Methods and processes for preparing MCT4 inhibitors

Abstract

Methods for preparing heterocyclic compounds and compositions useful as MCT4 inhibitors are provided.

Description

[0001] Disclosed herein are methods for preparing heterocyclic compounds and compositions useful as MCT4 inhibitors.

[0002] Lactate export from glycolytic cells is usually mediated by the monocarboxylate transporter MCT4. MCT4 exhibits a weak affinity for lactate (K m =28mM) and a high turnover rate enable rapid export of large amounts of lactate. MCT4 expression is usually limited to highly glycolytic tissues, such as white muscle fibers, lymphocytes, astrocytes, and supporting cells (Sertoli cells). Although MCT4 is not present in most normal tissues, it is highly upregulated in many cancer indications (including colorectal cancer, glioma, head and neck cancer, triple-negative breast cancer, prostate cancer, KRAS mutant lung cancer, liver cancer, and kidney cancer) and is associated with poor survival.

[0003] The correlation between MCT4 expression and adverse cancer outcomes appears to have important functional implications in multiple cancer models. In a respiratory-impaired, Ras-transformed fibroblast xenograft model, stable expression of MCT4 is highly tumorigenic. Conversely, MCT4 silencing slows or abolishes tumor growth in xenograft models of breast cancer, colorectal cancer, and glioma. In breast cancer and colon cancer xenograft models, MCT4 expression is required for angiogenesis mediated by the inflammatory cytokine IL-8. MCT4 has also been shown to play an important role in cancer cell migration, invasion, and various aspects of the Warburg effect (e.g., surges on glucose, extracellular acidification, and lactate secretion).

[0004] Inhibition of MCT4-mediated lactate export may be an effective strategy to attenuate the Warburg effect in cancer. Unfortunately, potent and selective MCT4 inhibitors have not yet been described. Moderate to weak MCT4 inhibitors are known (e.g., phloretin and α-CN-4-OH-cinnamate); however, these compounds promiscuously inhibit many other transporters, including MCT1.

[0005] For example, novel potent MCT4 inhibitors are described in WO 2016 / 201426, the contents of which are incorporated herein by reference in their entirety. Compound 2-([1-[2-(azetidin-1-yl)phenyl]-5-(3-cyclobutyloxyphenyl)-1H-pyrazol-3-yl]methoxy)-2-methylpropionic acid and related compounds thereof have been described in WO 2018 / 111904 as MCT4 inhibitors with good potential, the contents of which are incorporated herein by reference in their entirety.

[0006] There is a need for new and improved methods for the synthesis of 2-([1-[2-(azetidin-1-yl)phenyl]-5-(3-cyclobutyloxyphenyl)-1H-pyrazol-3-yl]methoxy)-2-methylpropanoic acid and related compounds that are amenable to large-scale synthesis.

[0007] The citation of any reference in this application shall not be construed as an admission that such reference is prior art to the present application. Summary of the invention

[0008] Provided is a method for preparing a compound of formula I or a salt thereof,

[0009]

[0010] The method comprises the following steps:

[0011] i) reacting a compound of formula II in the presence of a non-nucleophilic base in a polar aprotic solvent

[0012]

[0013] Contacting with a compound of formula III

[0014]

[0015] to prepare a compound of formula IV; and

[0016]

[0017] ii) hydrolyzing a compound of formula IV to prepare a compound of formula I or a salt thereof, wherein:

[0018] R 1 is a C1-C4 alkyl group; and

[0019] R 2 It is a halogen.

[0020] Also provided is a compound of formula

[0021] The compound

[0022] wherein the compound contains a detectable amount of one or more residual organic solvents of less than 3% by weight.

[0023] A formula is also provided

[0024] or a salt thereof.

[0025] A formula is also provided

[0026] or a salt thereof.

[0027] Also provided herein is a method for treating a disorder mediated by the monocarboxylate transporter MCT4 in a subject in need thereof, the method comprising the step of administering to the subject a therapeutically effective amount of a compound or salt thereof described herein, or a composition described herein.

[0028] These and other aspects of the invention disclosed herein will be set forth in greater detail as the patent publication proceeds. DETAILED DESCRIPTION

[0029] Provided is a method for preparing a compound of formula I or a salt thereof,

[0030]

[0031] The method comprises the following steps:

[0032] i) reacting a compound of formula II in the presence of a non-nucleophilic base in a polar aprotic solvent

[0033]

[0034] Contacting with a compound of formula III

[0035]

[0036] to prepare a compound of formula IV; and

[0037]

[0038] ii) hydrolyzing a compound of formula IV to prepare a compound of formula I or a salt thereof, wherein:

[0039] R 1 is a C1-C4 alkyl group; and

[0040] R 2 It is a halogen.

[0041] In some embodiments, R 1 is isopropyl, R 2 For bromine.

[0042] In some embodiments, the molar ratio of the compound of Formula III to the compound of Formula II is from about 7.0 to about 10.0.

[0043] In some embodiments, the non-nucleophilic base is selected from N,N-diisopropylethylamine (DIPEA), 8-diazabicycloundec-7-ene (DBU), 1,5-diazabicyclo(4.3.0)non-5-ene (DBN), 2,6-di-tert-butylpyridine, tert-butyllithium, tert-butylphosphazene, lithium diisopropylamide (LDA), sodium bis(trimethylsilyl)amide (NaHMDS), potassium tert-butoxide, potassium bis(trimethylsilyl)amide (KHMDS), lithium tetramethylpiperidinium (LiTMP), sodium hydride, potassium hydride and sodium tert-butoxide. In some embodiments, the non-nucleophilic base is potassium bis(trimethylsilyl)amide (KHMDS).

[0044] In some embodiments, the molar ratio of KHMDS to the compound of Formula II is from about 4.0 to about 6.0.

[0045] In some embodiments, the polar aprotic solvent is selected from acetone, acetonitrile, dichloromethane, dimethyl sulfoxide (DMSO), dimethylformamide (DMF), ethyl acetate, hexamethylphosphoric triamide (HMPT), pyridine, tetrahydrofuran (THF), and mixtures thereof.

[0046] In some embodiments, the polar aprotic solvent is a mixture of THF and DMF.

[0047] In some embodiments, hydrolyzing the compound of Formula IV comprises reacting the compound of Formula IV with a nucleophilic base.

[0048] In some embodiments, the nucleophilic base is selected from sodium hydroxide and sodium methoxide.

[0049] In some embodiments, the molar ratio of the nucleophilic base to the compound of Formula IV is from about 18.0 to about 20.0.

[0050] In some embodiments, wherein the compound of formula V is prepared in the presence of a palladium catalyst by reacting:

[0051]

[0052] The compound of formula II is prepared by contacting with azetidine, wherein R 3 It is a halogen.

[0053] In some embodiments, R 3 For bromine.

[0054] In some embodiments, the molar ratio of azetidine to the compound of Formula V is from about 2.0 to about 3.0.

[0055] In some embodiments, the molar ratio of the palladium catalyst to the compound of Formula V is from about 0.05 to about 0.15.

[0056] In some embodiments, the palladium catalyst is selected from Pd(OAc)2, palladium(II) pivalate, tetrakis(triphenylphosphine)palladium(0), bis(acetonitrile)palladium(II) dichloride, bis(triphenylphosphine)palladium(II) dichloride, [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride, tris(dibenzylideneacetone)dipalladium(0) and palladium(II) chloride.

[0057] In some embodiments, the palladium catalyst is Pd(OAc)2.

[0058] In some embodiments, the contacting is performed in the presence of a ligand.

[0059] In some embodiments, the ligand is selected from trimethylphosphine, triphenylphosphine, tricyclohexylphosphine, tri(o-tolyl)phosphine, 2-(dicyclohexylphosphine)-2',4',6'-triisopropyl-1,1'-biphenyl (XPhos), 2-(dicyclohexylphosphine)-2'-(N,N-dimethylamino)biphenyl, 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl, 2-dicyclohexylphosphine-2',6'-dimethoxy-1,1'-biphenyl, butyldi-1-adamantylphosphine, 2-(di-tert-butylphosphine)biphenyl, 2-(dicyclohexylphosphine)biphenyl, (R)-(-)-1-[(S)-2-(diphenylphosphine)biphenyl, phosphine) ferrocene] ethyldicyclohexylphosphine, 1,2-bis(diphenylphosphino)benzene (dppbenzene), 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (BINAP), bis(2-diphenylphosphinophenyl) ether (DPEphos), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos), 1,4-bis(diphenylphosphino)butane (dppb), 1,2-bis(diphenylphosphino)ethane (dppe), 1,1'-bis(diphenylphosphino)ferrocene (dppf), 1,3-bis(diphenylphosphino)propane (dppp), and [(t-Bu3)PH]BF4.

[0060] In some embodiments, the ligand is Xantphos.

[0061] In some embodiments, the molar ratio of ligand to compound of Formula V is from about 0.05 to about 0.15.

[0062] In some embodiments, by making the compound of formula VI

[0063]

[0064] With a compound of formula VII:

[0065]

[0066] contacting to form a compound of Formula VIII:

[0067]

[0068] and then contacting the compound of formula VIII with a reducing agent to produce a compound of formula V to prepare a compound of formula V, wherein R 3 It is a halogen.

[0069] In some embodiments, the reducing agent is selected from lithium aluminum hydride, sodium bis(2-methoxyethoxy)aluminum hydride (Red-Al), nascent hydrogen, sodium amalgam, zinc amalgam, sodium borohydride, lithium borohydride, SmI2, Fe-containing 2+ Ionic compounds, containing Sn 2+ Ionic compounds, hydrazine, diisobutylaluminum hydride and any combination thereof.

[0070] In some embodiments, the reducing agent is sodium borohydride.

[0071] In some embodiments, the reaction is carried out by reacting 1-(3-hydroxyphenyl)ethan-1-one with a compound of Formula IX in the presence of a non-nucleophilic base in a polar aprotic solvent:

[0072]

[0073] The compound of formula VI is prepared by contacting with dimethyl oxalate and a strong base to produce a compound of formula VII, wherein R 4 Selected from halogen.

[0074] In some embodiments, the polar aprotic solvent is selected from acetone, acetonitrile, dichloromethane, dimethyl sulfoxide (DMSO), dimethylformamide (DMF), ethyl acetate, hexamethylphosphoric triamide (HMPT), pyridine, tetrahydrofuran (THF), and mixtures thereof.

[0075] In some embodiments, the non-nucleophilic base is selected from cesium carbonate, sodium carbonate, and potassium carbonate.

[0076] In some embodiments, the strong base is selected from sodium hydroxide, sodium methoxide, sodium ethoxide, lithium diisopropylamide (LDA), sodium bis(trimethylsilyl)amide (NaHMDS), potassium tert-butoxide, potassium bis(trimethylsilyl)amide (KHMDS), lithium tetramethylpiperidinium (LiTMP), sodium hydride, potassium hydride and sodium tert-butoxide.

[0077] In some embodiments, the molar ratio of the non-nucleophilic base to 1-(3-hydroxyphenyl)ethan-1-one is from about 1.0 to about 2.0.

[0078] In some embodiments, the method further comprises converting the compound of formula I into

[0079] The tris (hydroxymethyl) aminomethane (tris) salt.

[0080] Also provided is a tris salt prepared by the method described herein.

[0081] Also provided is a compound of formula

[0082] The compound

[0083] The compound contains a detectable amount, and in some embodiments, less than 3% by weight, of residual organic solvent.

[0084] Also provided is a composition comprising at least 90%, such as at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or at least 99.5% of a compound of formula I or a salt thereof and a detectable amount of one or more impurities selected from a compound of formula IV, a compound of formula II, a compound of formula V, a compound of formula VIII, 1-(3-hydroxyphenyl)ethan-1-one, bromocyclobutane, cesium carbonate, hydrochloric acid, 2-bromophenylhydrazine, sodium borohydride, xan tphos, sodium tert-butoxide, isopropyl 2-bromo-2-methylpropionate, potassium bis(trimethylsilyl)amide, sodium hydroxide, sodium hydride, sodium tert-amyloxide, acetonitrile, dichloromethane, 4-dimethylaminopyridine, ethyl acetate, dimethylformamide, ethanol, water, isopropanol, isopropyl acetate, potassium bis(trimethylsilyl)amide, methanol, methyl tert-butyl ether, sodium borohydride, N-methyl-2-pyrrolidone, palladium diacetate, sodium triacetoxyborohydride, tetrahydrofuran and one or more heavy metals.

[0085] In some embodiments, the one or more heavy metals are selected from platinum, palladium, iridium, rhodium, rhenium, ruthenium, cadmium, mercury, lead, arsenic, manganese, chromium, cobalt, nickel, copper, zinc, selenium, silver, antimony, thallium, nickel, vanadium, and zinc.

[0086] Also provided herein is a method for treating a monocarboxylate transporter MCT4-mediated disorder in a subject in need thereof, the method comprising the step of administering to the subject a therapeutically effective amount of a compound described herein or a composition described herein.

[0087] In some embodiments, the monocarboxylate transporter MCT4-mediated disorder is cardiac hypertrophy.

[0088] In some embodiments, the monocarboxylate transporter MCT4-mediated disorder is heart failure.

[0089] In some embodiments, the monocarboxylate transporter MCT4-mediated disorder is a cancer expressing MCT4.

[0090] In some embodiments, the monocarboxylate transporter MCT4-mediated disorder is rheumatoid arthritis.

[0091] A formula is also provided

[0092] or a salt thereof.

[0093] A formula is also provided

[0094] or a salt thereof.

[0095] To facilitate understanding of the present disclosure, some terms and abbreviations used herein are defined as follows:

[0096] When introducing elements of the present disclosure or preferred embodiments thereof, the articles "a," "an," "the," and "said" are intended to mean that there are one or more elements. The terms "comprising," "including," and "having" are intended to be inclusive and mean that there are additional elements other than the listed elements.

[0097] When the term "and / or" is used in a list of two or more items, it means that any of the listed items can be used alone or in combination with one or more of the listed items. For example, the expression "A and / or B" is intended to mean either or both of A and B, i.e., A alone, B alone, or a combination of A and B. The expression "A, B, and / or C" is intended to mean A alone, B alone, C alone, a combination of A and B, a combination of A and C, a combination of B and C, or a combination of A, B, and C.

[0098] As used herein, the term "about" when referring to a measurable value, such as an amount of a compound, dosage, time, temperature, etc., is intended to encompass variations of 20%, 10%, 5%, 1%, 0.5% or even 0.1% from the specified amount.

[0099] When a numerical range is disclosed, the notation "n1 ... to n2" or "between n1 ... and n2" is used, where n1 and n2 are numbers, and unless otherwise specified, the notation is intended to include the numbers themselves and the range between them. The range may be a complete or continuous range between and including the end values. For example, the range "2 to 6 carbons" is intended to include two carbons, three carbons, four carbons, five carbons, and six carbons, because carbon appears in integer units. In contrast, for example, the range "1 to 3 μM (micromolar)" is intended to include 1 μM, 3 μM, and any significant number between the two (e.g., 1.255 μM, 2.1 μM, 2.9999 μM, etc.).

[0100] The term "alkyl" used herein, alone or in combination, refers to a straight or branched alkyl containing 1 to 20 carbon atoms. In certain embodiments, the alkyl will contain 1 to 10 carbon atoms. In further embodiments, the alkyl will contain 1 to 6 carbon atoms. The alkyl can be optionally substituted as defined herein. Examples of alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, octyl, nonyl, etc. The term "alkylene" used herein, alone or in combination, refers to a saturated aliphatic group derived from a straight or branched saturated hydrocarbon connected at two or more positions, such as methylene (-CH2-). Unless otherwise specified, the term "alkyl" may include an "alkylene" group.

[0101] The term "halogen," as used herein, alone or in combination, refers to fluorine, chlorine, bromine or iodine.

[0102] The term "non-nucleophilic base" used herein refers to a sterically hindered organic base, which is a weak nucleophilic agent. Examples of non-nucleophilic bases include N, N-diisopropylethylamine (DIPEA), 8-diazabicycloundec-7-ene (DBU), 1,5-diazabicyclo (4.3.0) non-5-ene (DBN), 2,6-di-tert-butylpyridine, tert-butyllithium, tert-butylphosphazene, lithium diisopropylamide (LDA), bis(trimethylsilyl) sodium amide (NaHMDS), potassium tert-butoxide, bis(trimethylsilyl) potassium amide (KHMDS), lithium tetramethylpiperidinium (LiTMP), sodium hydride, potassium hydride, sodium tert-butoxide, and potassium tert-butoxide. In certain embodiments, the non-nucleophilic base is potassium bis(trimethylsilyl) amide (KHMDS).

[0103] As used herein, the term "nucleophilic base" refers to a Bronsted-Lowry base that is a good nucleophile. Examples include sodium methoxide, methyllithium, sodium hydroxide, lithium hydroxide, sodium cyanide, potassium cyanide, sodium acetylide, sodium amide, sodium iodide, lithium bromide, potassium iodide, and sodium azide.

[0104] As used herein, the term "polar solvent" refers to a solvent having a large dipole moment.

[0105] The term "polar aprotic solvent" as used herein refers to a polar solvent lacking an acidic hydrogen. Therefore, they are not hydrogen bond donors. Examples of polar aprotic solvents include acetone, acetonitrile, dichloromethane, dimethyl sulfoxide (DMSO), dimethylformamide (DMF), ethyl acetate, hexamethylphosphoric triamide (HMPT), pyridine, tetrahydrofuran (THF). In certain embodiments, the polar aprotic solvent is a combination of THF, DMF, or THF and DMF.

[0106] As used herein, the term "disease" is generally intended to be synonymous with, and used interchangeably with, the terms "disorder" and "condition" (e.g., medical condition), all of which reflect an abnormal condition of the human or animal body or a part thereof that impairs normal function, which is usually manifested by distinctive signs and symptoms and results in a shortened life span or reduced quality of life for the human or animal.

[0107] The compounds disclosed herein may exist as therapeutically acceptable salts. The present invention includes the above compounds in salt form, including acid addition salts. Suitable salts include those formed with organic acids and inorganic acids. Such acid addition salts are generally pharmaceutically acceptable. However, non-pharmaceutically acceptable salts may be useful in the preparation and purification of the compounds in question. Base addition salts may also be formed and are pharmaceutically acceptable.

[0108] The term "therapeutically acceptable salt" as used herein means a salt or zwitterionic form of a compound disclosed herein that is water-soluble or oil-soluble or dispersible and is therapeutically acceptable as defined herein. Salts can be prepared during the final separation and purification of the compound, or prepared separately by reacting the appropriate compound in the form of a free base with a suitable acid. Representative acid addition salts include acetate, adipate, alginate, L-ascorbate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, citrate, digluconate, formate, fumarate, gentisate, glutarate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate (hydroxyethyl sulfonate), lactate, maleate Quaternary ammonium salts include quaternary ammonium salts, ... Examples of acids that can be used to form therapeutically acceptable addition salts include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid, and organic acids such as oxalic acid, maleic acid, succinic acid and citric acid. Salts can also be formed by coordination of compounds with alkali metal or alkaline earth metal ions. Therefore, the present invention contemplates sodium salts, potassium salts, magnesium salts and calcium salts of the compounds disclosed herein, etc.

[0109] In the final separation and purification process of the compound, base addition salts can be prepared by the reaction of a carboxyl group with a suitable base, such as a hydroxide, carbonate or bicarbonate of a metal cation or with ammonia or an organic primary amine, secondary amine or tertiary amine. The cation of the therapeutically acceptable salt includes lithium, sodium, potassium, calcium, magnesium and aluminum, and nontoxic quaternary ammonium cations, such as ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, dicyclohexylamine, procaine, dibenzylamine, N, N-dibenzylphenethylamine, 1-ephedrine (1-ephenamine) and N, N'-dibenzylethylenediamine. Other representative organic amines that can be used to form base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine and piperazine.

[0110] Salts of the compounds can be prepared by reaction of the free base form of the appropriate compound with an appropriate acid.

[0111] The compounds disclosed herein may exist in polymorphs and other different solid forms, such as solvates, hydrates, etc. The compound may be a polymorph, solvate or hydrate of a salt or a free base or a free acid.

[0112] In some embodiments, the method also includes formulating the product and / or its salt as a pharmaceutical composition. The pharmaceutical composition may include one or more pharmaceutically acceptable carriers. The pharmaceutical composition may be administered orally. The pharmaceutical composition may be delivered orally using tablets, lozenges, liquids, emulsions, suspensions, drops, capsules, caplets or gel caps, or may be delivered orally using other oral administration methods known to those skilled in the art. Excipients suitable for pharmaceutical compositions include one or more fillers, binders, surfactants, glidants, lubricants, disintegrants, expanders and antioxidants.

[0113] As used herein, the term "detectable" refers to a measurable amount as determined using an HPLC method having a detection limit of 0.01 area %.

[0114] As used herein, the term "non-detectable" in relation to the amount of an impurity means not detected by the HPLC method described herein having a detection limit of 0.01 area % for the impurity.

[0115] As used herein, "limit of detection (LOD)" or "limit of detection" refers to the lowest concentration of analyte that can be clearly detected above a baseline signal, which is approximately three times the baseline signal noise.

[0116] Fillers include, but are not limited to, lactose, sucrose, glucose, starch, microcrystalline cellulose, microfine cellulose, mannitol, sorbitol, calcium hydrogen phosphate, aluminum silicate, amorphous silicon dioxide, sodium chloride, starch, and calcium hydrogen phosphate dihydrate. In one embodiment, the filler is water-insoluble, although it can absorb water. In one embodiment, the filler is a spheronization aid. Spheronization aids can include one or more of cross-linked polyvinylpyrrolidone, carrageenan, chitosan, pectin acid, glyceride, beta-cyclodextrin (β-CD), cellulose derivatives, microcrystalline cellulose, powdered cellulose, cross-linked polyvinylpyrrolidone, and polyethylene oxide.

[0117] Binders include, but are not limited to, cellulose ethers, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, propyl cellulose, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, hydroxypropyl methyl cellulose (hydroxypropyl methyl cellulose, such as hydroxypropyl methyl cellulose 2910, Methocel TME), carboxymethyl cellulose, starch, pregelatinized starch, gum arabic, gum tragacanth, gelatin, polyvinyl pyrrolidone (povidone), cross-linked polyvinyl pyrrolidone, sodium alginate, microcrystalline cellulose and low alkyl substituted hydroxypropyl cellulose. In one embodiment, the binder is selected from a wet binder.

[0118] Surfactants include, but are not limited to, anionic surfactants, including sodium lauryl sulfate, sodium deoxycholate, dioctyl sodium sulfosuccinate, and sodium stearyl fumarate, nonionic surfactants, including polyoxyethylene ethers and polysorbate 80, and cationic surfactants, including quaternary ammonium compounds. In one embodiment, the surfactant is selected from anionic surfactants, such as sodium lauryl sulfate.

[0119] Disintegrants include, but are not limited to, starch, cross-linked sodium carboxymethylcellulose, sodium carboxymethylcellulose, calcium carboxymethylcellulose, cross-linked polyvinyl pyrrolidone, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, and hydroxypropyl starch.

[0120] Glidants include, but are not limited to, polyethylene glycol of various molecular weights, magnesium stearate, calcium stearate, calcium silicate, fumed silica, magnesium carbonate, magnesium lauryl sulfate, aluminum stearate, stearic acid, palmitic acid, cetyl alcohol, stearyl alcohol, and talc.

[0121] Lubricants include, but are not limited to, stearic acid, magnesium stearate, calcium stearate, aluminum stearate, and siliconized talc.

[0122] In certain embodiments, the formulation further comprises one or more antioxidants. Examples of pharmaceutically acceptable antioxidants include: (1) water-soluble antioxidants, such as ascorbic acid, cysteine ​​hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, etc.; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, α-tocopherol, etc.; and (3) metal chelators, such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, etc.

[0123] method

[0124] General synthetic methods for preparing compounds

[0125] The present invention is further illustrated by the following examples.

[0126] In the following examples and throughout the disclosure, the following abbreviations may be used: DMF = dimethylformamide; KHMDS = potassium bis(trimethylsilyl)amide; MTBE = methyl tert-butyl ether; TBME = tert-butyl methyl ether; NMP = N-methyl-2-pyrrolidone; THF = tetrahydrofuran;1 H-NMR = proton nuclear magnetic resonance; ICP = inductively coupled plasma mass spectrometry; IPC = process control / checkout. Other abbreviations may be used and will be familiar to those skilled in the art.

[0127] Example 1: Synthesis of 2-([1-[2-(azetidin-1-yl)phenyl]-5-(3-cyclobutyloxyphenyl)-1H-pyrazol-3-yl]methoxy)-2-methylpropanoic acid

[0128] 1. Synthesis of Compound 7

[0129] Compound 7 was synthesized by the method of Scheme 1.

[0130] Solution 1

[0131]

[0132]

[0133] Step 1:

[0134]

[0135] A mixture of 1-(3-hydroxyphenyl)ethan-1-one (20 kg), bromocyclobutane (1.3 eq.) and CsCO (1.5 eq.) was stirred in DMF (5 vol.) at 80 ± 5 °C for 16 h. Water (15 vol.) and methyl tert-butyl ether (MTBE, 15 vol.) were added to the reaction vessel. The organic layer was separated and washed twice with 20% brine (5 vol.), then concentrated to about 5 vol., and then solvent exchanged three times with methanol to about 5 vol. The crude methanol solution containing compound 1 was used in the next step without further purification.

[0136] Step 2:

[0137]

[0138] Sodium methoxide (2.0 eq.) and dimethyl oxalate (1.5 eq.) were added to the crude methanol solution (5 vol.) of step 1. The reaction vessel was stirred at 30 ± 5 °C for 16 hours. Upon completion, the reaction mixture was cooled to a temperature of 0-10 °C. The pH was adjusted to 2-3 with 4.0 M HCl in methanol, and the crude solution containing compound 2 was used in the next step without further purification.

[0139] Step 3:

[0140]

[0141] 2-Bromophenylhydrazine hydrochloride (1.0 equiv) was added to the reaction vessel containing the crude methanol solution of step 2. The reaction mixture was then stirred at 60±5°C for 10 hours and then cooled to 5-15°C. The resulting solid was filtered, washed with methanol (1 volume), and then slurried with water (20 volumes). The solid was filtered again and further washed with water (2 volumes). The product was dried in an oven at 50°C to give 54.9 kg of compound 3 (88% yield for steps 1-3).

[0142] Step 4:

[0143]

[0144] Compound 3 (4.0 kg; 1.0 eq) was added to THF (4 volumes), and methanol (0.4 volumes) was further added to the reaction vessel, which was then cooled to 10-25°C. Sodium borohydride (1.2 eq) was added, and the reaction was stirred at 10-25°C for 16 hours. Upon completion, the reaction was cooled to 0-10°C, and the pH was adjusted to 3-5 with 0.5M HCl, at which point the product precipitated from the solution. The mixture was stirred at 5-15°C for an additional 1-2 hours. The product was collected by filtration, washed with water, and dried in an oven at 50°C to give 3.5 kg of compound 4 in 85% yield.

[0145] Step 4 was repeated at a 5-fold scale, where compound 3 (20.0 kg; 1.0 eq) was added to THF (6.0 vols), and methanol (0.4 vols) was further added to the reaction vessel, which was then cooled to 25±5°C. Sodium borohydride (1.2 eq) was added and the reaction was stirred at 25±5°C for 16 hours. Upon completion, the reaction was cooled to 0-10°C and the pH was adjusted to 3-5 with 0.5M HCl, at which point the product precipitated from the solution. The mixture was stirred at 5-15°C for an additional 1-2 hours. The product was collected by filtration, washed with water, and dried in an oven at 50°C to give 18.2 kg of compound 4 with a purity of 99.4% and an isolated yield of 97%.

[0146] Step 5:

[0147]

[0148] Under nitrogen atmosphere, compound 4 (2.97 kg; 1.0 eq) was added to THF (10 vol) with stirring. Xantphos (0.11 eq), Pd(OAc)2 (0.11 eq) and t-BuONa (2.0 eq) were added to the reaction vessel. Azetidine (2.5 eq) was added and the resulting mixture was stirred at 25-35°C for 20 hours. MTBE (20 vol) and water (20 vol) were added to the vessel. The organic layer was separated and washed with 5% aqueous NH4Cl and 5% aqueous NaCl, then filtered through The resulting organic layer was concentrated and then solvent switched with ethyl acetate (10 volumes). The resulting solution was stirred at 70-80°C for 303 minutes, then cooled to 15-20°C and stirred for another 1-2 hours. The solid was collected by filtration, washed with ethyl acetate (0.5 volumes), and dried in an oven at 50°C to give 1.7 kg of compound 5 in 60% yield. When re-made with 18.0 kg of compound 4, 10.8 kg of compound 5 was obtained with a purity of 98.8% and an isolated yield of 63.8%.

[0149] Step 6:

[0150]

[0151] To a solution of compound 5 (700.0 g, 1 eq.) in DMF (8 vol.) was added isopropyl 2-bromo-2-methylpropanoate (8.0 eq.). The reaction mixture was cooled to -60°C to -50°C using liquid nitrogen. A THF solution of potassium bis(trimethylsilyl)amide (KHMDS, 5.0 eq.) was added dropwise over 1.5 hours; the reaction was then stirred for 30-50 minutes. Water (10 vol.) was added to the reaction vessel. The organic phase was collected, washed twice with NaCl (15%) (5 vol.), and then concentrated. The crude compound 6 (70% yield) was used directly in the next step without further purification.

[0152] Step 7:

[0153]

[0154] To the reaction vessel was added crude compound 6 from step 6 (1950.0 g, 1 eq), 30% aqueous NaOH (10 vol, 20 eq) and methanol (5 vol). The reaction was stirred at 50±5°C for 16 hours and then cooled to 15-30°C. The solution was washed twice with MTBE (10 vol) and the aqueous layer was separated and filtered. Filter. Use 2.0M HCl to adjust the pH of the obtained aqueous phase to 3-5. The solution is cooled to 5-10 ° C, stirred for 2-3 hours, and then filtered. The filter cake is dissolved in THF (10 volumes), and mercapto silica gel (300g, 15 weight %) is then added to the solution. The resulting mixture is heated to 50-60 ° C, stirred for 3 hours, and then filtered. The solution is concentrated, and the crude product is then dissolved in ethyl acetate (10 volumes). The resulting solution is heated to 70-80 ° C, stirred for 3-4 hours, and then cooled to 0-10 ° C. The solid is collected by filtration, washed with ethyl acetate (0.5 volume), and then dried in an oven at 50 ° C to obtain off-white solid compound 7 (1.4kg, yield 58%).

[0155] The reaction was repeated on a larger scale, and crude compound 6 (8.4 kg, 1 equivalent) from step 6, 30% aqueous KOH solution (10 volumes, 20 equivalents) and methanol (5 volumes) were added to the reaction vessel. Following the same steps as above, 8.76 kg of compound 7 was obtained over two steps with a purity of 97.7% and a yield of 67%.

[0156] 2. Use different propionates in step 6

[0157] Variations of the propionate ester in step 6 were explored. The results are shown in Table 1.

[0158]

[0159] Table 1.

[0160]

[0161]

[0162] * In addition, 13.4% of dimer byproduct was detected after the reaction was completed.

[0163] As shown in Table 1, the starting material with the isopropyl ester outperformed the tert-butyl and methyl esters. In addition, the use of the isopropyl ester limited the potential formation of dimer (or bis-adduct) byproducts, which were detected when the methyl ester was used in Run 13. The use of the isopropyl ester also allowed the use of solvents other than DMF / NaH. The reaction also proceeded much faster than with DMF / NaH.

[0164] 3. Formation of tris salt of compound 7

[0165]

[0166] Compound 7 (8.4 kg, 1 eq) was added to a reaction vessel with THF (42 L, 5.0 vols), mercapto silica gel (420 g, 5 wt%) was added, stirred and heated at 50-60°C for 3 hours. The reaction mixture was sampled and concentrated, and ICP analysis was performed to determine the residual Pd concentration (~15 ppm). The reaction mixture was filtered, and acetone (168 L, 20.0 vols) and an aqueous solution of tris(hydroxymethyl)aminomethane ("tris salt", 1.01 eq) (4.2 L, 0.5 vols) were added. The reaction mixture was stirred at 20-30°C for 5-10 minutes to dissolve most of the solids, and then continued to stir at 20-30°C for about 20 hours to precipitate the tris salt of compound 7. The precipitate was collected, washed with acetone (4.2 L, 0.5 vol), and dried under vacuum at 60 °C to afford 8.4 kg of tris salt of compound 7 with 99.5% purity and 79.2% yield, with 1690 ppm residual acetone and 962 ppm residual THF.

[0167] Example 2: Pharmacokinetic test

[0168] The tris salt and free acid of the compound of Formula I were tested in two animal models to evaluate pharmacokinetic parameters.

[0169] Rat Model

[0170] Grouping, dosage and collection. The pharmacokinetics of the free acid and tris salt of the compound of formula I were evaluated by oral gavage in male Sprague-Dawley rats. Three rats in each group were administered 20, 60 or 200 mg of free acid or 25, 75 or 250 mg of 0.5% methylcellulose in saline before the mouth, with a final concentration of 2, 6 or 20 mg / mL free acid or 2.5, 7.5 or 20 mg / mL. Plasma was collected by jugular vein at 5 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours and 24 hours after administration. No abnormal clinical symptoms were observed.

[0171] Preparation of stock solutions and dosing solutions. Stock solutions were prepared by dissolving 2.47 mg of the compound of Formula I (free acid) in 2.470 mL DMSO and vortexing to obtain a 1 mg / mL free acid solution, or 2.09 mg of the tris salt in 1.655 mL DMSO and vortexing to obtain a 1 mg / mL tris salt solution. Dosing solutions were prepared by vortexing / sonicating the following solids in the solvent:

[0172] Table 2. Preparation of dosing solutions

[0173]

[0174] LC MS-MS Analysis. Liquid chromatography tandem mass spectrometry was used to determine the plasma concentrations of the free acid of the compound of Formula I and the tris salt of the compound of Formula I in plasma samples collected at the specified time points.

[0175] By diluting the stock solution of the analyte with 50% acetonitrile in water, a working solution of appropriate serial concentrations was achieved. 5 μL of working solution (10, 20, 50, 100, 500, 1000, 5000, 8000, 10000 ng / mL) was added to 50 μL of blank male SD rat plasma to achieve a calibration standard of 1 to 1000 ng / mL (1, 2, 5, 10, 50, 100, 500, 800, 1000 ng / mL) with a total volume of 55 μL. Five plasma quality control (QC) samples of 2 ng / mL, 5 ng / mL, 10 ng / mL, 50 ng / mL and 800 ng / mL were prepared independently of the samples used for the calibration curve. These QC samples were prepared in the same manner as the calibration standards on the day of analysis. 55 μL of standard, 55 μL of QC sample and 55 μL of unknown sample (50 μL of plasma / blood and 5 μL of blank solution) were added to 200 μL of methanol containing internal standard (dexamethasone) mixture to precipitate protein and vortexed for 30 seconds. After centrifugation at 4°C and 4000 rpm for 15 minutes, the supernatant was diluted with water at a ratio of 1:2. 2 μL of supernatant was injected into the LC / MS / MS system for quantitative analysis.

[0176] The instruments included a HALO 90A C18 2.7 μm 2.1×50 mm HPLC column, a Prominence degasser DGU-20A5R(C), a Shimadzu LC-30AD liquid chromatograph with a communication bus module CBM-20A and Auto SIL-20AC HT; and an AB Sciex Triple Quad 5500 LC / MS / MS instrument. The following conditions were used:

[0177] Mobile phase solution A: 5% acetonitrile in water (0.1% formic acid)

[0178] Solution B: 95% acetonitrile in water (0.1% formic acid)

[0179] gradient

[0180]

[0181] Results The results are shown in Table 3 (free acid) and Table 4 (tris salt) below. Note that since the molecular weight of the tris salt (FW=582.7) is higher than the free acid (MW=461.6), the appropriate comparison is between 20 mg / kg free acid and 25 mg / kg tris salt. Overall, the total drug exposure (AUC last and AUC Inf ) were higher than the free acid group. The maximum exposure level (C 最大 ) were also higher than the free acid group, except for the 20 / 25 mg / kg females, in which the free acid C 最大 (78883ng / mL) slightly higher than tris salt C 最大 (68567ng / mL). Overall, exposures were higher in female subjects than in male subjects.

[0182] Table 3. PK parameters, free acid

[0183]

[0184] Table 4. PK parameters, tris salt

[0185]

[0186] Dog Model

[0187] Grouping, dosage and collection. The free acid and tris salt of the compound of formula I were administered orally in dogs to evaluate pharmacokinetics. Three male beagles received a single dose of 3 mg / kg free acid on the 1st day of the study and a single dose of 3 mg / kg tris salt on the 8th day of the study. Plasma was collected by puncturing a peripheral vein before administration and 0.5, 1, 2, 4, 8, 12 and 24 hours after administration. No abnormal clinical symptoms were observed.

[0188] In a subsequent study, the pharmacokinetics of the tris salt of the compound of formula I was studied by oral gavage of a saline formulation of 0.5% methylcellulose. Two groups of animals were tested. In Group 1, three male beagles received a single dose of 3 mg / kg tris salt. In Group 2, three male beagles received a single dose of 30 mg / kg tris salt. Plasma was collected by puncturing a peripheral vein before and 0.5, 1, 2, 4, 8, 12 and 24 hours after administration. No abnormal clinical symptoms were observed.

[0189] LC MS-MS Analysis. Liquid chromatography tandem mass spectrometry was used to determine the plasma concentrations of the free acid and tris salt of the compound of Formula I in plasma samples collected at defined time points. The instrument included a YMC-Triart C 18, S-5μm (50×2.1mm) HPLC column, Shimadzu LC-30AD liquid chromatograph with communication bus module CBM-20A and Auto SIL-20AC HT; and Triple Quad 5500 LC / MS / MS instrument. Tolbutamide was used as internal standard. The following conditions were used:

[0190] HPLC conditions:

[0191] Injection volume: 20 μl

[0192]

[0193] Retention time: Free acid and salt: 1.37 minutes; Tolbutamide 1.22 minutes

[0194] Gradient flow rate: 600 (μL / min)

[0195]

[0196] Mass spectrometer conditions:

[0197] Ionization mode: Cathode Monitoring method: MRM

[0198] Capillary(V): -4500

[0199] Gas temperature: 550℃

[0200] Ion Transformation:

[0201]

[0202] Results Results from the powder in capsules are shown below in Table 5. Results from the oral gavage suspension are shown below in Table 6. Overall, the total drug exposure (AUC 0.05) over time for the tris salt (powder in capsules and suspension formulations) was significantly higher than that for the free acid. last and AUC Inf ) were higher. The half-life of the tris salt appears to be shorter compared to the free acid, but the mean residence time is increased. One animal in the salt powder in capsule experiment showed abnormally high plasma concentrations (30-50 times that of the other two subjects) at the first two time points, so SD and CV% were not calculated.

[0203] Table 5. PK parameters in dogs tested using powder in capsule formulation

[0204]

[0205] Table 6. PK parameters in dogs tested using oral suspension

[0206]

[0207] Other Implementations

[0208] The above specific embodiments are provided to help those skilled in the art to practice the present disclosure. However, the disclosure described and claimed herein is not limited by the scope of the specific embodiments disclosed herein, because these embodiments are intended to illustrate several aspects of the present disclosure. Any equivalent embodiments are intended to be within the scope of the present disclosure. In fact, in addition to what is shown and described herein, various modifications of the present disclosure will become apparent to those skilled in the art based on the foregoing description, and these modifications do not deviate from the spirit or scope of the present invention. These modifications are also intended to fall within the scope of the appended claims.

Claims

1. A method for preparing a compound of formula I or a salt thereof, The method comprises the following steps: i) reacting a compound of formula II in the presence of a non-nucleophilic base in a polar aprotic solvent Contacting with a compound of formula III To prepare a compound of formula IV; and ii) hydrolyzing a compound of formula IV to prepare a compound of formula I or a salt thereof, wherein: R 1 is a C1-C4 alkyl group; and R 2 It is a halogen.

2. The method according to claim 1, wherein R 1 is isopropyl, R 2 For bromine.

3. The method of claim 1 or 2, wherein the molar ratio of the compound of formula III to the compound of formula II is from about 7.0 to about 10.

0.

4. The method according to any one of claims 1 to 3, wherein the non-nucleophilic base is selected from N,N-diisopropylethylamine (DIPEA), 8-diazabicycloundec-7-ene (DBU), 1,5-diazabicyclo(4.3.0)non-5-ene (DBN), 2,6-di-tert-butylpyridine, tert-butyllithium, tert-butylphosphazene, lithium diisopropylamide (LDA), sodium bis(trimethylsilyl)amide (NaHMDS), potassium tert-butoxide, potassium bis(trimethylsilyl)amide (KHMDS), lithium tetramethylpiperidinium (LiTMP), sodium hydride, potassium hydride and sodium tert-butoxide.

5. The method of claim 4, wherein the non-nucleophilic base is potassium bis(trimethylsilyl)amide (KHMDS).

6. The method of claim 5, wherein the molar ratio of KHMDS to the compound of formula II is from about 4.0 to about 6.

0.

7. The method according to any one of claims 1 to 6, wherein the polar aprotic solvent is selected from the group consisting of acetone, acetonitrile, dichloromethane, dimethyl sulfoxide (DMSO), dimethylformamide (DMF), ethyl acetate, hexamethylphosphoric triamide (HMPT), pyridine, tetrahydrofuran (THF) and mixtures thereof.

8. The method according to claim 7, wherein the polar aprotic solvent is a mixture consisting of THF and DMF.

9. The method of any one of claims 1 to 8, wherein hydrolyzing the compound of formula IV comprises reacting the compound of formula IV with a nucleophilic base.

10. The method of claim 9, wherein the nucleophilic base is selected from sodium hydroxide and sodium methoxide.

11. The method of claim 9 or 10, wherein the molar ratio of the nucleophilic base to the compound of formula IV is from about 18.0 to about 20.

0.

12. The process according to any one of claims 1 to 11, wherein the reaction is carried out in the presence of a palladium catalyst by reacting a compound of formula V: The compound of formula II is prepared by contacting with azetidine, wherein R 3 It is a halogen.

13. The method according to claim 12, wherein R 3 For bromine.

14. The method of claim 12 or 13, wherein the molar ratio of azetidine to the compound of formula V is from about 2.0 to about 3.

0.

15. The process of any one of claims 12 to 14, wherein the molar ratio of the palladium catalyst to the compound of formula V is from about 0.05 to about 0.

15.

16. The method according to any one of claims 12 to 15, wherein the palladium catalyst is selected from Pd(OAc)2, palladium(II) pivalate, tetrakis(triphenylphosphine)palladium(0), bis(acetonitrile)palladium(II) dichloride, bis(triphenylphosphine)palladium(II) dichloride, [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride, tris(dibenzylideneacetone)dipalladium(0) and palladium(II) chloride.

17. The method of claim 16, wherein the palladium catalyst is Pd(OAc)2.

18. The method according to any one of claims 12 to 17, wherein the contacting is performed in the presence of a ligand.

19. The method of claim 18, wherein the ligand is selected from the group consisting of trimethylphosphine, triphenylphosphine, tricyclohexylphosphine, tri(o-tolyl)phosphine, 2-(dicyclohexylphosphine)-2',4',6'-triisopropyl-1,1'-biphenyl (XPhos), 2-(dicyclohexylphosphine)-2'-(N,N-dimethylamino)biphenyl, 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl, 2-dicyclohexylphosphine-2',6'-dimethoxy-1,1'-biphenyl, butyldi-1-adamantylphosphine, 2-(di-tert-butylphosphine)biphenyl, 2-(dicyclohexylphosphine)biphenyl, (R)-(-)-1-[(S)-2 -(diphenylphosphino)ferrocene]ethyldicyclohexylphosphine, 1,2-bis(diphenylphosphino)benzene (dppbenzene), 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (BINAP), bis(2-diphenylphosphinophenyl) ether (DPEphos), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos), 1,4-bis(diphenylphosphino)butane (dppb), 1,2-bis(diphenylphosphino)ethane (dppe), 1,1'-bis(diphenylphosphino)ferrocene (dppf), 1,3-bis(diphenylphosphino)propane (dppp), and [(t-Bu3)PH]BF4.

20. The method of claim 19, wherein the ligand is Xantphos.

21. The method of any one of claims 18 to 20, wherein the molar ratio of ligand to compound of formula V is from about 0.05 to about 0.

15.

22. The method according to any one of claims 12 to 21, wherein the step of With a compound of formula VII: contacting to form a compound of Formula VIII: and then contacting the compound of formula VIII with a reducing agent to produce a compound of formula V to prepare a compound of formula V, wherein R 3 It is a halogen.

23. The method according to claim 22, wherein the reducing agent is selected from lithium aluminum hydride, sodium bis(2-methoxyethoxy)aluminum hydride (Red-Al), nascent hydrogen, sodium amalgam, zinc amalgam, sodium borohydride, lithium borohydride, SmI2, Fe-containing 2+ Ionic compounds, containing Sn 2+ Ionic compounds, hydrazine, diisobutylaluminum hydride and any combination thereof.

24. The method of claim 23, wherein the reducing agent is sodium borohydride.

25. The process according to any one of claims 22 to 24, wherein the reaction is carried out in a polar aprotic solvent by reacting 1-(3-hydroxyphenyl)ethan-1-one with a compound of formula IX in the presence of a non-nucleophilic base: The compound of formula VI is prepared by contacting with dimethyl oxalate and a strong base to produce a compound of formula VII, wherein R 4 It is a halogen.

26. The method of claim 25, wherein the polar aprotic solvent is selected from the group consisting of acetone, acetonitrile, dichloromethane, dimethyl sulfoxide (DMSO), dimethylformamide (DMF), ethyl acetate, hexamethylphosphoric triamide (HMPT), pyridine, tetrahydrofuran (THF), and mixtures thereof.

27. The method of claim 25 or 26, wherein the non-nucleophilic base is selected from cesium carbonate, sodium carbonate and potassium carbonate.

28. The method of claim 27, wherein the strong base is selected from the group consisting of sodium hydroxide, sodium methoxide, sodium ethoxide, lithium diisopropylamide (LDA), sodium bis(trimethylsilyl)amide (NaHMDS), potassium tert-butoxide, potassium bis(trimethylsilyl)amide (KHMDS), lithium tetramethylpiperidinium (LiTMP), sodium hydride, potassium hydride, and sodium tert-butoxide.

29. The method of any one of claims 25 to 29, wherein the molar ratio of the non-nucleophilic base to 1-(3-hydroxyphenyl)ethan-1-one is from about 1.0 to about 2.

0.

30. The method according to any one of the preceding claims, further comprising converting a compound of formula I to of tris salt.

31. A tris salt prepared according to the method of claim 30.

32. A compound of the formula prepared by the method according to any one of claims 1 to 29 wherein the compound contains a detectable amount of one or more residual organic solvents of less than 3% by weight.

33. A composition comprising at least 90% of a compound of formula I or a salt thereof and a detectable amount of one or more impurities selected from the group consisting of a compound of formula IV, a compound of formula II, a compound of formula V, a compound of formula VIII, 1-(3-hydroxyphenyl)ethan-1-one, bromocyclobutane, cesium carbonate, hydrochloric acid, 2-bromophenylhydrazine, sodium borohydride, xantphos, sodium tert-butoxide, isopropyl 2-bromo-2-methylpropionate, potassium bis(trimethylsilyl)amide, sodium hydroxide, sodium hydride, sodium tert-amylate, acetonitrile, dichloromethane, 4-dimethylaminopyridine, ethyl acetate, dimethylformamide, ethanol, water, isopropanol, isopropyl acetate, potassium bis(trimethylsilyl)amide, methanol, methyl tert-butyl ether, sodium borohydride, N-methyl-2-pyrrolidone, palladium diacetate, sodium triacetoxyborohydride, tetrahydrofuran, and one or more heavy metals.

34. The composition of claim 33, wherein the one or more heavy metals are selected from platinum, palladium, iridium, rhodium, rhenium, ruthenium, cadmium, mercury, lead, arsenic, manganese, chromium, cobalt, nickel, copper, zinc, selenium, silver, antimony, thallium, nickel, vanadium and zinc.

35. A method for treating a condition mediated by the monocarboxylate transporter MCT4 in a subject in need thereof, the method comprising the step of administering to the subject a therapeutically effective amount of a compound or salt thereof according to claim 32, a salt according to claim 31, or a composition according to claim 33 or 34.

36. The method of claim 35, wherein the monocarboxylate transporter MCT4-mediated disorder is cardiac hypertrophy.

37. The method of claim 35, wherein the monocarboxylate transporter MCT4-mediated disorder is heart failure.

38. The method of claim 35, wherein the monocarboxylate transporter MCT4-mediated disorder is a cancer expressing MCT4.

39. The method of claim 35, wherein the monocarboxylate transporter MCT4-mediated disorder is rheumatoid arthritis.

40. One type or a salt thereof.

41. A type or a salt thereof.

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