Salts of heterocyclic inhibitors of monocarboxylic acid transporter 4 for treatment of disease

Abstract

Disclosed herein are novel salts of substituted pyrazole compounds that inhibit the activity of the monocarboxylic acid transporter MCT4 or a mutant thereof. Also disclosed herein are compounds, pharmaceutical compositions, and methods of treating MCT4-mediated diseases, such as inflammatory and proliferative disorders.

Description

[0001] This application claims the benefit of priority to U.S. Provisional Application No. 63 / 370,972, filed on August 10, 2022, the contents of which are incorporated by reference as if fully written herein.

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

[0003] The correlation of MCT4 expression with poor cancer outcomes appears to have significant functional consequences in a variety of cancer models. Stable expression of MCT4 is highly tumorigenic in a respiratory-impaired, Ras-transformed fibroblast xenograft model. In contrast, MCT4 silencing slows or eliminates tumor growth in xenograft models of breast cancer, colorectal cancer, and glioma. MCT4 expression is required for angiogenesis mediated by the inflammatory cytokine IL-8 in xenograft models of breast cancer and colon cancer. MCT4 has also been shown to play an important role in various aspects of cancer cell migration, invasion, and the Warburg effect (e.g., glucose-dependent proliferation, 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, no potent and selective MCT4 inhibitors have been described. Moderate to weak MCT4 inhibitors are known (e.g., phloretin and α-CN-4-OH-cinnamate); however, these compounds indiscriminately inhibit many other transporters, including MCT1.

[0005] Novel salts and pharmaceutical compositions have been discovered that have been found to inhibit MCT4, as well as methods of synthesizing and using these salts, including methods for treating MCT4-mediated diseases in patients by administering these compounds. Summary of the invention

[0006] A compound having a form A of formula I is provided

[0007] Also provided is a compound having structural formula I, which is amorphous

[0008] Also provided is a compound having structural formula II

[0009] Also provided is a compound of Form A having structural formula II

[0010] Also provided is a compound having a form B of formula II

[0011] Also provided is a pharmaceutical composition comprising a compound described herein and a pharmaceutically acceptable carrier, adjuvant or vehicle.

[0012] Also provided is a method for inhibiting the activity of monocarboxylate transporter MCT4 or a mutant thereof in a biological sample, the method comprising the step of contacting the biological sample with a compound as described herein.

[0013] Also provided is a method for inhibiting the activity of monocarboxylate transporter MCT4 or a mutant thereof in a patient, the method comprising the step of administering to the patient a compound as described herein.

[0014] Also provided is a method for selectively inhibiting the activity of monocarboxylate transporter MCT4 or a mutant thereof relative to monocarboxylate transporter MCT1 or a mutant thereof in a patient, the method comprising the step of administering to the patient a compound as described herein.

[0015] Also provided 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 patient a compound as described herein.

[0016] Also provided is a method of treating a monocarboxylate transporter MCT4-mediated disorder in a subject in need thereof, the method comprising sequentially or co-administering a compound as described herein and another therapeutic agent.

[0017] Also provided is a method for achieving an effect in a patient, the method comprising administering to the patient a therapeutically effective amount of a compound as described herein, wherein the effect is selected from the group consisting of a reduction in triglycerides, a reduction in cholesterol, and a reduction in hemoglobin A1c.

[0018] These and other aspects of the invention will become apparent upon reference to the following description.To this end, various references are set forth herein that describe in more detail certain background information, procedures, compounds and / or compositions, and each of which is hereby incorporated by reference in its entirety. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figure 1 The FT-Raman spectrum of the compound of formula I is shown.

[0020] Figure 2 The DSC and TGA traces of the compound of formula I are shown.

[0021] Figure 3 The XRPD diffraction pattern of the compound having structural formula I is shown.

[0022] Figure 4 The compound of formula I is shown 1 H-NMR spectrum.

[0023] Figure 5 The FT-Raman spectrum of the compound of Form A of formula II is shown.

[0024] Figure 6 Shown are the DSC and TGA traces of the compound having Form A of structural formula II.

[0025] Figure 7 An XRPD diffraction pattern of a compound having Form A of structural formula II is shown.

[0026] Figure 8 The compound of Form A of Formula II is shown 1 H-NMR spectrum.

[0027] Fig. 9 A dynamic vapor sorption graph is shown for the compound having Form B of structural formula II.

[0028] Fig.10 Shown are the DSC and TGA traces of the compound having Form B of structural formula II.

[0029] Fig.11 An XRPD diffraction pattern of a compound having Form B of structural formula II is shown.

[0030] Fig.12 The compound of Form B of Formula II is shown 1 H-NMR spectrum.

[0031] Fig.13 Shown are mean plasma concentrations following oral administration of the compound of formula I at 20 mg / kg, 60 mg / kg and 200 mg / kg in male rats.

[0032] Fig.14Shown are mean plasma concentrations following oral administration of the compound of formula I at 20 mg / kg, 60 mg / kg and 200 mg / kg in female rats.

[0033] Fig.15 Shown are mean plasma concentrations following oral administration of the compound of formula II at 25 mg / kg, 75 mg / kg and 250 mg / kg in male rats.

[0034] Fig.16 Shown are mean plasma concentrations following oral administration of the compound of formula II at 25 mg / kg, 75 mg / kg and 250 mg / kg in female rats.

[0035] Fig.17 Shown are mean plasma concentrations following oral administration of the compound of formula I at 3 mg / kg in male dogs.

[0036] Fig.18 Shown are mean plasma concentrations following oral administration of the compound of formula II at 3 mg / kg in male dogs.

[0037] Fig.19 Shown are plasma concentrations following oral administration of the compound of formula II at 3 mg / kg in male dogs.

[0038] Fig. 20 Shown are plasma concentrations following oral administration of the compound of formula II at 30 mg / kg in male dogs.

[0039] Fig.21 Schematic representation of potential dose groups for Parts A and C of the Phase 1 regimen is shown.

[0040] Fig. 22 A schematic diagram showing potential dose groups for Parts B and D of the Phase 1 regimen.

[0041] Fig.23 Results of the bleomycin-induced pulmonary fibrosis model in mice are shown. Compound 1 (VB253) was dosed at 3 mg / kg, BID; pirfenidone was dosed at 100 mg / kg, BID; and nintedanib was dosed at 50 mg / kg, QD, all via oral gavage. DETAILED DESCRIPTION

[0042] A compound having a form A of formula I is provided

[0043] The compound having structural formula I is also referred to herein as compound 1 or 2-((1-(2-(azetidin-1-yl)phenyl)-5-(3-cyclobutoxyphenyl)-1H-pyrazol-3-yl)methoxy)-2-methylpropanoic acid. In certain embodiments, compound 1 is administered as a pharmaceutically acceptable salt, such as the tris salt of 2-((1-(2-(azetidin-1-yl)phenyl)-5-(3-cyclobutoxyphenyl)-1H-pyrazol-3-yl)methoxy)-2-methylpropanoic acid.

[0044] In certain embodiments, compounds having Form A of Formula I are unsolvated.

[0045] In certain embodiments, compounds having Form A of structural formula I have differential scanning calorimetry data showing a major melting endotherm with an onset temperature of about 157 °C.

[0046] In certain embodiments, compounds having Form A of Formula I have substantially Figure 2 Differential scanning calorimetry trace shown.

[0047] In certain embodiments, compounds having Form A of Formula I have substantially Figure 2 TGA trace shown.

[0048] In certain embodiments, compounds having Form A of Formula I have substantially Figure 3 X-ray powder diffraction (XRPD) pattern shown.

[0049] In certain embodiments, compounds having Form A of Formula I have substantially Figure 1 FT-Raman spectrum shown.

[0050] Also provided is a compound having Form A of structural formula I, prepared by the process described herein.

[0051] Also provided is a compound having structural formula I, which is amorphous

[0052] Also provided is a compound having structural formula II

[0053] The compound having structural formula II is also referred to herein as the tris salt or Compound 1 tris salt.

[0054] In certain embodiments, the compound of formula II has a 1:1 stoichiometry of active ingredient to counterion.

[0055] Also provided is a compound of Form A having structural formula II

[0056] In certain embodiments, the compound having Form A of Formula II is unsolvated.

[0057] In certain embodiments, compounds having Form A of structural formula II have a 1:1 stoichiometry of active ingredient to counterion.

[0058] In certain embodiments, the compound of Form A of Formula II has an X-ray powder diffraction (XRPD) pattern having peaks at approximately 7.79, 15.61, 16.71, 20.00, and 20.88 ± 0.3 degrees 2θ, wherein the XRPD is measured using a Cu radiation incident beam.

[0059] In certain embodiments, the compound of Form A of Formula II has an X-ray powder diffraction (XRPD) pattern having peaks at approximately 7.79, 12.59, 15.61, 16.71, 20.00, 20.88, and 21.50 ± 0.3 degrees 2θ, wherein the XRPD is measured using a Cu radiation incident beam.

[0060] In certain embodiments, the compound of Form A of Formula II has an X-ray powder diffraction (XRPD) pattern having peaks at approximately 7.79, 12.18, 12.59, 15.61, 16.71, 17.38, 17.72, 19.16, 20.00, 20.88, and 21.50 ± 0.3 degrees 2θ, wherein the XRPD is measured using a Cu radiation incident beam.

[0061] In certain embodiments, compounds of Form A of Formula II have d-spacings of about 11.34, 5.67, 5.30, 4.44, and An X-ray powder diffraction (XRPD) pattern having a peak at, wherein the XRPD is measured using a Cu radiation incident beam.

[0062] In certain embodiments, compounds of Form A of Formula II have d-spacings of about 11.34, 7.02, 5.67, 5.30, 4.44, 4.25, and An X-ray powder diffraction (XRPD) pattern having a peak at, wherein the XRPD is measured using a Cu radiation incident beam.

[0063] In certain embodiments, compounds of Form A of Formula II have d-spacings of about 11.34, 7.26, 7.02, 5.67, 5.30, 5.10, 5.00, 4.63, 4.44, 4.25, and An X-ray powder diffraction (XRPD) pattern having a peak at, wherein the XRPD is measured using a Cu radiation incident beam.

[0064] In certain embodiments, the compound of Form A of Formula II has substantially Figure 7 X-ray powder diffraction (XRPD) pattern shown.

[0065] In certain embodiments, the compound of Form A of Formula II is characterized by the presence of a -1 、1438cm -1 and 995cm -1 FT-Raman peak.

[0066] In certain embodiments, the compound of Form A of Formula II is characterized by the presence of a -1 、1438cm -1 、1372cm -1 、995cm -1 、332cm -1 、234cm -1 and 173cm -1 FT-Raman peak.

[0067] In certain embodiments, the compound of Form A of Formula II has substantially Figure 5 FT-Raman spectrum shown.

[0068] In some embodiments, the compound is characterized by a weight loss of no more than 0.5% between about 25°C and 150°C as determined by thermogravimetric analysis (TGA).

[0069] In some embodiments, the compound of Form A of Formula II has substantially Figure 6 TGA trace shown.

[0070] In certain embodiments, the compound having Form A of structural formula II has differential scanning calorimetry data showing a melting endotherm with an onset temperature of about 148 °C.

[0071] In certain embodiments, the compound of Form A of Formula II has substantially Figure 6 Differential scanning calorimetry trace shown.

[0072] Also provided is a process for preparing a compound of Form A of Formula II, comprising combining a compound of Formula I with tris(hydroxymethyl)aminomethane in a solvent and isolating the compound of Form A of Formula II. In some embodiments, the solvent is selected from water, acetone, and acetonitrile, or a mixture thereof. In some embodiments, the combining occurs at room temperature.

[0073] Also provided is a compound having Form B of structural formula II, prepared by the process described herein.

[0074] Also provided is a compound having a form B of formula II

[0075] In certain embodiments, the compound having Form B of Formula II is unsolvated.

[0076] In certain embodiments, the compound having Form B of Structural Formula II has a 1:1 stoichiometry of active ingredient to counterion.

[0077] In certain embodiments, the compound of Form B of Formula II has substantially Fig.10 Differential scanning calorimetry trace shown.

[0078] In certain embodiments, the compound of Form B of Formula II has substantially Fig. 9 The dynamic vapor adsorption curve is shown.

[0079] In certain embodiments, the compound having Form B of structural formula II has an X-ray powder diffraction (XRPD) pattern having peaks at approximately 9.29, 9.70, 16.36, 19.12, and 20.15 degrees 2θ, wherein the XRPD is measured using a Cu radiation incident beam.

[0080] In certain embodiments, the compound having Form B of Structural Formula II has an X-ray powder diffraction (XRPD) pattern having peaks at approximately 9.29, 9.70, 10.03, 16.36, 19.12, 19.49, 19.61, 20.15, and 21.68 degrees 2θ, wherein the XRPD is measured using a Cu radiation incident beam.

[0081] In certain embodiments, the compound of Form B of Formula II has an X-ray powder diffraction (XRPD) pattern having peaks at approximately 9.29, 9.70, 10.03, 11.14, 11.73, 16.36, 16.71, 19.12, 19.49, 19.61, 20.15, 20.52, 20.73, and 21.68 degrees 2θ, wherein the XRPD is measured using a Cu radiation incident beam.

[0082] In certain embodiments, compounds having Form B of Formula II have d-spacings of about 9.51, 9.11, 5.41, 4.64, and An X-ray powder diffraction (XRPD) pattern having a peak at, wherein the XRPD is measured using a Cu radiation incident beam.

[0083] In certain embodiments, compounds of Form B of Formula II have d-spacings of about 9.51, 9.11, 8.81, 5.41, 4.64, 4.55, 4.52, 4.40, and An X-ray powder diffraction (XRPD) pattern having a peak at, wherein the XRPD is measured using a Cu radiation incident beam.

[0084] In certain embodiments, compounds having Form B of Formula II have d-spacings of about 9.51, 9.11, 8.81, 7.93, 7.54, 5.41, 5.30, 4.64, 4.55, 4.52, 4.40, 4.32, 4.28, and An X-ray powder diffraction (XRPD) pattern having a peak at, wherein the XRPD is measured using a Cu radiation incident beam.

[0085] In certain embodiments, the compound of Form B of Formula II has substantially Fig.11 X-ray powder diffraction (XRPD) pattern shown.

[0086] In certain embodiments, the compound of Form B of Formula II is characterized by a monoclinic lattice type with unit cell lengths of three axes of about (a) 26.526A, (b) 5.940A, (c) 19.055A and three unit cell angles of about (a) 90.00°, (β) 90.00°, and (γ) 93.123° and P2 1 / c space group.

[0087] In certain embodiments, the compound of Form B of Formula II is characterized by the presence of about 1601 cm -1 、1545cm -1 、1468cm -1 、1437cm -1 、999cm -1 、995cm -1 and 234cm -1 FT-Raman peak.

[0088] In certain embodiments, the compound of Form B of Formula II is characterized by the presence of a -1 、1601cm-1 、1545cm -1 、1507cm -1 、1468cm -1 、1437cm -1 、1374cm -1 、1345cm -1 、1043cm -1 、999cm -1 、995cm -1 、284cm -1 、234cm -1 and 186cm -1 FT-Raman peak.

[0089] In certain embodiments, the compound having Form B of structural formula II has differential scanning calorimetry data showing a melting endotherm with an onset temperature of about 148 °C.

[0090] In some embodiments, the compound is characterized by a weight loss of no more than 0.1% between about 25°C and 145°C as determined by thermogravimetric analysis (TGA).

[0091] In some embodiments, the compound of Form B of Formula II has substantially Fig.10 TGA trace shown.

[0092] Also provided is a process for preparing a compound having Form B of formula II, the process comprising stirring a compound having Form A of formula II with a suitable solvent, adding seed crystals of a compound having Form B of formula II, and isolating the compound having Form B of formula II. Also provided is a compound having Form B of formula II, which is prepared by the process described herein.

[0093] Also provided are embodiments in which any of the above embodiments may be combined with any one or more of these embodiments, provided that the combinations are not mutually exclusive.

[0094] As used herein, two embodiments are "mutually exclusive" when one embodiment is defined as being different from the other. For example, the embodiment in which two groups combine to form a cycloalkyl group is mutually exclusive with the embodiment in which one group is ethyl and the other group is hydrogen. Similarly, the embodiment in which one group is CH 2 The embodiment in which is mutually exclusive with the embodiment in which the same group is NH.

[0095] Certain compounds disclosed herein may have useful MCT4 inhibitory activity and may be used in the treatment or prevention of diseases or conditions in which MCT4 plays an active role. Therefore, in a broad sense, certain embodiments also provide pharmaceutical compositions comprising one or more compounds disclosed herein and a pharmaceutically acceptable carrier, as well as methods for preparing and using these compounds and compositions. Certain embodiments provide methods for inhibiting MCT4. Other embodiments provide methods for treating MCT4-mediated disorders in patients in need of such treatment, comprising administering to the patient a therapeutically effective amount of a compound or composition according to the present invention. Also provided is the use of certain compounds disclosed herein for the manufacture of a medicament for treating a disease or condition improved by inhibiting MCT4.

[0096] A method of inhibiting at least one MCT4 function is provided, the method comprising the step of contacting MCT4 with a compound as described herein. Cell phenotype, cell proliferation, activity of MCT4, changes in biochemical output produced by active MCT4, expression of MCT4, or binding of MCT4 to a natural binding partner can be monitored. Such a method can be a model for disease treatment, bioassay, cell assay, biochemical assay, etc.

[0097] Also provided herein is a method of treating a MCT4-mediated disease, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound as disclosed herein.

[0098] In certain embodiments, the disease is selected from a proliferative inflammatory disease.

[0099] In certain embodiments, the disease is a metabolic disease.

[0100] In certain embodiments, the metabolic disease is selected from metabolic syndrome, diabetes, dyslipidemia, fatty liver disease, nonalcoholic steatohepatitis, obesity, and insulin resistance.

[0101] In certain embodiments, the diabetes is type II diabetes.

[0102] In certain embodiments, the dyslipidemia is hyperlipidemia.

[0103] Further provided is a method for achieving an effect in a patient, the method comprising administering to the patient a therapeutically effective amount of a compound as disclosed above, wherein the effect is selected from the group consisting of a reduction in triglycerides, a reduction in cholesterol, and a reduction in hemoglobin A1c.

[0104] There is further provided a method as disclosed above, wherein the cholesterol is selected from LDL and VLDL cholesterol.

[0105] There is further provided a method as disclosed above, wherein the triglycerides are selected from plasma triglycerides and liver triglycerides.

[0106] Also provided herein is a method of inhibiting MCT4, the method comprising contacting MCT4 with a compound as disclosed herein.

[0107] Also provided herein is a method for achieving an effect in a patient, the method comprising administering to the patient a therapeutically effective amount of a compound as disclosed herein, wherein the effect is selected from cognitive enhancement.

[0108] In certain embodiments, the MCT4-mediated disease is selected from a proliferative inflammatory disease.

[0109] Also provided is a method of modulating MCT4-mediated function in a subject, the method comprising administering a therapeutically effective amount of a compound as disclosed herein.

[0110] Also provided is a pharmaceutical composition comprising a compound as disclosed herein and a pharmaceutically acceptable carrier.

[0111] In certain embodiments, the pharmaceutical composition is formulated for oral administration.

[0112] In certain embodiments, the oral pharmaceutical composition is selected from tablets and capsules. Abbreviations and definitions

[0113] As used herein, the following terms have the indicated meanings.

[0114] 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 taken alone or in combination with any 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, that is, A alone, B alone, or A and B in combination. The expression "A, B, and / or C" is intended to mean A alone, B alone, C alone, A and B in combination, A and C in combination, B and C in combination, or A, B and C in combination.

[0115] When disclosing a range of values ​​and using the notation "from n 1 ... to n 2 " or "in n 1… With n 2 Between” (where n 1 and n 2When " is a number), unless otherwise specified, this symbol is intended to include these numbers themselves and the range between them. This range can be integer or continuous between these end values ​​and include these end values. By way of example, the range "from 2 to 6 carbons" is intended to include two, three, four, five and six carbons, because carbon appears in integer units. By way of example, the range "from 1 to 3 μM (micromolar)" (which is intended to include 1 μM, 3 μM and all numbers in between) is compared with any number of significant figures (e.g., 1.255 μM, 2.1 μM, 2.9999 μM, etc.).

[0116] As used herein, the term "about" is intended to qualify the numerical value it modifies, indicating that this value may vary within a margin of error. When no specific margin of error (such as the standard deviation of the mean value given in a graph or data table) is stated, the term "about" should be understood to mean a range that encompasses the stated value and also a range that is included by rounding to that number, taking into account significant figures.

[0117] Asymmetric centers are present in the compounds disclosed herein. These centers are designated by the symbol "R" or "S", depending on the configuration of the substituents around the chiral carbon atom. It should be understood that the disclosure encompasses all stereochemical isomeric forms, including diastereomeric forms, enantiomeric forms and epimeric forms, as well as d-isomers and 1-isomers, and mixtures thereof. Individual stereoisomers of compounds can be prepared synthetically from commercially available starting materials containing chiral centers, or by preparing a mixture of enantiomeric products, followed by separation (such as conversion into a mixture of diastereoisomers, followed by separation or recrystallization, chromatography techniques, direct separation of enantiomers on a chiral chromatographic column, or any other suitable method known in the art). Starting compounds with specific stereochemistry are commercially available, or can be prepared and split by techniques known in the art. In addition, compounds disclosed herein can exist as geometric isomers. The present disclosure includes all cis, trans, synonymous, antisense, hetero (E) and homo (Z) isomers and suitable mixtures thereof. In addition, the compound may exist as a tautomer; the present disclosure provides all tautomeric isomers. In addition, the compounds disclosed herein may exist in a non-solvated form and in a solvated form with a pharmaceutically acceptable solvent (such as water, ethanol, etc.). Generally speaking, the solvated form is considered to be equivalent to the non-solvated form.

[0118] As used herein, the term "disease" is intended to be generally synonymous with the terms "disorder," "syndrome," and "condition" (as in medical conditions) and may be used interchangeably with these terms because all reflect an abnormal condition of the human or animal body or one of its parts that impairs normal function, typically manifests itself as distinctive signs and symptoms, and causes the human or animal to have a reduced life span or decreased quality of life.

[0119] The term "combination therapy" means the administration of two or more therapeutic agents to treat the therapeutic conditions or disorders described in this disclosure. Such administration encompasses the co-administration of these therapeutic agents in a substantially simultaneous manner, such as in a single capsule with a fixed ratio of active ingredients or in multiple separate capsules for each active ingredient. In addition, such administration also encompasses the use of each type of therapeutic agent in a sequential manner. In either case, the treatment regimen will provide a beneficial effect of the drug combination in treating the conditions or disorders described herein.

[0120] The term "MCT4 inhibitor" as used herein refers to a compound that exhibits an IC50 of no more than about 100 μM and more typically no more than about 50 μM for MCT4 activity, as measured in the MCT4 enzyme assay generally described below. IC50 is the concentration of an inhibitor that reduces the activity of an enzyme (e.g., MCT4) to half of the maximum level. It has been found that certain compounds disclosed herein exhibit inhibition against MCT4. In certain embodiments, the compound will exhibit an IC50 of no more than about 10 μM for MCT4; in further embodiments, the compound will exhibit an IC50 of no more than about 5 μM for MCT4; in yet further embodiments, the compound will exhibit an IC50 of no more than about 1 μM for MCT4; in yet further embodiments, the compound will exhibit an IC50 of no more than about 200 nM for MCT4, as measured in the MCT4 binding assay described herein.

[0121] The phrase "therapeutically effective" is intended to qualify the amount of active ingredient used in the treatment of a disease or disorder or to produce an effect on a clinical endpoint.

[0122] The term "therapeutically acceptable" refers to those compounds (or salts, prodrugs, tautomers, zwitterionic forms, etc.) that are suitable for contact with patient tissues without excessive toxicity, irritation and allergic response, commensurate with a reasonable benefit / risk ratio, and effective for the intended use.

[0123] As used herein, the term "treat," "treating," or "treatment" means administering therapy to an individual who has exhibited at least one symptom of a disease or condition or has previously exhibited at least one symptom of a disease or condition. For example, "treating" can include alleviating, attenuating, or ameliorating the symptoms of a disease or condition, preventing additional symptoms, ameliorating potential metabolic causes of symptoms, inhibiting a disease or condition (e.g., preventing the development of the disease or condition), alleviating the disease or condition, causing regression of the disease or condition, alleviating a condition caused by the disease or condition, or stopping the symptoms of the disease or condition. For example, the term "treat" with respect to a disorder means reducing the severity of one or more symptoms associated with that particular disorder. Thus, treating a disorder does not necessarily mean reducing the severity of all symptoms associated with the disorder, nor does it necessarily mean completely reducing the severity of one or more symptoms associated with the disorder.

[0124] The term "patient" is often synonymous with the term "subject" and includes all mammals, including humans. Examples of patients include humans, livestock (such as cattle, goats, sheep, pigs and rabbits) and companion animals (such as dogs, cats, rabbits and horses). Preferably, the patient is a human.

[0125] Although the compounds of the present invention may be applied as raw chemical substances, they may also be provided as pharmaceutical formulations. Therefore, pharmaceutical formulations are provided herein, which include one or more of certain compounds disclosed herein, or one or more pharmaceutically acceptable salts, esters, prodrugs, amides or solvates thereof, and one or more pharmaceutically acceptable carriers thereof and optionally one or more other therapeutic ingredients. The one or more carriers must be "acceptable" in the sense that they are compatible with the other ingredients of the formulation and harmless to the recipient thereof. Appropriate formulations depend on the selected route of administration. Any well-known technology, carrier and excipient can be suitably used and used as understood in the art. Pharmaceutical compositions disclosed herein can be manufactured in any manner known in the art, for example, by conventional mixing, dissolving, granulating, making dragees, grinding, emulsifying, encapsulating, embedding or tableting methods.

[0126] Formulations include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous, intraarticular and intramedullary), intraperitoneal, transmucosal, transdermal, rectal and topical (including skin, buccal, sublingual and intraocular) administration, but the most suitable route may depend on, for example, the condition and disorder of the recipient. The formulations can be conveniently presented in unit dosage form and can be prepared by any method well known in the art of pharmacy. Typically, these methods include the step of mixing a compound of the invention or a pharmaceutically acceptable salt, ester, amide, prodrug or solvate thereof ("active ingredient") with a carrier constituting one or more auxiliary ingredients. In general, the formulation is prepared by uniformly and intimately combining the active ingredient with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation.

[0127] Formulations of the compounds disclosed herein suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary or paste.

[0128] Pharmaceutical preparations that can be used orally include tablets, push-fit capsules made of gelatin, and sealed capsules made of gelatin and plasticizers (such as glycerol or sorbitol). Tablets can be made by compressing or molding, optionally with one or more auxiliary ingredients. Compressed tablets can be prepared by compressing the active ingredient in a free-flowing form (such as powder or granules) in a suitable machine, and the active ingredient is optionally mixed with a binder, an inert diluent, or a lubricant, a surfactant or a dispersant. Molded tablets can be prepared by molding a mixture of powdered compounds moistened with an inert liquid diluent in a suitable machine. Tablets can be optionally coated or scored, and can be formulated to provide a slow or controlled release of the active ingredient therein. All formulations for oral administration should be doses suitable for such administration. Push-fit capsules can contain active ingredients mixed with fillers (such as lactose), binders (such as starches) and / or lubricants (such as talc or magnesium stearate) and optionally stabilizers. In soft capsules, the active compound can be dissolved or suspended in a suitable liquid, such as fatty oil, liquid paraffin or liquid polyethylene glycol. In addition, a stabilizing agent can be added. The dragee core has a suitable coating. For this purpose, concentrated sugar solutions can be used, and these solutions can optionally contain gum arabic, talcum, polyvinyl pyrrolidone, carbomer gel, polyethylene glycol and / or titanium dioxide, lacquer solution and suitable organic solvent or solvent mixture. Dye or pigment can be added to tablet or dragee coating, to be used to identify or characterize the different combinations of active compound dosage.

[0129] Compounds can be formulated for parenteral administration by injection (e.g., by bolus injection or continuous infusion). Preparations for injection can be presented in unit dosage forms with the addition of preservatives, such as in ampoules or in multi-dose containers. These compositions can be in the form of suspensions, solutions or emulsions such as in oily or aqueous vehicles, and can contain preparatons, such as suspending agents, stabilizers and / or dispersants. Preparations can be presented in unit doses or multi-dose containers (e.g., sealed ampoules and vials), and can be stored in powder form or stored under freeze drying (lyophilization) conditions, requiring only the immediate addition of sterile liquid carriers (e.g., saline or sterile pyrogen-free water) before use. Temporary injection solutions and suspensions can be prepared by sterile powders, granules and tablets of previously described types.

[0130] Preparations for parenteral administration include aqueous and non-aqueous (oily) sterile injections of the active compound (which may contain antioxidants, buffers, bacteriostats, and solutes that make the preparation isotonic with the blood of the intended recipient); and aqueous and non-aqueous sterile suspensions that may contain suspending agents and thickening agents. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran. Optionally, the suspension may also contain a suitable stabilizer or an agent that increases the solubility of the compound to allow the preparation of a highly concentrated solution.

[0131] In addition to the preparations described previously, these compounds can also be formulated into depot preparations. Such long-acting preparations can be administered by implantation (e.g., subcutaneous or intramuscular) or by intramuscular injection. Therefore, for example, these compounds can be formulated with suitable polymers or hydrophobic materials (e.g., as an emulsion in an acceptable oil) or ion exchange resins, or be formulated into slightly soluble derivatives, for example, are formulated into slightly soluble salts.

[0132] For buccal or sublingual administration, these compositions may take the form of tablets, lozenges, pastilles or gels in conventional manner.Such compositions may comprise the active ingredient in a flavored basis such as sucrose and acacia or tragacanth.

[0133] The compounds may also be formulated in rectal compositions such as suppositories or retention enemas, eg, containing conventional suppository bases such as cocoa butter, polyethylene glycol, or other glycerides.

[0134] Certain compounds disclosed herein can be administered topically, i.e., by non-systemic administration. This includes external application of the compounds disclosed herein to the epidermis or oral cavity and instillation of such compounds into the ears, eyes, and nose, so that the compounds do not enter the bloodstream in large quantities. In contrast, systemic administration refers to oral, intravenous, intraperitoneal, and intramuscular administration.

[0135] Preparations suitable for topical application include liquid or semi-liquid preparations suitable for permeating the skin to the site of inflammation, such as gels, liniments, lotions, creams, ointments or pastes, and drops suitable for application to the eyes, ears or noses. The active ingredient for topical application can account for, for example, 0.001% w / w to 10% w / w (by weight) of the preparation. In certain embodiments, the active ingredient can account for up to 10% w / w. In other embodiments, it can account for less than 5% w / w. In certain embodiments, the active ingredient can account for 2% w / w to 5% w / w. In other embodiments, it can account for 0.1% w / w to 1% w / w of the preparation.

[0136] For administration by inhalation, the compound can be conveniently delivered from an insufflator, a nebulizer pressurized pack or other convenient means of delivering an aerosol spray. The pressurized pack may contain a suitable propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. Alternatively, for administration by inhalation or insufflation, the compound according to the present invention may be in the form of a dry powder composition, for example a powder mixture of the compound and a suitable powder matrix such as lactose or starch. The powder composition may be presented in a unit dosage form, for example, in a capsule, cartridge, gelatin or blister pack, from which the powder may be administered by means of an insufflator or insufflator.

[0137] Preferred unit dosage formulations are those containing an effective dose, as hereinafter recited, or an appropriate fraction thereof, of an active ingredient.

[0138] It should be understood that in addition to the ingredients particularly mentioned above the formulations described above may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.

[0139] The compound can be administered orally or via injection at a dosage of 0.1 mg / kg to 500 mg / kg per day. The dosage range for adults is generally 5 mg to 2 g / day. Tablets or other presentation forms provided in discrete units can conveniently contain an amount of one or more compounds, which is effective at such a dosage or as a plurality of identical units containing, for example, 5 mg to 500 mg, usually about 10 mg to 200 mg.

[0140] The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.

[0141] Compounds can be used in various ways, such as orally, topically or by injection. The exact amount of the compound used to the patient will be the responsibility of the attending physician. The specific dosage level for any particular patient will depend on multiple factors, including the activity, age, body weight, general health, sex, diet, time of application, route of administration, excretion rate, drug combination, the definite obstacle treated and the severity of the indication or disease treated of the specific compound adopted. In addition, the route of administration can change according to the disease and its severity.

[0142] In some cases, it may be appropriate to administer at least one compound described herein (or a pharmaceutically acceptable salt, ester, or prodrug thereof) in combination with another therapeutic agent. By way of example only, if one of the side effects experienced by a patient when receiving one of the compounds herein is hypertension, it may be appropriate to administer an antihypertensive agent in combination with an initial therapeutic agent. Alternatively, by way of example only, the therapeutic effectiveness of one of the compounds described herein may be enhanced by administering an adjuvant (i.e., the adjuvant itself may have only minimal therapeutic benefit, but when combined with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced). Alternatively, by way of example only, the benefit experienced by the patient may be increased by administering one of the compounds described herein with another therapeutic agent (which also includes a treatment regimen) that also has a therapeutic benefit. By way of example only, in a diabetes treatment involving the administration of one of the compounds described herein, the therapeutic benefit may also be increased by providing the patient with another diabetes therapeutic agent. In any case, regardless of the disease, disorder, or condition being treated, the overall benefit experienced by the patient may be simply the sum of the two therapeutic agents, or the patient may experience a synergistic benefit.

[0143] Thus, in another aspect, certain embodiments provide methods for treating a MCT4-mediated disorder in a human or animal subject in need of such treatment, the methods comprising administering to the subject a combination of a compound disclosed herein in an amount effective to reduce or prevent the disorder in the subject and at least one additional agent known in the art for treating the disorder. In a related aspect, certain embodiments provide therapeutic compositions comprising a combination of at least one compound disclosed herein and one or more additional agents for treating a MCT4-mediated disorder.

[0144] Also provided herein is a method of treating a monocarboxylate transporter MCT4-mediated disorder in a subject in need thereof, the method comprising sequentially or co-administering a compound as disclosed herein and another therapeutic agent.

[0145] In certain embodiments, the therapeutic agent is a protein kinase inhibitor.

[0146] In certain embodiments, the protein kinase inhibitor is selected from Aurora B, EGFR, PLK-1, CDK inhibitors.

[0147] In certain embodiments, the therapeutic agent is selected from antimetabolites, bcr-abl inhibitors, DNA damaging agents, EGFR inhibitors, microtubule stabilization inhibitors, mitotic arrest inhibitors, S phase inhibitors, and taxanes.

[0148] In certain embodiments, the therapeutic agent is a DNA damaging agent selected from alkylating agents, anthracyclines, antimetabolites, cross-linking agents, DNA replication inhibitors, intercalators, microtubule disrupting agents, PARP inhibitors, radiomimetic agents, radiosensitizers, strand breakers, and topoisomerase II inhibitors.

[0149] In certain embodiments, the therapeutic agent is selected from aminoglutethimide, amsacrine, anastrozole, asparaginase, barasertib, bacillus Calmette-Guérin, bicalutamide, bleomycin, buserelin, busulfan, camptothecin, capecitabine, carboplatin, carmustine, chlorambucil, chloroquine, cisplatin, cladribine, clodronate, colchicine, cyclophosphamide, cyproterone, cytarabine, dacarbazine, dactinomycin, daunomycin, demethoxyviridin, dichloroacetate, dienestrol, diethylstilbestrol, docetaxel, doxorubicin, epirubicin, estradiol, estramustine, etoposide, everolimus, exemestane, filgrastim, fludarabine, fludrocortisone, fluorouracil, fluoxymesterone, flutamide, gemcitabine, genistein, goserelin, hydroxy Urea, idarubicin, ifosfamide, imatinib, interferon, irinotecan, irinotecan, letrozole, folinic acid, leuprorelin, levamisole, lomustine, lonidamine, nitrogen mustard, medroxyprogesterone, megestrol, melphalan, mercaptopurine, mesna, metformin, methotrexate, mitomycin, mitotane, mitoxantrone, nilutamide, nocodazole, olaparib, octreotide, oxaliplatin, paclitaxel, pamidronate, pentostatin, perifosine, plicamycin, porfibril sodium, procarbazine, raltitrexed, rituximab, sorafenib, streptozotocin, sunitinib, suramin, tamoxifen, temozolomide, temsirolimus, teniposide, testosterone, thioguanine, thiotepa, titanocene dichloride, topotecan, trastuzumab, tretinoin, vinblastine, vincristine, vindesine, and vinorelbine.

[0150] In certain embodiments, the therapeutic agent is selected from paracetamol, acetaminophen, pirfenidone, nintedanib, and non-hormonal contraceptives.

[0151] For use in cancer and neoplastic diseases, MCT4 inhibitors may be optimally used with one or more of the following non-limiting examples of anticancer agents: (1) alkylating agents, including but not limited to cisplatin (PLATIN), carboplatin (PARAPLATIN), oxaliplatin (ELOXATIN), streptozotocin (ZANOSAR), busulfan (MYLERAN), and cyclophosphamide (ENDOXAN); (2) antimetabolites, including but not limited to mercaptopurine (PURINETHOL), thioguanine, pentostatin (NIPENT), cytarabine (ARA-C), gemcitabine (GEMZAR), fluorouracil (CARAC), folinic acid (FUSILEV), and methotrexate (RHEUMATREX); (3) plant alkaloids and terpenoids, including but not limited to vincristine. alkali (ONCOVIN), vinblastine and paclitaxel (TAXOL); (4) topoisomerase inhibitors, including but not limited to irinotecan (CAMPTOSAR), topotecan (HYCAMTIN) and etoposide (EPOSIN); (5) cytotoxic antibiotics, including but not limited to actinomycin D (COSMEGEN), doxorubicin (ADRIAMYCIN), bleomycin (BLENOXANE) and mitomycin (MITOSOL); (6) angiogenesis inhibitors, including but not limited to sunitinib (SUTENT) and bevacizumab (AVASTIN); and (7) tyrosine kinase inhibitors, including but not limited to imatinib (GLEEVEC), erlotinib (TARCEVA), lapatinib (TYKERB) and axitinib (INLYTA).

[0152] Where the subject has or is at risk of having an inflammatory disorder, the MCT4 inhibitor compounds described herein are optionally used in any combination with one or more agents or methods for treating the inflammatory disorder. Therapeutic agents / treatments for treating autoimmune and / or inflammatory disorders include, but are not limited to, any of the following examples: (1) corticosteroids, including, but not limited to, cortisone, dexamethasone, and methylprednisolone; (2) nonsteroidal anti-inflammatory drugs (NSAIDs), including, but not limited to, ibuprofen, naproxen, acetaminophen, aspirin, fenoprofen (NALFON), flurbiprofen (ANSAID), ketoprofen, oxaprozin (DAYPRO), diclofenac sodium (VOLTAREN), diclofenac potassium (CATAFLAM), etodolac (LODINE), indomethacin (INDOCIN), ketorolac (TORADOL), sulindac (CLINORIL), tolmetin (TOLECTIN), meclofenamic acid (MECLOMEN), mefenamic acid (PONSTEL), nabumetone (RELAFEN), and piroxicam (FELDENE); (3) immunosuppressants, including, but not limited to, methotrexate (RHEUMATRE X), leflunomide (ARAVA), azathioprine (IMURAN), cyclosporine (NEORAL, SANDIMMUNE), tacrolimus and cyclophosphamide (CYTOXAN); (4) CD20 blockers, including but not limited to rituximab (RITUXAN); (5) tumor necrosis factor (TNF) blockers, including but not limited to etanercept (ENBREL), infliximab (REMICADE) and adalimumab (HUMIRA); (6) interleukin-1 receptor antagonists, including but not limited to anakinra (KINERET); (7) interleukin-6 inhibitors, including but not limited to tocilizumab (ACTEMRA); (8) interleukin-17 inhibitors, including but not limited to AIN457; (9) Janus kinase inhibitors, including but not limited to tasocitinib; and (10) SYK inhibitors, including but not limited to fostamatinib.

[0153] In certain embodiments, the method further comprises administering a non-chemical method of cancer treatment.

[0154] In certain embodiments, the method further comprises administering radiation therapy.

[0155] In certain embodiments, the method further comprises administering surgery, thermal ablation, focused ultrasound therapy, cryotherapy, or any combination thereof.

[0156] In any case, multiple therapeutic agents (at least one of which is a compound disclosed herein) can be administered in any order or even simultaneously. If administered simultaneously, the multiple therapeutic agents can be provided in a single, unified form or in multiple forms (by way of example only, as a single pill or as two separate pills). One of the therapeutic agents can be administered in multiple doses, or both can be administered in multiple doses. If not simultaneously, the time interval between multiple doses can be any duration ranging from a few minutes to four weeks.

[0157] Also provided are methods for treating MCT4-mediated disorders in a human or animal subject in need of such treatment, comprising administering to the subject a combination of a compound disclosed herein in an amount effective to reduce or prevent the subject's disorder and at least one additional agent known in the art for treating the disorder. In a related aspect, certain embodiments provide therapeutic compositions comprising a combination of at least one compound disclosed herein and one or more additional agents for treating MCT4-mediated disorders.

[0158] Also provided are compounds and pharmaceutical compositions that inhibit glutaminase activity, particularly MCT4 activity, and are therefore useful for treating or preventing disorders associated with MCT4. The compounds and pharmaceutical compositions described herein selectively modulate MCT4, and are therefore useful for treating or preventing a range of disorders associated with MCT4, and include, but are not limited to, proliferative and inflammatory diseases.

[0159] Therefore, provided herein is a method for inhibiting the activity of monocarboxylate transporter MCT4 or a mutant thereof in a biological sample, the method comprising the step of contacting the biological sample with a compound as disclosed herein.

[0160] Also provided herein is a method for inhibiting the activity of monocarboxylate transporter MCT4 or a mutant thereof in a patient, the method comprising the step of administering to the patient a compound as disclosed herein.

[0161] Also provided herein is a method for selectively inhibiting the activity of monocarboxylate transporter MCT4 or a mutant thereof relative to monocarboxylate transporter MCT1 or a mutant thereof in a patient, the method comprising the step of administering to the patient a compound as disclosed herein.

[0162] In certain embodiments, the inhibition is at least 100-fold selective for MCT4 over MCT1.

[0163] In certain embodiments, the compounds, salts, and pharmaceutical compositions described herein can be used to treat or prevent cancer.

[0164] In certain embodiments, the compounds and salts described herein can be used to prevent or treat cancer, wherein the cancer is one or a variant of the following: acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), adrenocortical carcinoma, AIDS-related cancers (Kaposi Sarcoma and lymphoma), anal cancer, appendix cancer, atypical teratoid / rhabdoid tumor, basal cell carcinoma, bile duct cancer (including extrahepatic), bladder cancer, bone cancer (including osteosarcoma and malignant fibrous histiocytoma), brain tumors (e.g., astrocytoma, brain and spinal cord tumors, brain stem glioma, atypical teratoid / rhabdoid tumor of the central nervous system, embryonal tumors of the central nervous system, craniopharyngioma, ependymoma, ependymoma, medulloblastoma, medullary epithelioma, intermediately differentiated cancellous parenchymal tumors, supratentorial primitive neuroectodermal tumors and pineoblastoma), breast cancer, bronchial carcinoma, Burkitt's lymphoma (Burkitt Lymphoma, Carcinoid tumor, Metastatic cancer of unknown primary site, Central nervous system (such as atypical teratoid / rhabdoid tumor, embryonal tumors and lymphoma), Cervical cancer, Childhood cancer, Chordoma, Chronic lymphocytic leukemia (CLL), Chronic myeloid leukemia (CML), Chronic myeloproliferative disorders, Colon cancer, Colorectal cancer, Craniopharyngioma, Primary cutaneous T-cell lymphoma (mycosis fungoides and Sézary syndrome), Bile duct, bile (extrahepatic), Ductal carcinoma in situ (DCIS), Embryonic tumor (CNS), Endometrial cancer, Ependymoma, Ependymoma, Esophageal cancer, Nasal glioma, Ewing Sarcoma Family of tumors ( Cancer of the gallbladder (including endocranial, pancreatic, ovarian), Gastrointestinal stromal tumors (GIST), Gastrointestinal stromal tumors (including ovarian, ... Histiocytosis), laryngeal cancer, leukemia (including acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), hairy cell), lip and oral cavity cancer, liver cancer (primary), lobular carcinoma in situ (LCIS), lung cancer (non-small cell and small cell), lymphoma (AIDS-related, Burkitt,T cells of the skin (mycosis fungoides and Sezary syndrome), Hodgkin, non-Hodgkin, primary central nervous system (CNS), macroglobulinemia, Waldenstrom's disease, Male Breast Cancer, Malignant Fibrous Histiocytoma and Osteosarcoma of Bone, Medulloblastoma, Medullary Epithelioma, Melanoma (including Intraocular (Eye)), Merkel Cell Carcinoma, Mesothelioma (Malignant), Metastatic Squamous Neck Cancer with Occult Primary, Midline Tract Cancer Involving NUT Gene, Mouth Cancer, Multiple Endocrine Neoplasms, Multiple Myeloma / Plasma Cell Neoplasms, Mycosis Fungoides, Myelodysplastic Syndrome, Myelodysplastic / Myeloproliferative Neoplasms, Granulocytic Leukemia, Chronic Myeloid Leukemia (CML), Myeloid Leukemia, Acute Myeloid Leukemia (AML), Myeloma and Multiple Myeloma, Myeloproliferative Disorders (Chronic), Nasal and Paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer, oral cancer, oral cavity cancer, lip and oropharyngeal cancer, osteosarcoma and malignant fibrous histiocytoma of bone, ovarian cancer (such as epithelial, germ cell tumors and tumors of low malignant potential), pancreatic cancer (including islet cell tumors), papillomatous hyperplasia, paraganglioma, paranasal sinus and nasal cavity cancer, parathyroid cancer, penile cancer, nasopharyngeal cancer, pheochromocytoma, intermediately differentiated cancellous parenchymal tumors, pineoblastoma and supratentorial primitive neuroectodermal tumors, vertical Somatic tumors, plasma cell neoplasms / multiple myeloma, pleuropulmonary blastoma, breast cancer during pregnancy, primary central nervous system (CNS) lymphoma, prostate cancer, colorectal cancer, renal cell (kidney) cancer, transitional cell carcinoma of the renal pelvis and ureter, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcomas (such as Ewing sarcoma family tumors, Kaposi, soft tissue, uterine tumors), Sezary syndrome, skin cancers (such as melanoma, Merkel cell carcinoma, non-melanoma), small cell lung cancer, small intestine cancer, soft tissue Sarcoma, squamous cell carcinoma, squamous neck cancer with occult primary, metastatic gastric (stomach) cancer, supratentorial primitive neuroectodermal tumors, T-cell lymphomas (cutaneous, mycosis fungoides, and Sezary syndrome), testicular cancer, laryngeal cancer, thymic cancer, thyroid cancer, renal pelvis and ureter cancer, transitional cell carcinoma, trophoblastic tumor (pregnancy), cancer of unknown primary, childhood abnormalities, ureter and renal pelvis cancer, transitional cell carcinoma, urethral cancer, uterine cancer, endometrial sarcoma, uterine sarcoma, Waldenstrom's macroglobulinemia ( Macroglobulinemia or Wilms Tumor.

[0165] In certain embodiments, the cancer to be treated is one that is specific for T cells, such as T-cell lymphoma and lymphoblastic T-cell leukemia.

[0166] In certain embodiments, the methods described herein are used to treat a disease condition comprising administering to a subject in need thereof a therapeutically effective amount of a compound as described herein, wherein the condition is cancer that is resistant to chemotherapeutic drugs and / or ionizing radiation.

[0167] In certain embodiments, the compounds, salts, and pharmaceutical compositions described herein are useful for treating or preventing inflammatory diseases.

[0168] In certain embodiments, the compounds and salts described herein can be used to prevent or treat an inflammatory disease, wherein the inflammatory disease is one or a variant of the following: acid-induced lung injury, acne (PAPA), acute respiratory distress syndrome, Addison's disease, adrenal hyperplasia, adrenocortical insufficiency, aging, AIDS, alcoholic hepatitis, alcoholic liver disease, allergen-induced asthma, allergic bronchopulmonary aspergillosis, allergic conjunctivitis, alopecia, Alzheimer's disease, amyloidosis, amyotrophic lateral sclerosis, angina pectoris, angioedema, anhidrotic ectodermal dysplasia (e.g., with immunodeficiency), ankylosing spondylitis, anterior segment inflammation, antiphospholipid syndrome, aphthous stomatitis, appendicitis, asthma, atherosclerosis, atopic dermatitis, autoimmune Diseases, autoimmune hepatitis, inflammation caused by bee stings, Behcet's disease, Bell's palsy, beryllium poisoning, Blau syndrome, bone pain, bronchiolitis, burns, bursitis, cardiac hypertrophy, carpal tunnel syndrome, catabolism disorders, cataracts, cerebral aneurysms, inflammation caused by chemical irritants, chorioretinitis, chronic heart failure, chronic lung disease of prematurity, chronic obstructive pulmonary disease, colitis, complex regional pain syndrome, connective tissue disease, corneal ulcers, Crohn's disease, periodic syndrome associated with cold pyrines, cryptococcosis, cystic fibrosis, interleukin-1 receptor antagonist deficiency, dermatitis, dermatitis endotoxemia, dermatomyositis, endometriosis, endotoxemia, epicondylitis, erythroblastosis, familial amyloid polyneuropathy, Familial cold urticaria, familial Mediterranean fever, fetal growth retardation, glaucoma, glomerular disease, glomerulonephritis, gout, gouty arthritis, graft-versus-host disease, intestinal disease, head injury, headache, hearing loss, heart disease, hemolytic anemia, Henoch-Schwann syndrome, hepatitis, hereditary periodic fever syndrome, herpes zoster and herpes simplex, HIV-1, Huntington's disease, hyaline membrane disease, hyperammonemia, hypercalcemia, hypercholesterolemia, hyperimmunoglobulinemia D with recurrent fever, dysplasia and other anemias, idiopathic pulmonary fibrosis, idiopathic thrombocytopenic purpura, incontinence jaundice, infectious mononucleosis, inflammatory bowel disease, inflammatory lung disease, inflammatory neuropathy, inflammatory pain, inflammation caused by insect bites, iritis, Ischemia / reperfusion, juvenile rheumatoid arthritis, keratitis, kidney disease, parasitic infection-induced renal damage, prevention of renal transplant rejection, leptospirosis, Loeffler syndrome, lung injury, lupus, lupus nephritis, meningitis, mesothelioma, mixed connective tissue disease, Mu-Wei syndrome (urticarial deafness amyloidosis), multiple sclerosis, muscular dystrophy, muscular dystrophy, myasthenia gravis, myocarditis, mycosis fungoides, myelodysplastic syndrome, myositis, sinusitis, necrotizing enterocolitis, neonatal onset multisystem inflammatory disease (NOMID), nephrotic syndrome, neuritis, neuropathic diseases, non-allergenic asthma, obesity, eye allergy, optic neuritis, organ transplantation, osteoarthritis, otitis media, Paget's disease,pain, pancreatitis, Parkinson's disease, pemphigus, pericarditis, periodic fever, periodontitis, whooping cough, perineal or peritoneal endometriosis, pharyngitis and adenitis (PFAPA syndrome), inflammation caused by plant irritants, Pneumocystis infection, pneumonia, localized pneumonia, inflammation caused by poison ivy / urushiol oil, polyarteritis nodosa, polychondritis, polycystic kidney disease, polymyositis, psoriasis, psychosocial stress disorder, lung disease, pulmonary fibrosis, pulmonary hypertension, pyoderma gangrenosum, suppurative sterile arthritis, kidney disease, retinal disease, rheumatic disease, rheumatoid arthritis, rheumatic carditis, Arthritis, seborrhea, sepsis, severe pain, sickle cell, sickle cell anemia, silica-induced disease, Sjögren's syndrome, skin diseases, sleep apnea, spinal cord injury, Stevens-Johnson syndrome, stroke, subarachnoid hemorrhage, sunburn, systemic sclerosis (scleroderma), temporal arteritis, tenosynovitis, thrombocytopenia, thyroiditis, tissue transplant, TNF receptor associated periodic syndrome (TRAPS), toxoplasmosis, transplant, traumatic brain injury, tuberculosis, type 1 diabetes, type 2 diabetes, ulcerative colitis, urticaria, uveitis, Wegener's granulomatosis, and weight loss.

[0169] Thus, in another aspect, certain embodiments provide methods for treating a monocarboxylate transporter MCT4-mediated disorder in a subject in need thereof, the methods comprising the step of administering to the patient a therapeutically effective amount of a compound as disclosed herein.

[0170] In certain embodiments, the subject is a human.

[0171] In certain embodiments, the subject is in a fed state.

[0172] In certain embodiments, the subject is in a fasting state.

[0173] In certain embodiments, the monocarboxylate transporter MCT4-mediated disorder is selected from an inflammatory disorder and a proliferative disorder.

[0174] In certain embodiments, the monocarboxylate transporter MCT4-mediated disorder is a proliferative disorder.

[0175] In certain embodiments, the proliferative disorder is cancer.

[0176] In certain embodiments, the cancer is selected from adenocarcinoma, adult T-cell leukemia / lymphoma, bladder cancer, blastoma, bone cancer, breast cancer, brain cancer, epithelial cancer, myeloid sarcoma, cervical cancer, colorectal cancer, esophageal cancer, gastrointestinal cancer, glioblastoma multiforme, glioma, gallbladder cancer, gastric cancer, head and neck cancer, Hodgkin lymphoma, non-Hodgkin lymphoma, intestinal cancer, kidney cancer, laryngeal cancer, leukemia, lung cancer, lymphoma, liver cancer, small cell lung cancer, non-small cell lung cancer, mesothelioma, multiple myeloma, eye cancer, optic nerve tumor, oral cancer, ovarian cancer, pituitary tumor, primary central nervous system lymphoma, prostate cancer, pancreatic cancer, pharyngeal cancer, renal cell carcinoma, rectal cancer, sarcoma, skin cancer, spinal cord tumor, small intestine cancer, gastric cancer, T-cell lymphoma, testicular cancer, thyroid cancer, laryngeal cancer, genitourinary tumors, urothelial carcinoma, uterine cancer, vaginal cancer, and Wilms' tumor.

[0177] In certain embodiments, the monocarboxylate transporter MCT4-mediated disorder is an inflammatory disorder.

[0178] In certain embodiments, the inflammatory disorder is selected from Crohn's disease, ulcerative colitis, idiopathic pulmonary fibrosis, muscular dystrophy, rheumatoid arthritis, and systemic sclerosis (scleroderma). In certain embodiments, the inflammatory disorder is idiopathic pulmonary fibrosis.

[0179] In certain embodiments, the therapeutically effective amount is between about 30 mg and about 200 mg. In certain embodiments, the therapeutically effective amount is between about 30 mg and about 80 mg. In certain embodiments, the therapeutically effective amount is selected from 50 mg, 75 mg, 100 mg, 150 mg, and 200 mg.

[0180] Also provided herein are compounds as disclosed herein for use in human therapy.

[0181] Also provided herein are compounds as disclosed herein for use in treating monocarboxylate transporter MCT4-mediated disorders, for example, as disclosed in any of the examples and paragraphs above regarding methods of treatment.

[0182] Also provided herein is the use of a compound as disclosed herein for the manufacture of a medicament for treating a monocarboxylate transporter MCT4-mediated disorder, for example, as disclosed in any of the embodiments and paragraphs above regarding methods of treatment.

[0183] Metabolic syndrome (also called metabolic syndrome X) is characterized by having at least three of the following symptoms: insulin resistance; abdominal fat - in men, this is defined as a waist circumference of 40 inches or more, in women, 35 inches or more; high blood sugar levels - at least 110 milligrams per deciliter (mg / dL) after fasting; high triglycerides - at least 150 mg / dL in the bloodstream; low HDL - less than 40 mg / dL; a prothrombotic state (such as high fibrinogen or plasminogen activator inhibitor in the blood); or a blood pressure of 130 / 85 mmHg or higher. Links have been found between metabolic syndrome and other conditions such as obesity, high blood pressure, and high levels of LDL cholesterol, all of which are risk factors for cardiovascular disease. For example, an increased link between metabolic syndrome and atherosclerosis has been shown. People with metabolic syndrome are also more likely to develop type 2 diabetes, as well as PCOS (polycystic ovary syndrome) in women and prostate cancer in men.

[0184] As mentioned above, insulin resistance can manifest in several ways, including type 2 diabetes. Type 2 diabetes is the condition most obviously associated with insulin resistance. Before overt diabetes develops, compensatory hyperinsulinemia helps maintain normal glucose levels, usually for decades. Eventually, the beta cells of the pancreas cannot overcome insulin resistance by oversecreting. Glucose levels rise, and diabetes can be diagnosed. Patients with type 2 diabetes remain hyperinsulinemic until they are in the late stages of the disease. As mentioned above, insulin resistance can also be associated with hypertension. Half of patients with essential hypertension are insulin resistant and hyperinsulinemic, and there is evidence that blood pressure is related to the degree of insulin resistance. Hyperlipidemia is also associated with insulin resistance. The lipid profile of patients with type 2 diabetes includes an increase in serum very low-density lipoprotein cholesterol and triglyceride levels, and sometimes a decrease in low-density lipoprotein cholesterol levels. Insulin resistance is found in people with low levels of high-density lipoproteins. Insulin levels are also related to very low-density lipoprotein synthesis and plasma triglyceride levels.

[0185] Thus, also disclosed are methods of treating insulin resistance in a subject, the methods comprising selecting a subject in need of treatment for insulin resistance; and administering to the subject an effective amount of a compound that inhibits MCT4.

[0186] The specific disease to be treated by the compounds, compositions and methods disclosed herein is a disease mediated at least in part by MCT4. Therefore, disclosed herein is a method for reducing glycogen accumulation in a subject; increasing HDL or HDLc, reducing LDL or LDLc, converting LDL particle size from small density to normal LDL, reducing VLDL, reducing triglycerides or inhibiting cholesterol absorption in a subject; reducing insulin resistance, enhancing glucose utilization or lowering blood pressure in a subject; reducing visceral fat in a subject; reducing serum transaminases in a subject; or treating a disease; all of these methods include administering a therapeutic amount of a compound as described herein to a patient in need. In a further embodiment, the disease to be treated may be a metabolic disease. In a further embodiment, a metabolic disease may be selected from the group consisting of: obesity, diabetes (especially type 2 diabetes), hyperinsulinemia, glucose intolerance, metabolic syndrome X, dyslipidemia, hypertriglyceridemia, hypercholesterolemia and hepatic steatosis. In other embodiments, the disease to be treated may be selected from the group consisting of cardiovascular disease (including vascular disease), atherosclerosis, coronary heart disease, cerebrovascular disease, heart failure and peripheral vascular disease. In a preferred embodiment, the above method does not result in the induction or maintenance of a hypoglycemic state.

[0187] In addition to being useful for human treatment, certain compounds and formulations disclosed herein may also be used in veterinary treatment of companion animals, exotic animals, and farm animals, including mammals, rodents, etc. More preferred animals include horses, dogs, and cats. Examples

[0188] The present invention is further illustrated by the following examples. Compound synthesis

[0189] Compounds and salts can be prepared using the methods described in the general synthetic schemes and experimental procedures detailed below. The general synthetic schemes and experimental procedures are presented for illustrative purposes and are not intended to be limiting. The starting materials used to prepare the compounds and salts described herein are commercially available or can be prepared using conventional methods known in the art. Example 1: 2-([1-[2-(azetidin-1-yl)phenyl]-5-(3-cyclobutyloxyphenyl)-1H-pyrazol-3-yl] (methoxy)-2-methylpropanoic acid

[0190] The compound having structural formula I (ie, compound 1) was synthesized by the process of Scheme 1. Solution 1 Step 1:

[0191] 1-(3-Hydroxyphenyl)ethan-1-one (20 kg), bromocyclobutane (1.3 equivalents) and Cs 2 CO 3 A mixture of (1.5 equiv.) in DMF (5 volumes) was stirred at 80°C ± 5°C for 16 hours. Water (15 volumes) and methyl tert-butyl ether (MTBE, 15 volumes) were charged to the reaction vessel. The organic layer was separated and washed twice with 20% brine (5 volumes), then concentrated to about 5 volumes, and then solvent switched three times with methanol to about 5 volumes. The crude methanol solution containing compound 7 was used in the next step without further purification. Step 2:

[0192] Sodium methoxide (2.0 eq.) and dimethyl oxalate (1.5 eq.) were added to the crude methanol solution (5 volumes) of step 1. The reaction vessel was stirred at 30°C ± 5°C for 16 hours. Upon completion, the reaction mixture was cooled to a temperature between 0°C and 10°C. The pH was adjusted to 2-3 with 4.0M HCl in methanol, and the crude solution containing compound 2 was used in the next step without further purification. Step 3:

[0193] 2-Bromophenylhydrazine hydrochloride (1.0 equivalent) was added to the reaction vessel containing the crude methanol solution of step 2. The reaction mixture was then stirred at 60°C ± 5°C for 10 hours and then cooled to 5°C-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 obtain 54.9 kg of compound 3 (the yield of steps 1-3 was 88%). Step 4:

[0194] Compound 3 (4.0 kg; 1.0 equivalent) was added to THF (4 volumes), after which methanol (0.4 volume) was further added to the reaction vessel, which was then cooled to 10-25°C. Sodium borohydride (1.2 equivalents) was added, and the reaction was stirred at 10-25°C for 16 hours. After 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 for another 1-2 hours at 5-15°C. The product was collected via filtration, washed with water, and dried in an oven at 50°C to obtain 3.5 kg of compound 4 with a yield of 85%.

[0195] Step 4 was repeated on a 5x scale, adding compound 3 (20.0 kg; 1.0 eq) to THF (6.0 volumes), after which methanol (0.4 volumes) was further added to the reaction vessel, which was then cooled to 25°C ± 5°C. Sodium borohydride (1.2 eq) was added, and the reaction was stirred at 25°C ± 5°C for 16 hours. Upon completion, the reaction was cooled to 0°C–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°C–15°C for an additional 1–2 hours. The product was collected via 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%. Step 5:

[0196] Compound 4 (2.97 kg; 1.0 eq.) was added to THF (10 volumes) under stirring and nitrogen atmosphere. Xantphos (0.11 eq.) and Pd(OAc) were added. 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°C-35°C for 20 hours. MTBE (20 volumes) and water (20 volumes) were charged to the vessel. The organic layer was separated and washed with 5% NH 4 The mixture was washed with 5% aqueous Cl solution and 5% aqueous NaCl solution and then The obtained organic layer was concentrated and then solvent switched with ethyl acetate (10 volumes). The obtained solution was stirred at 70°C-80°C for 303 minutes, then cooled to 15°C-20°C and stirred for another 1-2 hours. The solid was collected via filtration, washed with ethyl acetate (0.5 volumes), and dried in an oven at 50°C to obtain 1.7kg of compound 5 with a yield of 60%. When reproduced with 18.0kg of compound 4, 10.8kg of compound 5 was obtained with a purity of 98.8% and an isolated yield of 63.8%. Step 6

[0197] To a solution of compound 5 (700.0 g, 1 eq.) in DMF (8 volumes) was added isopropyl 2-bromo-2-methylpropionate (8.0 eq.). The reaction mixture was cooled to -60°C - -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 volumes) was added to the reaction vessel. The organic phase was collected, washed twice with NaCl (15%) (5 volumes), and then concentrated. The crude compound 6 (70% yield) was used directly in the next step without further purification. Step 7

[0198] The crude compound 6 (1950.0 g, 1 eq) from step 6 was added to the reaction vessel along with 30% KOH (aq) (10 volumes, 20 eq) and methanol (5 volumes). The reaction was then stirred at 50°C ± 5°C for 16 hours and then cooled to 15°C-30°C. The solution was washed twice with MTBE (10 volumes) and then the aqueous layer was separated and filtered through The obtained aqueous phase was filtered. The pH of the obtained aqueous phase was adjusted to 3-5 using 2.0M HCl. The solution was cooled to 5°C-10°C and stirred for 2-3 hours, then filtered. The filter cake was dissolved in THF (10 times of volume), and then mercapto silica gel (300g, 15% w / w) was added to the solution. The obtained mixture was heated to 50°C-60°C, stirred for 3 hours, and then filtered. The solution was concentrated, and the crude product was then dissolved in ethyl acetate (10 times of volume). The obtained solution was heated to 70°C-80°C and stirred for 3-4 hours, then cooled to 0°C-10°C. Solids were collected via filtration, washed with ethyl acetate (0.5 times of volume), then dried in an oven at 50°C, to obtain compound 1 (1.4kg, 58% yield) as an off-white solid. 1 H NMR (C 2 D 6OS)δ12.66(s,1H),7.20(dd,2H),6.98(t,2H),6.73(m,3H),6.60(d,1H),6.53(d,1H),4.45(s,2H),4.32(t,1H ),3.48(dd,4H),3.32(s,3H),2.27(d,2H),2.05(m,2H),1.93(m,2H),1.73(m,1H),1.56(m,1H),1.415(s,6H). Example 2: 2-([1-[2-(azetidin-1-yl)phenyl]-5-(3-cyclobutyloxyphenyl)-1H-pyrazol-3-yl] Large-Scale Synthesis of 2-Methylpropionic Acid and Tris Salt 1. Synthesis of Compound 1

[0199] Compound 1 was synthesized by the process of Scheme 1. Solution 1 Step 1:

[0200] 1-(3-Hydroxyphenyl)ethan-1-one (20 kg), bromocyclobutane (1.3 equivalents) and Cs 2 CO 3 A mixture of (1.5 equiv.) in DMF (5 volumes) was stirred at 80°C ± 5°C for 16 hours. Water (15 volumes) and methyl tert-butyl ether (MTBE, 15 volumes) were charged to the reaction vessel. The organic layer was separated and washed twice with 20% brine (5 volumes), then concentrated to about 5 volumes, and then solvent switched three times with methanol to about 5 volumes. The crude methanol solution containing compound 7 was used in the next step without further purification. Step 2:

[0201] Sodium methoxide (2.0 eq.) and dimethyl oxalate (1.5 eq.) were added to the crude methanol solution (5 volumes) of step 1. The reaction vessel was stirred at 30°C ± 5°C for 16 hours. Upon completion, the reaction mixture was cooled to a temperature between 0°C and 10°C. The pH was adjusted to 2-3 with 4.0M HCl in methanol, and the crude solution containing compound 2 was used in the next step without further purification. Step 3:

[0202] 2-Bromophenylhydrazine hydrochloride (1.0 equivalent) was added to the reaction vessel containing the crude methanol solution of step 2. The reaction mixture was then stirred at 60°C ± 5°C for 10 hours and then cooled to 5°C-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 obtain 54.9 kg of compound 3 (the yield of steps 1-3 was 88%). Step 4:

[0203] Compound 3 (4.0 kg; 1.0 equivalent) was added to THF (4 volumes), after which methanol (0.4 volume) was further added to the reaction vessel, which was then cooled to 10-25°C. Sodium borohydride (1.2 equivalents) was added, and the reaction was stirred at 10-25°C for 16 hours. After 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 for another 1-2 hours at 5-15°C. The product was collected via filtration, washed with water, and dried in an oven at 50°C to obtain 3.5 kg of compound 4 with a yield of 85%.

[0204] Step 4 was repeated on a 5x scale, adding compound 3 (20.0 kg; 1.0 eq) to THF (6.0 volumes), after which methanol (0.4 volumes) was further added to the reaction vessel, which was then cooled to 25°C ± 5°C. Sodium borohydride (1.2 eq) was added, and the reaction was stirred at 25°C ± 5°C for 16 hours. Upon completion, the reaction was cooled to 0°C–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°C–15°C for an additional 1–2 hours. The product was collected via 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%. Step 5:

[0205] Compound 4 (2.97 kg; 1.0 eq.) was added to THF (10 volumes) under stirring and nitrogen atmosphere. Xantphos (0.11 eq.) and Pd(OAc) were added. 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°C-35°C for 20 hours. MTBE (20 volumes) and water (20 volumes) were charged to the vessel. The organic layer was separated and washed with 5% NH 4 The mixture was washed with 5% aqueous Cl solution and 5% aqueous NaCl solution and then The obtained organic layer was concentrated and then solvent switched with ethyl acetate (10 volumes). The obtained solution was stirred at 70°C-80°C for 303 minutes, then cooled to 15°C-20°C and stirred for another 1-2 hours. The solid was collected via filtration, washed with ethyl acetate (0.5 volumes), and dried in an oven at 50°C to obtain 1.7kg of compound 5 with a yield of 60%. When reproduced with 18.0kg of compound 4, 10.8kg of compound 5 was obtained with a purity of 98.8% and an isolated yield of 63.8%. Step 6

[0206] To a solution of compound 5 (700.0 g, 1 eq.) in DMF (8 volumes) was added isopropyl 2-bromo-2-methylpropionate (8.0 eq.). The reaction mixture was cooled to between -60°C and -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 volumes) was added to the reaction vessel. The organic phase was collected, washed twice with NaCl (15%) (5 volumes), and then concentrated. The crude compound 6 (70% yield) was used directly in the next step without further purification. Step 7

[0207] The crude compound 6 (1950.0 g, 1 eq) from step 6 was added to the reaction vessel along with 30% NaOH (aqueous solution) (10 volumes, 20 eq) and methanol (5 volumes). The reaction was then stirred at 50°C ± 5°C for 16 hours and then cooled to 15°C-30°C. The solution was washed twice with MTBE (10 volumes) and then the aqueous layer was separated and filtered through The obtained aqueous phase was filtered. The pH of the obtained aqueous phase was adjusted to 3-5 using 2.0M HCl. The solution was cooled to 5°C-10°C and stirred for 2-3 hours, then filtered. The filter cake was dissolved in THF (10 times of volume), and then mercapto silica gel (300g, 15% w / w) was added to the solution. The obtained mixture was heated to 50°C-60°C, stirred for 3 hours, and then filtered. The solution was concentrated, and the crude product was then dissolved in ethyl acetate (10 times of volume). The obtained solution was heated to 70°C-80°C and stirred for 3-4 hours, then cooled to 0°C-10°C. Solids were collected via filtration, washed with ethyl acetate (0.5 times of volume), then dried in an oven at 50°C, to obtain compound 1 (1.4kg, 58% yield) as an off-white solid.

[0208] This reaction was repeated on a larger scale, and the crude compound 6 (8.4 kg, 1 equivalent) from step 6 was added to the reaction vessel together with 30% KOH (aqueous solution) (10 volumes, 20 equivalents) and methanol (5 volumes). After following the same work-up as above, 8.76 kg of compound 1 was obtained via two steps with a purity of 97.7% and a yield of 67%. 2. Use of different propionates in step 6 Variations of the propionate ester were explored in step 6. The results are shown in Table 1. Table 1. * In addition, 13.4% of dimer byproduct was detected at the completion of the reaction.

[0209] As shown in Table 1, the performance of the starting material with the isopropyl ester is superior to the tert-butyl and methyl esters. In addition, the use of the isopropyl ester limits the potential formation of dimer (or bis-adduct) byproducts that were detected when the methyl ester was used in Run 13. The use of the isopropyl ester also allows the use of solvents other than DMF / NaH. The reaction also proceeds much faster than with DMF / NaH. 3. Formation of Tris Salt of Compound 1

[0210] Compound 1 (8.4 kg, 1 equivalent) was added to a reaction vessel along with THF (42 L, 5.0 volumes), charged with mercapto silica gel (420 g, 5 wt.%), and stirred and heated at 50-60°C for three hours. The reaction mixture was sampled and concentrated for ICP analysis to determine the residual Pd concentration (about 15 ppm). The reaction mixture was filtered and charged with a solution of acetone (168 L, 20.0 volumes) and tris(hydroxymethyl)aminomethane ("Tris", 1.01 equivalents) in water (4.2 L, 0.5 volumes). The reaction mixture was stirred at 20°C-30°C for 5-10 minutes so that most of the solids dissolved, and stirring was continued at 20°C-30°C for about 20 hours to allow the Tris salt of Compound 1 to precipitate. The precipitant was charged, washed with acetone (4.2 L, 0.5 volumes), and dried under vacuum at 60° C. to obtain 8.4 kg of Compound 1 Tris with a purity of 99.5% and a yield of 79.2%, with 1690 ppm residual acetone and 962 ppm residual THF. Example 3: Salt Formulation method

[0211] Polarized light microscopy (PLM) was performed with an Olympus BX60 polarized light microscope equipped with an Olympus DP70 camera.

[0212] The diffractometer was a PANalytical X'Pert Pro using Ni-filtered Cu Ka (45 kV / 40 mA) radiation and a step size of 0.02o 2Θ and an X'celerator TM X-ray powder diffraction ("XRPD") was performed with an RTMS (real-time multiple stripe) detector. Configuration on the incident beam side: fixed divergence slit (0.25°), 0.04 rad Soller slit, anti-scatter slit (0.25°) and 10 mm beam mask. Configuration on the diffracted beam side: fixed divergence slit (0.25°) and 0.04 rad Soller slit. The sample was mounted flat on a zero-background Si wafer.

[0213] The calorimeter was a TA Instruments Q100 differential scanning calorimeter equipped with an autosampler and a refrigerated cooling system at 40 mL / min N 2 Differential Scanning Calorimetry ("DSC") was performed under purge. DSC thermograms were obtained at 15°C / min in a crimped Al pan.

[0214] The TA Instruments Q500 thermogravimetric analyzer was used to analyze the 2 Thermogravimetric analysis ("TGA") was performed in Pt or Al pans at 15°C / min with purge.

[0215] Thermogravimetric analysis coupled to IR exhaust gas detection (TGA-IR) was performed using a TA Instruments Q5000 thermogravimetric analyzer connected to a Nicolet 6700 FT-IR spectrometer (Thermo Electron, USA) equipped with an external TGA-IR module with a gas flow cell and a DTGS detector. 2 TGA was performed on Pt or Al pans at a flow rate of 15 °C / min and a heating rate of 15 °C / min. -1 IR spectra were collected at 400 nm resolution and 32 scans per time point.

[0216] The Agilent DD2 500 MHz spectrometer was used to collect the TMS reference. 1 H NMR spectroscopy. The samples were dissolved in DMSO-d6.

[0217] Ion chromatography (IC) was performed on a Dionex ICS-5000. Column: Dionex IonPac CS12 4x250 mm; Detection: Suppressed conductivity, CERS 500, suppressed current 59 mA; Eluent (20 mM methanesulfonic acid) at 1.0 mL / min. Preliminary salt formation experiments using the compound of Example 1

[0218] The following general procedure is used to carry out the salt experiment of use example 1. About 20mg of example 1 compound is weighed into a separate vial. 200 μL or 1000 μL of solvent and the counterion of the stoichiometric amount are added into a separate vial. The resulting solution / suspension / gel is stirred while the temperature is circulated between 40°C and 5°C for two days (TC1). The solvent of the glue / solution after TC1 is evaporated under reduced pressure, and then 200 μL of solvent is redistributed into the vial. The resulting solution / suspension / gel is stirred again while the temperature is circulated between 40°C and 5°C for two days (TC2). The solution / gel / gel is quickly cooled to 4°C and kept at 4°C for two days (RC). The solvent is then evaporated under ambient conditions for seven days (SEV). The birefringence of the sample is checked in situ by PLM at each step, and if it is birefringent, it is separated, analyzed and grouped by FT-Raman and / or XRPD. The representative samples of each group are also characterized by DSC. Samples with promising DSC results were further characterized by TGA-IR, XRPD, HNMR and / or IC. Table 2. Summary of salt experiments. A=Amorphous / Glue B = Birefringence hit P = Crystalline matrix C = counter ion

[0219] Compound 1 tris salt form A (4088.62 mg) was transferred to a 125-mL conical flask, and 70 mL of solvent (95:5 acetone: water v / v) was added and stirred with a magnetic stirring bar. After stirring for 5 minutes, compound 1 tris salt form B seeds (53.19 mg) produced by the primary polymorph screening described above were added and continued stirring. After stirring for 15 min, the sample solid had been stuck (seized), and the stirring bar no longer moved. The flask was manually shaken to break up the lumps. A small aliquot was obtained and analyzed by PXRD, which indicated that the solid was form B. The remaining solid was separated with Whatman No. 1 filter paper on a Buchner funnel. The solid was washed with 20 mL of acetone cooled at -20 ° C. The funnel with the separated solid was covered with a Kimwipe, and dried on the filter, and vacuum was applied overnight. NMR indicated that the compound 1: tris molar ratio was 1: 1. Chromatographic purity was 99.8% area (254 nm).

[0220] After drying for approximately 14 hours, the solid was isolated (3804.50 mg, 93% yield). PXRD confirmed the sample to be the Form B tris salt, with no detectable Form A tris salt and no detectable Compound 1 precursor. Prior to thermal decomposition by TGA, the sample exhibited negligible weight loss. Characterization of Form A tris salt

[0221] During the salt study, one crystalline tris salt was isolated from six experiments. The hit was designated as Form A tris salt. The remaining experiments produced either the parent Form A or amorphous / gum. Thermal analysis indicated that Form A tris was a non-solvated form.

[0222] DSC data showed a melting endotherm with an onset temperature of 147.4° C. TGA-IR analysis showed negligible weight loss of water (0.3%) between 25° C. and 150° C., indicating that the salt was unsolvated. 1 H-NMR indicated a monosalt stoichiometry (API / CI ratio 1:1). Characterization of Form B tris salt

[0223] The form B tris salt is an off-white crystalline powder consisting of small particles. By PXRD, it shows relatively steep diffraction peaks between 2°–40° 2θ, consistent with crystalline material. DSC analysis shows a melting / decomposition endotherm (ΔH=111 J / g) with an onset temperature of 148°C. TGA analysis shows a negligible (0.1%) total weight loss up to 145°C, indicating that form B is non-solvated. DVS shows that the API is non-hygroscopic, with a weight change of approximately 0.1% between 5% RH and 95% RH at 25°C. The sample recovered after the dynamic vapor sorption experiment did not indicate a change in solid form by PXRD.

[0224] Kinetic solubility was evaluated in biologically relevant media at room temperature at 1 hour, 4 hours and 24 hours and is summarized in Table 3. Form B tris salt is virtually insoluble in fasting state simulated gastric fluid (FaSSGF) after 1 hour, 4 hours and 24 hours (0.46 μg / mL, 0.35 μg / mL and 0.39 μg / mL, respectively). The solubility in fasting state simulated intestinal fluid (FaSSIF) is at least 3 mg / mL (parent equivalent), but gradually decreases from 1 hour (1112 μg / mL), 4 hours (851 μg / mL) to 24 hours (733 μg / mL).

[0225] The fed state simulated intestinal fluid (FeSSIF) kinetic solubility was also 3 mg / mL (parent equivalent) in solution followed by precipitation (99 μg / mL at 1 hour, 96 μg / mL at 4 hours, and 95 μg / mL at 24 hours). Table 3. Kinetic solubility of tris salt form B in biorelevant media

[0226] The stability of the solid API was evaluated after 2 weeks of storage under the following conditions: 25℃ / 58%RH(off) 25℃ / 58%RH(open) 40℃ / 75% RH (off) 40℃ / 75%RH(open) 80℃ / ambient RH (off)

[0227] No significant chemical or physical changes were observed for tris salt Form B samples stored for 2 weeks at 25°C / 58% RH (off and on), 40°C / 75% RH (off and on), and 80°C / ambient RH (off). PXRD analysis of all stability samples also showed no significant changes. The results of the evaluation of the solid state stability of the API are summarized in Table 4. Pharmacokinetic assays

[0228] The tris salt and free acid of compound 1 were tested in two animal models to evaluate pharmacokinetic parameters. Rat Model

[0229] Group, administration and collection. The pharmacokinetics of the free acid and tris salt of compound 1 by oral gavage were evaluated in male Sprague-Dawley rats. Three rats in each group were orally administered 20mg, 60mg or 200mg of compound 1 free acid, or 25mg, 75mg or 250mg in 0.5% methylcellulose in saline, with a final concentration of 2mg / mL, 6mg / mL or 20mg / mL compound 1 free acid or 2.5mg / mL, 7.5mg / mL or 20mg / mL. Plasma was collected via the jugular vein 5min, 15min, 30min, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours and 24 hours after administration. No abnormal clinical symptoms were observed.

[0230] Stock solutions and dose preparation. Stock solutions were prepared by dissolving 2.47 mg of Compound 1 (free acid) in 2.470 mL of DMSO while vortexing to obtain a solution of 1 mg / mL Compound 1 (free acid), or by dissolving 2.09 mg of Compound 1 (Tris salt) in 1.655 mL of DMSO while vortexing to obtain a solution of 1 mg / mL Compound 1 (Tris salt). Dosing solutions were prepared by vortexing / sonicating the following solids in the solvent: Table 5. Preparation of dosing solutions Dosage, mg / mL solid Solvents 2 40.1 mg free acid 20.050 mL 0.5% MC in saline 6 119.26 Free acid 19.877 mL 0.5% MC in saline 20 396.69 Free acid 19.835 mL 0.5% MC in saline 2.5 62.94 tris salt 19.942 mL 0.5% MC in saline 7.5 180.32 tris salt 19.044 mL 0.5% MC in saline 25 595.39 tris salt 18.864 mL 0.5% MC in saline

[0231] LC MS-MS Analysis. Liquid chromatography tandem mass spectrometry was used to determine the plasma concentrations of Compound 1 free acid and Compound 1 Tris salt in plasma samples collected at defined time points.

[0232] By diluting the stock solution of analyte with the aqueous solution of 50% acetonitrile, realize the working solution of appropriate series concentration.5 μL working solution (10ng / mL, 20ng / mL, 50ng / mL, 100ng / mL, 500ng / mL, 1000ng / mL, 5000ng / mL, 8000ng / mL, 10000ng / mL) is added in 50 μL blank male SD rat plasma, to realize the calibration standard of 1-1000ng / mL (1ng / mL, 2ng / mL, 5ng / mL, 10ng / mL, 50ng / mL, 100ng / mL, 500ng / mL, 800ng / mL, 1000ng / mL) in 55 μL cumulative volume.Independently from the sample for calibration curve, 2ng / mL, 5ng / mL, 10ng / mL, 50ng / mL and 800ng / mL five kinds of quality control (QC) plasma samples were prepared. On the analysis day, these QC samples were prepared in the same manner as the calibration standards. 55 μL standards, 55 μL QC samples and 55 μL unknown samples (50 μL plasma / blood with 5 μL blank solutions) were added to 200 μL methanol containing internal standard (dexamethasone) mixtures respectively, for protein precipitation, 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 supernatant was injected into the LC / MS / MS system for quantitative analysis.

[0233] 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: Mobile phase Solution A: 5% acetonitrile (0.1% formic acid) in water Solution B: 95% acetonitrile (0.1% formic acid) in water gradient

[0234] Results. The results are shown in Table 6 (free acid) and Table 7 (tris salt) below. Figure 13-16It is noted that because the formula weight of the tris salt (FW = 582.7) is higher than that of the free acid (MW = 461.6), the appropriate comparison is 20 mg / kg free acid compared to 25 mg / kg tris salt. Overall, the total drug exposure (AUC last and AUC Inf ) was higher. The maximum exposure level (C max ) were also higher, except in females dosed at 20 / 25 mg / kg, where the free acid C max (78,883ng / mL) slightly higher than tris salt C max (68,567 ng / mL). In general, exposures were higher in female subjects than in male subjects. Table 6. PK parameters, free acid Table 7. PK parameters, Tris salt Dog Model

[0235] Group, administration and collection. The pharmacokinetics of the free acid and tris salt of compound 1 administered by oral capsules were evaluated in dogs. A single dose of 3 mg / kg compound 1 free acid was administered to three male beagles on the first day of the study, and a single dose of 3 mg / kg compound 1 tris salt was administered on the 8th day of the study. Before administration, and at 0.5 hour, 1 hour, 2 hours, 4 hours, 8 hours, 12 hours and 24 hours after administration, plasma was collected via peripheral vein puncture. No abnormal clinical symptoms were observed.

[0236] In a follow-up study, the pharmacokinetics of the tris salt of compound 1 was studied via oral gavage of a saline formulation of 0.5% methylcellulose. Two groups of animals were tested. In Group 1, a single dose of 3 mg / kg tris salt of compound 1 was administered to three male beagles. In Group 2, a single dose of 30 mg / kg tris salt of compound 1 was administered to three male beagles. Plasma was collected via peripheral vein puncture before administration, and at 0.5 hours, 1 hour, 2 hours, 4 hours, 8 hours, 12 hours, and 24 hours after administration. No abnormal clinical symptoms were observed.

[0237] LC MS-MS Analysis. Liquid chromatography tandem mass spectrometry was used to determine the plasma concentrations of Compound 1 free acid and Compound 1 Tris salt in plasma samples collected at defined time points. Instrumentation included 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: HPLC conditions: Mobile phase: A: 0.1% formic acid in DI water; B: 0.1% formic acid in acetonitrile Injection volume: 20μl Autosampler temperature Degree: 4℃ Retention time: Free acid and salt: 1.37min; Tolbutamide 1.22min gradient Mass spectrometer conditions: Ionization mode: Negative Monitoring mode: MRM Capillary (Volts): -4500 Gas temperature: 550℃ Ion Transition:

[0238] Results. The results for the powder in capsules are given in Table 8 below and Fig.17 and 18 The results of the oral gavage suspension are given in Table 9 below and Fig.19 and 20 Overall, the total drug exposure (AUC ) over time for the tris salt (both powder in capsule and suspension formulations) was significantly higher than that for the free acid. last and AUC Inf ) was higher. The half-life of the tris salt appears to be lower compared to the free acid, but the mean residence time is increased. One animal in the salt powder in the capsule experiment showed abnormally high plasma concentrations at the first two time points (30-50x that of the other two subjects), so SD and CV% were not calculated. Table 8. PK parameters in dogs tested with powder in capsule formulation. Table 9. PK parameters in dogs tested with the oral suspension. Example 4: Single Crystal

[0239] A variety of solvent systems (n=4-8) were selected to grow single crystals of the compounds. The solvents employed represented a range of polarities, dielectric constants, and dipole moments, and had various hydrogen bond donor / acceptor properties. Solvents were selected based on solubility properties (values ​​and temperature dependence) and their suitability for single crystal growth experiments.

[0240] Attempts to produce single crystals have included the following crystallization techniques: Two cooling modes using 5 solvent systems. • Slow evaporation using a 5 solvent system. • Vapor diffusion, which uses a 4-solvent combination. • Convection mode, which uses 1 solvent if the solubility is relatively low and sufficient material is supplied. · Layering, which uses 2 solvent systems

[0241] Polarized light microscopy and PXRD were used to assess the crystallinity, size and quality of the solids from each crystallization experiment.PXRD was used to confirm that the desired Form 2 (Panel B) was obtained.

[0242] The single crystal growth study involved 24 experiments. Of the 24 experiments, 10 experiments produced solids. The observed crystals were generally acicular in nature, such as needles or thin blades. Most of the crystals were considered too small and too thin to be suitable for SCXRD using laboratory-based equipment. A batch of crystals from vapor diffusion (produced over a period of 7 weeks from a DMF solution of a tris salt and acetonitrile vapor diffused into the DMF solution) produced larger crystals and were submitted to a crystallometer for single crystal X-ray diffraction analysis. The results of the crystal growth experiments are summarized below. Results of single crystal growth experiments by slow evaporation at ambient temperature Solvent (v:v) Group 2-Methoxyethanol Colorless liquid. No solid. IPA:water (90:10) glue THF: Water (90:10) Viscous liquid to glue MeCN:water (95:5) Yellow solution. No solids Methanol Colorless liquid. No solids Results of single crystal growth experiments by slow cooling *Performed using 90:10 v / v IPA:water and slow cooling from 50° C. to 5° C. The solution used for cooling was subsaturated with tris salt. **Performed using 90:10 v / v IPA:water and slow cooling from 50°C to 5°C. SC-011 was saturated with tris salt. Results of single crystal growth experiments by vapor diffusion at ambient temperature Solvents Antisolvent Group Notes Methanol Dichloromethane NA NA Chloroform Pentane Undetermined Needle too small for PXRD Trifluoroethanol Acetonitrile NA NA dimethylformamide Acetonitrile B(Form 2) Sent for SCXRD Results of single crystal growth experiments by convection Solvents Temperature(℃) Group Notes Ethanol 50 B(Form 2) Crystals too small for SCXRD Results of single crystal growth experiments by layering (liquid-liquid diffusion) Solvents Antisolvent Temperature(℃) Group Chloroform Pentane Ambient temperature B(Form 2) dimethylformamide Acetonitrile Ambient temperature Undetermined dimethylformamide Acetonitrile 5 Undetermined

[0243] Single crystals of Form 2 (Group B) were grown by diffusing acetonitrile vapor as an antisolvent into a solution of tris salt in dimethylformamide for single crystal X-ray diffraction analysis, which was analyzed by single crystal X-ray diffraction analysis and also used for seed crystals. Simulated powder X-ray diffraction patterns were calculated using Panalytical X'Pert Pro High Score Plus, v. 2.2.0 using low temperature structure and room temperature unit cell parameters. Simulated and experimental PXRD patterns were based on copper K-α X-radiation as the X-ray source. Example 5: Summary of Safety, Toxicology and Nonclinical Pharmacology and Pharmacokinetics

[0001] The safety pharmacology of compound 1 and its tris salt was evaluated in an in vitro human ether-à-go-go related gene (hERG) assay, behavioral studies in Sprague-Dawley rats, and cardiovascular assessments in beagle dogs using electrocardiogram (ECG) telemetry. The half-maximal inhibitory concentration (IC 50 ) value > 300 μM. Since it may be cytotoxic at doses > 300 μM, the IC value against hERG channel was excluded 50 Determination. After oral doses up to 400mg / kg (the highest dose tested) in male rats, there were no compound 1 related behavioral effects. After oral doses up to 150mg / kg (the highest dose tested) in dogs, there were no significant respiratory effects. Cardiovascular safety pharmacology assessment noted a reduction in PR interval duration, which was detected up to 9 hours after administration of compound 1 and was generally dose-related and associated with potential changes in heart rate. These changes are considered to be biologically insignificant because their magnitudes are small (compared to vehicle controls, up to 10msec), associated with a potential increase in heart rate and there is no related finding.

[0002] The absorption, distribution, metabolism and excretion characteristics of compound 1 have been characterized in vitro and in vivo studies. Sensitive and selective bioanalytical methods for rat and dog plasma have been developed and verified. After intravenous administration, the systemic clearance of compound 1 in all species evaluated is considered to be low. After oral administration, the bioavailability is generally greater than 30% in the species evaluated. Initial studies have utilized compound 1 free form. However, due to higher bioavailability, the tris salt form of compound 1 is selected for further development. See Tables 6, 7 and 10. All good laboratory practice (GLP) studies are carried out using compound 1 tris salt form. Unless otherwise stated, dose levels indicate compound 1 free form equivalents. Table 10. Summary of pharmacokinetic parameters following oral gavage administration of Compound 1 free form or tris salt form in rats (mean ± SD). AUC 0-24 = Area under the concentration-time curve from time zero to 24 h; C max = maximum observed concentration; NA = not applicable; PO = oral; SD = standard deviation; T max = time to reach maximum observed concentration.

[0003] Compound 1 was administered to Sprague-Dawley rats by oral gavage at doses of 25, 75 and 250 mg / kg / day (females) and 40, 120 and 400 mg / kg / day (males) for 28 days. From day 8 to day 24, 8 of 15 toxic male rats administered at 400 mg / kg / day experienced Compound 1-related deaths. The Compound 1-related effects in male rats administered at 400 mg / kg / day and female rats administered at 250 mg / kg / day were weight loss, reduced food consumption, clinical pathological changes in hematology and serum chemistry parameters, and histopathological changes. Target tissues included bone marrow, spleen, thymus, liver, lymph nodes, epididymis, seminal vesicles, prostate, testis, uterus, and ovary. Administration of 40 or 120 mg / kg / day of Compound 1 to male rats and 25 or 75 mg / kg / day of the compound to female rats via oral gavage, once daily (QD), for 4 weeks with a 4-week recovery period was well tolerated. Based on these adverse findings, the no-observed-adverse-effect level (NOAEL) was considered to be 120 mg / kg / day in male rats and 75 mg / kg / day in female rats, with the maximum observed concentration (C max ) were 180,000 ng / mL and 198,000 ng / mL, respectively, and the area under the concentration-time curve (AUC) in the time interval from 0 to 24 hours after administration (AUC 0-24) were 2,780,000 ng·h / mL and 3,230,000 ng·h / mL respectively.

[0004] In a range finding study, compound 1 was administered to beagles at doses of 30 mg / kg, 79 mg / kg, 240 mg / kg, or 790 mg / kg by oral gavage. Watery stools and vomiting were occasionally observed in dogs at all dose levels. Male dogs administered 790 mg / kg of compound 1 had increased potassium and decreased sodium and chloride, indicating that compound 1-related effects on electrolyte homeostasis may occur. Reduced thymus weight was observed at ≥240 mg / kg, and it was associated with reduced thymic lymphocyte structure found under the microscope. In a key repeated dose toxicity study, compound 1 was administered at doses of 10, 50, and 150 mg / kg / day for 28 days. Based on the lack of adverse findings, the NOAEL in dogs is considered to be 150 mg / kg / day, with the relevant gender combined C max The AUC was 80,400 ng / mL and the gender combined AUC 0-24 It is 474,000ng·h / mL. Example 6: Effect of the combination of Compound 1 and approved IPF drugs in a bleomycin-induced pulmonary fibrosis mouse model (therapeutic treatment)

[0005] Compound 1 weakens the transition of fibroblasts to myofibroblasts and reduces the production of extracellular matrix protein α-smooth muscle actin (αSMA) in primary human lung fibroblasts. Compound 1 also reduces pulmonary fibrosis in the IPF mouse model induced by bleomycin, where the minimum effective dose is 3 mg / kg, twice a day (BID). The reduction of pulmonary fibrosis after MCT4 inhibition is linked to changes in serum metabolites, which indicate increased turnover and fatty acid oxidation of extracellular matrix proteins. In the IPF mouse model induced by bleomycin in elderly (>60 weeks) mice, compound 1 has also demonstrated a reduction in pulmonary fibrosis and a reduction in lung lactate levels.

[0006] The effects of Compound 1 alone or in combination with the approved IPF drugs pirfenidone or nintedanib were investigated therapeutically in a bleomycin-induced pulmonary fibrosis model. Compound 1 was dosed at 3 mg / kg, BID; pirfenidone was dosed at 100 mg / kg, BID; and nintedanib was dosed at 50 mg / kg, QD, all via oral gavage. The results of this study are shown in Fig.23 .

[0007] The addition of pirfenidone or nintedanib to compound 1 did not produce a statistically significant additive effect on either Ashcroft score or αSMA quantification. Example 7: Phase I regimen

[0008] Phase 1 studies will be randomized, double-blind, placebo-controlled, single ascending dose and multiple ascending dose studies in sequential groups within each study portion. Unless otherwise specified, all Phase I studies will be conducted using the tris salt form of Compound 1. The objectives and endpoints of the studies are presented in Table 11. Table 11. Objectives and endpoints Abbreviations: AE = adverse event; AR AUC =Based on AUC 0-τ Accumulation ratio; AUC 0-∞ = Area under the concentration-time curve extrapolated from time 0 to infinity; AUC 0-tlast = Area under the concentration-time curve from time 0 to the time of the last quantifiable concentration; AUC 0-τ = area under the concentration-time curve within the dosing interval (τ); C max = maximum observed concentration; DL CO = diffusion capacity for carbon monoxide; ECG = electrocardiogram; [ 18 F]FDG-PET = 2-[Fluoro-18]-fluoro-2-deoxy-D-glucose positron emission tomography; fe t1-t2 = percentage of the administered dose recovered within the time interval t1 to t2; FEV 1 = forced expiratory volume in 1 second; FVC = forced vital capacity; FVC%pred = percentage of predicted forced vital capacity; IPF = idiopathic pulmonary fibrosis; PK = pharmacokinetics; QTc = QT interval corrected for heart rate; SpO 2 = oxygen saturation; t 1 / 2 = apparent terminal elimination half-life; t max = time to reach maximum observed concentration.

[0009] Part A will evaluate the safety, tolerability, pharmacokinetics (PK) and food effects of a single dose of compound 1 tris salt in healthy subjects, and Part B will evaluate multiple oral doses in healthy subjects. Part C will evaluate the safety, tolerability and PK of a single dose of compound 1 tris salt in healthy elderly subjects. Part D will be an exploratory, multiple dose, placebo-controlled, safety, tolerability, PK and pharmacokinetics (PD) study in patients with idiopathic pulmonary fibrosis (IPF). Parts A, B and C will be conducted at a single site; Part D will be conducted at multiple clinical sites.

[0010] Doses may be adjusted down or up, delayed, not administered, or repeated. Dose increases between groups in Parts A and B will not exceed 5-fold for predicted nonpharmacologically active dose levels and will not exceed 3-fold for predicted pharmacologically active dose levels. There will be a minimum of 6 days between dose escalations to allow adequate time for a full safety review. Schematics of the planned groups for Parts A and C and Parts B and D, respectively, are presented in Fig.21 and 22 In Part A, it was assumed that the dose level of each subsequent group increased and each single ascending dose (SAD) group in Part A was sentinel dosing. Part A: Single ascending dose

[0011] Part A will include a single-dose, sequential group design. Five dose groups of healthy subjects are planned, and healthy subjects are randomized to a single oral dose of compound 1 tris salt or placebo, with one group including a 2-period crossover group to study the effect of food. Sentinel dosing will be used for all SAD groups. The SAD part will include: • Screening visit was conducted 2 days to 4 weeks prior to the dose of investigational medicinal product (IMP). • A 4-day in-clinic treatment period with enrollment at the study site on Day -1, including a 48-hour period after dosing. On Day 1, prior to dosing, eligible subjects were randomized to either Compound 1 tris salt or placebo. • Safety follow-up will be conducted 10 (± 1) days after dosing.

[0012] Dosing will be performed on Day 1. Safety assessments will include adverse events (AEs), laboratory evaluations (hematology, clinical chemistry, and urinalysis), electrocardiograms (ECGs), vital signs, and physical examinations. Blood and urine samples will be collected from pre-dose to 48 hours post-dose to determine the PK profile of Compound 1 tris salt. Part B: Multiple ascending doses

[0013] Part B will include a multiple-dose, sequential group study. Three dose groups of healthy subjects are planned, and healthy subjects are randomized to multiple oral doses of Compound 1 tris salt or placebo. If the apparent terminal elimination half-life (t 1 / 2 ) is shorter or longer than predicted by nonclinical data, further dose escalation may be required to include revised dose schedules for Parts B and D. The multiple ascending dose parts will include: • A screening visit is performed 2 days to 4 weeks prior to the first dose of IMP. • A 10-day in-clinic treatment period with enrollment at the study site on Day -1, including a 48-hour period after the last dose. On Day 1, prior to administration, eligible subjects were randomized to either Compound 1 tris salt or placebo. A safety follow-up will be conducted 10 (± 2) days after the final dose.

[0014] For all subjects, it is planned to be administered once a day (QD) from the 1st day to the 7th day (including the end value), at approximately the same time in each morning. The total daily dose administered will not exceed the exposure shown to be safe and well tolerated in Part A. Safety assessment will include AE, laboratory evaluation (hematology, clinical chemistry and urinalysis), ECG, vital signs and physical examination. Blood samples will be collected 4 hours after administration on the day 1 before the first dose and the last dose on the day of administration for analysis of 3-methylhistidine and metabolomics set. Blood samples will be collected before administration on the 1st day to 24 hours after administration, before administration on the 4th day to the 6th day, and before administration on the 7th day to 48 hours after administration, to determine the PK characteristics of compound 1tris salt. Part C: Single dose in healthy elderly subjects

[0015] Part C will include a single-dose, single-group, randomized design to evaluate safety, tolerability, and PK in healthy elderly subjects to ensure safety in elderly subjects before dosing in IPF patients. A healthy elderly subject group is planned to randomize healthy elderly subjects to a single oral dose of Compound 1 tris salt or placebo. The single-dose evaluation will include: • The screening visit is performed 2 days to 4 weeks prior to the dose of IMP. • A 4-day in-clinic treatment period with enrollment at the study site on Day -1, including a 48-hour period after dosing. On Day 1, prior to dosing, eligible subjects were randomized to either Compound 1 tris salt or placebo. • Safety follow-up will be conducted 10 (± 1) days after dosing.

[0016] Dosing will be performed on Day 1. Safety assessments will include AEs, laboratory evaluations (hematology, clinical chemistry, and urinalysis), ECG, vital signs, and physical examinations. Blood and urine samples will be collected from pre-dose to 48 hours post-dose to determine the PK profile of Compound 1 tris salt. Part D: Multiple Doses in Patients with Idiopathic Pulmonary Fibrosis

[0017] Part D will include a multiple-dose, single-arm, randomized design to evaluate safety, tolerability, PK, and PD in IPF patients. The patient portion of the study will include: • Screening visit 2 days to 5 weeks prior to the first dose of IMP. • Outpatient treatment period of minimum 7 days to maximum 28 days, including a Day 1 clinic visit and weekly clinic visits thereafter. On Day 1, prior to administration, eligible patients were randomized to either Compound 1 tris salt or placebo. A safety follow-up will be conducted 10 (± 2) days after the final dose.

[0018] For all patients, QD administration is planned at approximately the same time in each morning. The dosage will be administered at the research site on the 1st day and all other outpatient visits, and will be administered by the patient on the remaining days. The dosage level selected for Part D will be equal to or lower than the dosage level assessed as safe and well tolerated in Part B. Safety assessment will include AE, laboratory evaluation (hematology, clinical chemistry and urinalysis), ECG, vital signs and physical examination. The time point of the PK analysis results based on Part A, Part B and Part C on the last day of the 1st day and dosage administration, and before the administration on any other outpatient visit day, blood samples will be collected for PK analysis.

[0019] Dynamic positron emission tomography imaging of the lungs using the radiotracer 2[Fluoro-18]-fluoro-2-deoxy-D-glucose will be used to assess glucose uptake in the lungs at screening and weekly. Blood samples will be collected before the first dose on Day 1 and 4 hours after the last dose on the day of administration for analysis of 3-methylhistidine and the metabolomics panel. Pulse oximetry (SpO2) assessments; spirometry for forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1), and FEV1 / FVC assessments; and a diffusion capacity for carbon monoxide (DLCO) test will be performed at screening and clinic visits. Number of subjects

[0020] Each group in Part A, Part B, and Part C will have 8 subjects randomized 6:2 to Compound 1 tris salt:placebo. • For Part A, there will be approximately 40 subjects in total (8 subjects x 5 groups). • For Part B, there will be approximately 24 subjects in total (8 subjects x 3 groups). • For Part C, there will be approximately 8 subjects in total (8 subjects x 1 group). • For Part D, at least 8 and potentially up to 16 IPF patients will be studied in 1 group at a ratio of approximately 3 active substances to 1 placebo.

[0021] Additional groups may be utilized based on the need for more evaluations, or groups may be removed based on the data obtained. Main criteria for diagnosis and inclusion

[0022] Part A and Part B: healthy male and female subjects between 18 and 60 years of age (inclusive) with a body mass index of 18.0 kg / m at screening. 2 and 32.0kg / m 2 between.

[0023] Part C: healthy male and female subjects aged between 65 and 80 years (inclusive) with a body mass index of 18.0 kg / m at screening 2 and 32.0kg / m 2 between.

[0024] Part D: Male and female patients between 40 and 80 years of age (inclusive) with a diagnosis of IPF according to the 2018 American Thoracic Society / European Respiratory Society / Japanese Respiratory Society / Latin American Thoracic Society clinical practice guideline for the diagnosis of IPF based on multidisciplinary team discussion and high-resolution computed tomography performed within 1 year before informed consent. Patients must have a SpO2 measured by pulse oximetry at rest while breathing ambient air. 2 ≥ 90% for FVC and FEV1 1 ≥ 50% predicted, FEV1 1 Ratio to FVC ≥ 0.7 and DL corrected for hemoglobin CO 30% to 79% of the predicted value, inclusive. Exclusion criteria

[0025] Part A, Part B, and Part C: Unless otherwise specified or approved by the Investigator (or designee), subjects in Part A, Part B, and Part C will be excluded from the study if they meet any of the following criteria at the Screening Visit: Significant history or clinical manifestations of any metabolic, allergic, dermatologic, hepatic, renal, hematologic, pulmonary, cardiovascular, gastrointestinal, neurologic, respiratory, endocrine, or psychiatric disorder, history of significant hypersensitivity, intolerance, or allergy to any drug compound, food, or other substance, and / or history of gastric or intestinal surgery or resection that could alter the absorption and / or excretion of orally administered drugs (uncomplicated appendectomy and hernia repair would be permitted; cholecystectomy would not be permitted). Any of the following on a single 12-lead ECG at screening: o QTcF>450 ms in males or QTcF>470 ms in females, confirmed by calculating the raw value and the mean of 2 replicates. o QRS duration >110ms, confirmed by calculating the raw value and the average of 2 repetitions. o PR interval >220 ms, confirmed by calculating the raw value and the average of 2 repetitions. o Findings that make measurement of the QT interval (QTc) corrected for heart rate difficult or that make QTc data uninterpretable. oHistory of other risk factors for Torsades de Points (e.g., heart failure, hypokalemia, family history of long QT syndrome). Pulse rate ≥100 beats / minute or <40 beats / minute at screening. Positive hepatitis panel and / or positive human immunodeficiency virus test. Administered a coronavirus disease 2019 (COVID-19) vaccine within the past 30 days prior to administration. Use or intended use of any drug / product known to alter drug absorption, metabolism, or elimination, including St. John's wort, within 30 days prior to dosing; use or intended use of any prescription drug / product within 14 days prior to dosing; use or intended use of a slow-release drug / product that was believed to be active within 14 days prior to registration; and / or use or intended use of any over-the-counter drug / product, including vitamins, minerals, and phytotherapy / herbs / plant-derived preparations, within 7 days prior to registration. Participation in a clinical study involving administration of an investigational drug (new chemical entity) within the past 30 days or 5 half-lives (whichever is longer) prior to dosing. Have previously completed or withdrawn from this study of study compound 1 and have previously received compound 1. Men consuming >21 units / week and women consuming >14 units / week. A positive urine drug screen result at screening or registration or a positive alcohol test result at registration. · History of alcohol or drug / chemical abuse within 2 years prior to registration. Use of tobacco or nicotine-containing products within 3 months prior to enrollment or cotinine-positive at screening or enrollment. Consuming food or drinks containing poppy seeds, Seville orange, or grapefruit within 7 days prior to registration. · Received blood products within 2 months prior to registration. Donated blood within 3 months before screening, donated plasma within 2 weeks before screening, or donated platelets within 6 weeks before screening. Poor peripheral venous access. Part A and Part B: Systolic blood pressure >140 mmHg or <90 mmHg, or diastolic blood pressure >90 mmHg or <50 mmHg at screening and enrollment. Minor deviations from this range may be allowed if judged by the investigator to be not clinically significant. Part C: Systolic blood pressure >150 mmHg or <90 mmHg, or diastolic blood pressure >100 mmHg or <50 mmHg at screening and enrollment. Minor deviations from this range may be allowed if judged by the investigator to be not clinically significant.

[0026] Part D: Unless otherwise specified or approved by the Investigator (or designee), patients in Part D will be excluded from the study if they meet any of the following criteria at the Screening Visit. Serious or uncontrolled medical, surgical, or psychiatric illness that, in the opinion of the investigator, would compromise the patient's safety. History of acute exacerbation of IPF within 3 months prior to screening, history of malignancy within 5 years prior to screening (except treated squamous and basal cell skin cancer and treated stage 0 / in situ cervical cancer), and / or history of emphysema or clinically significant respiratory disease (except IPF). Planned surgery during the study period (Day 1 to follow-up). • Findings on surgical lung biopsy (history), HRCT imaging, transbronchial lung biopsy (history), or bronchoalveolar lavage (history) that diagnose an alternative condition other than UIP. Other known causes of interstitial lung disease (eg, drug toxicity, environmental exposures, connective tissue disorders). End-stage fibrotic disease with an expected need for organ transplantation within 6 months. Clinically significant findings that could compromise patient safety based on medical history (other than IPF), 12-lead ECG, vital sign measurements, or clinical laboratory evaluations. Positive hepatitis panel and / or positive human immunodeficiency virus test. Killed and inactivated vaccines (e.g., pneumonia and influenza) administered ≤ 14 days before screening, or live attenuated vaccines (e.g., varicella) administered ≤ 2 months before screening. Taking systemic corticosteroids, cytotoxic therapy (e.g., chlorambucil, azathioprine, cyclophosphamide, or methotrexate), vasodilator therapy for pulmonary hypertension (e.g., bosentan), or unapproved treatment for IPF (e.g., interferon-γ, penicillamine, cyclosporine, mycophenolate mofetil, or N-acetylcysteine) within 4 weeks before screening. o Treatment with pirfenidone or nintedanib, but not concurrently, was permitted provided that the patient had been receiving a stable dose for at least 4 weeks prior to screening and that the dose was expected to remain constant throughout enrollment (i.e., from signing of the ICF to the last protocol-specified assessment, whether scheduled or unscheduled). Use or intended use of any drug / product known to alter drug absorption, metabolism, or elimination, including St. John's wort, within 30 days prior to dosing; use or intended use of any new prescription drug / product within 14 days prior to dosing; use or intended use of a slow-release drug / product that was thought to be active within 14 days prior to the Day 1 dose; and / or use or intended use of any over-the-counter drug / product, including vitamins, minerals, and phytotherapy / herbs / plant-derived preparations, within 7 days prior to the Day 1 dose. Participation in a clinical study involving administration of an investigational drug (new chemical entity) within the past 30 days or 5 half-lives (whichever is longer) prior to the Day 1 dose. Have previously completed or withdrawn from this study of study compound 1 and have previously received compound 1. Men consume >21 units of alcohol per week and women consume >14 units per week. One unit of alcohol is equal to 12 oz (360 mL) of beer, 1 1 / 2 oz (45 mL) of liquor, or 5 oz (150 mL) of wine. Positive urine drug screen (including cotinine) or positive alcohol test result at Screening or Day 1. · History of alcohol or drug / chemical abuse within 2 years prior to Day 1 dose. Use of tobacco or nicotine-containing products within 3 months prior to the Day 1 dose. Consuming foods or drinks containing poppy seeds, lime, or grapefruit, or green, white leaf, or oolong tea or extracts within 7 days before the Day 1 dose. Received blood products within 2 months prior to the Day 1 dose. Donated blood within 3 months before screening, donated plasma within 2 weeks before screening, or donated platelets within 6 weeks before screening. Poor peripheral venous access. Dose selection

[0027] The safety of compound 1 tris salt was evaluated in 7-day and 28-day studies in rats and dogs. The effects associated with compound 1 tris salt in the 28-day rat GLP study were weight loss, reduced food consumption, clinical pathological changes in hematology and serum chemistry parameters, and histopathological changes at 400 mg / kg / day in males and 250 mg / kg / day in females. The NOAEL for this rat study was 120 mg / kg / day for males and 75 mg / kg / day for females. There were no adverse effects associated with compound 1 tris salt in the 28-day dog ​​GLP study. The NOAEL determined in the 28-day dog ​​GLP study was 150 mg / kg / day. These correspond to the human equivalent doses (HEDs) of the following: Rat: 75 mg / kg × 0.16 = 12 mg / kg Dog: 150 mg / kg x 0.54 = 81 mg / kg

[0028] The 0.16 and 0.54 are conversion factors used to extrapolate animal doses to HED based on body surface area.

[0029] Rats are the most sensitive species (ie, have the lowest HED), and assuming a 10-fold safety margin, this equates to the following recommended maximum starting doses: Or 1.2 mg / kg × 60 kg = 72 mg in a 60-kg subject

[0030] Using the principle of allometry, human PK parameters were predicted based on single-dose oral PK parameters. Based on the predicted human PK parameters and the minimum effective dose in the mouse IPF study, the clinically effective dose was predicted to be approximately 30 mg to 80 mg. Study Drugs, Dosages, and Routes of Administration

[0031] 25 mg and 100 mg Compound 1 tris salt capsules. Route of administration: Oral.

[0032] The proposed dose levels for Part A are: a single dose of 50 mg is initiated, with subsequent planned doses of 75 mg, 100 mg, 150 mg, and 200 mg of compound 1 tris salt. The dose increase between groups will not exceed 3-fold. Dose escalation will be performed only if data from a minimum of 6 subjects from the previous lower dose group have been reviewed, so that the data from a minimum of 4 subjects receiving compound 1 tris salt will be used to make dose escalation decisions.

[0033] Proposed Dose Levels for Part B: The dose levels, dosing frequency, and dosing duration for Part B will be determined in consultation with the Sponsor based on the data from Part A of the study. The total daily exposure to the tris salt of Compound 1 administered during this part of the study will not exceed that shown to be safe and well tolerated in Part A. Dose escalation will be performed only if data from a minimum of 6 subjects from the previous lower dose group have been reviewed, so that data from a minimum of 4 subjects receiving the tris salt of Compound 1 will be used to make dose escalation decisions. The dose increase between groups will not exceed 3-fold.

[0034] Proposed Dose Levels for Part C: The dose levels for Part C will be determined in consultation with the sponsor based on the data from Part A of the study. Healthy elderly subjects will be dosed at a dose level lower than the highest dose level found to be safe and well tolerated in Part A.

[0035] Proposed dose level for Part D: The dose level, dosing frequency, and duration of dosing for Part D will be determined in consultation with the sponsor based on preliminary data from Part B of the study. The total daily exposure to the tris salt of Compound 1 administered in Part D will not exceed that shown to be safe and well tolerated in Part B. Part D may be initiated after review of the safety and tolerability data obtained from single-dose administration in healthy elderly subjects in Part C.

[0036] The dietary status of the groups in Part A will be fasting prior to the food effect evaluation group. The dietary status of subsequent groups in Part A may be fasting or fed based on review of preliminary PK data from the food effect evaluation group. The dietary status for dosing in Parts B, C, and D will be determined after review of the food effect evaluation in Part A and preliminary PK data for early groups in Part B, as applicable.

[0037] All references, patents, or applications (whether U.S. or foreign) cited in this application are hereby incorporated by reference as if fully written herein. In the event of any inconsistency, the material disclosed in this text shall prevail.

[0038] From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of the present disclosure, and without departing from the spirit and scope of the disclosure, can make various changes and modifications of the disclosure to adapt it to various usages and conditions.

Claims

1. A compound having form A of formula I 2. The compound of claim 1, which is non-solvated.

3. The compound of claim 1 or 2, wherein the compound has differential scanning calorimetry data showing a major melting endotherm with an onset temperature of about 157°C.

4. The compound of claim 3, wherein the compound has a differential scanning calorimetry trace substantially as shown in Figure 2.

5. A compound as claimed in any one of claims 1 to 4, wherein the compound has a TGA trace substantially as shown in Figure 2.

6. A compound as claimed in any one of claims 1 to 5 having a FT-Raman spectrum substantially as shown in Figure 1.

7. A compound according to claim 6 having an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 3.

8. A compound having structural formula I, which is amorphous 9. A compound having form A of formula II 10. The compound of claim 9 which is non-solvated.

11. The compound of claim 9 or 10, wherein the compound has differential scanning calorimetry data showing a melting endotherm with an onset temperature of about 147°C.

12. The compound of claim 11, wherein the compound has a differential scanning calorimetry trace substantially as shown in Figure 6.

13. A compound as claimed in any one of claims 9 to 12, wherein the compound has a TGA trace substantially as shown in Figure 6.

14. The compound of any one of claims 9 to 13, characterized by the presence of about 1604 cm -1 、1438cm -1 and 995cm -1 FT-Raman peak.

15. The compound of claim 14 characterized by a -1 、1438cm -1 、1372cm -1 、995cm -1 、332cm -1 、234cm -1 and 173cm -1 FT-Raman peak.

16. A compound as claimed in claim 14 having a FT-Raman spectrum substantially as shown in Figure 5.

17. The compound of any one of claims 9 to 16, having an X-ray powder diffraction (XRPD) pattern having peaks at about 7.79, 15.61, 16.71, 20.00, and 20.88 ± 0.3 degrees 2θ, wherein the XRPD is measured using a Cu radiation incident beam.

18. The compound of claim 17, having an X-ray powder diffraction (XRPD) pattern having peaks at about 7.79, 12.59, 15.61, 16.71, 20.00, 20.88, and 21.50 ± 0.3 degrees 2θ, wherein the XRPD is measured using a Cu radiation incident beam.

19. The compound of claim 17, having an X-ray powder diffraction (XRPD) pattern having peaks at about 7.79, 12.18, 12.59, 15.61, 16.71, 17.38, 17.72, 19.16, 20.00, 20.88, and 21.50 ± 0.3 degrees 2θ, wherein the XRPD is measured using a Cu radiation incident beam.

20. The compound of claim 17 having d-spacings of about 11.34, 5.67, 5.30, 4.44, and An X-ray powder diffraction (XRPD) pattern having a peak at, wherein the XRPD is measured using a Cu radiation incident beam.

21. The compound of claim 17 having d-spacings of about 11.34, 7.02, 5.67, 5.30, 4.44, 4.25, and An X-ray powder diffraction (XRPD) pattern having a peak at, wherein the XRPD is measured using a Cu radiation incident beam.

22. The compound of claim 17 having d-spacings of about 11.34, 7.26, 7.02, 5.67, 5.30, 5.10, 5.00, 4.63, 4.44, 4.25, and An X-ray powder diffraction (XRPD) pattern having a peak at, wherein the XRPD is measured using a Cu radiation incident beam.

23. The compound of claim 17 having an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 7.

24. A process for preparing a compound having Form A of formula II, the process comprising combining a compound having formula I with tris(hydroxymethyl)aminomethane in a solvent and isolating the compound having Form A of formula II.

25. A compound having form B of formula II 26. The compound of claim 25 which is non-solvated.

27. The compound of claim 25 or 26, wherein the compound has differential scanning calorimetry data showing a melting endotherm with an onset temperature of about 148°C.

28. The compound of claim 27, wherein the compound has a differential scanning calorimetry trace substantially as shown in Figure 10.

29. A compound as claimed in any one of claims 25 to 28, wherein the compound has a TGA trace substantially as shown in Figure 10.

30. The compound of any one of claims 25 to 29, characterized by the presence of about 1601 cm -1 、1545cm -1 、1468cm -1 、1437cm -1 、999cm -1 、995cm -1 and 234cm -1 FT-Raman peak.

31. The compound of claim 30 characterized by the presence of about 2946 cm -1 、1601cm -1 、1545cm -1 、1507cm -1 、1468cm -1 、1437cm -1 、1374cm -1 、1345cm -1 、1043cm -1 、999cm -1 、995cm -1 、284cm -1 、234cm -1 and 186cm -1 FT-Raman peak.

32. The compound of any one of claims 25 to 31 having an X-ray powder diffraction (XRPD) pattern having peaks at about 9.29, 9.70, 16.36, 19.12 and 20.15 degrees 2θ, wherein the XRPD is measured using a Cu radiation incident beam.

33. The compound of claim 32, having an X-ray powder diffraction (XRPD) pattern having peaks at about 9.29, 9.70, 10.03, 16.36, 19.12, 19.49, 19.61, 20.15, and 21.68 degrees 2θ, wherein the XRPD is measured using a Cu radiation incident beam.

34. The compound of claim 32 having an X-ray powder diffraction (XRPD) pattern having peaks at about 9.29, 9.70, 10.03, 11.14, 11.73, 16.36, 16.71, 19.12, 19.49, 19.61, 20.15, 20.52, 20.73, and 21.68 degrees 2θ, wherein the XRPD is measured using a Cu radiation incident beam.

35. The compound of claim 32 having d-spacings of about 9.51, 9.11, 5.41, 4.64, and An X-ray powder diffraction (XRPD) pattern having a peak at, wherein the XRPD is measured using a Cu radiation incident beam.

36. The compound of claim 32 having d-spacings of about 9.51, 9.11, 8.81, 5.41, 4.64, 4.55, 4.52, 4.40, and An X-ray powder diffraction (XRPD) pattern having a peak at, wherein the XRPD is measured using a Cu radiation incident beam.

37. The compound of claim 32 having d-spacings of about 9.51, 9.11, 8.81, 7.93, 7.54, 5.41, 5.30, 4.64, 4.55, 4.52, 4.40, 4.32, 4.28, and An X-ray powder diffraction (XRPD) pattern having a peak at, wherein the XRPD is measured using a Cu radiation incident beam.

38. The compound of claim 32 having an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 11.

39. A compound as described in claim 32, characterized by a monoclinic lattice type and a P21 / c space group having unit cell lengths of three axes of approximately (a) 26.526A, (b) 5.940A, and (c) 19.055A and three unit cell angles of approximately (a) 90.00°, (β) 90.00°, and (γ) 93.123°.

40. The compound of any one of claims 25 to 39, wherein the compound is stable at 25°C and 58% relative humidity for at least 2 weeks.

41. The compound of any one of claims 25 to 39, wherein the compound is stable at 40°C and 75% relative humidity for at least 2 weeks.

42. The compound of any one of claims 25 to 39, wherein the compound is stable at 80°C and ambient relative humidity for at least 2 weeks.

43. A process for preparing a compound having Form B of structural formula II, the process comprising stirring a compound having Form A of structural formula II with a suitable solvent, adding seed crystals of a compound having Form B of structural formula II, and isolating the compound having Form B of structural formula II.

44. A pharmaceutical composition comprising a compound as claimed in any one of claims 1 to 42 and a pharmaceutically acceptable carrier, adjuvant or vehicle.

45. A pharmaceutical composition comprising a compound as described in any one of claims 1 to 42 and a pharmaceutically acceptable carrier, adjuvant or vehicle, wherein the composition does not contain a detectable Group A tris salt.

46. ​​A method for inhibiting the activity of monocarboxylate transporter MCT4 or a mutant thereof in a biological sample, the method comprising the step of contacting the biological sample with a compound according to any one of claims 1 to 42.

47. A method for inhibiting the activity of monocarboxylate transporter MCT4 or a mutant thereof in a patient, the method comprising the step of administering to the patient a compound as claimed in any one of claims 1 to 42.

48. A method for selectively inhibiting the activity of monocarboxylate transporter MCT4 or a mutant thereof relative to monocarboxylate transporter MCT1 or a mutant thereof in a patient, the method comprising the step of administering to the patient a compound as claimed in any one of claims 1 to 42.

49. The method of claim 48, wherein the inhibition is at least 100-fold selective for MCT4 over MCT1.

50. 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 as claimed in any one of claims 1 to 42.

51. The method of claim 50, wherein the subject is a human.

52. The method of claim 50, wherein the subject is in a fed state.

53. The method of claim 50, wherein the subject is in a fasting state.

54. The method of claim 50, wherein the monocarboxylate transporter MCT4-mediated disorder is selected from an inflammatory disorder and a proliferative disorder.

55. The method of claim 50, wherein the monocarboxylate transporter MCT4-mediated disorder is a proliferative disorder.

56. The method of claim 55, wherein the proliferative disorder is cancer.

57. The method of claim 56, wherein the cancer is selected from adenocarcinoma, adult T-cell leukemia / lymphoma, bladder cancer, blastoma, bone cancer, breast cancer, brain cancer, epithelial cancer, myeloid sarcoma, cervical cancer, colorectal cancer, esophageal cancer, gastrointestinal cancer, glioblastoma multiforme, glioma, gallbladder cancer, gastric cancer, head and neck cancer, Hodgkin's lymphoma, non-Hodgkin's lymphoma, intestinal cancer, kidney cancer, laryngeal cancer, leukemia, lung cancer, lymphoma, liver cancer, Small cell lung cancer, non-small cell lung cancer, mesothelioma, multiple myeloma, eye cancer, optic nerve tumors, oral cancer, ovarian cancer, pituitary tumors, primary central nervous system lymphoma, prostate cancer, pancreatic cancer, pharyngeal cancer, renal cell carcinoma, rectal cancer, sarcoma, skin cancer, spinal cord tumors, small intestine cancer, stomach cancer, T-cell lymphoma, testicular cancer, thyroid cancer, laryngeal cancer, genitourinary system tumors, urothelial carcinoma, uterine cancer, vaginal cancer and Wilms' tumor.

58. The method of claim 54, wherein the monocarboxylate transporter MCT4-mediated disorder is an inflammatory disorder.

59. The method of claim 58, wherein the inflammatory disorder is selected from Crohn's disease, ulcerative colitis, idiopathic pulmonary fibrosis, muscular dystrophy, rheumatoid arthritis, and systemic sclerosis (scleroderma).

60. The method of claim 59, wherein the inflammatory disorder is idiopathic pulmonary fibrosis.

61. The method of any one of claims 50-60, wherein the therapeutically effective amount is between about 30 mg and about 200 mg.

62. The method of claim 61, wherein the therapeutically effective amount is between about 30 mg and about 80 mg.

63. The method of claim 61, wherein the therapeutically effective amount is selected from 50 mg, 75 mg, 100 mg, 150 mg and 200 mg.

64. A method of treating a monocarboxylate transporter MCT4-mediated disorder in a subject in need thereof, the method comprising sequentially or co-administering a compound as described in any one of claims 1 to 42 and another therapeutic agent.

65. The method of claim 64, wherein the monocarboxylate transporter MCT4-mediated disorder is a metabolic disease.

66. The method of claim 65, wherein the metabolic disease is selected from metabolic syndrome, diabetes, dyslipidemia, fatty liver disease, nonalcoholic steatohepatitis, obesity, and insulin resistance.

67. The method of claim 66, wherein the diabetes is type II diabetes.

68. The method of claim 66, wherein the dyslipidemia is hyperlipidemia.

69. The method of claim 64, wherein the therapeutic agent is selected from paracetamol, acetaminophen, pirfenidone, nintedanib, and non-hormonal contraceptives.

70. A method for achieving an effect in a patient, the method comprising administering to the patient a therapeutically effective amount of a compound as described in any one of claims 1 to 42, wherein the effect is selected from the group consisting of: Triglyceride reduction, cholesterol reduction, and hemoglobin A1c reduction.

71. The method of claim 70, wherein the cholesterol is selected from LDL and VLDL cholesterol.

72. The method of claim 70, wherein the triglycerides are selected from plasma triglycerides and liver triglycerides.

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