1H-6-chlorobenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate), TCFH (chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate), phenylboronic acid, silicon tetrachloride, and tetraethyl orthosilicate. In some embodiments, the coupling agent is HOBT and EDCI. In some embodiments, the coupling agent is thionyl chloride. In some embodiments, the coupling agent is oxalyl chloride. In some embodiments, the coupling agent is COMU (1-[((1-(cyano-2-ethoxyl-2-oxoethylideneaminooxy)dimethylaminomorpholino)]uronium hexafluorophosphate). In some embodiments, the coupling agent is HBTU (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate). In some embodiments, the coupling agent is HCTU (O-(1H-6-chlorobenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate). In some embodiments, the coupling agent is tetraethyl orthosilicate (tetramethylformamidinium hexafluorophosphate). In some embodiments, the coupling agent is TCFH (chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate). In some embodiments, the coupling agent is phenylboronic acid. In some embodiments, the coupling agent is silicon tetrachloride. In some embodiments, the coupling agent is tetraethyl orthosilicate. In some embodiments, the solvent is selected from N-methyl-2-pyrrolidone, DMF, DMAc, toluene, MeTHF, and acetonitrile.In some embodiments, the solvent is N-methyl-2-pyrrolidone. In some embodiments, the solvent is DMF. In some embodiments, the solvent is DMAc. In some embodiments, the solvent is toluene. In some embodiments, the solvent is MeTHF. In some embodiments, the solvent is acetonitrile.

[0085] The following structure

[0086] [ka] In some embodiments of the process for preparing the compound (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one (Compound 1), having the following structure:

[0087] [ka] The present invention includes contacting a compound having the formula: with a coupling agent and a base in the presence of a solvent. In some embodiments, the coupling agent is selected from HATU, thionyl chloride, oxalyl chloride, COMU (1-[(1-(cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylaminomorpholino)]uronium hexafluorophosphate), HBTU (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate), HCTU (O-(1H-6-chlorobenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate), TCFH (chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate), phenylboronic acid, silicon tetrachloride, and tetraethyl orthosilicate. In some embodiments, the coupling agent is HATU. In some embodiments, the coupling agent is thionyl chloride. In some embodiments, the coupling agent is oxalyl chloride. In some embodiments, the coupling agent is COMU (1-[((1-(cyano-2-ethoxyl-2-oxoethylideneaminooxy)dimethylaminomorpholino)]uronium hexafluorophosphate). In some embodiments, the coupling agent is HBTU (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate). In some embodiments, the coupling agent is HCTU (O-(1H-6-chlorobenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate). In some embodiments, the coupling agent is phenylboronic acid. In some embodiments, the coupling agent is silicon tetrachloride. In some embodiments, the coupling agent is tetraethyl orthosilicate. In some embodiments, the base is selected from diisopropylethylamine, triethylamine, N-methylmorpholine, N-methylimidazole, and N-methylpiperidine.In some embodiments, the base is triethylamine. In some embodiments, the base is diisopropylethylamine. In some embodiments, the base is N-methylmorpholine. In some embodiments, the base is N-methylpyrrolidine. In some embodiments, the base is N-methylpiperidine. In some embodiments, the solvent is selected from dichloromethane, THF, MeTHF, acetonitrile, NMP, DMAc, DMF, and toluene. In some embodiments, the solvent is dichloromethane. In some embodiments, the solvent is THF. In some embodiments, the solvent is N-methylpyrrolidone (NMP). In some embodiments, the solvent is MeTHF. In some embodiments, the solvent is acetonitrile. In some embodiments, the solvent is DMAc. In some embodiments, the solvate is DMF. In some embodiments, the solvent is toluene.

[0088] In some embodiments of the process for preparing (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxypiperidin-2-one (Compound 1), a compound having the following structure:

[0089] [ka] The compound having the following structure:

[0090] [ka] with hydroxylamine in the presence of a solvent. In some embodiments, the solvent is selected from dimethyl sulfoxide, DMF, DMAc, NMP, MeOH, EtOH, and 2-PrOH. In some embodiments, the solvent is dimethyl sulfoxide. In some embodiments, the solvent is DMF. In some embodiments, the solvent is DMAc. In some embodiments, the solvent is NMP. In some embodiments, the solvent is MeOH. In some embodiments, the solvent is EtOH. In some embodiments, the solvent is 2-PrOH.

[0091] In some embodiments of the process for preparing (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one (Compound 1), a compound having the following structure:

[0092] [ka] The compound having the following structure:

[0093] [ka] with a base in the presence of a solvent. In some embodiments, the base is selected from potassium carbonate, DBU, sodium t-butoxide, potassium t-butoxide, LiHMDS, NaHMDS, and KHMDS. In some embodiments, the base is potassium carbonate. In some embodiments, the base is potassium carbonate. In some embodiments, the base is DBU. In some embodiments, the base is triethylamine. In some embodiments, the base is sodium t-butoxide. In some embodiments, the base is LiHMDS. In some embodiments, the base is NaHMDS. In some embodiments, the base is KHMDS. In some embodiments, the solvent is selected from 2-butanone, DMF, DMAc, NMP, THF, and acetonitrile. In some embodiments, the solvent is 2-butanone. In some embodiments, the solvent is DMF. In some embodiments, the solvent is DMAc. In some embodiments, the solvent is NMP. In some embodiments, the solvent is THF. In some embodiments, the solvent is acetonitrile.

[0094] In some embodiments, the structure:

[0095] [ka] There is a compound having the formula:

[0096] In some embodiments, the structure:

[0097] [ka] There is a compound having the formula:

[0098] Pharmaceutical Compositions and Methods of Administration Administration of Compound 1 described herein can be in any pharmacological form, including a therapeutically effective amount of Compound 1 alone or in combination with a pharmaceutically acceptable carrier.

[0099] Pharmaceutical compositions can be formulated in a conventional manner using one or more physiologically acceptable carriers, including excipients and auxiliaries that help process active compounds into pharmaceutically usable preparations.Suitable formulations depend on the route of administration selected.More details about suitable excipients for the pharmaceutical compositions described herein can be found in, for example, Remington: The Science and Practice of Pharmacy, Nineteenth Edition (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, HA and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980, and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Edition (Lippincott Williams & Wilkins 1999), and these documents are incorporated herein by reference for this disclosure.

[0100] 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, thickeners, and / or excipients. A pharmaceutical composition facilitates administration of a compound to an organism. In carrying out the treatment or use methods provided herein, a therapeutically effective amount of a compound described herein is administered as a pharmaceutical composition to a mammal suffering from the disease, disorder, or condition being treated. In some embodiments, the mammal is a human. The therapeutically effective amount may vary depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used, and other factors. Compound 1 may be used alone or in combination with one or more therapeutic agents as a component of a mixture (as in a combination therapy).

[0101] The pharmaceutical formulations described herein can be administered to a subject by many routes of administration, including, but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular), intranasal, buccal, topical, rectal, or transdermal routes of administration. Furthermore, the pharmaceutical compositions described herein, including Compound 1 described herein, can be formulated into any suitable dosage form, including, but not limited to, aqueous oral dispersions, liquids, gels, syrups, elixirs, slurries, suspensions, aerosols, controlled-release formulations, fast-dissolve formulations, effervescent formulations, lyophilized formulations, tablets, powders, pills, dragees, capsules, delayed-release formulations, sustained-release formulations, pulsed-release formulations, multiparticulate formulations, and combined immediate-release and controlled-release formulations.

[0102] 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 in a suspension dosage form. In some embodiments, Compound 1 is formulated as a powder dosage form in a capsule. In some embodiments, Compound 1 is formulated as a powder in a bottle for reconstitution as a suspension.

[0103] Pharmaceutical compositions containing the compounds described herein may be manufactured by conventional means, such as, by way of example only, by means of conventional mixing, dissolving, granulating, dragee-making, gelling, emulsifying, encapsulating, entrapping, or compressing processes.

[0104] The administration of the dose may be repeated depending on the pharmacokinetic parameters of the dosage formulation and the route of administration used.

[0105] For ease of administration and uniformity of dosage, it is particularly advantageous to formulate pharmaceutical compositions in dosage unit form. As used herein, dosage unit form refers to a physically discrete unit suitable as a unitary dosage for a mammalian subject to be treated, each unit containing a predetermined amount of active compound calculated to produce a desired therapeutic effect together with the necessary pharmaceutical carrier. The specifications of dosage unit form are dictated by and directly depend on (a) the inherent characteristics of Compound 1 and the specific therapeutic effect to be achieved, and (b) the inherent limitations in the art of formulating such active compounds with respect to the sensitivity of the individual to treatment. Specific doses can be easily calculated by those skilled in the art, for example, according to the approximate body weight or body surface area of ​​the patient or the volume of the body cavity to be occupied. The dose is also calculated depending on the specific route of administration selected. Further refinement of the calculations required to determine the appropriate dosage for treatment is routinely performed by those skilled in the art. The exact dosage is determined in conjunction with standard dose-response tests. It will be understood that the amount of composition actually administered will be determined by the physician in light of the relevant circumstances, including the disease(s) being 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 chosen route of administration. [Example]

[0106] All chemicals, reagents, and solvents were purchased from commercial sources when available and used without further purification.

[0107] Standard abbreviations and acronyms are used herein as defined in J. Org. Chem. 2007 72(1):23A-24A. Other abbreviations and acronyms used herein are as follows:

[0108] [Table 1]

[0109] Example 1: Synthesis of (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one (Compound 1)

[0110] [ka] To a solution of compound B (62.8 g, 1.05 equiv.) in NMP (250.0 mL) was added HOBt (36.7 g, 1.2 equiv.) at 10° C. The mixture was stirred at 10° C. for 0.5 h, and EDCI (52.0 g, 1.2 equiv.) was added. The mixture was stirred at 10° C. for 2 h, and then compound A (50.0 g) was added. The reaction mixture was warmed to 25° C. and stirred for 2 h. The mixture was warmed to 80° C. and stirred for 7 h. The mixture was cooled to 50° C., and water (300 mL) was added. The mixture was stirred for 1 h. The mixture was cooled to 25° C. and stirred for 5 h. The mixture was filtered, and the filter cake was washed with HO (2×100 mL). The wet cake was dissolved in 2-MeTHF (250 mL) and stirred at 60° C. for 1 h. Heptane (500 mL) was added at 60° C., and the mixture was stirred for 1 hour. The mixture was cooled to 25° C. and filtered. The filter cake was washed with n-heptane (2×100 mL) and dried at 60° C. for 24 hours to give compound D (88.9 g, 73%). 1 H NMR(400MHz,DMSO) δ 11.51(s,1H),9.29(q,J=1.4Hz,1H),9.00(s,1H),7.99-7.98(m,2H),7.18(s,1H);MS ESI+:448.9[M+H] + .

[0111] DMA / CPME=1 / 3 (5.0 V, 250.0 mL) was charged to a reactor at 25±5°C under N2. To a solution of compound D (50.0 g, 1.0 equiv.) in DMA / CPME::1 / 3 (250 mL) was added compound E (50.9 g, 1.7 equiv.) and Cs2CO3 (34.4 g, 0.95 equiv.) at 25°C. The reaction mixture was heated to 80°C and stirred for 15 hours. The mixture was cooled to 25°C and stirred for 10 hours. The mixture was filtered, and the filter cake was washed with CPME (2 × 100 mL). The wet cake was slurried with HO (500 mL) and stirred for 3 hours. The mixture was filtered, and the filter cake was washed with HO (2 × 100 mL). The filter cake was dried at 60°C for 24 hours to give compound 1 (50.2 g, 82% yield). 1 H NMR(300MHz,DMSO) δ 9.32(t,J=1.5Hz,1H),9.05(s,1H),8.10(s,1H),8.04(d,J=1.6Hz,1H),7.71(s,1H),7.50-7.43(m,1H) ,5.15(t,J=3.8Hz,1H),3.56-3.47(m,1H),3.40-3.35(m,1H),2.41-2.20(m,2H),2.15-2.05(m,2H). ESI+:546.0[M+H] + .

[0112] Example 2: Synthesis of (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one (Compound 1) (Alternate Synthesis)

[0113] [ka] To a solution of compound H (1.0 equivalent, 50.0 g) in 2-butanone (500 mL) was added KCO (55.1 g, 1.5 equivalents) and compound I (1.3 equivalents, 93.1 g) at 25 °C. The reaction mixture was heated to 80 °C and stirred for 24 hours. The mixture was then cooled to 25 °C. Water (500 mL) was added, and the mixture was stirred for 1 hour. The mixture was extracted with DCM (4 × 250 mL). The combined organic phase was washed with water (250 mL) and partially concentrated. MTBE (300 mL) was added, and the mixture was stirred at 40 °C for 1 hour, then at 25 °C for 1 hour. The mixture was filtered, and the filter cake was washed with MTBE (2 × 100 mL). The filter cake was dried at 60 °C for 16 hours to give compound J (36.0 g, 45%). 1 H NMR(300MHz,DMSO) δ 8.19(s,1H),7.76(s,1H),7.45(d,J=2.8Hz,1H),5.14(p,J=3.7Hz,1H),3.5 3-3.44(m,1H),3.32-3.29(m,1H),2.33-2.20(m,2H),2.11-2.02(m,2H);MS ESI+:285.0[M+H] + .

[0114] To a solution of compound J (25.0 g, 1.0 equivalent) in DMSO (125 mL) at 25° C. was added NHOH (50% by weight in water, 14.5 g, 2.5 equivalents). The mixture was heated to 50° C. and stirred for 20 hours. The mixture was cooled to 0° C., and water (250 mL) and NaCl (100 g) were added. The mixture was stirred at 0° C. for 1 hour. The mixture was filtered, and the filter cake was washed with water (2×50 mL). The filter cake was dried at 60° C. for 16 hours to give compound K (21.6 g, 76%). 1 H NMR(400MHz,DMSO) δ 9.51(s,1H),7.47-7.42(m,3H),5.83(s,2H),5.01(p,J=3.7Hz,1H),3.45(ddd,J= 13.5,3.5,1.4Hz,1H),3.33-3.27(m,1H),2.36-2.17(m,2H),2.09-1.98(m,2H);MS ESI+:318.0[M+H] + .

[0115] To a solution of compound B (4.4 g, 1.0 equiv.) in DCM (50.0 mL) was added HATU (6.6 g, 1.1 equiv.) and compound K (1.0 equiv., 5.0 g) at 25±5° C. The mixture was stirred for 0.5 h. DIEA (4.1 g, 1.1 equiv.) was added, and the reaction mixture was stirred for 5 h. DMSO (30 mL) was added, and the mixture was partially concentrated. Water (100 mL) was added, and the mixture was stirred for 1 h. The mixture was filtered and washed with HO (2×10.0 mL). The filter cake was dried at 60° C. for 18 h to give compound L (8.3 g, 90% yield). 1 H NMR(400MHz,DMSO) δ 9.32(s,1H),9.05(s,1H),8.09(s,1H),8.03(s,1H),7.71(s,1H),7.46(s,1H),5.15(s,1H) ),3.52(d,J=13.5Hz,1H),3.38(d,J=13.3Hz,1H),2.36-2.24(m,2H),2.13-2.07(m,2H);MS ESI+:564.0[M+H] + .

[0116] To a solution of compound L (5.0 g, 1.0 equiv.) in DCM (30 mL) was added DBU (2.2 g, 2.0 equiv.) at 25° C. The reaction mixture was heated to 40° C. and stirred for 6 h. DMAc (100 mL) was added, and the mixture was partially concentrated at 45° C. Water (225.0 mL) was added dropwise, and the mixture was stirred for 1 h. The mixture was filtered, and the filter cake was washed with HO (2×10 mL). The filter cake was dried at 60° C. for 18 h to give compound 1 (4.3 g, 87%). 1 H NMR(300MHz,DMSO):9.32(t,J=1.5Hz,1H),9.05(s,1H),8.10(s,1H),8.04(d,J=1.6Hz,1H),7.71(s,1H),7.50-7. 43(m,1H),5.15(t,J=3.8Hz,1H),3.56-3.47(m,1H),3.40-3.35(m,1H),2.41-2.20(m,2H),2.15-2.05(m,2H).;MS ESI+:546.0[M+H] + .

[0117] Example 3: Synthesis of (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one acetate (Compound 1A)

[0118] [ka] Acetic acid (400 mL) and compound 1 (47.4 g) were heated at 95° C. for 1 hour. The mixture was cooled to 55° C. and filtered through activated charcoal. The activated charcoal was washed with acetic acid (2×100 mL) and partially concentrated. Heptane (900 mL) was added and the mixture was stirred at 55° C. for 1 hour. The mixture was cooled to 25° C. and stirred for 12 hours. The mixture was filtered and the filter cake was washed with heptane (2×250 mL). The filter cake was dried at 25° C. for 1 hour to give compound 1A (39.3 g, 71%). 1 H NMR(300MHz,DMSO):11.93(s,1H),9.34-9.29(m,1H),9.05(s,1H),8.10(s,1H),8.04(d,J=1.6Hz,1H),7.72(s,1H),7.47( MS ESI+:546.0[M+H] + .

[0119] Example 4: GTPγS binding assay Prepare S1P1 membranes from CHO-K1 Gαqi5 cells expressing full-length human S1P1. Membrane, GTPγ 35 Scintillation proximity assay (SPA) is performed by incubating S with various concentrations of compound for 60 minutes. Wheat germ agglutinin-coated SPA beads are added and incubated for 60 minutes, followed by centrifugation and scintillation counting. The EC50 of compound 1 is less than 1 μM.

[0120] The examples and embodiments described herein are for illustrative purposes only, and in some embodiments, various modifications or alterations are intended to fall within the scope of the disclosure and the appended claims.

Claims

1. 1. A process for (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one (compound 1), comprising: A) The following structure: 【Chemistry 1】 with HOBT and EDCI to give a compound having the following structure: 【Chemistry 2】 and producing a compound having the formula: B) Next, the following structure 【Transformation 3】 with cesium carbonate to give a compound having the following structure: 【Chemistry 4】 and producing (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one (compound 1), having the formula The process includes:

2. 1. A process for (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one (compound 1), comprising: A) The following structure: 【Transformation 5】 with potassium carbonate to give a compound having the following structure: 【Transformation 6】 and producing a compound having the formula: B) Next, the following structure 【Transformation 7】 reacting said compound having the structure 【Transformation 8】 and producing a compound having the formula: C) The following structure: 【Chemistry 9】 with HATU and DIEA to give the compound having the structure 【Chemistry 10】 and producing (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one (compound 1), having the formula The process includes:

3. 3. The process of claim 1 or claim 2, further comprising reacting (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one (Compound 1) with acetic acid to produce (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one acetate (Compound 1A).

4. (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one (Compound 1) 【Chemistry 11】 1. A process for preparing a compound having the following structure: 【Chemistry 12】 with a base in the presence of a solvent.

5. 5. The process of claim 4, wherein the base is selected from cesium carbonate, potassium carbonate, potassium phosphate, DBU, sodium t-butoxide, potassium t-butoxide, LiHMDS, NaHMDS, KHMDS, and mixtures thereof.

6. 6. The process of claim 4 or claim 5, wherein the base is cesium carbonate.

7. 6. The process of claim 4 or claim 5, wherein the base is a mixture of cesium carbonate and potassium phosphate.

8. 8. The process of any one of claims 4 to 7, wherein the solvent is selected from dimethylacetamide, cyclopentyl methyl ether, DMF, NMP, THF, MeTHF, acetonitrile, toluene, and mixtures thereof.

9. 9. The process of any one of claims 4 to 8, wherein the solvent is a mixture of dimethylacetamide and cyclopentyl methyl ether.

10. The following structure 【Chemistry 13】 The compound having the following structure: 【Chemistry 14】 10. The process of any one of claims 4 to 9, wherein the compound is prepared by a process comprising contacting a compound having the formula: with a coupling agent in the presence of a solvent.

11. 11. The process of claim 10, wherein the coupling agent is selected from HOBT and EDCI, thionyl chloride, oxalyl chloride, COMU (1-[(1-(cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylaminomorpholino)]uronium hexafluorophosphate), HBTU (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate), HCTU (O-(1H-6-chlorobenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate), TCFH (chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate), phenylboronic acid, silicon tetrachloride, and tetraethyl orthosilicate.

12. 12. The process of claim 10 or claim 11, wherein the coupling agents are HOBT and EDCI.

13. The process of any one of claims 10 to 12, wherein the solvent is selected from N-methyl-2-pyrrolidone, DMF, DMAc, toluene, MeTHF, and acetonitrile.

14. 9. The process of claim 7 or claim 8, wherein the solvent is N-methyl-2-pyrrolidone.

15. (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one (Compound 1) 【Chemistry 15】 1. A process for preparing a compound having the following structure: 【Chemistry 16】 with a coupling agent and a base in the presence of a solvent.

16. 16. The process of claim 15, wherein the coupling agent is selected from HATU, thionyl chloride, oxalyl chloride, COMU (1-[(1-(cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylaminomorpholino)]uronium hexafluorophosphate), HBTU (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate), HCTU (O-(1H-6-chlorobenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate), TCFH (chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate), phenylboronic acid, silicon tetrachloride, and tetraethyl orthosilicate.

17. 17. The process of claim 15 or claim 16, wherein the coupling agent is HATU.

18. 18. The process of any one of claims 15 to 17, wherein the base is selected from diisopropylethylamine, triethylamine, N-methylmorpholine, N-methylimidazole, and N-methylpiperidine.

19. 19. The process of any one of claims 15 to 18, wherein the base is diisopropylethylamine.

20. 20. The process of any one of claims 15 to 19, wherein the solvent is selected from dichloromethane, THF, MeTHF, acetonitrile, NMP, DMAc, DMF, and toluene.

21. The process of any one of claims 15 to 20, wherein the solvent is dichloromethane.

22. The following structure 【Chemistry 17】 The compound having the following structure: [Chemistry 18] 22. The process of any one of claims 15 to 21, wherein the compound is prepared by a process comprising contacting a compound having the formula: with hydroxylamine in the presence of a solvent.

23. 23. The process of claim 22, wherein the solvent is selected from dimethyl sulfoxide, DMF, DMAc, NMP, MeOH, EtOH, and 2-PrOH.

24. 24. The process of claim 22 or claim 23, wherein the solvent is dimethyl sulfoxide.

25. The following structure 【Chemistry 19】 The compound having the following structure: 【Chemistry 20】 25. The process of any one of claims 15 to 24, wherein the compound is prepared by a process comprising contacting a compound having the formula: with a base in the presence of a solvent.

26. 26. The process of claim 25, wherein the base is selected from potassium carbonate, DBU, sodium t-butoxide, potassium t-butoxide, LiHMDS, NaHMDS, and KHMDS.

27. 27. The process of claim 25 or claim 26, wherein the base is potassium carbonate.

28. 28. The process of any one of claims 25 to 27, wherein the solvent is selected from 2-butanone, DMF, DMAc, NMP, THF, and acetonitrile.

29. The process of any one of claims 25 to 28, wherein the solvent is 2-butanone.

30. The following structure 【Chemistry 21】 A compound having the formula:

31. The following structure 【Chemistry 22】 A compound having the formula:

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