Compositions and methods for inducing ferroptosis

Abstract

The disclosure provides compounds, e.g., compounds of Formula I, and their use in treating medical diseases or disorders, such as cancer. The compounds are contemplated to be modulators of, e.g., inducers of, ferroptosis.

Description

COMPOSITIONS AND METHODS FOR INDUCING FERROPTOSISCROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of, and priority to, U.S. Provisional Patent Application No. 63 / 550,698, filed on February 7, 2024; the content of which is hereby incorporated by reference herein in its entirety.BACKGROUND

[0002] Diseases such as cancer, autoimmune diseases, and fibrosis manifest when cells in the body exhibit uncontrolled, abnormal cell growth and proliferation. In order to treat hyperproliferative diseases, the standard of care therapies induce cell death by a cellular process called apoptosis. The apoptosis pathway is engaged by many common types of anticancer therapies and ionizing radiation, which contributes to the regression of tumors or the toxic side effects of treatment.

[0003] Given the ability for hyperproliferative cells to resist cell death by current apoptosis-driven therapeutics, there is a need for the development of new methods, compounds, and compositions of and for inducing cell death in hyperproliferative cells.SUMMARY

[0004] The disclosure is directed, in part, to compounds that modulate, for example, induce, ferroptosis in a cell, a tissue, or a tumor in a patient or subject. Also disclosed herein are pharmaceutical compositions comprising at least one disclosed compound and a pharmaceutically acceptable carrier or excipient. In some embodiments, the present disclosure provides a method of treating a disease or disorder amenable to modulation, e.g., induction, of ferroptosis. In some embodiments, the disease or disorder is a cancer.

[0005] For example, disclosed herein is a compound represented by Formula I:or a pharmaceutically acceptable salt and / or a stereoisomer thereof, wherein:R1is selected from the group consisting of C1-C10alkyl, C2-Cioalkenyl, C2-Cioalkynyl, 5-6 membered monocyclic heteroaryl, and 8-10 membered bicyclic heteroaryl; wherein R1may optionally be substituted with one more substituents each independently selected from R11;R11is independently selected for each occurrence from the group consisting of halogen, deuterium, hydroxyl, -CN, -NO2, -NRaRb, oxo, -C(=O)NRaRb, -NRa(C=O)Rb, - O(C=O)NRaRb, -NRa(C=O)ORb, -NRa(C=O)NRaRb, -(C=O)C1-C6alkyl, -(C=O)OC1-C6alkyl, -0(C=0)Ci-C2oalkyl, -0(C=0)Ci-C2ohaloalkyl, -0(C=0)Ci-C2oheteroalkyl, -O(C=O)OCi- C6alkyl, -SH, -SC1-C6alkyl, -S(O)C1-C6alkyl, -S(O)2Ci-C6alkyl, -S(O)2NRaRb, -NRaS(O)2Ci- C6alkyl, C1-C6alkyl, C1-C6alkoxy, C3-C6cycloalkyl. -Z -phenyl, -Z -naphthyl, -Z-(5-6 membered monocyclic heteroaryl), -Z-(8-10 membered bicyclic heteroaryl), -Z-(4-7 membered heterocyclyl), (phenyl)-Z-(phenyl), (phenyl)-Z-(5-6 membered heteroaryl), (5-6 membered heteroaryl)-Z-(phenyl), and (5-6 membered heteroaryl)-Z-(5-6 membered heteroaryl); wherein each alkyl, cycloalkyl, phenyl, heterocyclyl, and heteroaryl may optionally be substituted with one or more substituents each independently selected from R12; or two geminal R11groups, together with the carbon atom to which they are attached, may be joined together to form a C3-C6cycloalkyl or a 4-7 membered heterocyclyl optionally substituted with one or more substituents each independently selected from the group consisting of halogen, deuterium, hydroxyl, -NRaRb, -CF3, C1-C6alkyl, and C1-C6alkoxy;Z is selected from the group consisting of a bond, -O-, -C=C-, -CH2O-, -OCH2-, - O(CO)-, -C(O)O-, -NRa, -S-, -S(O), -S(O)2, and -HC=CH-;R12is independently selected for each occurrence from the group consisting of halogen, deuterium, hydroxyl, -CN, -NO2, -NRaRb, oxo, C1-C6alkyl, C1-C6alkoxy, C3- C6cycloalkyl, -C(=O)NRaRb, -NRa(C=O)Rb, -O(C=O)NRaRb, -NRa(C=O)ORb, - NRa(C=O)NRaRb, -(C=O)C1-C6alkyl, -(C=O)OC1-C6alkyl, -O(C=O)OC1-C6alkyl, -SH, -SCi- C6alkyl, -S(O)C1-C6alkyl, -S(O)2Ci-C6alkyl, -S(O)2NRaRb, and -NRaS(O)2Ci-C6alkyl; wherein each alkyl, alkoxy, and cycloalkyl may optionally be substituted with one or more substituents each independently selected from the group consisting of halogen, hydroxyl, and C1-C3alkoxy;R2is independently selected for each occurrence from the group consisting of halogen, hydroxyl, -CF3, -OCF3, C1-C6alkyl, and C1-C6alkoxy;R3is selected from the group consisting of hydrogen, C1-C6alkyl, -C(O)C1-C6alkyl, and -C(O)OC1-C6alkyl, -S(O)2C1-C6alkyl, and -P(O)(phenyl)2;Raand Rbare each independently selected for each occurrence from the group consisting of hydrogen and C1-C6alkyl, wherein C1-C6alkyl may optionally be substituted with one or more substituents each independently selected from the group consisting of halogen, deuterium, hydroxyl, and C1-C6alkoxy; orRaand Rb, together with the nitrogen to which they are attached, may be joined together to form a 4-7 membered heterocyclyl optionally substituted by one or more substituents each independently selected from the group consisting of halogen, deuterium, hydroxyl, -NRaRb, C1-C6alkyl, and C1-C6alkoxy; and p is 0, 1, 2, 3, or 4.

[0006] Also herein is a compound represented by Formula II:or a pharmaceutically acceptable salt and / or a stereoisomer thereof, wherein:R1is selected from the group consisting ofR13is selected from the group consisting of hydrogen, halogen, hydroxyl, -OCH3, - OCF3, and C2-Cealkoxy;R14is selected from the group consisting ofX and Y and Z are each independently selected from N and CR’, wherein R’ is selected independently for each occurrence from the group consisting of hydrogen, halogen, and C1-C6alkyl; andR15is independently selected for each occurrence from the group consisting of halogen, hydroxyl, -CH3, -CH(CH3)2, -C(CH3)2OH, -0(C0)CH3, -CF3, -OCH3, and -OCF3.

[0007] Also disclosed herein are pharmaceutical compositions comprising at least one compound of the disclosure and at least one pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical compositions comprise at least one additional therapeutic agent.

[0008] Further disclosed herein are methods of modulating, e.g., inducing, ferroptosis in a cell, tissue, or tumor, or a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound disclosed herein, or a pharmaceutical composition thereof.

[0009] For example, disclosed herein are methods of treating a patient suffering from a condition, disease, or disorder that is affected by, associated with, or would benefit from induction of ferroptosis in a cell, tissue, or tumor, or a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound disclosed herein, or a pharmaceutical composition thereof.

[0010] In some embodiments, the methods described herein may be useful to treat cancers including, but not limited to, a carcinoma, a sarcoma, or a melanoma. In some embodiments, the cancer may be, for example, a clear cell renal carcinoma, a non-clear cellrenal carcinoma, or a liver carcinoma. In some embodiments, the methods described herein may be useful to treat, for example, a fibrosis or a kidney disorder.DETAILED DESCRIPTION

[0011] The features and other details of the disclosure will now be more particularly described. Before further description of the present disclosure, certain terms employed in the specification, examples and appended claims are collected here. These definitions should be read in light of the remainder of the disclosure and as understood by a person of skill in the art. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by a person of ordinary skill in the art.Definitions

[0012] The term “treating” includes any effect, e.g., lessening, reducing, modulating, or eliminating, that results in the improvement of the condition, disease, disorder and the like.

[0013] The term “alkyl” as used herein refers to a saturated straight or branched hydrocarbon. Exemplary alkyl groups include, but are not limited to, straight or branched hydrocarbons of 1-6, 1-4, or 1-3 carbon atoms, referred to herein as Ci-ealkyl, Ci-4alkyl, and Ci-3alkyl, respectively. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-l -butyl, 3-methyl-2-butyl, 2-methyl-l -pentyl, 3-methyl-l- pentyl, 4-methyl-l -pentyl, 2-methyl-2 -pentyl, 3-methyl -2 -pentyl, 4-methyl-2-pentyl, 2,2- dimethyl-1 -butyl, 3, 3 -dimethyl- 1 -butyl, 2 -ethyl- 1 -butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, etc.

[0014] The term “alkenyl” as used herein refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon double bond. Exemplary alkenyl groups include, but are not limited to, a straight or branched group of 2-6 or 3-4 carbon atoms, referred to herein as Ci-Csalkenyl, C2-Cealkenyl, and Q-Cralkcnyl. respectively.Exemplary alkenyl groups include, but are not limited to, vinyl, allyl, butenyl, pentenyl, etc.

[0015] The term “alkynyl” as used herein refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon triple bond. Exemplary alkynyl groups include, but are not limited to, straight or branched groups of 2-6, or 3-6 carbon atoms, referred to herein as C2-6alkynyl, and Cvealkynyl. respectively. Exemplary alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, methylpropynyl, etc.

[0016] The term “alkoxy” as used herein refers to a straight or branched alkyl group attached to oxygen (alkyl-O-). Exemplary alkoxy groups include, but are not limited to, alkoxy groups of 1-6 or 2-6 carbon atoms, referred to herein as Ci-Csalkoxy, C1-C6alkoxy, and C2-Cealkoxy, respectively. Exemplary alkoxy groups include, but are not limited to methoxy, ethoxy, isopropoxy, etc.

[0017] The term “aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 p electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“Ce-14 aryl”). In some embodiments, an aryl group has six ring carbon atoms (“Ce aryl”; e.g., phenyl). In some embodiments, an aryl group has ten ring carbon atoms (“C10 aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has fourteen ring carbon atoms (“Cu aryl”; e.g., anthracyl). “Aryl” also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system. Typical aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, and trinaphthalene. Particularly aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl. Examples of representative substituted aryls include the followingwherein one of R56and R57may be hydrogen and at least one of R56and R57is each independently selected from Ci-Cs alkyl, Ci-Cs haloalkyl, 4-10 membered heterocyclyl, alkanoyl, Ci-Cs alkoxy, heteroaryloxy, alkylamino, arylamino, heteroarylamino, NR58COR59, NR58SOR59NR58SO2R59, COOalkyl, COOaryl, CONR58R59, CONR58OR59, NR58R59, SO2NR58R59, S-alkyl, SOalkyl, SChalkyl, Saryl, SOaryl, SCharyl; or R56and R57may be joined to form a cyclic ring (saturated or unsaturated) from 5 to 8 atoms, optionally containing one or more heteroatoms selected from the group N, O, or S. R60and R61are each independently hydrogen, Ci-Cs alkyl, C1-C4 haloalkyl, C3-C10 cycloalkyl, 4-10membered heterocyclyl, C6-C10 aryl, substituted C6-C10 aryl, 5-10 membered heteroaryl, or substituted 5-10 membered heteroaryl.

[0018] The term “carbonyl” as used herein refers to the radical -C(O)-.

[0019] The term “cyano” as used herein refers to the radical -CN.

[0020] The terms “cycloalkyl” or a “carbocyclic group” as used herein refers to a saturated or partially unsaturated hydrocarbon group of, for example, 3-6, or 4-6 carbons, referred to herein as C3-C10cycloalkyl, C3-6cycloalkyl or C4-6cycloalkyl, respectively. Exemplary cycloalkyl groups include, but are not limited to, cyclohexyl, cyclopentyl, cyclopentenyl, cyclobutyl or cyclopropyl.

[0021] The terms “halo” or “halogen” as used herein refer to F, Cl, Br, or I.

[0022] The terms “haloalkyl” as used herein refers to an alkyl radical in which the alkyl group is substituted with one or more halogens. Typical haloalkyl groups include, but are not limited to, trifluoromethyl (i.e., CF3), difluoromethyl, fluoromethyl, chloromethyl, dichloromethyl, dibromoethyl, tribromomethyl, tetrafluoroethyl, and the like. Exemplary haloalkyl groups include, but are not limited to, straight or branched hydrocarbons of 1-6, 1-4, or 1-3 carbon atoms substituted with a halogen (i.e., Cl, F, Br and I), referred to herein as Ci-ehaloalkyl, C1-4 haloalkyl, and Ci-3haloalkyl, respectively.

[0023] The term “hetero” when used to describe a compound or a group present on a compound means that one or more carbon atoms in the compound or group have been replaced by a nitrogen, oxygen, or sulfur heteroatom. Hetero may be applied to any of the hydrocarbyl groups described above such as alkyl, e.g., heteroalkyl, cycloalkyl, e.g., heterocyclyl, aryl, e.g., heteroaryl, cycloalkenyl, e.g., cycloheteroalkenyl, and the like having from 1 to 5, and particularly from 1 to 3 heteroatoms.

[0024] The terms “heteroaryl” or “heteroaromatic group” as used herein refers to an aromatic 5-10 membered ring system containing one or more heteroatoms, for example one to three heteroatoms, such as nitrogen, oxygen, and sulfur. The term may also be used to refer to a 5-7 membered monocyclic heteroaryl or an 8-10 membered bicyclic heteroaryl. Where possible, said heteroaryl ring may be linked to the adjacent radical though carbon or nitrogen. Examples of heteroaryl rings include but are not limited to furan, thiophene, pyrrole, pyrrolopyridine, indole, thiazole, oxazole, isothiazole, isoxazole, imidazole, benzoimidazole, imidazopyridine, pyrazole, triazole, pyridine or pyrimidine, etc.

[0025] The terms “heterocyclyl,” “heterocycle,” or “heterocyclic group” are art- recognized and refer to saturated or partially unsaturated 3-12 membered ring structures, for example, 4-10 membered ring structures, for example, 4-8 membered ring structures, whose ring structures include one to three heteroatoms, such as nitrogen, oxygen, and sulfur, wherein the sulfur atom may be oxidized to SO or SO2.. Where possible, heterocyclyl rings may be linked to the adjacent radical through carbon or nitrogen. The term may also be used to refer to 4-10 membered saturated or partially unsaturated ring structures that are bridged, fused or spirocyclic ring structures, whose ring structures include one to three heteroatoms, such as nitrogen, oxygen, and sulfur. Examples of heterocyclyl groups include, but are not limited to, pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine, oxetane, azetidine, tetrahydrofuran, dihydrofuran, dihydropyran, tetrahydropyran, etc. Further examples include Examples of heterocyclic groups include, without limitation, epoxy, azetidinyl, aziridinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, pyrrolidinonyl, piperidinyl, piperazinyl, imidazolidinyl, imidazopyridinyl, thiazolidinyl, dithianyl, trithianyl, dioxolanyl, oxazolidinyl, oxazolidinonyl, decahydroquinolinyi, piperidonyl, 4-piperidinonyl, quinudidinyl, thiomorpholinyl, thiomorpholinyl 1,1 dioxide, morpholinyl, azepanyl, oxazepanyl, azabicyclohexanyls, azabicycloheptanyl, azabicyclooctanyls, azabicyclononanyls (e.g., octahydroindolizinyl), and azaspiroheptanyls. In some embodiments, the heterocycle is a spiro heterocycle. In some embodiments, the heterocycle is a bridged heterocycle. "Spiro heterocyclyl," or “spiro heterocycle” refers to a polycyclic heterocyclyl with rings connected through one common atom (called a spiro atom), wherein the rings have one or more heteroatoms selected from the group consisting of N, O, and S(O)m(wherein m is an integer of 0 to 2) as ring atoms.

[0026] The terms “hydroxy” and “hydroxyl” as used herein refers to the radical -OH.

[0027] The term “oxo” as used herein refers to the radical =0.

[0028] “Pharmaceutically or pharmacologically acceptable” include molecular entities and compositions that do not produce an adverse, allergic or other untoward reaction when administered to an animal, or a human, as appropriate. For human administration, preparations should meet sterility, pyrogenicity, and general safety and purity standards as required by FDA Office of Biologies standards.

[0029] The term “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” as used herein refers to any and all solvents, dispersion media, coatings, isotonicand absorption delaying agents, and the like, that are compatible with pharmaceutical administration. The use of such media and agents for pharmaceutically active substances is well known in the art. The compositions may also contain other active compounds providing supplemental, additional, or enhanced therapeutic functions.

[0030] The term “pharmaceutical composition” as used herein refers to a composition comprising at least one compound as disclosed herein formulated together with one or more pharmaceutically acceptable carriers.

[0031] ‘Individual,” “patient,” or “subject” are used interchangeably and include any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans. The compounds of the disclosure can be administered to a mammal, such as a human, but can also be administered to other mammals such as an animal in need of veterinary treatment, e.g., domestic animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, sheep, pigs, horses, and the like) and laboratory animals (e.g., rats, mice, guinea pigs, and the like). “Modulation” includes antagonism (e.g., inhibition), inverse agonism, agonism, biased agonism, biased signal transduction, functionally selective agonism, partial antagonism and / or partial agonism.

[0032] In the present specification, the term “therapeutically effective amount” means the amount of the subject compound that will elicit the biological or medical response of a tissue, system or animal, (e.g., mammal or human) that is being sought by the researcher, veterinarian, medical doctor or other clinician. The compounds of the disclosure are administered in therapeutically effective amounts to treat a disease. Alternatively, a therapeutically effective amount of a compound is the quantity required to achieve a desired therapeutic and / or prophylactic effect.

[0033] The term "pharmaceutically acceptable salt(s)" as used herein refers to salts of acidic or basic groups that may be present in compounds used in the compositions.Compounds included in the present compositions that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids. The acids that may be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, including, but not limited to, malate, oxalate, chloride, bromide, iodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate,gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluene sulfonate and pamoate (i.e., l,l'-methylene-bis-(2-hydroxy-3-naphthoate)) salts. Compounds included in the present compositions that are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations. Examples of such salts include alkali metal or alkaline earth metal salts, particularly calcium, magnesium, sodium, lithium, zinc, potassium, and iron salts. Compounds included in the present compositions that include a basic or acidic moiety may also form pharmaceutically acceptable salts with various amino acids. The compounds of the disclosure may contain both acidic and basic groups; for example, one amino and one carboxylic acid group. In such a case, the compound can exist as an acid addition salt, a zwitterion, or a base salt.

[0034] The compounds of the disclosure may contain one or more chiral centers and, therefore, exist as stereoisomers. The term “stereoisomers” when used herein consist of all enantiomers or diastereomers. These compounds may be designated by the symbols “(+),” “R” or “S,” depending on the configuration of substituents around the stereogenic carbon atom, but the skilled artisan will recognize that a structure may denote a chiral center implicitly. The present disclosure encompasses various stereoisomers of these compounds and mixtures thereof. Mixtures of enantiomers or diastereomers may be designated “(±)” in nomenclature, but the skilled artisan will recognize that a structure may denote a chiral center implicitly.

[0035] The compounds of the disclosure may contain one or more double bonds and, therefore, exist as geometric isomers resulting from the arrangement of substituents around a carbon-carbon double bond. The symbol — denotes a bond that may be a single, double or triple bond as described herein. Substituents around a carbon-carbon double bond are designated as being in the “Z” or “E” configuration wherein the terms “Z” and “E” are used in accordance with IUPAC standards. Unless otherwise specified, structures depicting double bonds encompass both the “E” and “Z” isomers. Substituents around a carboncarbon double bond alternatively can be referred to as “cis” or “trans,” where “cis” represents substituents on the same side of the double bond and “trans” represents substituents on opposite sides of the double bond.

[0036] Compounds of the disclosure may contain a carbocyclic or heterocyclic ring and therefore, exist as geometric isomers resulting from the arrangement of substituents around the ring. The arrangement of substituents around a carbocyclic or heterocyclic ring aredesignated as being in the “Z” or “E” configuration wherein the terms “Z” and “E” are used in accordance with IUPAC standards. Unless otherwise specified, structures depicting carbocyclic or heterocyclic rings encompass both “Z” and “E” isomers. Substituents around a carbocyclic or heterocyclic rings may also be referred to as “cis” or “trans,” where the term “cis” represents substituents on the same side of the plane of the ring and the term “trans” represents substituents on opposite sides of the plane of the ring. Mixtures of compounds wherein the substituents are disposed on both the same and opposite sides of plane of the ring are designated “cis / trans.”

[0037] Compounds described herein may be depicted to show stereochemistry using hashed or wedged bonds as shown below. For compounds with a stereogenic atom, when only one substituent is hashed or wedged, a 4thsubstituent can be interpreted to have the opposite orientation in space. For compounds with a stereogenic sulfoximine sulfur atom, when two substituents are both hashed or both wedged, the third and fourth substituents can be interpreted to have the opposite orientation in space.

[0038] Individual enantiomers and diastereomers of compounds of the present disclosure can be prepared synthetically from commercially available starting materials that contain asymmetric or stereogenic centers, or by preparation of racemic mixtures followed by resolution methods well known to those of ordinary skill in the art. These methods of resolution are exemplified by (1) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography and liberation of the optically pure product from the auxiliary, (2) salt formation employing an optically active resolving agent, (3) direct separation of the mixture of optical enantiomers on chiral liquid chromatographic columns or (4) kinetic resolution using stereoselective chemical or enzymatic reagents. Racemic mixtures can also be resolved into their component enantiomers by well-known methods, such as chiral-phase liquid chromatography or crystallizing the compound in a chiral solvent. Stereoselective syntheses, a chemical or enzymatic reaction in which a single reactant forms an unequal mixture of stereoisomers during the creation of a new stereocenter or during the transformation of a pre-existing one, are well known in the art. Stereoselective syntheses encompass both enantio- and diastereoselective transformations and may involve the use of chiral auxiliaries. For examples, see Carreira and Kvaemo, Classics in Stereoselective Synthesis, Wiley-VCH: Weinheim, 2009.

[0039] The compounds disclosed herein can exist in solvated as well as unsolvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the disclosure embrace both solvated and unsolvated forms. In one embodiment, the compound is amorphous. In one embodiment, the compound is a single polymorph. In another embodiment, the compound is a mixture of polymorphs. In another embodiment, the compound is in a crystalline form.

[0040] The disclosure also embraces isotopically labeled compounds of the disclosure which are identical to those recited herein, except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as2H,3H,13C,14C,15N,180,170,31P,32P,35S,18F, and36C1, respectively. For example, a compound of the disclosure may have one or more H atom replaced with deuterium.

[0041] Certain isotopically labeled disclosed compounds (e.g., those labeled with3H and14C) are useful in compound and / or substrate tissue distribution assays. Tritiated (i.e.,3H) and carbon-14 (i.e.,14C) isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e.,2H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances. Isotopically labeled compounds of the disclosure can generally be prepared by following procedures analogous to those disclosed in the examples herein by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0042] The term “prodrug” refers to compounds that are transformed in vivo to yield a disclosed compound or a pharmaceutically acceptable salt, hydrate or solvate of the compound. The transformation may occur by various mechanisms (such as by esterase, amidase, phosphatase, oxidative and or reductive metabolism) in various locations (such as in the intestinal lumen or upon transit of the intestine, blood or liver). Prodrugs are well known in the art (for example, see Rautio, Kumpulainen, et al, Nature Reviews Drug Discovery 2008, 7, 255). For example, if a compound of the disclosure or a pharmaceutically acceptable salt, hydrate or solvate of the compound contains a carboxylic acid functional group, a prodrug can comprise an ester formed by the replacement of the hydrogen atom of the acid group with a group such as (Ci-s)alkyl, (C2-i2)alkylcarbonyloxymethyl, l-(alkylcarbonyloxy)ethyl having from 4 to 9 carbon atoms, 1- methyl-l-(alkylcarbonyloxy)-ethyl having from 5 to 10 carbon atoms, alkoxy carbonyloxymethyl having from 3 to 6 carbon atoms, l-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, 1 -methyl- l-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms, l-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms, 3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl, di-N,N-(C1-2)alkylamino(C2-3)alkyl (such as [3- dimethylaminoethyl), carbamoyl-(Ci-2)alkyl, N,N-di(C1-2)alkylcarbamoyl-(C1-2)alkyl and piperidino-, pyrrolidino- or morpholino(C2-3)alkyl.

[0043] Similarly, if a compound of the disclosure contains an alcohol functional group, a prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a group such as (C1-6)alkylcarbonyloxymethyl, l-((Ci-6)alkylcarbonyloxy)ethyl, l-methyl-l-((C1-6)alkylcarbonyloxy)ethyl (C1-6)alkoxycarbonyloxymethyl, N-(C1- 6)alkoxycarbonylaminomethyl, succinoyl, (C1-6)alkylcarbonyl, a-amino(Ci-4)alkylcarbonyl, arylalkylcarbonyl and a-aminoalkylcarbonyl, or a-aminoalkylcarbonyl-a- aminoalkylcarbonyl, where each a -aminoalkylcarbonyl group is independently selected from the naturally occurring L-amino acids, P(O)(OH)2, -P(O)(O(C1-6)alkyl)2 or glycosyl (the radical resulting from the removal of a hydroxyl group of the hemiacetal form of a carbohydrate).

[0044] If a compound of the disclosure incorporates an amine functional group, a prodrug can be formed, for example, by creation of an amide or carbamate, an N- alkylcarbonyloxyalkyl derivative, an (oxodioxolenyl)methyl derivative, an N-Mannich base, imine or enamine. In addition, a secondary amine can be metabolically cleaved to generate a bioactive primary amine, or a tertiary amine can metabolically cleaved to generate a bioactive primary or secondary amine. For examples, see Simplicio, et al., Molecules 2008, 13, 519 and references therein.

[0045] Throughout this disclosure, various embodiments can be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of any embodiments. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range to the tenth of the unit of the lower limit unless the context clearly dictates otherwise. For example, description of a range such as from 1 to 6 should be considered tohave specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual values within that range, for example, 1.1, 2, 2.3, 5, and 5.9. This applies regardless of the breadth of the range. The upper and lower limits of these intervening ranges may independently be included in the smaller ranges, and are also encompassed within the disclosure, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the disclosure, unless the context clearly dictates otherwise.

[0046] Unless specifically stated or obvious from context, as used herein, the term “about” is understood as within a range of normal tolerance in the art, for example within 2 standard deviations of the mean. “About” can be understood as within plus or minus: 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, or 0.01% of the stated value. Unless otherwise clear from the context, all numerical values provided herein are modified by the term “about.” Where particular values are described in the application and claims, unless otherwise stated, the term “about” is implicit and in this context means within an acceptable error range for the particular value.

[0047] The term “anti-cancer agent” or “chemotherapeutic agent” and its grammatical equivalents as used herein refer to an agent that is capable of killing cells that divide rapidly (e.g., cancer cells), preventing the cells that divide rapidly from further dividing, of slowing the division of rapidly dividing cells. Exemplary anti -cancer agents provided herein can include ferroptosis inducing agents, can be used be used in combination with one or more additional ferroptosis inducing agents, can be used in combination with an iron-dependent cell death inducing agent, and / or can be used in combination with a second therapeutic agent or second active agent. The second therapeutic agent or second active agent can be in the form of a prodrug. The second therapeutic agent or second active agent can be in the form of a pharmaceutically acceptable salt. The second therapeutic agent or second active agent can be an alkylating agent such as a nitrogen mustard, can be chlorouracil, cyclophosphamide, isosfamide, melphalan, or bisulfan; a nitrosourea, which can be, for example, streptozocin, carmustine, or lomustine; an alkyl sulfonate such as busulfan; a triazine, such as dacarbazine or temozolomide; or an ethylenimine, such as thiotepa- or altretamine. The second therapeutic agent or second active agent can be an antimetabolite, which can be a purine antagonist, a pyrimidine antagonist or a folate antagonist, for example, 5 -fluorouracil, 6-mercaptopurine, capecitabine, cladribine, or clofarabine. Thesecond therapeutic agent or second active agent can be an anti-tumor antibiotic. The second therapeutic or second active agent can be a mitotic inhibitor. The second therapeutic or second active agent can be a corticosteroid. The second therapeutic agent or second active agent can be a plant alkaloid, for example, actinomycin D, a doxorubicin, or a mitomycin, such as mitomycin C. The second therapeutic agent or second active agent can be an antitumor antibiotic, for example, a doxorubicin, a mitoxantrone, or a bleomycin. The second therapeutic or the second active agent can be, for example, mechlorethamine, leucovorin, methotrexate, mercaptopurine, busulfan, chlorambucil, cyclophosphamide, vincristine, dactinomycin, vinblastine, thioguanine, procarbazine, floxuridine, fluorouracil, mitotane, bleomycin, doxorubicin, dacarbazine, lomustine, carmustine, cisplatin, asparaginase, streptozocin etoposide, ifosfamide, carboplatin,altretamine, fludarabine, pentostatin, paclitaxel, melphalan, teniposide, cladribine, vinorelbine, pegaspargase, thiotepa, docetaxel, gemcitabine, irinotecan, toptecan, idarubicin, capecitabine, daunorubicin, valrubicin, temozolomide, cytarabine, epirubicin, arsenic trioxide, mitomycin, oxaliplatin, pemetrexed disodium, clofarabine, nelarabine, ixabepilone, bendamustine hydrochloride, paratrexate, carbazitazel, erbulin mesylate, asparaginaseerwinia chrsanthemi, omacetaxine mepesuccinate, radium 223 dichloride, fluoxymesterone, methyltestosterone, tamoxifen, tamoxifen citrate, estramustine, interferon alpha 2b (recombinant), gosrelin, flutamide, aldeslukin, bicalutamide, anastrozole, porfimer, nilutamide, imiquimod, letrazole, rituximab. Toremifene, thalidomide, trastuzmad, alitretinonin, bexarotene, denileukin diftitox, exemestane, gemfluzumab ozogamicin, exemestane, gemtuzumab ozogamicin, triptorelin, alemtuzamub, imatinib, imatinim mesylate, peginterferon alpha 2-B, fulvestrant, iron, an iron comprising nanoparticle, ibritumomab tiuxetan, leuprolide, leuprolide acetate, abarelix, bortezomib, genfitinib, tositumomab and iodine I 131, tositumomab, bevacizumab, cetuximab, erlotinib, erlotinib hydrochloride, lenalidomide, sorafenib, sorafenib tosylate, dasatinib, decitabine, panitumamab, sunitinib, sunitinib malate, vorinostat, lapatinib, lapatinib ditosylate, nilotinib, temsirolimus, degarelix, everolimus, ofatumumab, pazopanib, pazopanib hydrochloride, romidepsin, denosumab, hydroxyurea, spuleucel-T, abiraterone, abiratone acetate, brentuximab vedotin, crizotinib, iplimumab, ruxolitinib, ruxolitinib phosphate, vandetanib, vemurafenib, pertuzumab, axitinib, bosutinib, carbozantinib, carfilzomib, enzalutamide, ponatinib, ponatinib hydrochloride, regorafenib, vismodegrib, ziv-aflibercept, dabrafenib, trametinib, obinutuzumab, adotrastuzumab emtansine, afatinib, ibrutinib, pomalidomide, idelalisib, belinostat, ceritinib, perbrolizumab, ramucirumab, lanreotide, blinatumomab, nivolumab, olaparib, a checkpoint inhibitor, ipilimumab,nivolumab, pembrolizumab, atezolizumab, avelumab, durvalumab, cemiplimab, a chimeric antigen receptor T cell therapy (CAR-T cell therapy), CAR natural killer cell therapy (CAR NK therapy), tisagenlecleucel, axicabtagene ciloleucel, brexucabtagene autoleucel, lisocabtagene maraleucel, idecabtagene vicleucel, or ciltacabtegene autoleucel.

[0048] The term “cancer” and its grammatical equivalents as used herein refer to a hyperproliferation of cells whose unique trait — loss of normal controls — results in unregulated growth, lack of differentiation, local tissue invasion, and metastasis. With respect to the methods provided herein, the cancer can be any cancer, including but not limited to any one of: acute lymphocytic cancer, acute myeloid leukemia, alveolar rhabdomyosarcoma, bladder cancer, bone cancer, brain cancer, breast cancer, cancer of the anus, anal canal, rectum, cancer of the eye, cancer of the intrahepatic bile duct, cancer of the joints, cancer of the neck, gallbladder, or pleura, cancer of the nose, nasal cavity, or middle ear, cancer of the oral cavity, cancer of the vulva, chronic lymphocytic leukemia, chronic myeloid cancer, colon cancer, esophageal cancer, cervical cancer, fibrosarcoma, gastrointestinal cancer, Hodgkin lymphoma, hypopharynx cancer, kidney cancer, larynx cancer, leukemia, liquid tumors, liver cancer, lung cancer, lymphoma, malignant mesothelioma, mastocytoma, melanoma, dedifferentiated melanoma, multiple myeloma, nasopharynx cancer, non-Hodgkin lymphoma, ovarian cancer, pancreatic cancer, peritoneum, omentum, and mesentery cancer, pharynx cancer, prostate cancer, colorectal cancer, renal cancer, a carcinoma, renal carcinoma, non-clear cell renal carcinoma, clear cell renal carcinoma, skin cancer, small intestine cancer, soft tissue cancer, solid tumors, stomach cancer, testicular cancer, thyroid cancer, ureter cancer, and / or urinary bladder cancer. As used herein, the term “tumor” refers to an abnormal growth of cells or tissues, e.g., of malignant type or benign type. Any cancer or neoplastic condition, tumor, or population of cancerous cells can be SWI / SNF deficient. In some instances, any cancer or neoplastic condition, tumor, or population of cancerous cells is not SWI / SNF deficient.

[0049] The term “drug resistant cancer” and its grammatical equivalents as used herein refers to a cancer that does not respond, or exhibits a decreased response to, one or more chemotherapeutic agents.

[0050] The term “expression” and its grammatical equivalents as used herein refers to the biosynthesis of a gene product. For example, in the case of a structural gene, expression involves transcription of the structural gene into mRNA and the translation of mRNA into one or more polypeptides.

[0051] The term “in vitro” and its grammatical equivalents as used herein refers to events that occur in an artificial environment, e.g. , in a test tube or reaction vessel, in cell culture, etc., rather than within a multi-cellular organism.

[0052] The term “in vivo” and its grammatical equivalents as used herein refers to events that occur within a multi-cellular organism, such as a non-human animal.

[0053] The term “iron-dependent cell death agent” and its grammatical equivalents as used herein refers to an agent which induces, promotes or activates cell death mediated by iron. In some cases, within the disclosure, the term “iron-dependent cell death agent” is used interchangeably with ferroptosis-inducing agent. The term “normal cells” and its grammatical equivalents as used herein refers to cells that undergo controlled cell division, controlled activation, or quiescent cells.

[0054] The term “hyperproliferative cells” and its grammatical equivalents as used herein refers to cells characterized by unwanted cell proliferation, or abnormally high rate or sustained cell division, unrelated or uncoordinated with that of surrounding normal tissue. The term “normal cells” and its grammatical equivalents as used herein refers to cells that undergo controlled cell division, controlled activation, or quiescent cells.Ferroptosis

[0055] The term “ferroptosis” refers to a form of cell death involving generation of reactive oxygen species mediated by iron, and characterized by, in part, lipid peroxidation. The term “ferroptosis-inducing agent” or “ferroptosis activator” or “ferroptosis inducer” or “ferroptosis-inducing compound” or “ferroptosis modulator” refers to an agent which promotes or activates or modulates ferroptosis in a cell.

[0056] Cell death is a cellular process involved in development, cellular homeostasis, and prevention of proliferative diseases such as cancer. Programmed cell death can take different forms, such as apoptosis, mitotic catastrophe, necrosis, senescence, and autophagy. While each of these processes ultimately lead to cell death, the pathways and mechanisms appear to be unique, both at the molecular and cellular level.

[0057] Ferroptosis is a non-apoptotic, oxidative form of regulated cell death involving lipid hydroperoxides and the accumulation of lipid peroxide at the cellular plasma membrane. Cells undergoing ferroptosis do not display the cellular characteristics or functions associated with apoptosis, the canonical form of cell death. Examples of apoptotic cell features include, e.g., mitochondrial cytochrome c release, caspase activation, andchromatin fragmentation. Ferroptosis is also characterized by increased levels of intracellular reactive oxygen species (ROS) which can be prevented by iron chelation and genetic inhibition of cellular iron uptake. Addition of iron, but not by other divalent transition metal ions, can potentiate ferroptosis signaling in cells.

[0058] Cellular components implicated in and regulating ferroptosis include, among others, cysteine -glutamate antiporter (system Xc), glutathione peroxidase 4 (GPX4), p53, cargo receptor NC0A4, glutathione synthetase (GSH), glutamate-cysteine ligase (GCL).The inactivation or inhibition of some of these molecules, for example, system Xc, GPX4, or glutathione synthetase leads to iron-dependent cell death or ferroptosis.

[0059] Hyperproliferative cells in a drug-resistant state, such as, e.g. , drug resistant cancer cells have been found to exhibit a dysregulation in apoptosis cellular pathways. Surprisingly, drug-resistance to apoptotic agents by hyperproliferative cells can have an enhanced ability to undergo ferroptosis. Apoptosis-resistant cells can be killed via ferroptosis induction due to their “flammable” ferroptosis-sensitive state.Compounds

[0060] The disclosure is directed, in part, to compounds that modulate, for example, induce, ferroptosis in a cell, a tissue, or a tumor in a patient or subject. In some embodiments, the present disclosure provides a method of treating a disease or disorder amenable to modulation, e.g., induction, of ferroptosis. In some embodiments, the disease or disorder is a cancer.

[0061] For example, disclosed herein is a compound represented by Formula I:or a pharmaceutically acceptable salt and / or a stereoisomer thereof, wherein:R1is selected from the group consisting of Ci-Cioalkyl, C2-Cioalkenyl, C2-Cioalkynyl, 5-6 membered monocyclic heteroaryl, and 8-10 membered bicyclic heteroaryl; wherein R1may optionally be substituted with one more substituents each independently selected from R11;R11is independently selected for each occurrence from the group consisting of halogen, deuterium, hydroxyl, -CN, -NO2, -NRaRb, oxo, -C(=0)NRaRb, -NRa(C=0)Rb, -O(C=O)NRaRb, -NRa(C=O)ORb, -NRa(C=O)NRaRb, -(C=O)C1-C6alkyl, -(C=O)OC1-C6alkyl, -0(C=0)Ci-C2oalkyl, -0(C=0)Ci-C2ohaloalkyl, -0(C=0)Ci-C2oheteroalkyl, -O(C=O)OCi- C6alkyl, -SH, -SC1-C6alkyl, -S(O)C1-C6alkyl, -S(O)2C1-C6alkyl, -S(O)2NRaRb, -NRaS(O)2Ci- C6alkyl, C1-C6alkyl, C1-C6alkoxy, C3-C6cycloalkyl. -Z -phenyl, -Z -naphthyl, -Z-(5-6 membered monocyclic heteroaryl), -Z-(8-10 membered bicyclic heteroaryl), -Z-(4-7 membered heterocyclyl), (phenyl)-Z-(phenyl), (phenyl)-Z-(5-6 membered heteroaryl), (5-6 membered heteroaryl)-Z-(phenyl), and (5-6 membered heteroaryl)-Z-(5-6 membered heteroaryl); wherein each alkyl, cycloalkyl, phenyl, heterocyclyl, and heteroaryl may optionally be substituted with one or more substituents each independently selected from R12; or two geminal R11groups, together with the carbon atom to which they are attached, may be joined together to form a Cs-Cecycloalkyl or a 4-7 membered heterocyclyl optionally substituted with one or more substituents each independently selected from the group consisting of halogen, deuterium, hydroxyl, -NRaRb, -CF3, C1-C6alkyl, and C1-C6alkoxy;Z is selected from the group consisting of a bond, -O-, -C=C-, -CH2O-, -OCH2-, - O(CO)-, -C(O)O-, -NRa, -S-, -S(O), -S(O)2, and -HC=CH-;R12is independently selected for each occurrence from the group consisting of halogen, deuterium, hydroxyl, -CN, -NO2, -NRaRb, oxo, C1-C6alkyl, C1-C6alkoxy, C3- Cecycloalkyl, -C(=O)NRaRb, -NRa(C=O)Rb, -O(C=O)NRaRb, -NRa(C=O)ORb, - NRa(C=O)NRaRb, -(C=O)C1-C6alkyl, -(C=O)OC1-C6alkyl, -O(C=O)OC1-C6alkyl, -SH, -SCi- Cealkyl, -S(O)C1-C6alkyl, -S(O)2C1-C6alkyl, -S(O)2NRaRb, and -NRaS(O)2Ci-C6alkyl; wherein each alkyl, alkoxy, and cycloalkyl may optionally be substituted with one or more substituents each independently selected from the group consisting of halogen, hydroxyl, and Ci-Csalkoxy;R2is independently selected for each occurrence from the group consisting of halogen, hydroxyl, -CF3, -OCF3, C1-C6alkyl, and C1-C6alkoxy;R3is selected from the group consisting of hydrogen, C1-C6alkyl, -C(O)C1-C6alkyl, and -C(O)OC1-C6alkyl, -S(O)2C1-C6alkyl, and -P(O)(phenyl)2;Raand Rbare each independently selected for each occurrence from the group consisting of hydrogen and C1-C6alkyl, wherein C1-C6alkyl may optionally be substituted with one or more substituents each independently selected from the group consisting of halogen, deuterium, hydroxyl, and C1-C6alkoxy; orRaand Rb, together with the nitrogen to which they are attached, may be joined together to form a 4-7 membered heterocyclyl optionally substituted by one or more substituents each independently selected from the group consisting of halogen, deuterium, hydroxyl, -NRaRb, C1-C6alkyl, and C1-C6alkoxy; and p is 0, 1, 2, 3, or 4.

[0062] For example, in some embodiments, R3is hydrogen or -C(O)O-tert-butyl. In othe embodiments, p is 0, 1, or 2. In still other embodiments, R12is selected from the group consisting of, for example, halogen, deuterium, hydroxyl, oxo, -CN, -NRaRb, -O(C=O)Ci- C6alkyl, -(C=O)OC1-C6alkyl, C1-C6alkyl, C1-C6alkoxy, and C3-C6cycloalkyk wherein each alkyl, alkoxy, and cycloalkyl may optionally be substituted with one or more substituents each independently selected from the group consisting of halogen, hydroxyl, and Ci- Csalkoxy.

[0063] For example, in some embodiments a compound of the present disclosure may be represented by

[0064] In some embodiments, R1is, for example:R13is selected from the group consisting of hydrogen, halogen, hydroxyl, -OCH3, - OCF3, C2-C6alkoxy, and -O(C=O)C1-C6alkyl;R14is selected from the group consisting of -Z -phenyl, -Z-(5-6 membered monocyclic heteroaryl), -Z-(5-6 membered monocyclic heterocyclyl), -Z-(8-10 membered bicyclic heteroaryl), (phenyl)-Z-(phenyl), (5-6 membered heteroaryl)-Z-(phenyl), (5-6 membered heteroaryl)-Z-(phenyl) and -O(C=O)Ci-C6alkyl; wherein each phenyl and heteroaryl may optionally be substituted with one or more substituents each independently selected from the group consisting of halogen, hydroxyl, -C1-C6alkyl, C1-C6alkoxy, and -0(C=0)CH3; wherein -C1-C6alkyl, and C1-C6alkoxy may optionally be substituted with one or more halogens or hydroxyl; andwherein any aforementioned -O(C=O)Ci-C6alkyl may optionally be substituted with one or more halogens.

[0065] In some embodiments, the compound is not (4.S)-4-amino- l-(3.3-dimcthylbutyl)- 5.6-dihydro- IZ6.2-thiazin-3(4 / / )-onc 1-oxide, (4S')-4-amino- l -(4.4.4-trifluorobiityl)-5.6- dihydro- I Z6.2-thiazin-3(4H)-onc 1-oxide, or (4S')-4-amino- l-((.S')-4.4.4-trifluoro-3- hydroxybutyl)-5,6-dihydro-lX6,2-thiazin-3(4H)-one 1-oxide.

[0066] In further embodiments, R13is selected from the group consisting of, for example, hydroxyl, -OCH3, halogen, hydrogen, and -O(C=O)Ci-C6alkyl optionally with one or more halogens. In additional embodiments, Z is selected from the group consisting of, for example, a bond, -O-, -C=C-, -OCH2-, and -O(CO)-.

[0067] In some embodiments, R14is selected from the group consisting ofX and Y and Z are each independently selected from N and CR’, wherein R’ is selected independently for each occurrence from the group consisting of hydrogen, halogen, and C1-C6alkyl; andR15is independently selected for each occurrence from the group consisting of halogen, hydroxyl, -CH3, -CH(CH3)2, -C(CH3)2OH, -O(CO)CH3, -CF3, -OCH3, and -OCF3.

[0068] For example, in certain embodiments R14is selected from the group consisting ofwherein R15is independently selected for each occurrence from the group consisting of hydrogen, halogen, hydroxyl, -CH3, -CF3, -OCH3, and -OCF3.

[0070] For example, in certain embodiments R1is selected from the group consisting of

[0071] Also disclosed herein is a compound represented by Formula II:or a pharmaceutically acceptable salt and / or a stereoisomer thereof, wherein:R1is selected from the group consisting ofR13is selected from the group consisting of hydrogen, halogen, hydroxyl, -OCH3, - OCF3, and C2-Cealkoxy;R14is selected from the group consisting ofX and Y and Z are each independently selected from N and CR’, wherein R’ is selected independently for each occurrence from the group consisting of hydrogen, halogen, and C1-C6alkyl; andR15is independently selected for each occurrence from the group consisting of halogen, hydroxyl, -CH3, -CH(CH3)2, -C(CH3)2OH, -0(C0)CH3, -CF3, -OCH3, and -OCF3.

[0072] In some embodiments, R14is selected from the group consisting of, for example:

[0073] In other embodiments, R1is selected from the group consisting of, for example,

[0074] In some embodiments, the compound is a compound identified in Table 1 below or a pharmaceutically acceptable salt thereof.Table 1. Exemplary compounds.

[0075] Procedures for making compounds described herein are provided in the examples below. In the reactions described below, it may be necessary to protect reactive functional groups (such as hydroxyl, amino, thio or carboxyl groups) to avoid their unwanted participation in the reactions. The incorporation of such groups, and the methods required to introduce and remove them are known to those skilled in the art (for example, see Greene, Wuts, Protective Groups in Organic Synthesis. 2nd Ed. (1999)). The deprotection step may be the final step in the synthesis such that the removal of protecting groups affords compounds as disclosed herein. Starting materials used in the following scheme can be purchased or prepared by methods described in the chemical literature, or by adaptationsthereof, using methods known by those skilled in the art. The order in which the steps are performed can vary depending on the groups introduced and the reagents used, but would be apparent to those skilled in the art.

[0076] Compounds disclosed herein, or any of the intermediates described in the schemes above, can be further derivatized by using one or more standard synthetic methods known to those skilled in the art. Such methods can involve substitution, oxidation or reduction reactions. These methods can also be used to obtain or modify disclosed compounds or any preceding intermediates by modifying, introducing or removing appropriate functional groups.

[0077] Where it is desired to obtain a particular enantiomer of a disclosed compound, this may be produced from a corresponding mixture of enantiomers by employing any suitable conventional procedure for resolving enantiomers known to those skilled in the art. For example, diastereomeric derivatives (such as salts) can be produced by reaction of a mixture of enantiomers of a disclosed compound (such a racemate) and an appropriate chiral compound (such as a chiral base). The diastereomers can then be separated by any conventional means such as crystallization or chromatography, and the desired enantiomer recovered (such as by treatment with an acid in the instance where the diastereomer is a salt). Alternatively, a racemic mixture of esters can be resolved by kinetic hydrolysis using a variety of biocatalysts (for example, see Patel Stereoselective Biocatalysts, Marcel Decker; New York 2000).

[0078] In another resolution process a racemate of disclosed compounds can be separated using chiral High Performance Liquid Chromatography. Alternatively, a particular enantiomer can be obtained by using an appropriate chiral intermediate in one of the processes described above. Chromatography, recrystallisation and other conventional separation procedures may also be used with intermediates or final products where it is desired to obtain a particular geometric isomer of the disclosure.

[0079] In an alternative embodiment, disclosed compounds may also comprise one or more isotopic substitutions. For example, hydrogen may be2H (D or deuterium) or3H (T or tritium); carbon may be, for example,13C or14C; oxygen may be, for example,18O; nitrogen may be, for example,15N, and the like. In other embodiments, a particular isotope (e.g.,3H,13C,14C,18O, or15N) can represent at least 1%, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%,at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or at least 99.9% of the total isotopic abundance of an element that occupies a specific site of the compound.Methods

[0080] Further disclosed herein are methods of treating a patient suffering from a condition, disease, or disorder that is affected by, associated with, or would benefit from inducing ferroptosis, comprising administering to the patient a therapeutically effective amount of a compound disclosed herein, or a pharmaceutical composition thereof.

[0081] For example, provided herein is a method of treating a disease or condition in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound disclosed herein, or a pharmaceutical composition thereof. In some embodiments, the disease or condition can be a cancer, for example in a tissue of the subject. The cancer can be comprised in a mammal, or contained in a tissue of a mammal, which can be a human, which can be male, female. In other embodiments, the disease or condition can be an inflammatory disease, or a fibrosis.

[0082] For example, provided herein is a method of treating a cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound disclosed herein, or a pharmaceutical composition thereof. In some embodiments, the cancer is a carcinoma, a sarcoma, or a melanoma. In some embodiments, the carcinoma is a liver carcinoma. In some embodiments, the cancer is a clear cell renal carcinoma or non-clear cell renal carcinoma. In some embodiments, the cancer is an SWI / SNF deficient-complex cancer.

[0083] Further provided herein is a method of modulating, e.g., inducing, ferroptosis in a cell or tissue, which can be in a patient in need thereof, comprising contacting, for example directly or indirectly, optionally in a sustained manner, the cell or tissue with a therapeutically effective amount of a compound disclosed herein, or a pharmaceutical composition thereof. Also provided herein is a method of modulating, e.g., inducing, ferroptosis in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound disclosed herein, or a pharmaceutical composition thereof.

[0084] In addition, disclosed herein is a method of modulating, inhibiting, or partially inhibiting a target comprising glutamate-cysteine ligase (GCL) in a cell or tissue, which canbe in a patient in need thereof, comprising contacting, for example directly or indirectly, optionally in a sustained manner, the cell or tissue with a therapeutically effective amount of a compound disclosed herein, or a pharmaceutical composition thereof. Also provided herein is a method of modulating, inhibiting, or partially inhibiting a target comprising glutamate -cysteine ligase (GCL) in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound disclosed herein, or a pharmaceutical composition thereof.

[0085] For example, the methods described herein may be useful to treat, for example, a cancer. In some embodiments, the patient has, is suspected of having, or is at risk of developing cancer. In some embodiments, the patient has a benign tumor. In some embodiments, the patient has a pre-cancerous lesion. In some embodiments, the patient has a basal cell carcinoma (BCC) or a squamous cell carcinoma (SCC). In some embodiments, the patient has a metastatic tumor. In some embodiments, the cancer is a solid cancer or a blood cancer. In some embodiments, the blood cancer is a leukemia or a lymphoma. In some embodiments, the patient has a solid tumor. In some embodiments, the solid tumor is a carcinoma, a melanoma, or a sarcoma. In some embodiments, the melanoma is a dedifferentiated melanoma or amelanotic melanoma. In some embodiments, the patient has a melanoma with a B-Raf proto-oncogene, serine / threonine kinase (BRAF) mutation. In some embodiments the patient has a sarcoma with a Kirsten rat sarcoma (KRAS) mutation. In some embodiments, the sarcoma is a soft tissue sarcoma. In some embodiments, the sarcoma is leiomyosarcoma. In some embodiments, the carcinoma is a colon adenocarcinoma. In some embodiments, the carcinoma is a liver carcinoma. In some embodiments, the carcinoma is renal carcinoma. In some embodiments, the carcinoma is clear cell renal carcinoma. In some embodiments, the carcinoma is non-clear cell renal carcinoma.

[0086] Non-limiting examples of cancer that can be treated with an agent provided herein include: acoustic neuroma; adenocarcinoma; adrenal gland cancer; anal cancer; angiosarcoma (e.g., lymphangiosarcoma, lymphangioendotheliosarcoma, hemangiosarcoma); appendix cancer; benign monoclonal gammopathy; biliary cancer (e.g., cholangiocarcinoma); bladder cancer; breast cancer (e.g., adenocarcinoma of the breast, papillary carcinoma of the breast, mammary cancer, medullary carcinoma of the breast); brain cancer (e.g., meningioma, glioblastomas, glioma (e.g., astrocytoma, oligodendroglioma), medulloblastoma); bronchus cancer; carcinoid tumor; cervical cancer(e.g., cervical adenocarcinoma); choriocarcinoma; chordoma; craniopharyngioma; connective tissue cancer; epithelial carcinoma; ependymoma; endotheliosarcoma (e.g., Kaposi's sarcoma, multiple idiopathic hemorrhagic sarcoma); endometrial cancer (e.g., uterine cancer, uterine sarcoma); esophageal cancer (e.g., adenocarcinoma of the esophagus, Barrett's adenocarcinoma); Ewing's sarcoma; eye cancer (e.g., intraocular melanoma, retinoblastoma); familiar hypereosinophilia; gall bladder cancer; gastric cancer (e.g., stomach adenocarcinoma); gastrointestinal stromal tumor (GIST); germ cell cancer; head and neck cancer (e.g., head and neck squamous cell carcinoma, oral cancer (e.g., oral squamous cell carcinoma), throat cancer (e.g., laryngeal cancer, pharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer)); hematopoietic cancers (e.g., leukemia such as acute lymphocytic leukemia (ALL) (e.g., B cell ALL, T cell ALL), acute myelocytic leukemia (AML) (e.g., B cell AML, T cell AML), chronic myelocytic leukemia (CML) (e.g., B cell CIVIL, T cell CML), and chronic lymphocytic leukemia (CLL) (e.g., B cell CLL, T cell CLL)); lymphoma such as Hodgkin lymphoma (HL) (e.g., B cell HL, T cell HL) and non Hodgkin lymphoma (NHL) (e.g., B cell NHL such as diffuse large cell lymphoma (DLCL) (e.g., diffuse large B cell lymphoma), follicular lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), mantle cell lymphoma (MCL), marginal zone B cell lymphomas (e.g., mucosa associated lymphoid tissue (MALT) lymphomas, nodal marginal zone B cell lymphoma, splenic marginal zone B cell lymphoma), primary mediastinal B cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma (e.g., Waldenstrom's macroglobulinemia), hairy cell leukemia (HCL), immunoblastic large cell lymphoma, precursor B lymphoblastic lymphoma and primary central nervous system (CNS) lymphoma; and T cell NHL such as precursor T lymphoblastic lymphoma / leukemia, peripheral T cell lymphoma (PTCL) (e.g., cutaneous T cell lymphoma (CTCL) (e.g., mycosis fungoides, Sezary syndrome), angioimmunoblastic T cell lymphoma, extranodal natural killer T cell lymphoma, enteropathy type T cell lymphoma, subcutaneous panniculitis like T cell lymphoma, and anaplastic large cell lymphoma); a mixture of one or more leukemia / lymphoma as described above; and multiple myeloma (MM)), heavy chain disease (e.g., alpha chain disease, gamma chain disease, mu chain disease); hemangioblastoma; hypopharynx cancer; inflammatory myofibroblastic tumors; immunocytic amyloidosis; kidney cancer (e.g., nephroblastoma a.k.a. Wilms' tumor, renal cell carcinoma, clear cell renal carcinoma, non-clear cell renal carcinoma); liver cancer (e.g., hepatocellular cancer (HCC), malignant hepatoma); lung cancer (e.g., bronchogenic carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC),adenocarcinoma of the lung); leiomyosarcoma (LMS); mastocytosis (e.g., systemic mastocytosis); muscle cancer; myelodysplastic syndrome (MDS); mesothelioma; myeloproliferative disorder (MPD) (e.g., polycythemia vera (PV), essential thrombocytosis (ET), angiogenic myeloid metaplasia (AMM) a.k.a. myelofibrosis (MF), chronic idiopathic myelofibrosis, chronic myelocytic leukemia (CIVIL), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES); neuroblastoma; neurofibroma (e.g., neurofibromatosis (NF) type 1 or type 2, schwannomatosis); neuroendocrine cancer (e.g., gastroenteropancreatic neuroendocrine tumor (GEP NET), carcinoid tumor); osteosarcoma (e.g., bone cancer); ovarian cancer (e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma); papillary adenocarcinoma; pancreatic cancer (e.g., pancreatic adenocarcinoma, intraductal papillary mucinous neoplasm (IPMN), islet cell tumors); penile cancer (e.g., Paget's disease of the penis and scrotum); pinealoma; primitive neuroectodermal tumor (PNT); plasma cell neoplasia; paraneoplastic syndromes; intraepithelial neoplasms; prostate cancer (e.g., prostate adenocarcinoma); colorectal cancer; rhabdomyosarcoma; salivary gland cancer; skin cancer (e.g., squamous cell carcinoma (SCC), keratoacanthoma (KA), melanoma, basal cell carcinoma (BCC)); small bowel cancer (e.g., appendix cancer); soft tissue sarcoma (e.g., malignant fibrous histiocytoma (MFH), liposarcoma, malignant peripheral nerve sheath tumor (MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma); sebaceous gland carcinoma; small intestine cancer; sweat gland carcinoma; synovioma; testicular cancer (e.g., seminoma, testicular embryonal carcinoma); thyroid cancer (e.g., papillary carcinoma of the thyroid, papillary thyroid carcinoma (PTC), medullary thyroid cancer); urethral cancer; vaginal cancer; and vulvar cancer (e.g., Paget's disease of the vulva).

[0087] In other embodiments, the patient has, is suspected of having, or is at risk of developing a hyperproliferative disease or condition. In some embodiments, methods provided herein further comprise a step of obtaining a biopsy of the tissue for histological analysis. In some embodiments, the tissue comprises a histological abnormality, wherein the histological abnormality is hyperplasia or fibrosis.

[0088] In further embodiments, the patient has, is suspected of having, or is at risk of developing a disease or condition associated with abnormal angiogenesis or vascularization. Diseases or conditions associated with abnormal angiogenesis or vascularization can include but are not limited to: ocular neovascularization, macular degeneration, retinopathy, sarcomas, polycystic kidney disease, benign hyperplasias, leiomyomas, adenomas, lipomas,hemangiomas, fibromas, vascular occlusion, restenosis, atherosclerosis, pre-neoplastic lesions, carcinoma in situ, and cancer. In some embodiments, the patient has, is suspected of having, or is at risk of developing an autoimmune disease. Non-limiting examples of relevant autoimmune diseases include: rheumatoid arthritis, inflammatory bowel disease, osteoarthritis, oral hairy leukoplakia, and psoriasis. In some embodiments, the patient has, is suspected of having, or is at risk of developing fibrosis. Non-limiting examples of diseases and conditions associated with fibrosis include: keloid scars, hypertrophic scars, systemic sclerosis, pulmonary arterial hypertension, cardiac fibrosis, hypertrophic cardiomyopathy valvular disease, myelofibrosis, myelodysplastic syndrome, chronic myelogenous leukemia, portal hypertension, hepatocellular carcinoma, retroperitoneal fibrosis, intestinal fibrosis, enteropathies, subretinal fibrosis, epiretinal fibrosis, cystic fibrosis, emphysema, pancreatic fibrosis, chronic pancreatitis, duct obstruction, arthrofibrosis, renal fibrosis, nephrogenic systemic fibrosis, renal anemia, chronic kidney disease, Dupuytren’s disease, Ledderhose disease (plantar fibromatosis), primary biliary cholangitis (PBC), non-alcoholic steatohepatitis (NASH), scleroderma, diabetic neuropathy, hypertensive nephrosclerosis, allograft nephropathy, cirrhosis, and pulmonary fibrosis.

[0089] Further disclosed herein is a method of inducing immune cell recruitment to a tumor, the method comprising: administering to a patient in need thereof a compound disclosed herein by any of the methods provided herein. In some embodiments, the administering is sustained administration for at least about 10 hours, thereby recruiting immune cells to the tumor site. In some embodiments, the immune cells are leukocytes. In some embodiments, following contact with a mammalian tissue or administration of a ferroptosis-inducing agent, immune cell recruitment can be detected at a time point at or after contacting the mammalian tissue with the ferroptosis-inducing agent. In some embodiments, the administering reduces the size of the tumor and / or increases the number of leukocytes within the tumor.

[0090] Further disclosed herein is a method of inducing weight loss, fat loss, or both, in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound disclosed herein, or a pharmaceutical composition thereof. In some embodiments, the method is inducing weight loss. In other embodiments, the method is inducing fat loss. In still other embodiments, the method is inducing weight loss and inducing fat loss. In certain embodiments, the patient is obese or overweight. In some embodiments, the patient is suffering from one or more conditions selected from the groupconsisting of, for example, obesity, metabolic syndrome, elevated blood glucose, a diabetes, diabetes type 2, diabetes type 3, insulin resistance, high blood pressure, a cardiovascular disease, a coronary artery disease, a cerebrovascular disease, a stroke, a rheumatic heart disease, an arteriosclerosis, an atherosclerosis, a liver disease, a fatty liver disease, nonalcoholic fatty liver disease (NAFLD), and nonalcoholic steatohepatitis (NASH).

[0091] For example, disclosed herein is a method of treating one or more conditions selected from the group consisting of obesity, metabolic syndrome, elevated blood glucose, a diabetes, diabetes type 2, diabetes type 3, insulin resistance, high blood pressure, a cardiovascular disease, a coronary artery disease, a cerebrovascular disease, a stroke, a rheumatic heart disease, an arteriosclerosis, an atherosclerosis, a liver disease, a fatty liver disease, nonalcoholic fatty liver disease (NAFLD), and nonalcoholic steatohepatitis (NASH), in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound disclosed herein, or a pharmaceutical composition thereof.

[0092] Also disclosed herein is a method of inducing, regulating, or modulating weight loss, body composition, or fat loss or fat reduction in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound disclosed herein, or a pharmaceutical composition thereof.

[0093] Also disclosed herein is a method of treating, inducing, regulating, modulating, or diminishing cholesterol metabolism or a disease associated with cholesterol metabolism in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound disclosed herein, or a pharmaceutical composition thereof.

[0094] In particular, in certain embodiments, the disclosure provides a method of treating the medical indications contemplated herein comprising administering to a patient in need thereof a therapeutically effective amount of a compound described herein.Combination Therapy

[0095] The compounds described herein can be administered in combination with one or more additional therapeutic agents to treat a disorder described herein. For clarity, contemplated herein are both a fixed composition comprising a disclosed compound and another therapeutic agent such as disclosed herein, and methods of administering, separately a disclosed compound and a disclosed therapeutic. For example, provided in the present disclosure is a pharmaceutical composition comprising a compound described herein, one ormore additional therapeutic agents, and a pharmaceutically acceptable excipient. In some embodiments, a disclosed compound and one additional therapeutic agent is administered. In some embodiments, a disclosed compound as defined herein and two additional therapeutic agents are administered. In some embodiments, a disclosed compound as defined herein and three additional therapeutic agents are administered. Combination therapy can be achieved by administering two or more therapeutic agents, each of which is formulated and administered separately. For example, a disclosed compound and an additional therapeutic agent can be formulated and administered separately. Combination therapy can also be achieved by administering two or more therapeutic agents in a single formulation, for example a pharmaceutical composition comprising a disclosed compound as one therapeutic agent and one or more additional therapeutic agents. For example, a disclosed compound and an additional therapeutic agent can be administered in a single formulation. Other combinations are also encompassed by combination therapy. While the two or more agents in the combination therapy can be administered simultaneously, they need not be. For example, administration of a first agent (or combination of agents) can precede administration of a second agent (or combination of agents) by minutes, hours, days, or weeks. Thus, the two or more agents can be administered within minutes of each other or within 1, 2, 3, 6, 9, 12, 15, 18, or 24 hours of each other or within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14 days of each other or within 2, 3, 4, 5, 6, 7, 8, 9, or weeks of each other. In some cases, even longer intervals are possible. While in many cases it is desirable that the two or more agents used in a combination therapy be present in within the patient's body at the same time, this need not be so.

[0096] Combination therapy can also include two or more administrations of one or more of the agents used in the combination using different sequencing of the component agents. For example, if agent X and agent Y are used in a combination, one could administer them sequentially in any combination one or more times, e.g., in the order X-Y- X, X-X-Y, Y-X-Y, Y-Y-X, X-X-Y-Y, etc.

[0097] In some embodiments, the methods provided herein comprise administering at least one additional treatment to a subject. In some embodiments, the additional treatment is surgery. In some embodiments, the additional treatment is radiation therapy. In some embodiments, the additional treatment is radioligand therapy. In some embodiments, the additional treatment is a dietary supplement. Non-limiting examples of dietary supplements include: probiotics, selenium, iron, vitamins (e.g., vitamin A, vitamin C, vitamin E),curcumin, fish oils, beta carotene, hydrogen sulfides, fatty acids, methionine, cysteine, homocysteine, taurine, cystine or di -cysteine. In some embodiments, the dietary supplement is a high-selenium nutritional supplement.

[0098] In certain embodiments, the methods described herein further comprises administering to the patient one or more additional therapeutic agents that treats a disease or disorder that is affected by, associated with, or would benefit from modulating, e.g., inducing, ferroptosis.

[0099] In some embodiments, the methods provided herein comprise administering an additional agent in combination with a ferroptosis-inducing agent (e.g., a compound disclosed herein), an iron-dependent cell death inducing agent, and / or a priming agent provided herein. In some embodiments, the additional agent is a cell -death inducing agent. In some embodiments, the additional agent is an anti-cancer agent. In some embodiments, the anti-cancer agent is a chemotherapeutic agent. A chemotherapeutic agent or compound is any agent or compound useful in the treatment of cancer. The chemotherapeutic cancer agents that can be used in combination with ferroptosis-inducing agents or iron-dependent cell death agents provided herein which include, but are not limited to, mitotic inhibitors (vinca alkaloids). These include, for example, vincristine, vinblastine, vindesine and Navelbine™ (vinorelbine, 5’-noranhydroblastine). In yet other cases, chemotherapeutic cancer agents include topoisomerase I inhibitors, such as camptothecin compounds. As used herein, “camptothecin compounds” include Camptosar™ (irinotecan HCL), Hycamtin™ (topotecan HCL) and other compounds derived from camptothecin and its analogues. Another category of chemotherapeutic cancer agents that can be used in the methods and compositions disclosed herein are podophyllotoxin derivatives, such as etoposide, teniposide and mitopodozide. The present disclosure further encompasses other chemotherapeutic cancer agents known as alkylating agents, which alkylate the genetic material in tumor cells. These include without limitation cisplatin, cyclophosphamide, nitrogen mustard, trimethylene thiophosphoramide, carmustine, busulfan, chlorambucil, belustine, uracil mustard, chlomaphazin, and dacarbazine. The disclosure encompasses antimetabolites as chemotherapeutic agents. Examples of these types of agents include, for example, cytosine arabinoside, fluorouracil, methotrexate, mercaptopurine, azathioprime, and procarbazine.

[0100] In some embodiments, an additional category of therapeutic agents, e.g., chemotherapeutic cancer agents, that may be used in the methods and compositions disclosed herein include, for example, aldehyde dehydrogenase inhibitors. Examples ofcontemplated aldehyde dehydrogenase inhibitors include, but are not limited to, e.g., 4- amino-4-methyl-2-pentyne-l-al (AMP AL), N-acetyl-N-acetoxy-4- chlorobenzenesulfonamide, 2-allyl-6-(((l-propyl-lH-benzo[d]imidazol-2- yl)amino)methyl)phenol, 5-(l,3-benzodioxol-5-yl)-2-phenyl-pyrazolo[l,5-a]pyrimidine-7- carboxylic acid methyl ester, A-(l,3-benzodioxol-5-ylmethyl)-2,6-dichlorobenzamide, calcium carbamide, captan, 3-(4-chloro-2-methoxyphenyl)-l-(2'-methoxy-[l,l'-biphenyl]-4- yl)-l,5,6,7-tetrahydroimidazo[l,2-a]pyrimidine, chlorpropamide, citral, coprine, 8-[[4- (cyclopropylcarbonyl)-l-piperazinyl]methyl]-3,7-dihydro-l,3-dimethyl-7-(3-methylbutyl)- lH-purine-2, 6-dione hydrochloride, cyanamide, daidzin, daidzein, 2,6-diphenyl- imidazo[l,2-a]pyridine, dyclonine, dyclonine hydrochloride, disulfiram, diethylaminobenzaldehyde, 4-(diethylamino)-3-nitrobenzaldehyde, diethyldithiocarbamate, ethyl 2-[[3 ,4-dihydro-4-oxo-3- [3 -( 1 -pyrrolidinyl)propyl]

[0001] benzothieno [3 ,2-t / | py rim idin-2- yl]thio]acetate, 3-ethyl-N-(7-fluoro-l,2,3,4-tetrahydro-2-oxo-6-quinolinyl)-4- pyridinecarboxamide, eugenol, fomepizole, l-[4-[6-fluoro-3-(4-methylsulfonylpiperazine-l- carbonyl)quinolin-4-yl]phenyl]cyclopropane-l-carbonitrile, 6-[(3- fluorophenyl)methylsulfanyl]-5-(2-methylphenyl)-lH-pyrazolo[3,4-d]pyrimidin-4-one, furazolidone, glyceryl trinitrate, gossypol, 3 -hydroxybenzaldehyde N- hydroxybenzenesulfonamide, 4-hydroxynonenal, 3-hydroxypropionamide, kynurenine, 3- hydroxykynurenine, 3-hydroxyanthranilic acid, kynurenic acid, indol-3-ylpyruvic acid, methyl- [ 1 - [(butylamino)carbonyl] - 1 H-benzimidazol -2-y 1 ] carbamate (benomyl), 3-[[[3-[4- [(methylsulfonyl)amino]phenyl ]-4-oxo-4H- l-benzopyran-7-yl |oxy ]methyl ]benzoic acid, methyltetrazolethiol, molinate, 2-(a-naphthoyl)ethyltrimethylammonium iodide, nitrefazole, A.A- l .8-octancdiylbis(2.2-dichloroacctamidc. omeprazole, oxyfedrine, pargyline, phenylglyoxal, prunetin, puerarin, purgiline, a-pyridoin, quercetin, (£)-5-(2-(quinolin-4- yl)vinyl)benzene-l,3-diol, taraxerone, tolbutamide, trichloroacetaldehyde monohydrate, and pharmaceutically acceptable salts and / or analogs of any of the foregoing. For example, an aldehyde dehydrogenase inhibitor contemplated herein may be selected from those disclosed in W02020 / 230701A1, which is incorporated herein by reference in its entirety. In certain embodiments, the aldehyde dehydrogenase inhibitor is, for example, oxyfedrine.

[0101] For example, disclosed herein is a method of treating a cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, and an aldehyde dehydrogenase inhibitor, for example, oxyfedrine. Also disclosed herein is a pharmaceuticalcomposition comprising: a compound disclosed herein, or a pharmaceutically acceptable salt thereof; an aldehyde dehydrogenase inhibitor, for example, oxyfedrine; and a pharmaceutically acceptable excipient. Further disclosed herein is a method of treating a cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition comprising: a compound disclosed herein, or a pharmaceutically acceptable salt thereof; an aldehyde dehydrogenase inhibitor, for example, oxyfedrine; and a pharmaceutically acceptable excipient.

[0102] An additional category of chemotherapeutic cancer agents that may be used in the methods and compositions disclosed herein include antibiotics. Examples include without limitation doxorubicin, bleomycin, dactinomycin, daunorubicin, mithramycin, mitomycin, mytomycin C, and daunomycin. There are numerous liposomal formulations commercially available for these compounds. The present disclosure further encompasses other chemotherapeutic cancer agents including without limitation anti-tumor antibodies, dacarbazine, azacytidine, amsacrine, melphalan, ifosfamide and mitoxantrone.

[0103] The disclosed agents provided herein can be administered in combination with other anti-tumor agents, including cytotoxic / antineoplastic agents and anti-angiogenic agents. Cytotoxic / anti -neoplastic agents can be defined as agents who attack and kill cancer cells. Some cytotoxic / anti -neoplastic agents can be alkylating agents, which alkylate the genetic material in tumor cells, e.g., cis-platin, cyclophosphamide, nitrogen mustard, trimethylene thiophosphoramide, carmustine, busulfan, chlorambucil, belustine, uracil mustard, chlomaphazin, and dacabazine. Other cytotoxic / anti -neoplastic agents can be antimetabolites for tumor cells, e.g., cytosine arabinoside, fluorouracil, methotrexate, mercaptopuirine, azathioprime, and procarbazine. Other cytotoxic / anti -neoplastic agents can be antibiotics, e.g., doxorubicin, bleomycin, dactinomycin, daunorubicin, mithramycin, mitomycin, mytomycin C, and daunomycin. There are numerous liposomal formulations commercially available for these compounds. Still other cytotoxic / anti -neoplastic agents can be mitotic inhibitors (vinca alkaloids). These include, for example, vincristine, vinblastine and etoposide. Miscellaneous cytotoxic / anti -neoplastic agents include, for example, taxol and its derivatives, L- asparaginase, anti-tumor antibodies, dacarbazine, azacytidine, amsacrine, melphalan, VM-26, ifosfamide, mitoxantrone, and vindesine.

[0104] Anti-angiogenic agents can also be used. Suitable anti-angiogenic agents for use in the disclosed methods and compositions include, for example, anti-VEGF antibodies, including humanized and chimeric antibodies, anti-VEGF aptamers and antisenseoligonucleotides. Other inhibitors of angiogenesis include, for example, angiostatin, endostatin, interferons, interleukin 1 (including a and P) interleukin 12, retinoic acid, and tissue inhibitors of metalloproteinase- 1 and -2. (TIMP-1 and -2). Small molecules, including topoisomerases such as razoxane, a topoisomerase II inhibitor with anti-angiogenic activity, can also be used.

[0105] Other anti -cancer agents that can be used in combination with the ferroptosis- inducing agents provided herein can include, but are not limited to: acivicin; aclarubicin; acodazole hydrochloride; acronine; adozelesin; aldesleukin; altretamine; ambomycin; ametantrone acetate; aminoglutethimide; amsacrine; anastrozole; anthramycin; asparaginase; asperlin; avastin; azacitidine; azetepa; azotomycin; batimastat; benzodepa; bevacizumab; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate; bizelesin; bleomycin sulfate; brequinar sodium; bropirimine; busulfan; cactinomycin; calusterone; caracemide; carbetimer; carboplatin; carmustine; carubicin hydrochloride; carzelesin; cedefmgol; chlorambucil; cirolemycin; cisplatin; cladribine; crisnatol mesylate; cyclophosphamide; cytarabine; dacarbazine; dactinomycin; daunorubicin hydrochloride; decitabine; dexormaplatin; dezaguanine; dezaguanine mesylate; diaziquone; docetaxel; doxorubicin; doxorubicin hydrochloride; droloxifene; droloxifene citrate; dromostanolone propionate; duazomycin; edatrexate; eflomithine hydrochloride; elsamitrucin; enloplatin; enpromate; epipropidine; epirubicin hydrochloride; erbulozole; esorubicin hydrochloride; estramustine; estramustine phosphate sodium; etanidazole; etoposide; etoposide phosphate; etoprine; fadrozole hydrochloride; fazarabine; fenretinide; floxuridine; fludarabine phosphate; fluorouracil; flurocitabine; folinic acid; fosquidone; fostriecin sodium; gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubicin hydrochloride; ifosfamide; ilmofosine; interleukin II (including recombinant interleukin II, or rIL2), interferon alfa-2a; interferon alfa-2b; interferon alfa-nl; interferon alfa-n3; interferon beta-I a; interferon gamma-I b; iproplatin; irinotecan hydrochloride; lanreotide acetate; letrozole; leuprolide acetate; liarozole hydrochloride; lometrexol sodium; lomustine; losoxantrone hydrochloride; masoprocol; maytansine; mechlorethamine hydrochloride; megestrol acetate; melengestrol acetate; melphalan; menogaril; mercaptopurine; methotrexate; methotrexate sodium; metoprine; meturedepa; mitindomide; mitocarcin; mitocromin; mitogillin; mitomalcin; mitomycin; mitosper; mitotane; mitoxantrone hydrochloride; mycophenolic acid; nocodazole; nogalamycin; ormaplatin; oxisuran; paclitaxel; pegaspargase; peliomycin; pentamustine; peplomycin sulfate; perfosfamide; pipobroman; piposulfan; piroxantronehydrochloride; plicamycin; plomestane; porfimer sodium; porfiromycin; prednimustine; procarbazine hydrochloride; puromycin; puromycin hydrochloride; pyrazofurin; riboprine; rogletimide; safingol; safingol hydrochloride; semustine; simtrazene; sparfosate sodium; sparsomycin; spirogermanium hydrochloride; spiromustine; spiroplatin; streptonigrin; streptozocin; sulofenur; talisomycin; tecogalan sodium; tegafur; teloxantrone hydrochloride; temoporfin; teniposide; teroxirone; testolactone; thiamiprine; thioguanine; thiotepa; tiazofurin; tirapazamine; toremifene citrate; trestolone acetate; triciribine phosphate; trimetrexate; trimetrexate glucuronate; triptorelin; tubulozole hydrochloride; uracil mustard; uredepa; vapreotide; verteporfin; vinblastine sulfate; vincristine sulfate; vindesine; vindesine sulfate; vinepidine sulfate; vinglycinate sulfate; vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate; vinzolidine sulfate; vorozole; zeniplatin; zinostatin; zorubicin hydrochloride. Other anti-cancer agents include, but are not limited to: 20-epi-l,25 dihydroxyvitamin D3; 5- ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TK antagonists; altretamine; ambamustine; amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; andrographolide; angiogenesis inhibitors; antagonist D; antagonist G; antarelix; anti- dorsalizing morphogenetic protein- 1; antiandrogen, prostatic carcinoma; antiestrogen; antineoplaston; antisense oligonucleotides; aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators; apurinic acid; ara- CDP-DL-PTBA; arginine deaminase; asulacrine; atamestane; atrimustine; axinastatin 1; axinastatin 2; axinastatin 3; azasetron; azatoxin; azatyrosine; baccatin III derivatives; balanol; batimastat; BCR / ABL antagonists; benzochlorins; benzoylstaurosporine; beta lactam derivatives; beta-alethine; betaclamycin B; betulinic acid; bFGF inhibitor; bicalutamide; bisantrene; bisaziridinylspermine; bisnafide; bistratene A; bizelesin; breflate; bropirimine; budotitane; buthionine sulfoximine; calcipotriol; calphostin C; camptothecin derivatives; canarypox IL-2; capecitabine; carboxamide-amino-triazole; carboxyamidotriazole; CaRest M3; CARN 700; cartilage derived inhibitor; carzelesin; casein kinase inhibitors (ICOS); castanospermine; cecropin B; cetrorelix; chlorins; chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin; cladribine; clomifene analogues; clotrimazole; collismycin A; collismycin B; combretastatin A4; combretastatin analogue; conagenin; crambescidin 816; crisnatol; cryptophycin 8; cryptophycin A derivatives; curacin A; cyclopentanthraquinones; cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor; cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin; dexamethasone; dexifosfamide; dexrazoxane; dexverapamil; diaziquone; didemnin B; didox; diethylnorspermine; dihydro-5-azacytidine; dihydrotaxol, 9-;dioxamycin; diphenyl spiromustine; docetaxel; docosanol; dolasetron; doxifluridine; droloxifene; dronabinol; duocarmycin SA; ebselen; ecomustine; edelfosine; edrecolomab; eflomithine; elemene; emitefur; epirubicin; epristeride; estramustine analogue; estrogen agonists; estrogen antagonists; etanidazole; etoposide phosphate; exemestane; fadrozole; fazarabine; fenretinide; filgrastim; finasteride; flavopiridol; flezelastine; fluasterone; fludarabine; fluorodaunorunicin hydrochloride; forfenimex; formestane; fostriecin; fotemustine; gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix; gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfam; heregulin; hexamethylene bisacetamide; hypericin; ibandronic acid; idarubicin; idoxifene; idramantone; ilmofosine; ilomastat; imidazoacridones; imiquimod; immunostimulant peptides; insulin-like growth factor- 1 receptor inhibitor; interferon agonists; interferons; interleukins; iobenguane; iododoxorubicin; ipomeanol, 4-; iroplact; irsogladine; isobengazole; isohomohalicondrin B; itasetron; jasplakinolide; kahalalide F; lamellarin-N triacetate; lanreotide; leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole; leukemia inhibiting factor; leukocyte alpha interferon; leuprolide+estrogen+progesterone; leuprorelin; levamisole; liarozole; linear polyamine analogue; lipophilic disaccharide peptide; lipophilic platinum compounds; lissoclinamide 7; lobaplatin; lombricine; lometrexol; lonidamine; losoxantrone; lovastatin; loxoribine; lurtotecan; lutetium texaphyrin; lysofylline; lytic peptides; maitansine; mannostatin A; marimastat; masoprocol; maspin; matrilysin inhibitors; matrix metalloproteinase inhibitors; menogaril; merbarone; meterelin; methioninase; metoclopramide; MIF inhibitor; mifepristone; miltefosine; mirimostim; mismatched double stranded RNA; mitoguazone; mitolactol; mitomycin analogues; mitonafide; mitotoxin fibroblast growth factor-saporin; mitoxantrone; mofarotene; molgramostim; monoclonal antibody, human chorionic gonadotrophin; monophosphoryl lipid A+myobacterium cell wall sk; mopidamol; multiple drug resistance gene inhibitor; multiple tumor suppressor 1 -based therapy; mustard anticancer agent; mycaperoxide B; mycobacterial cell wall extract; myriaporone; N-acetyldinaline; N-substituted benzamides; nafarelin; nagrestip; naloxone+pentazocine; napavin; naphterpin; nartograstim; nedaplatin; nemorubicin; neridronic acid; neutral endopeptidase; nilutamide; nisamycin; nitric oxide modulators; nitroxide antioxidant; nitrullyn; O6-benzylguanine; octreotide; okicenone; oligonucleotides; onapristone; ondansetron; ondansetron; oracin; oral cytokine inducer; ormaplatin; osaterone; oxaliplatin; oxaunomycin; paclitaxel; paclitaxel analogues; paclitaxel derivatives; palauamine; palmitoylrhizoxin; pamidronic acid; panaxytriol; panomifene; parabactin; pazelliptine; pegaspargase; peldesine; pentosan polysulfate sodium; pentostatin; pentrozole;perflubron; perfosfamide; perillyl alcohol; phenazinomycin; phenylacetate; phosphatase inhibitors; picibanil; pilocarpine hydrochloride; pirarubicin; piritrexim; placetin A; placetin B; plasminogen activator inhibitor; platinum complex; platinum compounds; platinumtriamine complex; porfimer sodium; porfiromycin; prednisone; propyl bis-acridone; prostaglandin J2; proteasome inhibitors; protein A-based immune modulator; protein kinase C inhibitor; protein kinase C inhibitors, microalgal; protein tyrosine phosphatase inhibitors; purine nucleoside phosphorylase inhibitors; purpurins; pyrazoloacridine; pyridoxylated hemoglobin polyoxyethylene conjugate; raf antagonists; raltitrexed; ramosetron; ras famesyl protein transferase inhibitors; ras inhibitors; ras-GAP inhibitor; retelliptine demethylated; rhenium Re 186 etidronate; rhizoxin; ribozymes; RII retinamide; rogletimide; rohitukine; romurtide; roquinimex; rubiginone Bl; ruboxyl; safingol; saintopin; SarCNU; sarcophytol A; sargramostim; Sdi 1 mimetics; semustine; senescence derived inhibitor 1; sense oligonucleotides; signal transduction inhibitors; signal transduction modulators; single chain antigen binding protein; sizofiran; sobuzoxane; sodium borocaptate; sodium phenylacetate; solverol; somatomedin binding protein; sonermin; sparfosic acid; spicamycin D; spiromustine; splenopentin; spongistatin 1; squalamine; stem cell inhibitor; stem-cell division inhibitors; stipiamide; stromelysin inhibitors; sulfinosine; superactive vasoactive intestinal peptide antagonist; suradista; suramin; swainsonine; synthetic glycosaminoglycans; tallimustine; tamoxifen methiodide; tauromustine; tazarotene; tecogalan sodium; tegafur; tellurapyrylium; telomerase inhibitors; temoporfm; temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine; thaliblastine; thiocoraline; thrombopoietin; thrombopoietin mimetic; thymalfasin; thymopoietin receptor agonist; thymotrinan; thyroid stimulating hormone; tin ethyl etiopurpurin; tirapazamine; titanocene bichloride; topsentin; toremifene; totipotent stem cell factor; translation inhibitors; tretinoin; triacetyluridine; triciribine; trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinase inhibitors; tyrphostins; UBC inhibitors; ubenimex; urogenital sinus-derived growth inhibitory factor; urokinase receptor antagonists; vapreotide; variolin B; erythrocyte gene therapy; velaresol; veramine; verdins; verteporfin; vinorelbine; vinxaltine; vitaxin; vorozole; zanoterone; zeniplatin; zilascorb; and zinostatin stimalamer. Any of the aforementioned chemotherapeutics can be administered at a clinically effective dose. A chemotherapeutic can also be administered from about day: -14, -13, -12, -11, -10, -9, -8, -7, -6, -5, -4, -3, -2, - 1, 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or up to about day 14 after administration of an agent provided herein. In some cases, a subject can have a refractory cancer that is unresponsive to a chemotherapeutic.

[0106] The methods described herein include administering to the patient a therapeutically effective amount of at least one compound as described herein, which is optionally formulated in a pharmaceutical composition. In various embodiments, a therapeutically effective amount of at least one compound described herein present in a pharmaceutical composition is the only therapeutically active compound in a pharmaceutical composition. In certain embodiments, the method further comprises administering to the patient an additional therapeutic agent that treats a cancer, or that treats a disease or disorder that is affected by, associated with, or would benefit from modulating, e.g., inducing, ferroptosis.

[0107] In some embodiments, administering the compound(s) described herein to the patient allows for administering a lower dose of the additional therapeutic agent as compared to the dose of the additional therapeutic agent alone that is required to achieve similar results in treating, ameliorating, and / or preventing cancer, or in treating, ameliorating, and / or preventing a disease or disorder that is affected by, associated with, or would benefit from modulating, e.g., inducing, ferroptosis. For example, in certain embodiments, the compound(s) described herein enhance(s) the activity of the additional therapeutic compound, thereby allowing for a lower dose of the additional therapeutic compound to provide the same effect.

[0108] In some embodiments, a compound disclosed herein can be comprised as a ligand in a proteolysis-targeting chimera (PROTAC) protein degrader. In some instance, a bifunctional PROTAC molecule can comprise the ligand of the protein of interest (POI) and a covalently linked ligand of an E3 ubiquitin ligase (E3). In some instances, the POI can be any protein herein. In some instances, the POI can be cysteine -glutamate antiporter (system Xc), a glutathione peroxidase 4 (GPX4), a p53, a cargo receptor NCOA4, a glutathione synthetase (GSH), or a glutamate-cysteine ligase (GCL). The inactivation or inhibition of some of these molecules, for example, system Xc, GPX4, or glutathione synthetase PROTAC protein degraders can work by recruiting a chosen E3 ligase into close proximity with a specific disease-causing protein so that it can be tagged with ubiquitin and sent off for degradation by the proteasome. After the protein is degraded, the PROTAC can be released to continue to elicit further degradation.

[0109] In some embodiments, a compound described herein can be part of an antibodydrug conjugate (ADC) where the compound is optionally linked to the antibody by a linker.Dosing and Administration

[0110] A typical human dose of compound provided herein (e.g., a ferroptosis-inducing agent) may be from about 10 pg / kg body weight / day to 10,000 mg / kg / day. In some embodiments, the dose of an agent provided herein is from about 0.1 mg / kg to about 1000 mg / kg, from 1 mg / kg to 1000 mg / kg, 1 mg / kg to 800 mg / kg, from about 1 mg / kg to about 700 mg / kg, from about 2 mg / kg to about 500 mg / kg, from about 3 mg / kg to about 400 mg / kg, 4 mg / kg to about 300 mg / kg, or from about 5 mg / kg to about 200 mg / kg. In certain embodiments, the suitable dosages of the agent can be about 1 mg / kg, 5 mg / kg, 10 mg / kg, 15 mg / kg, 20 mg / kg, 25 mg / kg, 30 mg / kg, 35 mg / kg, 40 mg / kg, 45 mg / kg, 50 mg / kg, 60 mg / kg, 70 mg / kg, 80 mg / kg, 90 mg / kg, 100 mg / kg, 125 mg / kg, 150 mg / kg, 175 mg / kg, 200 mg / kg, 250 mg / kg, 300 mg / kg, 400 mg / kg, 500 mg / kg, 600 mg / kg, 700 mg / kg, 800 mg / kg, 900 mg / kg, 1000 mg / kg, 2,000 mg / kg, 3,000 mg / kg, 4,000 mg / kg, 5,000 mg / kg, 6,000 mg / kg, 7,000 / mg / kg, 8,000 mg / kg, 9,000 mg / kg, up to 9,600 mg / kg. In some embodiments, the dose of compound provided herein is from about 100 mg / kg / day to about 6,400 mg / kg / day four times per day. In some embodiments, the dose of a compound provided herein is from about 50 mg / kg / day to about 25 mg / kg / day. In some embodiments, the dose of a compound provided herein is from about 400 mg / kg / day to about 800 mg / kg / day. In certain embodiments, the dose of the compound can be administered once per day or divided into subdoses and administered in multiple doses, e.g., twice, three times, or four times per day.

[0111] In some embodiments, compounds provided herein are administered in an amount of at least about 10 nanograms (ng) or more, about 20 ng or more, about 30 ng or more, about 40 ng or more, about 50 ng or more, about 60 ng or more, about 70 ng or more, about 80 ng or more, about 90 ng or more, up to 100 ng. In some embodiments, the compound is administered in an amount of at least about 1 microgram (pg) or more, about 5 pg or more, about 10 pg or more, about 20 pg or more, about 30 pg or more, about 40 pg or more, about 50 pg or more, about 60 pg or more, about 70 pg or more, about 80 pg or more, about 90 pg or more, up to 100 pg.

[0112] In some embodiments, compounds provided herein are administered at a concentration of at least about 0.1 micromolar (pM) or more, about 1 pM or more, about 2 pM or more, about 3 pM or more, about 4 pM or more, about 5 pM or more, about 6 pM or more, about 7 pM or more, about 8 pM or more, about 9 pM or more, about 10 pM or more, about 15 pM or more, about 20 pM or more, about 25 pM or more, about 30 pM or more,about 35 pM or more, about 40 pM or more, about 45 pM or more, about 50 pM or more, about 55 pM or more, about 60 pM or more, about 65 pM or more, about 70 pM or more, about 75 pM or more, about 80 pM or more, about 85 pM or more, about 90 pM or more, about 95 pM or more, about 100 pM or more, about 110 pM or more, about 120 pM or more, about 130 pM or more, about 140 pM or more, about 150 pM or more, about 160 pM or more, about 170 pM or more, about 180 pM or more, about 190 pM or more, about 200 pM or more, about 300 pM or more, about 400 pM or more, about 500 pM or more, up to 1 mM. In some embodiments, compounds provided herein are administered at a concentration of at least about 0.1 pM up to about 500 pM. In some embodiments, compounds provided herein are administered at a concentration of at least about 1 pM up to 500 pM. In some embodiments, compounds provided herein are administered at a concentration of at least about 0. 1 pM up to 10 pM. In some embodiments, compounds provided herein are administered at a concentration of at least about 1 pM up to 10 pM.

[0113] In some embodiments, ferroptosis-inducing agents provided herein, e.g., compounds provided herein, are administered intravenously. In some embodiments, compounds provided herein are administered intravenously at a concentration of at least about 20 mg / kg, about 25 mg / kg, about 30 mg / kg, about 35 mg / kg, about 40 mg / kg, about 45 mg / kg, about 50 mg / kg, about 60 mg / kg, about 70 mg / kg, about 80 mg / kg, about 90 mg / kg, about 100 mg / kg, about 200 mg / kg, about 300 mg / kg, about 400 mg / kg, about 500 mg / kg, about 600 mg / kg, about 700 mg / kg, about 800 mg / kg, about 900 mg / kg, about 1000 mg / kg, about 1100 mg / kg, about 1200 mg / kg, about 1300 mg / kg, about 1400 mg / kg, about 1500 mg / kg, about 2000 mg / kg, about 2200 mg / kg, about 2400 mg / kg, up to about 2500 mg / kg. In some embodiments, compounds provided herein are administered intravenously at a concentration of about 25 mg / kg once per day. In some embodiments, compounds provided herein are administered intravenously at a concentration of about 25 mg / kg twice per day. In some embodiments, compounds provided herein are administered intravenously at a concentration of about 450 mg / kg / day. In some embodiments, compounds provided herein are administered intravenously at a concentration of about 650 mg / kg / day. In some embodiments, compounds provided herein are administered intravenously at a concentration of about 650 mg / kg / day for 3 continuous days. In some embodiments, compounds provided herein are administered intravenously at a concentration of about 1300 mg / kg / day. In some embodiments, compounds provided herein are administered intravenously at a concentration of about 2400 mg / kg / day.

[0114] In some embodiments, compounds provided herein are administered orally. In some embodiments, compounds provided herein are administered orally at a concentration of at least about 20 mg / kg, about 25 mg / kg, about 30 mg / kg, about 35 mg / kg, about 40 mg / kg, about 45 mg / kg, about 50 mg / kg, about 60 mg / kg, about 70 mg / kg, about 80 mg / kg, about 90 mg / kg, about 100 mg / kg, about 200 mg / kg, about 300 mg / kg, about 400 mg / kg, about 500 mg / kg, about 600 mg / kg, about 700 mg / kg, about 800 mg / kg, about 900 mg / kg, about 1000 mg / kg, about 1100 mg / kg, about 1200 mg / kg, about 1300 mg / kg, about 1400 mg / kg, about 1500 mg / kg, about 2000 mg / kg, about 2200 mg / kg, about 2400 mg / kg, up to about 2500 mg / kg. In some embodiments, compounds provided herein are administered orally at a concentration of about 25 mg / kg once per day. In some embodiments, compounds provided herein are administered orally at a concentration of about 25 mg / kg twice per day. In some embodiments, compounds provided herein are administered orally at a concentration of about 1300 mg / kg / day. In some embodiments, compounds provided herein are administered orally at a concentration of about 2400 mg / kg / day.

[0115] The methods provided herein can be characterized by or further comprise measuring the distribution of an agent in a target tissue. Distribution of a compound provided herein can be determined by the amount or concentration of the agent within a square millimeter (mm2) or cubic millimeter (mm3) of tissue. For example, for local administration of the compound to a tumor, the tissue may be from about 6 to 7 mm in diameter, 36 to 42 mm2, or 216 to 294 mm3. The data obtained from animal studies may be used in formulating a range of drug distribution in a mammalian tissue. Methods of determining tissue distribution of a compound include, for example, mass spectrometry, chromatography, imaging techniques, and immunoassays. The distribution of a compound provided herein can be determined using a system provided herein.

[0116] In some embodiments, the tissue is administered a therapeutic amount of a compound disclosed herein, wherein administration of comprises providing to a tissue the compound in an amount sufficient to achieve a desired drug distribution. In some embodiments, the compound may achieve a distribution within a tissue of at least about 1 ng / mm2or more, about 5 ng / mm2or more, about 10 ng / mm2or more, about 15 ng / mm2or more, about 20 ng / mm2or more, about 25 ng / mm2or more, about 30 ng / mm2or more, about 35 ng / mm2or more, about 40 ng / mm2or more, about 45 ng / mm2or more, about 50 ng / mm2or more, about 55 ng / mm2or more, about 60 ng / mm2or more, about 65 ng / mm2or more, about 70 ng / mm2or more, about 75 ng / mm2or more, about 80 ng / mm2or more, about 85ng / mm2or more, about 90 ng / mm2or more, about 95 ng / mm2or more, about 100 ng / mm2or more, about 110 ng / mm2or more, about 120 ng / mm2or more, about 130 ng / mm2or more, about 140 ng / mm2or more, about 150 ng / mm2or more, about 160 ng / mm2or more, about 170 ng / mm2or more, about 180 ng / mm2or more, about 190 ng / mm2or more, about 200 ng / mm2or more, about 300 ng / mm2or more, about 400 ng / mm2or more, up to 500 ng / mm2. In some embodiments, the compound may achieve a distribution within a tissue of at least about 1 ng / mm3or more, about 5 ng / mm3or more, about 10 ng / mm3or more, about 15 ng / mm3or more, about 20 ng / mm3or more, about 25 ng / mm3or more, about 30 ng / mm3or more, about 35 ng / mm3or more, about 40 ng / mm3or more, about 45 ng / mm3or more, about 50 ng / mm3or more, about 55 ng / mm3or more, about 60 ng / mm3or more, about 65 ng / mm3or more, about 70 ng / mm3or more, about 75 ng / mm3or more, about 80 ng / mm3or more, about 85 ng / mm3or more, about 90 ng / mm3or more, about 95 ng / mm3or more, about 100 ng / mm3or more, about 110 ng / mm3or more, about 120 ng / mm3or more, about 130 ng / mm3or more, about 140 ng / mm3or more, about 150 ng / mm3or more, about 160 ng / mm3or more, about 170 ng / mm3or more, about 180 ng / mm3or more, about 190 ng / mm3or more, about 200 ng / mm3or more, about 300 ng / mm3or more, about 400 ng / mm3or more, up to 500 ng / mm3.

[0117] In some embodiments, a compound disclosed herein may be administered at least about once per day, twice per day, three times per day, four times per day, or five times per day. In some embodiments of any of the aspects, compounds are administered at least about every week, at least about every 2 weeks, or at least about every 3 weeks. The amount of compound administered depends on the size of the tissue, the type of disease being treated, and the type of administration (e.g., local administration to a tissue in vivo using a system provided herein). Effective doses will vary, depending on the types of diseases treated, route of administration, excipient usage, and the possibility of co-usage with other therapeutic treatments. In some embodiments, administering comprises, for example, intratumoral injection, oral administration, transdermal injection, inhalation, nasal administration, topical administration, vaginal administration, ophthalmic administration, intracerebral administration, rectal administration, intravenous administration, intra-arterial administration, intramuscular administration, or subcutaneous administration.Pharmaceutical Compositions and Kits

[0118] Another aspect of the disclosure provides pharmaceutical compositions comprising compounds as disclosed herein formulated together with a pharmaceuticallyacceptable carrier. In particular, the present disclosure provides pharmaceutical compositions comprising compounds as disclosed herein formulated together with one or more pharmaceutically acceptable carriers. These formulations include those suitable for oral, rectal, topical, intranasal, buccal, parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous) rectal, vaginal, or aerosol administration, although the most suitable form of administration in any given case will depend on the degree and severity of the condition being treated and on the nature of the particular compound being used. For example, disclosed compositions may be formulated as a unit dose, and / or may be formulated for oral or subcutaneous administration.

[0119] Exemplary pharmaceutical compositions of this disclosure may be used in the form of a pharmaceutical preparation, for example, in solid, semisolid or liquid form, which contains one or more of the compounds of the disclosure, as an active ingredient, in admixture with an organic or inorganic carrier or excipient suitable for external, enteral or parenteral applications. The active ingredient may be compounded, for example, with the usual non-toxic, pharmaceutically acceptable carriers for tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, and any other form suitable for use. The active object compound is included in the pharmaceutical composition in an amount sufficient to produce the desired effect upon the process or condition of the disease.

[0120] For preparing solid compositions such as tablets, the principal active ingredient may be mixed with a pharmaceutical carrier, e.g., conventional tableting ingredients such as com starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g., water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the disclosure, or a non-toxic pharmaceutically acceptable salt thereof. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.

[0121] In solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules and the like), the subject composition is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or any of the following: (1) fdlers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and / or acacia; (3) humectants, such asglycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, acetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such a talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and (10) coloring agents. In the case of capsules, tablets and pills, the compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.

[0122] A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface -active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the subject composition moistened with an inert liquid diluent. Tablets, and other solid dosage forms, such as dragees, capsules, pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art.

[0123] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the subject composition, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, com, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, cyclodextrins and mixtures thereof.

[0124] Suspensions, in addition to the subject composition, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

[0125] Formulations for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing a subject composition with one or more suitable non-irritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the body cavity and release the active agent.

[0126] Dosage forms for transdermal administration of a subject composition include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active component may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants which may be required.

[0127] The ointments, pastes, creams and gels may contain, in addition to a subject composition, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

[0128] Powders and sprays may contain, in addition to a subject composition, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays may additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

[0129] Compositions and compounds of the present disclosure may alternatively be administered by aerosol. This is accomplished by preparing an aqueous aerosol, liposomal preparation or solid particles containing the compound. A non-aqueous (e.g., fluorocarbon propellant) suspension could be used. Sonic nebulizers may be used because they minimize exposing the agent to shear, which may result in degradation of the compounds contained in the subject compositions. Ordinarily, an aqueous aerosol is made by formulating an aqueous solution or suspension of a subject composition together with conventional pharmaceutically acceptable carriers and stabilizers. The carriers and stabilizers vary with the requirements of the particular subject composition, but typically include non-ionic surfactants (Tweens, Pluronics, or polyethylene glycol), innocuous proteins like serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars or sugar alcohols.Aerosols generally are prepared from isotonic solutions.

[0130] Pharmaceutical compositions of this disclosure suitable for parenteral administration comprise a subject composition in combination with one or more pharmaceutically-acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.

[0131] Examples of suitable aqueous and non-aqueous carriers which may be employed in the pharmaceutical compositions of the disclosure include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate and cyclodextrins. Proper fluidity may be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

[0132] In another aspect, the disclosure provides enteral pharmaceutical formulations including a disclosed compound and an enteric material; and a pharmaceutically acceptable carrier or excipient thereof. Enteric materials refer to polymers that are substantially insoluble in the acidic environment of the stomach, and that are predominantly soluble in intestinal fluids at specific pHs. The small intestine is the part of the gastrointestinal tract (gut) between the stomach and the large intestine, and includes the duodenum, jejunum, and ileum. The pH of the duodenum is about 5.5, the pH of the jejunum is about 6.5 and the pH of the distal ileum is about 7.5. Accordingly, enteric materials are not soluble, for example, until a pH of about 5.0, of about 5.2, of about 5.4, of about 5.6, of about 5.8, of about 6.0, of about 6.2, of about 6.4, of about 6.6, of about 6.8, of about 7.0, of about 7.2, of about 7.4, of about 7.6, of about 7.8, of about 8.0, of about 8.2, of about 8.4, of about 8.6, of about 8.8, of about 9.0, of about 9.2, of about 9.4, of about 9.6, of about 9.8, or of about 10.0. Exemplary enteric materials include cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP), polyvinyl acetate phthalate (PVAP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), cellulose acetate trimellitate, hydroxypropyl methylcellulose succinate, cellulose acetate succinate, cellulose acetate hexahydrophthalate, cellulose propionate phthalate, cellulose acetate maleate, cellulose acetate butyrate, cellulose acetate propionate, copolymer of methylmethacrylic acid and methyl methacrylate, copolymer of methyl acrylate, methylmethacrylate and methacrylic acid, copolymer of methylvinyl etherand maleic anhydride (Gantrez ES series), ethyl methyacrylate-methylmethacrylate- chlorotrimethylammonium ethyl acrylate copolymer, natural resins such as zein, shellac and copal collophorium, and several commercially available enteric dispersion systems (e. g. , Eudragit L30D55, Eudragit FS30D, Eudragit LI 00, Eudragit SI 00, Kollicoat EMM30D, Estacryl 30D, Coateric, and Aquateric). The solubility of each of the above materials is either known or is readily determinable in vitro. The foregoing is a list of possible materials, but one of skill in the art with the benefit of the disclosure would recognize that it is not comprehensive and that there are other enteric materials that would meet the objectives of the present disclosure.

[0133] The disclosure also provides kits for use by a e.g., a consumer in need of treatment of a disease or disorder described herein. Such kits include a suitable dosage form such as those described above and instructions describing the method of using such dosage form to mediate, reduce or prevent inflammation. The instructions would direct the consumer or medical personnel to administer the dosage form according to administration modes known to those skilled in the art. Such kits could advantageously be packaged and sold in single or multiple kit units. An example of such a kit is a so-called blister pack. Blister packs are well known in the packaging industry and are being widely used for the packaging of pharmaceutical unit dosage forms (tablets, capsules, and the like). Blister packs generally consist of a sheet of relatively stiff material covered with a foil of a preferably transparent plastic material. During the packaging process recesses are formed in the plastic foil. The recesses have the size and shape of the tablets or capsules to be packed. Next, the tablets or capsules are placed in the recesses and the sheet of relatively stiff material is sealed against the plastic foil at the face of the foil which is opposite from the direction in which the recesses were formed. As a result, the tablets or capsules are sealed in the recesses between the plastic foil and the sheet. Preferably the strength of the sheet is such that the tablets or capsules can be removed from the blister pack by manually applying pressure on the recesses whereby an opening is formed in the sheet at the place of the recess. The tablet or capsule can then be removed via said opening.

[0134] It may be desirable to provide a memory aid on the kit, e.g., in the form of numbers next to the tablets or capsules whereby the numbers correspond with the days of the regimen which the tablets or capsules so specified should be ingested. Another example of such a memory aid is a calendar printed on the card, e.g., as follows “First Week, Monday, Tuesday, . . . etc. . . . Second Week, Monday, Tuesday, . . . “ etc. Other variations ofmemory aids will be readily apparent. A “daily dose” can be a single tablet or capsule or several pills or capsules to be taken on a given day. Also, a daily dose of a first compound can consist of one tablet or capsule while a daily dose of the second compound can consist of several tablets or capsules and vice versa. The memory aid should reflect this.EXAMPLES

[0135] The compounds described herein can be prepared in a number of ways based on the teachings contained herein and synthetic procedures known in the art. In the description of the synthetic methods described below, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, can be chosen to be the conditions standard for that reaction, unless otherwise indicated. It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule should be compatible with the reagents and reactions proposed. Substituents not compatible with the reaction conditions will be apparent to one skilled in the art, and alternate methods are therefore indicated. The starting materials for the examples are either commercially available or are readily prepared by standard methods from known materials. At least some of the compounds identified as “Intermediates” herein are contemplated as compounds of the disclosure.

[0136] The following abbreviations are used:A angstromsAIBN 2, 2'-azobis(2 -methylpropionitrile) aq. aqueousADDP 1 , T -(zzodicarbonyl)dipiperidine brine saturated aqueous sodium chlorideBoc tert-butoxy carbonylBn benzylBz benzoylCbz benzyloxycarbonylDBU 1,8 -diazabicyclo [5.4.0]undec-7 -eneDCM dichloromethaneDIAD diisopropyl azodicarboxylateDIPEA diisopropylethylamineDMAP 4-dimethylaminopyridineDMF N,N-dimcthylformamidcDMSO dimethyl sulfoxideEDCI l-ethyl-3-(3-dimethylaminopropyl)carbodiimideEtOAc ethyl acetateEtOH ethanolFA formic acid g gram(s) h hour(s)HATU 1 -[bis(dimethylamino)methylene] - 1H- 1 ,2,3 -triazolo [4,5 -b | pyridinium 3 -oxide hexafluorophosphateHPLC high performance liquid chromatography i-PrOH iso-propanol[Ir(dF (CF3)ppy)2(dtbbpy)] PF6bis [3 ,5 -difluoro-2-[5 -(trifluoromethyl)-2-pyridyl]phenyl]iridium( 1 +);4-tert- butyl-2-(4-tert-butyl-2-pyridyl)pyridine;hexafluorophosphateLAH lithium aluminum hydrideLCMS liquid chromatography-mass spectroscopyMeCN acetonitrileMeOD meth anol -AMe OH methanolMHz megahertzMS molecular sievesMsCl methanesulfonyl chlorideMS2O methanesulfonic anhydrideNMR Nuclear Magnetic ResonanceNs NosylPd(dppf)Ch [l,l'-bis(diphenylphosphino)ferrocene] dichloropalladium (II) pet ether petroleum etherPIDA (diacetoxyiodo)benzenePhI(OAc)2 (diacetoxyiodo)benzene[Rh(COD)CI]2 chloro(l,5-cyclooctadiene)rhodium(I) dimerRt retention timeSFC supercritical fluid chromatographyt-BuOH tert-butanolTBAF tetra-A-butylammonium fluorideTEA triethylamineTFA trifluoroacetic acidTFAA trifluoroacetic anhydrideTHF tetrahydrofuranTLC thin layer chromatographyTMSCF3 trimethyl(trifluoromethyl)silaneTrP 1,3,5,2,4,6-trioxatriphosphorinane, 2,4,6-tributyl-, 2,4,6-trioxideExample 1: Synthesis of tert-butyl ((4S)-l-butyl-l-oxido-3-oxo-3,4,5,6-tetrahydro- 116,2-thiazin-4-yl)carbamate (Compound 101)

[0137] To a solution of methyl (tert-butoxycarbonyl)-L-homocysteinate (4.3 g, 17.2 mmol, 1 eq) and 1-bromobutane (2.84 g, 20.7 mmol, 2.23 mL, 1.2 eq) in DMF (40 mL) was added K2CO3 (4.77 g, 34.4 mmol, 2 eq). The mixture was stirred at 15 °C for 1 h. The mixture was quenched with water (100 mL) and adjusted to pH ~7 with citric acid aqueous. The mixture was then extracted with MTBE (100 mL x 2). The organic layers were combined and dried over Na2SO4. filtered and concentrated under reduced pressure to afford the crude product. The crude product was purified by silica gel column chromatography to afford the title compound (4.3 g, 14.1 mmol, 81.6% yield) as a colorless oil.1H NMR (400MHz, CDCI3-d) δ 5.11 (br s, 1H), 4.55 - 4.25 (m, 1H), 3.76 (s, 3H), 2.59 - 2.47 (m, 4H), 2.12 (br d, J = 7.6 Hz, 1H), 1.92 (qd, J= 7.4, 14.4 Hz, 1H), 1.61 - 1.55 (m, 2H), 1.48 - 1.36 (m, 11H), 0.92 (t, J= 7.3 Hz, 3H).Step 2: methyl (2S)-2-((tert-butoxycarbonyl)amino)-4-(butylsulfinyl)butanoate):

[0138] To a solution of compound 1 (3.5 g, 11.4 mmol, 1 eq) in DCM (40 mL) was added m-CPBA (2.33 g, 11.4 mmol, 85% purity, 1 eq). The mixture was stirred at 20 °C for1 h. The reaction was quenched by NaHCO3(50 mL) and then extracted with DCM (50 mL x 2). The organic layers were combined and washed with Na2CO3(20 mL), dried over anhydrous Na2SOr, filtered and concentrated under vacuum to afford the crude product. The crude product was purified by silica gel column chromatography to afford the title compound (2.1 g, 6.53 mmol, 57.1% yield) as a yellow oil.1H NMR (400MHz, CDCI3-d) δ5.38 - 5.17 (m, 1H), 4.44 (br s, 1H), 3.82 - 3.72 (m, 3H), 2.84 - 2.58 (m, 4H), 2.38 (br dd, J = 5.1, 12.9 Hz, 1H), 2.20 - 2.07 (m, 1H), 1.83 - 1.70 (m, 4H), 1.46 (s, 9H), 0.98 (t, J= 7.3 Hz, 3H).Step 3: methyl (2S)-2-((tert-butoxycarbonyl)amino)-4-(butylsulfonimidoyl)butanoate:

[0139] To a solution of compound 2 (2.3 g, 7.16 mmol, 1 eq) in MeOH (25 mL) was added PhI(OAc)2 (6.91 g, 21.4 mmol, 3 eq) and ammonium carbamate (2.79 g, 35.7 mmol, 5 eq). The mixture was stirred at 25 °C for 1 h. The solution was diluted with H2O (10 mL) and extracted with EtOAc (100 mL x 2). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to afford the crude product. The crude product was purified by silica gel column chromatography to afford the title compound (1.60 g, 4.76 mmol, 66.4% yield) as a yellow oil.1H NMR (400MHz, DMSO-d6) 5 7.40 (br d, J= 7.8 Hz, 1H), 4.16 - 4.07 (m, 1H), 3.64 (s, 4H), 3.13 - 2.86 (m, 4H), 2.17 - 2.05 (m, 1H), 1.91 (br s, 1H), 1.75 - 1.53 (m, 2H), 1.46 - 1.29 (m, 11H), 0.89 (t, J = 7.3 Hz, 3H).Step 4: (2S)-2-((tert-butoxycarbonyl)amino)-4-(butylsulfonimidoyl)butanoic acid:

[0140] To a solution of compound 3 (50.0 mg, 149 pmol, 1 eq) in THF (1 mL) and H2O (0.2 mL) was added LiOH.H2O (12.7 mg, 297 pmol, 2 eq). The mixture was stirred at 60 °C for 2 h. The solution was adjusted to pH ~ 5 with HC1 (0.5 M) and extracted with EtOAc (3 mL x 5). The combined organic layers were dried over Na2SO4. fdtered and concentrated under reduced pressure to afford the title compound (45.0 mg, 139 pmol, 93.9% yield) as a yellow oil.1H NMR (400 MHz, CDCI3-d) δ 5.89 - 5.55 (m, 1H), 5.34 - 4.75 (m, 3H), 4.65 -4.38 (m, 1H), 3.67 - 3.25 (m, 3H), 2.57 - 2.26 (m, 2H), 2.15 - 1.81 (m, 2H), 1.63 - 1.39 (m, 9H), 1.02 (br dd, J = 7.3, 10.8 Hz, 3H).Step 5: tert-butyl ((4S)-l-butyl-l-oxido-3-oxo-3,4,5,6-tetrahydro-ll6,2-thiazin-4- yl) carbamate:

[0141] To a solution of compound 4 (10.0 mg, 31.2 pmol, 1 eq) and 2,2,2- trifluoroethanamine (15.6 mg, 156 pmol, 12.1 μL, 5 eq) in DMF (1 mL) was added DIPEA(12.3 mg, 93.5 pmol, 16.1 μL, 3 eq) and HATU (14.1 mg, 37.2 pmol, 1.2 eq). The mixture was stirred at 20 °C for 45 min. The mixture was purified by prep-HPLC (column: Phenomenex Gemini-NX C18 75x30mmx3um; mobile phase: [water (0.2% FA)-MeCN]; B%: 10%-30%, 12 min) to afford the title compound (30 mg, 42.2 pmol, 63.8% yield) as a white solid. LCMS: Rt = 3.171 min., (ES+) m / z (M+H)+= 305.1.1HNMR (400 MHz, D2O) δ 4.07 (br s, 2H), 3.88 (br s, 1H), 3.80 - 3.68 (m, 1H), 3.55 - 3.40 (m, 2H), 2.62 - 2.31 (m, 2H), 1.87 - 1.70 (m, 2H), 1.51 - 1.26 (m, 11H), 0.89 (br t, J= 6.7 Hz, 3H).Example 2: Synthesis of (4S)-4-amino-l-(benzo[d]thiazol-2-yl)-5,6-dihydro-116,2- thiazin-3(4H)-one 1-oxide (Compound 102)

[0142] To a solution of 2-bromobenzo[d]thiazole (551 mg, 2.57 mmol, 1.5 eq) and tertbutyl (tert-butoxycarbonyl)-L-homocysteinate (500 mg, 1.72 mmol, 1 eq) in THF (3 mL) was added Cu2O (147 mg, 1.03 mmol, 105 μL, 0.6 eq) and K2CO3 (356 mg, 2.57 mmol, 1.5 eq). The mixture was stirred at 70 °C for 12 h. The reaction mixture was filtered and concentrated under reduced pressure to afford the crude product. The crude product was purified by silica gel column chromatography to afford the title compound (680 mg, 1.60 mmol, 93.3% yield) as yellow oil.1H NMR (400 MHz, CDCI3-d) δ 7.94 (br d, J= 8.0 Hz, 1H), 7.78 - 7.74 (m, 1H), 7.43 (t, J= 7.2 Hz, 1H), 7.34 - 7.28 (m, 1H), 5.68 (br s, 1H), 4.30 (br s, 1H), 3.51 - 3.30 (m, 2H), 2.42 - 2.30 (m, 1H), 2.27 - 2.13 (m, 1H), 1.49 (s, 9H), 1.48 (s, 9H).Step 2: tert-butyl (2S)-4-(benzo[d]thiazole-2-sulfonimidoyl)-2-((tert-butoxycarbonyl)amino) butanocite:

[0143] A mixture of compound 3 (340 mg, 801 pmol, 1 eq), ammonium carbamate (250 mg, 3.20 mmol, 4 eq) and PhI(OAc)2 (516 mg, 1.60 mmol, 2 eq) in i-PrOH (4 mL) waspurged with N2 for. The mixture was then allowed to stir at 20 °C for 24 h. Upon completion of the reaction, the mixture was concentrated under reduced pressure. The resulting residue was diluted with water (10 mL), extracted with DCM (5 mL x 2). The combined organic layers were washed with brine (10 mL), dried over Na2SOr, fdtered and concentrated under reduced pressure to afford the crude product. The crude product was purified by silica gel column chromatography to afford the title compound (230 mg, 505 pmol, 63.0% yield) as yellow oil. *HNMR (400 MHz, CDCI3-d) δ 8.21 (d, J= 7.6 Hz, 1H), 8.04 - 7.98 (m, 1H), 7.69 - 7.54 (m, 2H), 5.16 (br s, 1H), 4.27 (br s, 1H), 3.68 - 3.47 (m, 2H), 2.57 - 2.11 (m, 2H), 1.44 (d, J = 2.4 Hz, 9H), 1.41 (d, J= 4.4 Hz, 9H).Step 3: (4S)-4-amino-l-(benzo[d]thiazol-2-yl)-5, 6-dihydro-ll6,2-thiazin-3(4H)-one 1 -oxide:

[0144] Compound 4 (60 mg, 132 pmol, 1 eq) in TFA (1 mL) and DCM (3 mL) was allowed to stir at 20 °C for 8 h under N2 atmosphere. The reaction was concentrated under reduced pressure to afford the crude product. The crude product was purified by prep-HPLC (column: Phenomenex Luna C18 100*30 mm*5 pm; mobile phase: [water (TFA)-MeCN]; B%: 1 %-25%, 10 min) to afford the title compound (2.5 mg, 2.75 pmol, 2.09% yield) as a white solid. LCMS: Rt = 2.108 min, (ES+) m / z (M+H)+= 282.0.1HNMR (400MHz, MeOD-d4) δ 8.24 (dd, J= 1.2, 8.4 Hz, 2H), 7.79 - 7.68 (m, 2H), 4.73 (td, J= 3.6, 15.2 Hz, 1H), 4.41 - 4.33 (m, 1H), 4.20 - 4.07 (m, 1H), 2.73 - 2.63 (m, 2H).Example 3: Synthesis of (4S)-4-amino-l-(3,3-dimethylbutyl)-5,6-dihydro-116,2-thiazin- 3(4H)-one 1-oxide (Compound 103)

[0145] To a solution of methyl (tert-butoxycarbonyl)-L-homocysteinate (10.0 g, 40.1 mmol, 1 eq) and l-bromo-3,3-dimethylbutane (9.93 g, 60.2 mmol, 1.5 eq) in DMF (70 mL) was added K2CO3 (16.6 g, 120 mmol, 3 eq) and KI (13.3 g, 80.2 mmol, 2 eq). The mixture was stirred at 25 °C for 16 h under N2. The mixture was poured into water (15 mL) andextracted with EtOAc (20 mL x 3). The combined organic layers were dried over Na2SO4. filtered and concentrated under reduced pressure to afford the title compound (12.5 g, 37.48 mmol, 93.45% yield) as a yellow oil .1H NMR (400MHz, CDCI3-d) δ 5.13 (br d, J = 7.8 Hz, 1H), 4.43 (br d, J= 4.5 Hz, 1H), 3.81 - 3.71 (m, 3H), 2.62 - 2.51 (m, 2H), 2.51 - 2.42 (m, 2H), 2.18 - 2.05 (m, 1H), 1.98 - 1.84 (m, 1H), 1.49 - 1.43 (m, 11H), 0.91 (s, 9H).Step 2: methyl (2S)-2-((tert-butoxycarbonyl)amino)-4-(3,3-dimethylbutylsulfonimidoyl) butanocite

[0146] To a solution of compound 1 (3.00 g, 9.00 mmol, 1 eq) in MeOH (24 mL) was added PhI(OAc)2 (11.9 g, 36.0 mmol, 4 eq) and ammonium carbamate (5.62 g, 71.9 mmol, 8 eq). The mixture was stirred at 20 °C for 16 h. The mixture was then concentrated under reduced pressure. The resulting residue was poured into water (30 mL) and extracted with EtOAc (45 mL x 3). The combined organic layers were dried over Na2SO4. fdtered and the fdtrate was concentrated under reduced pressure to afford the crude product. The crude product was purified by silica gel column chromatography to afford the title compound (1.60 g, 4.39 mmol, 48.8% yield), as a colorless oil.1H NMR (400MHz, CDCI3-d) δ 5.39 - 5.23 (m, 1H), 4.44 (br s, 1H), 3.79 (s, 3H), 3.23 - 2.94 (m, 4H), 2.50 - 2.36 (m, 1H), 2.24 - 2.10 (m, 1H), 1.78 - 1.67 (m, 2H), 1.46 (s, 9H), 0.96 (s, 9H).Step 3: (2S)-2-((tert-butoxycarbonyl)amino)-4-(3, 3-dimethylbutylsulfonimidoyl)butanoic acid:

[0147] To a solution of compound 2 (1.60 g, 4.39 mmol, 1 eq) in THE (12 mL) and H2O (4 mL) was added LiOH.H2O (368 mg, 8.78 mmol, 2 eq). The mixture was stirred at 25 °C for 2 h. The solution was adjusted to pH ~ 5 with citric acid and extracted with EtOAc (20 mL x 4). The combined organic layers were dried over Na2SOr, filtered and concentrated under reduced pressure to afford the title compound (1.30 g, 3.71 mmol, 84.5% yield) as a white solid.1H NMR (400MHz, CDCI3-d) δ 5.69 (br d, J= 6.5 Hz, 1H), 4.55 - 4.37 (m, 1H), 3.53 - 3.17 (m, 4H), 2.47 - 2.21 (m, 2H), 1.82 - 1.65 (m, 2H), 1.44 (s, 9H), 0.96 (d, J = 3.4 Hz, 9H).Step 4: tert-butyl ((4S)-l-(3,3-dimethylbutyl)-l-oxido-3-oxo-3,4,5,6-tetrahydro-ll6,2- thiazin-4-yl) carbamate :

[0148] To a solution of compound 3 (200 mg, 570 pmol, 1 eq) in DMF (2 mL) was added HATU (325 mg, 855 pmol, 1.5 eq) and DIPEA (295 mg, 2.28 mmol, 4. eq). The mixture was stirred at 25 °C for 16 h. The reaction mixture poured into water (5 mL),extracted with EtOAc (5 mL x 3). The combined organic layers were washed with brine (5 mL), dried over Na2SOr. filtered and concentrated under reduced pressure to afford the crude product. The crude product was purified by prep-TLC (SiO2, Petroleum ether: Ethyl acetate = 1: 1) to afford the title compound (55.0 mg, 165 pmol, 28.9% yield) as a colorless oil.Step 5: (4S)-4-amino-l-(3,3-dimethylbutyl)-5,6-dihydro-ll6,2-thicizin-3(4H)-one 1-oxide:

[0149] To a mixture of compound 4 (55.0 mg, 165 pmol, 1 eq) in DCM (0.9 mL) was added TFA (0.3 mL). The resulting mixture was allowed to stir at 25 °C for 2 h. The reaction mixture was then concentrated under reduced pressure. The resulting residue was poured into water (ImL), extracted with DCM (1 mL x 2). The aqueous phase was lyophilized to afford the title compound (34.0 mg, 142 pmol, 59.3% yield, TFA salt) as a white solid. LCMS: Rt = 1.929 min., (ES+) m / z (M+H)+= 233.1.1H NMR (400 MHz, D2O) δ 4.31 - 4.10 (m, 1H), 4.04 - 3.46 (m, 4H), 2.80 - 2.37 (m, 2H), 1.83 - 1.65 (m, 2H), 0.99 - 0.89 (m, 9H).Example 4: Synthesis of (4S)-4-amino-l-(4,4,4-trifluorobutyl)-5,6-dihydro-116,2- thiazin-3(4H)-one 1-oxide (Compound 104)Step 1 : tert-butyl N-(tert-butoxycarbonyl)-S-(4, 4, 4-trifluorobutyl)-L-homocysteinate:

[0150] A mixture of (S)-tert-butyl 2-((tert-butoxycarbonyl)amino)-4-mercaptobutanoate (400 mg, 1.37 mmol, 1 eq), l,l,l-trifluoro-4-iodobutane (327 mg, 1.37 mmol, 1 eq) and K2CO3 (379 mg, 2.75 mmol, 2 eq) in DMF (6 mL) was purged with N2. The mixture was then allowed to stir at 25 °C for 16 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was diluted with EtOAc (20 mL) and water (5 mL). The organic phase was separated and concentrated under reduced pressure to afford the crude product. The crude product was purified by silica gel column chromatography to afford the title compound (420 mg, 1.05 mmol, 76.2% yield) as a yellow oil.1H NMR (400MHz, CDCI3-d) δ 5.03 (br d, J= 7.2 Hz, 1H), 4.21 (br d, J= 5.0 Hz, 1H),2.59 - 2.38 (m, 4H), 2.24 - 2.07 (m, 2H), 2.01 (br d, J= 6.6 Hz, 1H), 1.87 - 1.67 (m, 3H), 1.46 - 1.29 (m, 18H).Step 2: tert-butyl (2S)-2-((tert-butoxycarbonyl)amino)-4-(4,4,4-trifluorobutylsulfonimidoyl) butanocite:

[0151] To a solution of compound 3 (410 mg, 1.02 mmol, 1 eq) in i-PrOH (10 mL) was added PhI(OAc)2 (987 mg, 3.06 mmol, 3 eq) and ammonium carbamate (399 mg, 5.11 mmol, 5 eq). The mixture was stirred at 25 °C for 16 h. The reaction mixture was concentrated under reduced pressure to remove i-PrOH. The resulting residue was diluted with DCM (30 mL), washed with water (10 mL). The organic phase was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford the title compound (370 mg, 856 pmol, 83.8% yield) as a colorless oil.1H NMR (400MHz, CDCI3-d) δ 5.23 (br s, 1H), 4.35 - 4.19 (m, 1H), 3.28 - 2.97 (m, 4H), 2.51 - 2.23 (m, 4H), 2.22 - 2.05 (m, 4H), 1.46 (d, J= 15.1 Hz, 18H).Step 3: (2S)-2-amino-4-(4, 4, 4-trifluorobutylsulfonimidoyl)butanoic acid:

[0152] To a solution of compound 4 (70.0 mg, 162 pmol, 1 eq) in DCM (1.5 mL) was added TFA (616 mg, 5.40 mmol, 0.4 mL, 33.4 eq). The mixture was stirred at 25 °C for 16 h. The reaction mixture was concentrated under reduced pressure to afford the title compound (54 mg, 131 pmol, 81.1% yield, 94.9% purity, TFA) as a yellow oil. LCMS: Rt = 0.607 min, (ES+) m / z (M+H)+= 277.0.1H NMR (400MHz, D2O) δ 4.13 (br t, J= 6.5 Hz, 1H), 4.04 - 3.60 (m, 4H), 2.56 - 2.27 (m, 4H), 2.14 (quin, J= 7.8 Hz, 2H).Step 4: (4S)-4-amino-l-(4,4,4-trifluorobutyl)-5,6-dihydro-ll6,2-thiazin-3(4H)-one 1-oxide:

[0153] (2S)-2-amino-4-(4,4,4-trifhrorobutylsulfonimidoyl)butanoic acid (30.0 mg, 108 pmol) was dissolved in water / MeOH (2:1, 1.5 mL) and purified by prep-HPLC (column: Phenomenex C18 75*30 mm*3 pm; mobile phase: [water( NH4HCO3)-MeCN]; B%: 5%- 35%, 12 min) to give the title compound (4.94 mg, 19.1 pmol, 17.1% yield) as a yellow oil. LCMS: Rt = 0.697 min, (ES+) m / z (M+H)+= 259.0.1H NMR (400 MHz, DMSO-d6) δ 4.12 - 3.71 (m, 1H), 3.62 - 3.39 (m, 4H), 3.25 (br s, 1H), 2.44 - 2.04 (m, 3H), 2.03 - 1.87 (m, 2H).Example 5: Synthesis of (lR,4S)-4-amino-l-((S)-4,4,4-trifluoro-3-hydroxybutyl)-5,6- dihydro-116,2-thiazin-3(4H)-one 1-oxide (Compound 105)Step 1 : (1R, 4S)-4-amino-l-( (S)-4, 4, 4-trifluoro-3-hydroxybutyl)-5, 6-dihydro-ll6, 2-thiazin- 3(4H)-one 1-oxide:

[0154] To a solution of benzyl (S)-2-(((benzyloxy)carbonyl)amino)-4-((R,3S)-4,4,4- trifluoro-3-hydroxybutylsulfonimidoyl)butanoate (4.66 g, 9.02 mmol) in Me-THF (70 mL) and HC1 (0.5 M, 15.34 mL) was added 10% Pd / C (4.66 g). The suspension was purged with H2. The mixture was stirred under H2 (50 psi) at 30 °C for 2 hours. The reaction mixture was filtered and the filtrate was concentrated under vacuum to afford the crude product. 150 mg of the crude product was purified by prep-HPLC (column: Phenomenex C18 75*30 mm*3 pm; mobile phase: [water (NH4HCO3)-MeCN]; B%: 1 %-20%, 10 min) to afford the title compound ((1.24 mg, 4.52 pmol) as white solid. LCMS: Rt = 0.516 min., (ES+) m / z (M+H)+= 275.0.1H NMR (400 MHz, D2O) δ 4.12-4.31 (m, 2H), 3.48 - 3.81 (m, 4H), 2.44 - 2.50 (m, 4H).Example 6: Synthesis of (lR,4S)-4-amino-l-((R)-4,4,4-trifluoro-3-hydroxybutyl)-5,6- dihydro-116,2-thiazin-3(4H)-one 1-oxide (Compound 106)

[0155] To a solution of compound 1 (300 mg, 795 pmol, 1 eq) in MeOH (5 mL) was added PhI(OAc)2 (768 mg, 2.38 mmol, 3 eq) and CH3COONH4 (245 mg, 3.18 mmol, 4 eq), the mixture was stirred at 20° C for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Waters Xbridge BEH C18 100*30 mm* 10 pm; mobile phase: [H2O (10 mM NH4HCO3)-MeCN]; gradient: 1%- 30% B over 12.0 min) to afford the title compound (170 mg, 433.24 pmol, 54.50 % yield) asa white solid.1H NMR (400 MHz, MeOD-d4) δ 4.20 - 3.89 (m, 2H), 3.29 - 3.20 (m, 2H), 3.19 - 3.06 (m, 1H), 2.93 - 2.81 (m, 1H), 2.35 - 1.93 (m, 4H), 1.45 (s, 9H).Step 2: tert-butyl ((lR4S)-l-oxido-3-oxo-l-((R)-4,4,4-trifluoro-3-hydroxybutyl)-3,4,5,6- tetrahydro-ll6,2-thiazin-4-yl)carbamate:

[0156] A mixture of compound 2 (150 mg, 382 pmol, 1 eq), T4P (551 mg, 765 pmol, 50% purity, 2 eq) and DIPEA (98.8 mg, 765 pmol, 133 μL, 2 eq) in DCM (3 mL) was degassed with N2 for 3 times. The mixture was stirred at 0-15 °C for 16 h under N2. The reaction mixture was poured into water (5 mL), extracted with DCM (10 mL x 4). The combined organic layers were dried over Na2SOr, fdtered and concentrated under reduced pressure. The residue was purified by prep-TLC (EtOAc:MeOH = 10: 1, Rr = 0.6) to afford the title compound (65 mg, 173.62 pmol, 45.42% yield) as a yellow solid.1H NMR (400 MHz, MeOD-di) δ 4.21 - 4.03 (m, 3H), 3.67 - 3.54 (m, 3H), 2.48 (qd, J= 4.8, 14.2 Hz, 1H), 2.36 - 2.22 (m, 2H), 2.20 - 2.05 (m, 1H), 1.45 (s, 9H).Step 3: (lR,4S)-4-amino-l-((R)-4,4,4-trifluoro-3-hydroxybutyl)-5, 6-dihydro-ll6,2-thiazin- 3(4H)-one 1-oxide:

[0157] To a solution of compound 3 (65 mg, 173.62 pmol, 1 eq) in DCM (1 mL) was added TLA (461 mg, 4.04 mmol, 0.3 mL, 23.26 eq). The mixture was stirred at 0-15 °C for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Kromasil C18 (w) 100*40 mm 10 pm; mobile phase: [H2O (lOmM NH4HCO3)-MeCN]; gradient: l%-20% B over 10.0 min) to afford the title compound (19.84 mg, 68.70 pmol, 39.57% yield, 94.97% purity) as a white solid. LCMS: Rt = 0. 168 min, (ES+) m / z (M+H)+= 275.0.1H NMR (400 MHz, D2O) δ4.34 - 4.08 (m, 2H), 3.87 - 3.59 (m, 4H), 2.61 - 2.47 (m, 1H), 2.39 - 2.07 (m, 3H).Example 7: Synthesis of (lR,4S)-4-amino-l-((S)-3-(5-(2,4-dichlorophenyl)pyridin-2-yl)-4,4,4-trifluoro-3-hydroxybutyl)-5,6-dihydro-116,2-thiazin-3(4H)-one 1-oxide(Compound 107)

[0158] To a solution of N,O-dimethylhydroxylamine hydrogen chloride (4.83 g, 49.5 mmol, 1 eq), TEA (25.1 g, 248 mmol, 34.5 mL, 5 eq) and 5 -bromopicolinic acid (10 g, 49.5 mmol, 1 eq) in DCM (100 mL) was added TiP (71.3 g, 99.0 mmol, 50% purity, 2 eq) at 0 °C. The resulting mixture was stirred at 25 °C for 12 h. The reaction mixture was quenched by ice water (100 mL) and extracted with DCM (100 mL x 2). The combined organic layers were washed with brine (150 mL), dried over Na2SOr, fdtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to affordthe title compound (11 g, 44.9 mmol, 90.7% yield) as yellow oil.1H NMR (400 MHz, CDCI3-d) δ 8.69 (d, J= 2.0 Hz, 1H), 7.93 (dd, J= 2.0, 8.4 Hz, 1H), 7.69 - 7.48 (m, 1H), 3.76 (br s, 3H), 3.41 (s, 3H).Step 2: tert-butyl S-(3-(5-bromopyridin-2-yl)-3-oxopropyl)-N-(tert-butoxyccirboriyl)-L- homocysteinate:

[0159] To a solution of compound 2 (1 g, 4.08 mmol, 1 eq) in THF (10 mL) was added vinylmagnesium bromide (1 M, 8.16 mL, 2 eq) at -65 °C under N2. tert-Butyl (tert- butoxycarbonyl)-L-homocysteinate (595 mg, 2.04 mmol, 0.5 eq) and TEA (1.24 g, 12.2 mmol, 1.70 mL, 3 eq) was then added after 5 minutes and the resulting mixture was stirred at -65 °C for 1 h. The reaction mixture was poured into aq. NH4Q (100 mL) at 0 °C and extracted with EtOAc (100 mL x 2). The combined organic layers were washed with brine (150 mL), dried over Na2SOr, filtered and concentrated under reduced pressure to afford the crude product. (Totally 4 batches (compound 2: 5 g) were carried out and combined for purification. Batch 1: compound 2 (1 g); Batch 2: compound 2 (2 g); Batch 3: compound 2 (1 g x 2).). The residue was purified by silica gel column chromatography and reverse-phase HPLC (0.1% FA condition) to afford the title compound (4 g, 7.95 mmol, 38.9% yield) as yellow oil. *HNMR (400 MHz, CDCI3-d) δ 8.74 (d, J= 1.6 Hz, 1H), 8.02 - 7.91 (m, 2H), 5.18 - 5.08 (m, 1H), 4.33 - 4.21 (m, 1H), 3.55 - 3.43 (m, 2H), 2.92 (t, J= 7.2 Hz, 2H), 2.70 - 2.53 (m, 2H), 2.18 - 2.06 (m, 1H), 1.97 - 1.84 (m, 1H), 1.48 (s, 9H), 1.45 (s, 9H).Step 3: tert-butyl S-(3-(5-bromopyridin-2-yl)-4, 4, 4-trifluoro-3-hydroxybutyl)-N-(tert- butoxycarbonyl)-L-homocysteinate:

[0160] To a solution of compound 4 (875 mg, 1.74 mmol, 1 eq) in THF (20 mL) was added TMSCF3 (1.24 g, 8.69 mmol, 5 eq), and TBAF (1 M, 174 μL, 0.1 eq) at 0 °C. The mixture was stirred at 0 °C for 10 min. Additional TBAF (1 M, 5.21 mL, 3 eq) was added and the resulting mixture was stirred at 15 °C for 1 h. The reaction mixture was poured into water (30 mL) and extracted with EtOAc (30 mL x 2). The combined organic layers were washed with brine (30 mL), dried over Na2SO4. filtered and concentrated under reduced pressure. The residue was purified by silica gel column to afford the title compound (1.63 g, 2.84 mmol, 35.8% yield) as yellow oil.1H NMR (400 MHz, CDCI3-d) δ 8.68 (d, J= 2.0 Hz, 1H), 7.98 (td, J= 2.4, 8.4 Hz, 1H), 7.46 (d, J= 8.8 Hz, 1H), 5.98 - 5.79 (m, 1H), 5.09 (br s, 1H), 4.29 - 4.18 (m, 1H), 2.61 - 2.45 (m, 4H), 2.34 - 2.25 (m, 1H), 2.12 - 1.96 (m, 2H), 1.87 - 1.73 (m, 1H), 1.46 (s, 9H), 1.45 (s, 9H).Step 4: tert-butyl N-(tert-butoxycarbonyl)-S-(3-(5-(2,4-dichlorophenyl)pyridin-2-yl)-4,4,4- trifluoro-3-hydroxybutyl)-L-homocysteinate:

[0161] To a solution of compound 5 (1.63 g, 2.84 mmol, 1 eq), Na2CO3(904 mg, 8.53 mmol, 3 eq) and phenylboronic acid (816 mg, 4.26 mmol, 1.5 eq) in t-BuOH (21 mL) and H2O (7 mL) was added Pd(dppf)C12.CH2C12 (464 mg, 568 pmol, 0.2 eq) under N2. The resulting mixture was stirred at 90 °C for 2 h. The reaction mixture was poured into water (40 mL) and extracted with EtOAc (40 mL x 2). The combined organic layers were washed with brine (40 mL), dried over Na2SO4. filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford the title compound (1.4 g, 2.19 mmol, 77.0% yield) as yellow oil.1H NMR (400 MHz, CDCI3-d) δ 8.69 - 8.62 (m, 1H), 7.94 (td, J= 1.6, 8.0 Hz, 1H), 7.63 (d, J= 8.0 Hz, 1H), 7.58 - 7.55 (m, 1H), 7.42 - 7.37 (m, 1H), 7.35 - 7.31 (m, 1H), 5.15 - 5.02 (m, 1H), 4.30 - 4.15 (m, 1H), 2.63 - 2.47 (m, 4H), 2.43 - 2.33 (m, 1H), 2.13 - 1.95 (m, 2H), 1.85 - 1.77 (m, 1H), 1.46 (s, 9H), 1.45 (d, J = 1.6 Hz, 9H).Step 5: tert-butyl (2S)-2-((tert-butoxycarbonyl)amino)-4-(3-(5-(2, 4-dichlorophenyl)pyridin- 2-yl)-4, 4, 4-trifluoro-3-hydroxybutylsulfonimidoyl)butanoate:

[0162] A mixture of compound 6 (1.1 g, 1.72 mmol, 1 eq), ammonium carbamate (1.07 g, 13.8 mmol, 8 eq) and PhI(OAc)2 (2.22 g, 6.88 mmol, 4 eq) in i-PrOH (11 mL) was stirred at 25 °C for 12 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water (30 mL) and extracted with EtOAc (30 mL x 2). The combined organic layers were washed with brine (30 mL), dried over Na2SO4. filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (SiO2, Petroleum ether / Ethyl acetate = 88 / 12 to 40 / 60) to afford the title compound (1.0 g, 1.48 mmol, 81.9% yield) as yellow oil.Step 6: Separation of Compounds 8 and 9

[0163] Compound 8 [SFC (ET39406-1818-P1A3, peak 1 : Rt = 3.197 mins; peak 2 : Rt = 3.321 mins)] was separated by SFC (column: DAICEL CHIRALPAK AD (250 mm*50 mm, 10 pm); mobile phase: [CO2-IPA (0.1% NH3H2O)]; B%:20%, isocratic elution mode) to afford the title compound (216 mg, 322 pmol, 18.7% yield) as colorless oil.

[0164] Compound 9 [SFC (ET39406-1818-P1A7, peak 1 : Rt = 2.755 mins; peak 2 : Rt = 3.052 mins)] was separated by SFC (column: DAICEL CHIRALPAK AD(250 mm*30mm, 10 pm); mobile phase: [CO2-EtOH (0.1% NH3H2O)]; B%: 23%, isocratic elution mode ) to give afford the title compound (150 mg, 223.69 pmol, 20.60% yield) as colorless oil.Step 7: (S)-2-amino-4-((R,3S)-3-(5-(2,4-dichlorophenyl)pyridin-2-yl)-4,4,4-trifluoro-3- hydroxybutylsulfonimidoyl)butanoic acid:Compound 8 (50 mg, 74.56 pmol, 1 eq) in HCl / dioxane (3 mL) (4M) was stirred at 25 °C for 12 h. The reaction mixture was concentrated under reduced pressure to afford the title compound (41 mg, 74.4 pmol, 99.8% yield, HC1) as yellow oil.Step 8: (S)-2-((tert-butoxycarbonyl)amino)-4-((R,3S)-3-(5-(2,4-dichlorophenyl)pyridin-2- yl)-4, 4, 4-trifluoro-3-hydroxybutylsulfonimidoyl)butanoic acid:

[0165] To a solution of compound 10 (56 mg, 102 pmol, 1 eq, HC1) in dioxane (0.1 mL) and H2O (0.5 mL) was added BOC2O (26.6 mg, 122 pmol, 28.0 μL, 1.2 eq) and Na2CO3(32.3 mg, 305 pmol, 3 eq). The resulting mixture was stirred at 25 °C for 12 h. The reaction mixture was adjusted to pH = 3 by IM HC1 and extracted with EtOAc (5 mL x 5). The combined organic layers were washed with brine (5 mL), dried over Na2SO4, fdtered and concentrated under reduced pressure to afford the title compound (53 mg, 86.3 pmol, 42.4% yield) as yellow oil. ' H NMR (400 MHz, CDCI3-d) δ 8.66 (s, 1H), 7.95 (br d, J= 7.2 Hz, 1H), 7.70 (br d, J= 8.0 Hz, 1H), 7.56 (d, J= 1.6 Hz, 1H), 7.42 - 7.37 (m, 1H), 7.35 - 7.30 (m, 1H), 5.55 (br s, 1H), 4.54 - 4.33 (m, 1H), 3.45 - 3.15 (m, 3H), 3.04 - 2.92 (m, 1H), 2.83 - 2.65 (m, 2H), 2.46 - 2.24 (m, 2H).Step 9: tert-butyl ((lR,4S)-l-((S)-3-(5-(2,4-dichlorophenyl)pyridin-2-yl)-4,4,4-trifluoro-3- hydroxybutyl)-l-oxido-3-oxo-3,4,5,6-tetrahydro-ll6,2-thiazin-4-yl)carbamate:

[0166] To a solution of Compound 11 (53 mg, 86.3 pmol, 1 eq) and TEA (52.4 mg, 518 pmol, 72.0 μL, 6 eq) in DCM (1 mL) was added T4P (186 mg, 259 pmol, 50% purity, 3 eq) at 0 °C. The resulting mixture was stirred at 15 °C for 1 h. The reaction mixture was poured into water (5 mL), extracted with DCM (5 mL x 2). The combined organic layers were washed with brine (5 mL), dried over Na2SO4, fdtered and concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2, Petroleum ether: Ethyl acetate = 1: 2) to afford the title compound (28 mg, 46.9 pmol, 54.4% yield) as a yellow oil.Step 10: (lR,4S)-4-amino-l-((S)-3-(5-(2,4-dichlorophenyl)pyridin-2-yl)-4,4,4-trifluoro-3- hydroxybutyl)-5, 6-dihydro-ll6,2-thiazin-3(4H)-one 1 -oxide:

[0167] Compound 12 (28 mg, 46.9 pmol, 1 eq) in TFA (0.4 mL) and DCM (2 mL) was stirred at 25°C for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex luna C18 100*40 mm*3 pm; mobile phase: [H2O (0.2% FA)-MeCN]; gradient: 20%-50% B over 10.0 min) to afford the title compound (14.9 mg, 27.5 pmol, 58.6% yield, 99.8% purity, FA) as a white solid. LC- MS: Rt = 2.259 min, (ES+) m / z (M+H)+= 496.0.1H NMR (400 MHz, MeOD-d4) δ = 8.71 (d, J= 1.6 Hz, 1H), 8.42 (s, 1H), 8.04 (dd, J= 2.4, 8.4 Hz, 1H), 7.92 (d, J= 8.0 Hz, 1H), 7.66 (d, J= 1.6 Hz, 1H), 7.55 - 7.41 (m, 2H), 4.20 (td, J= 4.4, 14.8 Hz, 1H), 3.91 (dd, J = 4.4, 11.6 Hz, 1H), 3.64 - 3.49 (m, 2H), 3.21 - 3.05 (m, 2H), 2.70 - 2.59 (m, 1H), 2.53 (qd, J = 4.8, 13.6 Hz, 1H), 2.32 - 2.16 (m, 1H).Example 8: Synthesis of (lR,4S)-4-amino-l-((S)-4,4,4-trifluoro-3-hydroxy-3- phenylbutyl)-5,6-dihydro-116,2-thiazin-3(4H)-one 1-oxide (Compound 108) p

[0168] Compound 1 (1 g, 1.91 mmol, 1 eq) was separated by SFC (column: DAICEL CHIRALCEL OZ 250*25 mm ED. 10 pm; mobile phase: [Heptane-EtOH (0.1% NH3H2O)]; B%: 5%, isocratic elution mode) to afford the title compound (160 mg, 305.00 pmol, 1 eq) as white solid.1H NMR (400 MHz, MeOD-A) δ 7.61 (s, 2H), 7.43 (s, 3H), 4.12 - 4.00 (m, 1H), 3.24 - 3.05 (m, 3H), 2.76 - 2.65 (m, 2H), 2.61 - 2.52 (m, 1H), 2.24 - 2.14 (m, 1H), 2.04 - 1.92 (m, 1H), 1.45 (d, J= 6.5 Hz, 18H).Step 2: (S)-2-amino-4-( (R, 3S)-4, 4, 4-trifluoro-3-hydroxy-3- phenylbutylsulfonimidoyl)butanoic acid:

[0169] A solution of compound 2 (100 mg, 190.62 pmol, 1 eq in HCl / dioxane (2 mL) was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure to afford the title compound (70 mg, 190.03 pmol, 99.69% yield, HC1 salt) as a colorless oil.Step 3: (S)-2-( ( tert-butoxycarbonyl)amino)-4-((R, 3S)-4, 4, 4-trifluoro-3-hydroxy-3- phenylbutylsulfonimidoyl)butanoic acid:

[0170] A solution of compound 3 (70 mg, 190 pmol, 1 eq, HC1), BOC2O (49.8 mg, 228 pmol, 52.4 μL, 1.2 eq) and Na2CO3(60.4 mg, 570 pmol, 3 eq) in H2O (2.5 mL) and dioxane (0.5 mL) was stirred at 25 °C for 12 h. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (5 mL x 3), dried over Na2SO4. filtered and concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2, Petroleum ether: Ethyl acetate = 0: 1) to afford the title compound (80 mg, 153.69 pmol, 80.88% yield, 90% purity) as a colorless oil.1H NMR (400 MHz, MeOD-A) δ 7.62 (br d, J= 7.6 Hz, 2H), 7.43 (br d, J= 7.7 Hz, 3H), 4.30 - 4.15 (m, 1H), 3.24 - 3.08 (m, 3H), 2.75 - 2.65 (m, 2H), 2.63 - 2.49 (m, 1H), 2.31 - 2.19 (m, 1H), 2.03 (br d, J= 8.9 Hz, 1H), 1.45 (s, 9H).Step 4: tert-butyl ((lR,4S)-l-oxido-3-oxo-l-((S)-4,4,4-trifluoro-3-hydroxy-3-phenylbutyl)- 3, 4, 5, 6-tetrahydro-ll6, 2-thiazin-4-yl) carbamate:

[0171] To a solution of compound 4 (70 mg, 149 pmol, 1 eq) in DCM (1 mL) was added TEA (75.6 mg, 747 pmol, 104 μL, 5 eq) and T4P (215 mg, 299 pmol, 50% purity, 2 eq) at 0 °C. The mixture was stirred at 15 °C for 1 h. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (5 mL x 3). dried over Na2SOr. fdtered and concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2, Petroleum ether: Ethyl acetate = 0: 1) to afford the title compound (40 mg, 88.80 pmol, 59.43% yield) as colorless oil.1H NMR (400 MHz, MeOD-A) δ 7.63 (d, J= 7.5 Hz, 2H), 7.48 - 7.36 (m, 3H), 4.08 (br dd, J= 4.8, 10.6 Hz, 1H), 4.03 - 3.91 (m, 1H), 3.60 - 3.48 (m, 1H), 3.46 - 3.37 (m, 1H), 3.02 (dt, J= 3.9, 13.1 Hz, 1H), 2.83 - 2.73 (m, 1H), 2.72 - 2.62 (m, 1H), 2.46 - 2.34 (m, 1H), 2.25 - 2.12 (m, 1H), 1.43 (s, 9H).Step 5: (1R, 4S)-4-amino-l-( (S)-4, 4, 4-trifluoro-3-hydroxy-3-phenylbutyl)-5, 6-dihydro-ll6, 2- thiazin-3(4H)-one 1-oxide:

[0172] To a solution of compound 5 ((45 mg, 99.90 pmol, 1 eq) and in DCM (2.5 mL) and TFA (0.5 mL) was stirred at 15 °C for Ih. The reaction mixture was concentrated underreduced pressure. The residue was purified by prep-HPLC (column: Phenomenex Luna Cl 8 100*30 mm*3 pm; mobile phase: [H2O (0.2% FA)-MeCN]; gradient: l%-35% B over 10.0 min) to afford the title compound (12.97 mg, 37.02 pmol, 37.06% yield, 100% purity) was obtained as white solid. LCMS: Rt = 1.768 min, (ES+) m / z (M+H)+= 351.1.1H NMR (400 MHz, MeOD-A) δ 8.43 (br s, 1H), 7.63 (d, J= 7.5 Hz, 2H), 7.50 - 7.38 (m, 3H), 4.12 (br d, J= 14.5 Hz, 1H), 3.93 (br d, J= 9.1 Hz, 1H), 3.64 - 3.53 (m, 1H), 3.51 - 3.41 (m, 1H), 3.10 - 3.00 (m, 1H), 2.82 - 2.62 (m, 2H), 2.50 (br d, J= 10.8 Hz, 1H), 2.28 - 2.09 (m, 1H).Example 9: (lR,4S)-4-amino-l-((R)-3-(5-(2,4-dichlorophenyl)pyridin-2-yl)-4,4,4- trifluoro-3-hydroxybutyl)-5,6-dihydro-116,2-thiazin-3(4H)-one 1-oxide (Compound 109)

[0173] Compound 1 (52.0 mg, 77.6 pmol, 1 eq) in HCl / dioxane (10 mL) (4M) was stirred at 25 °C for 8 h. The reaction mixture was concentrated under reduced pressure to afford the title compound (42 mg, 76.3 pmol, 98.3% yield, HC1) as yellow oil.Step 2: (S)-2-((tert-butoxycarbonyl)amino)-4-( (R, 3R)-3-(5-(2, 4-dichlorophenyl)pyridin-2- yl)-4, 4, 4-trifluoro-3-hydroxybutylsulfonimidoyl)butanoic acid:

[0174] To a solution of compound 2 (42 mg, 76.3 pmol, 1 eq, HC1) in dioxane (0.1 mL) and H2O (0.5 mL) was added BOC2O (21.6 mg, 99.1 pmol, 22.8 μL, 1.3 eq) and Na2CO3(24.3 mg, 229 pmol, 3 eq). The resulting mixture was stirred at 25 °C. The reaction mixture was adjusted to pH = 3 by IM HC1 and extracted with EtOAc (2 mL x 5). The combined organic layers were washed with brine (2 mL), dried over Na2SOr, filtered, and concentrated under reduced pressure to afford the title compound (46.8 mg, 76.2 pmol, 99.9% yield) as yellow oil.Step 3: tert-butyl ((lR,4S)-l-((R)-3-(5-(2,4-dichlorophenyl)pyridin-2-yl)-4,4,4-trifluoro-3- hydroxybutyl)-l-oxido-3-oxo-3,4,5,6-tetrahydro-ll6,2-thiazin-4-yl)carbamate:

[0175] To a solution of compound 3 (46.8 mg, 76.2 pmol, 1 eq) and TEA (46.2 mg, 457 pmol, 63.6 μL, 6 eq) in DCM (1 mL) was added T4P (165 mg, 228 pmol, 50% purity, 3 eq). The resulting mixture was stirred at 15 °C for 1 h under N2. The reaction mixture was poured into water (5 mL) and extracted with DCM (5 mL x 2). The combined organic layers were washed with brine (5 mL), dried over Na2SOr, filtered, and concentrated under reduced pressure to afford the title compound (43 mg, 72.1 pmol, 94.7% yield) as a yellow oil.1H NMR (400 MHz. MeOD-d4) δ 8.71 (d, J= 1.6 Hz, 1H), 8.03 (dd, J= 2.0, 8.0 Hz, 1H), 7.93 (d, J= 8.0 Hz, 1H), 7.66 (d, J= 1.6 Hz, 1H), 7.50 - 7.44 (m, 2H), 4.09 (br dd, J= 4.4, 10.4 Hz, 2H), 3.57 - 3.43 (m, 3H), 3.17 - 3.09 (m, 2H), 2.76 - 2.62 (m, 1H), 2.43 (qd, J= 4.8, 14.4 Hz, 1H), 2.30 - 2.12 (m, 1H), 1.42 (s, 9H).Step 4: (lR,4S)-4-amino-l-((R)-3-(5-(2,4-dichlorophenyl)pyridin-2-yl)-4,4,4-trifluoro-3- hydroxybutyl)-5, 6-dihydro-ll6,2-thiazin-3(4H)-one 1 -oxide:

[0176] Compound 4 (43 mg, 72. 1 pmol, 1 eq) in TLA (1 mL) and DCM (5 mL) was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 100*30 mm*3 pm; mobile phase: [H2O (0.2% LA)-MeCN]; gradient: 20%-50% B over 8.0 min) to afford the title compound (14.6 mg, 29.4 pmol, 40.8% yield) as a white solid. LC-MS: Rt = 2.150 min, (ES+) m / z (M+H)+= 496.0.1H NMR (400 MHz, MeOD-d4) δ 8.72 (d, J= 1.6 Hz, 1H), 8.42 (s, 1H), 8.04 (dd, J= 2.4, 8.0 Hz, 1H), 7.92 (d, J= 8.0 Hz, 1H), 7.66 (d, J= 1.6 Hz, 1H), 7.53 - 7.43 (m, 2H), 4.21 (td, J= 4.4, 14.8 Hz, 1H), 3.89 (dd, J= 4.8, 11.6 Hz, 1H), 3.62 - 3.46 (m, 2H), 3.22 - 3.03 (m, 2H), 2.78 - 2.63 (m, 1H), 2.51 (qd, J= 4.8, 14.0 Hz, 1H), 2.28 - 2.10 (m, 1H).Example 10: Synthesis of (lS,4S)-4-amino-l-(2-(trifluoromethyl)phenethyl)-5,6- dihydro-116,2-thiazin-3(4H)-one 1-oxide (Compound 110)butanoic acid:

[0177] To a solution of (S)-2-((tert-butoxycarbonyl)amino)-4-((S)- methylsulfinyl)butanoic acid (0.5 g, 1.88 mmol, 1 eq) in THF (20 mL) was added LDA (2 M, 3.77 mL, 4 eq) dropwise at -70 °C under nitrogen, the mixture was stirred at -70 °C for 15 min. l-(bromomethyl)-2-(trifluoromethyl)benzene (450 mg, 1.88 mmol, 287 μL, 1 eq) was then added. The mixture was stirred at -70 °C for 1.5 h. The mixture was quenched with NHrCI solution (10 mL) and adjusted to pH = 8. The mixture was extracted with EtOAC (10 mL*5). The combined organic phase was washed with brine (10 mL), dried over Na2SOr, fdtered, and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex luna C18 100*40 mm*3 pm; mobile phase: [H2O (0.2% FA)-MeCN]; gradient: 30%-60% B over 8.0 min) to afford the title compound (100 mg, 236. 16 pmol, 12.53% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 7.71 (d, J= 7.9 Hz, 1H), 7.68 - 7.61 (m, 1H), 7.61 - 7.53 (m, 1H), 7.51 - 7.41 (m, 1H), 7.20 (br d, J= 8.1 Hz, 1H), 4.15 - 3.94 (m, 1H), 3.19 - 3.01 (m, 3H), 2.99 - 2.75 (m, 3H), 2.15 - 2.02 (m, 1H), 1.97 - 1.92 (m, 1H), 1.37 (s, 9H).Step 2: (S)-2-((tert-butoxycarbonyl)amino)-4-((S)-2-(2- (trifluoromethyl)phenyl)ethylsulfonimidoyl)butanoic acid:

[0178] To a solution of compound 3 (360 mg, 850 pmol, 1 eq) in MeOH (3.5 mL) was added ammonium carbamate (265 mg, 3.40 mmol, 4 eq) PhI(OAc)2 (548 mg, 1.70 mmol, 2 eq). The mixture was stirred at 10 °C for 2 h. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (30 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by re -crystallization from Petroleum ether (4 mL) at 15°C to give compound 4 (210 mg, 478.95 pmol, 56.34% yield) as a white solid. ' H NMR (400 MHz, DMSO-d6) δ 12.67 (br d, J= 1.6 Hz, 1H), 7.71 (d, J= 7.8 Hz, 1H), 7.68 - 7.62 (m, 1H), 7.61 - 7.55 (m,1H), 7.50 - 7.42 (m, 1H), 7.20 (br d, J= 8.1 Hz, 1H), 4.07 - 3.95 (m, 1H), 3.21 - 3.01 (m, 3H), 2.99 - 2.87 (m, 1H), 2.81 (br t, J= 7.9 Hz, 2H), 2.16 - 2.01 (m, 1H), 1.99 - 1.82 (m, 1H), 1.37 (s, 9H).Step 3: tert-butyl ((lS,4S)-l-oxido-3-oxo-l-(2-(trifluoromethyl)phenethyl)-3,4,5,6- tetrahydro-ll6,2-thiazin-4-yl)carbamate:

[0179] To a solution of compound 4 (190 mg, 433 pmol, 1 eq) in DCM (2 mL) was added TEA (263 mg, 2.60 mmol, 362 μL, 6 eq) and TiP (624 mg, 867 pmol, 50% purity, 2 eq). The mixture was stirred at 0 °C for 2 h. The reaction mixture was diluted with H2O (20 mL) and extracted with DCM (20 mL x 3). The combined organic layers were washed with brine (5 mL x 3). dried over Na2SO4. filtered, and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (Petroleum ether: Ethyl acetate =0: 1, Rr = 0.6) to afford the title compound (115 mg, 273.52 pmol, 63.12% yield) as a white solid. 'HNMR (400 MHz, CDCI3-d) δ 7.70 (d, J= 7.7 Hz, 1H), 7.62 - 7.53 (m, 1H), 7.49 - 7.40 (m, 2H), 5.84 (br s, 1H), 4.26 (td, J= 4.1, 11.8 Hz, 1H), 3.7O (ddd, J= 2.8, 6.1, 14.5 Hz, 1H), 3.54 - 3.43 (m, 3H), 3.42 - 3.34 (m, 2H), 3.01 - 2.88 (m, 1H), 2.04 - 1.93 (m, 1H), 1.63 (br s, 1H), 1.46 (s, 9H).Step 4: (lS,4S)-4-amino-l-(2-(trifluoromethyl)phenethyl)-5, 6-dihydro-ll6,2-thiazin-3(4H)- one 1 -oxide:

[0180] A solution of compound 5 (100 mg, 237.84 pmol, 1 eq) in HCl / EtOAc (6 mL) was stirred at 15 °C for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 100*30 mm* 3 pm; mobile phase: [H2O (0.2% LA)-MeCN]; gradient: l%-30% B over 8.0 min) to afford the title compound (46.22 mg, 125.93 pmol, 52.95% yield, 99.819% purity, PA salt) as a white solid. LCMS: Rt = 2.215 min., (ES+) m / z (M+H)+= 321.0. ' H NMR (400 MHz, MeOD-A) δ 8.44 (s, 1H), 7.72 (d, J= 7.9 Hz, 1H), 7.66 - 7.55 (m, 2H), 7.52 - 7.42 (m, 1H), 4.24 (br d, J= 14.7 Hz, 1H), 4.07 (br dd, J= 3.5, 11.9 Hz, 1H), 3.91 - 3.62 (m, 3H), 3.50 - 3.34 (m, 2H), 2.73 - 2.53 (m, 1H), 2.37 (dq, J= 4.4, 12.7 Hz, 1H).Example 11: Synthesis of (lS,4S)-4-amino-l-(2-(trifluoromethoxy)phenethyl)-5,6- dihydro-116,2-thiazin-3(4H)-one 1-oxide (Compound 111)

[0181] To a solution of (S)-2-((tert-butoxycarbonyl)amino)-4-((S)- methylsulfinyl)butanoic acid (500 mg, 1.88 mmol, 1 eq) in THF (20 mL) was added LDA (2 M, 3.77 mL, 4 eq) at -65°C under N2. The mixture was stirred at -65 °C for 30 min. 1- (bromomethyl)-2-(trifluoromethoxy)benzene (481 mg, 1.88 mmol, 1 eq) in THF (1 mL) was then added and the mixture was stirred at -65 °C for another 30 min. The reaction mixture was quenched by saturated NH4Q (10 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were dried over Na2SOr, fdtered, and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex luna C18 100*40 mm*5 pm; mobile phase: [H2O (0.2% FA)-MeCN]; gradient: 40%-75% B over 8.0 min) to afford the title compound (320 mg, 715 pmol, 37.9% yield) as a white solid.1H NMR (400 MHz, CDCI3-d) δ 7.39 - 7.30 (m, 2H), 7.28 (br d, J= 1.1 Hz, 2H), 5.57 (br d, J= 6.1 Hz, 1H), 4.41 (br d, J= 5.4 Hz, 1H), 3.34 - 2.82 (m, 6H), 2.52 - 2.15 (m, 2H), 1.46 (s, 9H).Step 2: (S)-2-((tert-butoxycarbonyl)amino)-4-((S)-2-(2- (trifluoromethoxy)phenyl)ethylsulfonimidoyl)butanoic acid:

[0182] A mixture of compound 3 (320 mg, 728 pmol, 1 eq), [acetoxy (phenyl) -iodanyl] acetate (938 mg, 2.91 mmol, 4 eq), ammonium carbamate (455 mg, 5.83 mmol, 8 eq) in i- PrOH (15 mL) and MeOH (4 mL) was stirred at 25 °C for 24 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water (15 mL) and extracted with DCM (20 mL x 3). The combined organic layers were dried over Na2SOr, filtered, and concentrated under reduced pressure. The residue was triturated with petroleumether (30 mL) to afford the crude product. The crude product was purified by prep-HPLC (column: Phenomenex luna C18 100*40 mm*5 pm; mobile phase: [H2O (0.2% FA)-MeCN]; gradient: 25%-60% B over 8.0 min) to afford the title compound (155 mg, 341 pmol, 46.8% yield) as a white solid. ' H NMR (400 MHz, CDCI3-d) δ 7.29 - 7.23 (m, 2H), 7.20 (br s, 1H), 7.18 (br s, 1H), 6.61 - 6.11 (m, 2H), 5.31 (d, J= 6.6 Hz, 1H), 4.67 - 4.40 (m, 1H), 3.52 - 3.40 (m, 1H), 3.39 - 3.28 (m, 1H), 3.23 - 3.05 (m, 4H), 2.48 - 2.18 (m, 2H), 1.37 (s, 9H).Step 3: tert-butyl ((lS,4S)-l-oxido-3-oxo-l-(2-(trifluoromethoxy)phenethyl)-3,4,5,6- tetrahydro-ll6,2-thiazin-4-yl)carbamate:

[0183] To a solution of compound 4 (60.0 mg, 132 pmol, 1 eq) in DCM (3 mL) was added DIPEA (102 mg, 792 pmol, 138 μL, 6 eq) and T4P (190 mg, 264 pmol, 50% purity, 2 eq) at 0 °C under N2. The mixture was stirred at 15 °C for 1 h. The reaction mixture was quenched by water (5 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over Na2SOr, filtered, and concentrated under reduced pressure to afford the crude product. The crude product was used directly in the next step.Step 4: (IS, 4S)-4-amino-l-(2-(trifluoromethoxy)phenethyl)-5,6-dihydro-ll6,2-thiazin- 3(4H)-one 1-oxide:

[0184] To a mixture of compound 5 (30.0 mg, 68.7 pmol, 1 eq) in DCM (3 mL) was added TFA (768 mg, 6.73 mmol, 0.5 mL, 97.9 eq). The reaction mixture was stirred at 15 °C for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Waters Xbridge BEH C18 100*30 mm* 10 pm; mobile phase: [H2O (lOmM NH4HCO3)-MeCN]; gradient: l%-40% B over 8.0 min) to afford the title compound (34.8 mg, 103 pmol, 74.8% yield) as a white solid. LCMS: Rt = 2.921 min, (ES+) m / z (M+H)+= 337.1 ' H NMR (400 MHz, MeOD-d4) δ 7.55 - 7.47 (m, 1H), 7.45 - 7.29 (m, 3H), 4.04 (td, J= 4.7, 14.6 Hz, 1H), 3.80 - 3.63 (m, 2H), 3.61 - 3.45 (m, 2H), 3.32 - 3.24 (m, 2H), 2.46 (qd, J= 4.8, 14.3 Hz, 1H), 2.23 - 2.05 (m, 1H).Example 12: Synthesis of (4S)-4-amino-l-(4,4,4-trifluoro-3-hydroxy-3-(5- phenoxypyridin-2-yl)butyl)-5,6-dihydro-116,2-thiazin-3(4H)-one 1-oxide (Compound 112)

[0185] To a solution of compound 1 (940 mg, 1.82 mmol, 1 eq) in THF (17.6 mL) was added TMSCF3 (1.29 g, 9.10 mmol, 5 eq) and TBAF (1 M, 363.88 μL, 0.2 eq) at 0 °C. The mixture was stirred at 20 °C for 0.5 h. Additional TBAF (1 M, 5.46 mL, 3 eq) was then added at 0 °C. The mixture was stirred at 20 °C for another 0.5 h. The reaction mixture was quenched by water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SOr, fdtered, and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex luna C18 100*40 mm*3 pm; mobile phase: [H2O (0.2% FA)-MeCN]; gradient: 65%-98% B over 8.0 min) to afford the title compound (244 mg, 402.60 pmol, 22. 13% yield) as a light-yellow oil. ' H NMR (400 MHz, CDCI3-d) δ = 8.40 - 8.33 (m, 1H), 7.53 - 7.42 (m, 4H), 7.26 (br s, 1H), 7.15 - 7.09 (m, 2H), 5.25 - 5.03 (m, 1H), 4.35 - 4.21 (m, 1H), 2.78 - 2.44 (m, 4H), 2.41 - 2.24 (m, 1H), 2.18 - 2.07 (m, 1H), 1.74 - 1.68 (m, 2H), 1.51 - 1.46 (m, 18H).Step 2: tert-butyl (2S)-2-((tert-butoxycarbonyl)amino)-4-(4,4,4-trifluoro-3-hydroxy-3-(5- phenoxypyridin-2-yl)butylsulfonimidoyl)butanoate:

[0186] To a solution of compound 2 (240 mg, 409 pmol, 1 eq) in i-PrOH (5 mL) was added [acetoxy (phenyl) -iodanyl] acetate (527 mg, 1.64 mmol, 4 eq) and ammonium carbamate (256 mg, 3.27 mmol, 8 eq). The reaction mixture was stirred at 20 °C for 12 h. The reaction mixture was quenched by water (20 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SOr, fdtered, and concentrated under reduced pressure. The residue was purified by prep-TLC (silica gel, petroleum ether: ethyl acetate = 1: 1, Rr= 0.5) to afford the title compound (164 mg, 254.89 pmol, 62.31% yield) as a light-yellow oil.1H NMR (400 MHz, CDCI3-d) δ = 8.35 - 8.31 (m, 1H), 7.66 - 7.59 (m, 1H), 7.47 - 7.40 (m, 3H), 7.26 - 7.21 (m, 1H), 7.11 (dd, J = 3.6, 8.2 Hz, 2H), 5.39 - 5.26 (m, 1H), 4.35 - 4.20 (m, 1H), 3.51 - 3.29 (m, 3H), 3.27 - 3.14 (m, 1H), 2.85 - 2.72 (m, 2H), 2.47 - 2.35 (m, 1H), 2.21 - 2.09 (m, 1H), 1.49 (d, J= 2.0 Hz, 9H), 1.45 (s, 9H).Step 3: (2S)-2-amino-4-(4, 4, 4-trifluoro-3-hydroxy-3-(5-phenoxypyridin-2- yl)butylsulfonimidoyl)butanoic acid:

[0187] A solution of compound 3 (160 mg, 259 pmol, 1 eq) in HCl / dioxane (5 mL) was stirred at 20 °C for 2 h. The reaction mixture was concentrated under reduced pressure to afford the crude product. The crude product was used directly in the next step.Step 4: (2S)-2-((tert-butoxycarbonyl)amino)-4-(4,4,4-trifluoro-3-hydroxy-3-(5- phenoxypyridin-2-yl)butylsulfonimidoyl)butanoic acid:

[0188] To a solution of compound 4 (128 mg, 257 pmol, 1 eq, HC1) in dioxane (0.2 mL) and H2O (1 mL) was added BOC2O (67.3 mg, 308 pmol, 70.9 μL, 1.2 eq) and Na2CO3(81.7 mg, 771 pmol, 3 eq). The reaction mixture was stirred at 20 °C for 2 h. The reaction mixture was adjusted to pH = 5 by aqueous HC1 (1 M) at 0 °C. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SOr, fdtered, and concentrated under reduced pressure to afford the crude product. The crude was used directly in the next step.Step 5: tert-butyl ((4S)-l-oxido-3-oxo-l-(4,4,4-trifluoro-3-hydroxy-3-(5-phenoxypyridin-2- yl)butyl)-3, 4, 5, 6-tetrahydro-ll6, 2-thiazin-4-yl)carbamate:

[0189] To a solution of compound 5 (144 mg, 256 pmol, 1 eq) and TEA (156 mg, 1.54 mmol, 214 μL, 6 eq) in DCM (3 mL) was added TiP (554 mg, 769 pmol, 50% purity, 3 eq) at 0 °C. The reaction mixture was stirred at 20 °C for 2 h. The reaction mixture was quenched by water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SOr, fdtered, and concentrated under reduced pressure. The residue was purified by prep-TLC (silica gel, petroleum ether: ethyl acetate = 1: 1, Ri= 0.5) to afford the title compound (78 mg, 134.89 pmol, 52.60% yield) as a light-yellow oil.1H NMR (400 MHz, DMSO-t / e) δ 8.43 (br s, 1H), 7.80 - 7.73 (m, 1H), 7.49 - 7.44 (m, 2H), 7.28 - 7.19 (m, 2H), 7.15 (br d, J= 7.5 Hz, 2H), 7.06 - 6.91 (m, 1H), 4.07 - 3.81 (m, 2H), 3.67 - 3.57 (m, 1H), 3.41 - 3.35 (m, 1H), 3.16 (d, J = 5.4 Hz, 1H), 3.10 - 2.86 (m, 2H), 2.46 - 2.38 (m, 1H), 2.26 - 2.15 (m, 1H), 1.38 (br s, 9H).Step 6: (4S)-4-amino-l-(4, 4, 4-trifluoro-3-hydroxy-3-(5-phenoxypyridin-2-yl)butyl)-5, 6- dihydro-116, 2-thiazin-3 ( 4H)-one 1 -oxide:

[0190] A solution of compound 6 (78 mg, 143.50 pmol, 1 eq) in DCM (0.65 mL) and TLA (0.13 mL) was stirred at 20 °C for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex luna Cl 8 100*40 mm*3 pm; mobile phase: [H2O (0.2% LA)-MeCN]; gradient: 10%-55% B over 10.0 min) to afford the title compound (41.13 mg, 92.57 pmol, 64.51% yield) as a white solid. LCMS: Rt = 1.987 min, (ES+) m / z (M+H)+= 444.1.1H NMR (400 MHz, MeOD-d4) δ 8.41 (s, 1H), 8.36 - 8.32 (m, 1H), 7.75 (d, J= 8.7 Hz, 1H), 7.46 - 7.39 (m, 3H), 7.25 - 7.19 (m, 1H), 7.12 - 7.07 (m, 2H), 4.22 - 3.85 (m, 1H), 3.84 - 3.37 (m, 3H), 3.22 - 3.11 (m, 1H), 3.09 - 2.95 (m, 1H), 2.68 - 2.12 (m, 3H).Example 13: Synthesis of (4S)-4-amino-l-(2-(4-(trifluoromethyl)-[l,l'-biphenyl]-3- yl)ethyl)-5,6-dihydro-116,2-thiazin-3(4H)-one 1-oxide (Compound 113)

[0191] To a solution of compound 1 (4.0 g, 14.9 mmol, 1 eq) in THF (40 mL) was added BHJ.THF (1 M, 74.2 mL, 5 eq) dropwise at 0 °C under N2. The mixture was stirred at 30°C for 24 h. The reaction was quenched by MeOH (150 mL) at 0 °C and the resulting mixture was stirred at 15 °C fori h. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford the title compound (3.40 g, 13.3 mmol, 89.6% yield) was obtained as a white solid.1H NMR (400 MHz, DMSO-d6) 3 7.92 (s, 1H), 7.72 - 7.57 (m, 2H), 5.67 (t, J= 5.6 Hz, 1H), 4.66 (br d, J= 5.0 Hz, 2H).Step 2: 5-bromo-2-(trifluoromethyl)benzaldehyde:

[0192] A solution of compound 2 (2.90 g, 11.3 mmol, 1 eq) in DCM (29 mL) was added to a solution of pyridinium chlorochromate (4.66 g, 21.6 mmol, 1.9 eq) in DCM (5 mL). The mixture was stirred at 15 °C for 12 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford the title compound (2.3 g, 9.09 mmol, 79.9% yield) was obtained as a colorless oil.1H NMR (400 MHz, DMSO-d6) 3 10.20 (br d, J= 1.3 Hz, 1H), 8.23 (s, 1H), 8.12 (br d, J= 8.3 Hz, 1H), 7.88 (d, J= 8.4 Hz, 1H).Step 3: 4-bromo-l -(trifluoromethyl)-2-vinylbenzene :

[0193] To a solution of compound 3A (3.25 g, 9.09 mmol, 658 μL, 1 eq) in THF (15 mL) was added t-BuOK (1 M, 13.6 mL, 1.5 eq) in portions at 0 °C under N2. The resulting mixture was stirred for 10 minutes, compound 3 (2.30 g, 9.09 mmol, 1 eq) in THF (23 mL) was then added. The mixture was stirred at 15 °C for 16 h under N2. The reaction mixture was quenched by saturated NH4Q aqueous solution (5 mL) at 0 °C. The reaction mixture was poured into water (25 mL) and extracted with petroleum ether (20 mL x 2). The combined organic layers were washed with brine (20 mL), dried over Na2SOr, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford the title compound (1.20 g, 4.78 mmol, 52.5% yield) as a colorless oil.1H NMR (400 MHz, DMSO-d6) 3 8.05 (s, 1H), 7.76 - 7.59 (m, 2H), 6.92 (ddd, J= 2.1, 11.2, 16.9 Hz, 1H), 6.06 (d, J= 17.2 Hz, 1H), 5.58 (d, J= 11.1 Hz, 1H).Step 4: tert-butyl S-(5-bromo-2-(trifluoromethyl)phenethyl)-N-(tert-butoxycarbonyl)-L- homocysteinate:

[0194] To a solution of compound 4 (0.75 g, 2.99 mmol, 1 eq) and tert-butyl (tert- butoxycarbonyl)-L-homocysteinate (696 mg, 2.39 mmol, 0.8 eq) in MeOH (0.1 mL) and H2O (0.01 mL) was added AIBN (98.1 mg, 597 pmol, 0.2 eq) at 15 °C under N2. The mixture was stirred at 60 °C for 16 h. The reaction mixture was poured into water (25 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed with brine (20 mL), dried over Na2SOr, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex luna C18 100*40 mm* 3 pm; mobile phase: [H2O (0.2%FA)-THF:MeCN=l:3]; gradient: 50%-100% B over 12.0 min) to afford the title compound (0.32 g, 589 pmol, 19.7% yield) as a colorless oil.1H NMR (400 MHz, CDCI3-d) 3 7.55 - 7.44 (m, 3H), 5.20 - 5.00 (m, 1H), 4.30 (br d, J= 1.5 Hz, 1H), 3.02 (br t, J= 7.6 Hz, 2H), 2.84 - 2.70 (m, 2H), 2.68 - 2.55 (m, 2H), 2.18 - 2.03 (m, 1H), 1.96 - 1.83 (m, 1H), 1.49 - 1.45 (m, 18H).Step 5: tert-butyl (2S)-4-(2-(5-bromo-2-(trifluoromethyl)phenyl)ethylsulfonimidoyl)-2-((tert- butoxycarbonyl)amino)butanoate:

[0195] To a solution of compound 5 (0.27 g, 497 pmol, 1 eq) in i-PrOH (5 mL) was added ammonium carbamate (310 mg, 3.98 mmol, 8 eq) and PhI(OAc)2 (641 mg, 1.99 mmol, 4 eq) at 15 °C under N2. The mixture was stirred at 25 °C for 3 h. The reaction mixture was poured into water (25 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, andconcentrated under reduced pressure. The residue was purified by prep-TLC (SiO2, Petroleum ether / Ethyl acetate = 1: 1) to afford the title compound (0.23 g, 401 pmol, yield: 82.1%) as a colorless oil.1H NMR (400 MHz, CDCI3-d) 3 7.61 (s, 1H), 7.55 - 7.50 (m, 2H), 5.30 - 5.20 (m, 1H), 4.36 - 4.22 (m, 1H), 3.38 - 3.07 (m, 6H), 2.53 - 2.29 (m, 1H), 2.25 - 2.09 (m, 1H), 1.47 (d, J= 17.7 Hz, 18H).Step 6: tert-butyl (2S)-2-((tert-butoxycarbonyl)amino)-4-(2-(4-(trifluoromethyl)-[l,l'- biphenyl]-3-yl)ethylsulfonimidoyl)butanoate:

[0196] To a mixture of compound 6 (0.21 g, 366 pmol, 1 eq), phenyl boronic acid (66.9 mg, 549 pmol, 1.5 eq) and Na2CO3(97.0 mg, 915 pmol, 2.5 eq) in t-BuOH (2.2 mL) and H2O (0.8 mL) was added Pd(dppf)C12.CH2Ch (59.8 mg, 73.2 pmol, 0.2 eq). The resulting mixture was degassed with N2 and the mixture was stirred at 90 °C for 2 h under. The reaction mixture was poured into water (25 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed with brine (20 mL), dried over Na2SOr, filtered, and concentrated under reduced pressure. The residue was purified by prep-TLC (SiC>2, Petroleum ether / Ethyl acetate = 1:2) to afford the title compound (0.23 g, crude) as a colorless oil.1H NMR (400 MHz, CDCI3-d) 8 7.77 - 7.70 (m, 1H), 7.67 - 7.56 (m, 4H), 7.53 - 7.41 (m, 3H), 5.30 - 5.18 (m, 1H), 4.41 - 4.24 (m, 1H), 3.54 - 3.05 (m, 6H), 2.52 - 2.32 (m, 1H), 2.20 - 2.07 (m, 1H), 1.52 - 1.40 (m, 18H).Step 7: (2S)-2-amino-4-(2-(4-(trifluoromethyl)-[l,r-biphenyl]-3-yl)ethylsulfonimidoyl) butanoic acid:

[0197] A solution of compound 7 (0. 18 g, 315 pmol, 1 eq) in HCl / dioxane (10 mL, 4M) was stirred at 30 °C for 8 h. The reaction mixture concentrated under reduced pressure to afford 150 mg of crude product. 100 mg of the crude product was used in next step directly.Step 8: (2S)-2-((tert-butoxycarbonyl)amino)-4-(2-(4-(trifluoromethyl)-[l,l'-biphenyl]-3- yl) ethylsulf onimidoyl)butanoic acid:

[0198] To a solution of Compound 8 (0.1 g, 221.7 pmol, 1 eq, HC1) in dioxane (0.2 mL), H2O (1 mL) was added BOC2O (62.9 mg, 288 pmol, 66.2 μL, 1.3 eq) and Na2CO3(70.5 mg, 665 pmol, 3 eq). The mixture was stirred at 25 °C for 16 h. The reaction mixture was poured into water (25 mL), adjusted to pH ~4 with citric acid and extracted with ethyl acetate (20 mL x 2). The combined organic layers were dried over Na2SO4. filtered, and concentrated under reduced pressure to afford the crude product. The crude product was progressed to the next step without further purification.Step 9: tert-butyl ((4S)-l-oxido-3-oxo-l-(2-(4-(trifluoromethyl)-[l,l'-biphenyl]-3-yl)ethyl)- 3, 4, 5, 6-tetrahydro-ll6, 2-thiazin-4-yl) carbamate:

[0199] To a solution of Compound 9 (80.0 mg, 155 pmol, 1 eq) in DCM (2 mL) was added TEA (94.3 mg, 932 pmol, 129 μL, 6 eq) and T4P (336 mg, 466 pmol, 50% purity, 3 eq) at 0 °C. The mixture was stirred at 25 °C for 1 h. The reaction mixture was poured into water (25 mL) and extracted with dichloromethane (10 mL x 2). The combined organic layers were washed with brine (20 mL), dried over Na2SOr, fdtered, and concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2, Petroleum ether / Ethyl acetate = 1: 1) to afford the title compound (50 mg, 100 pmol, 64.7% yield) as a colorless oil. 'HNMR (400 MHz, CDCI3-d) 87.77 (dd, J= 2.3, 8.2 Hz, 1H), 7.67 - 7.54 (m, 4H), 7.53 - 7.41 (m, 3H), 5.91 - 5.60 (m, 1H), 4.37 - 4.02 (m, 1H), 3.75 - 3.38 (m, 6H), 3.03 - 2.91 (m, 1H), 2.49 - 1.90 (m, 1H), 1.46 (s, 9H).Step 10: (4S)-4-amino-l-(2-(4-(trifluoromethyl)-[l, 1 '-biphenyl]-3-yl)ethyl)-5, 6-dihydro- 116, 2 -thiazin- 3 ( 4H)-one 1 -oxide :

[0200] A solution of compound 10 (50.0 mg, 100 pmol, 1 eq) in DCM (2 mL) and TLA (0.4 mL) was stirred at 25 °C for 1 h. The reaction mixture concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 100*30 mm*3 pm; mobile phase: [H2O (0.2% LA)-MeCN]; gradient: l%-40% B over 8.0 min) to afford the title compound (30 mg, 75.68 pmol, 75.15% yield) as a white solid. LCMS: Rt = 2.077 min., (ES+) m / z (M+H)+= 397.1. ‘HNMR (400 MHz, MeOD-A) 88.41 (s, 1H), 7.86 - 7.68 (m, 5H), 7.55 - 7.36 (m, 3H), 4.30 - 4.12 (m, 1H), 4.02 - 3.58 (m, 5H), 3.53 - 3.41 (m, 2H), 2.68 - 2.26 (m, 2H).Example 14: Synthesis of (4S)-4-amino-l-(2-(3-(trifluoromethyl)-[l,l'-biphenyl]-4- yl)ethyl)-5,6-dihydro-116,2-thiazin-3(4H)-one 1-oxide (Compound 114)

[0201] t-BuOK (1 M, 31.6 mL, 1.6 eq) was added to a solution of methyltriphenylphosphonium bromide (7.77 g, 21.74 mmol, 1.1 eq) in THF (60 mL) at 0°C under N2 atmosphere. The mixture was stirred at 0 °C for 1 h. A solution of 4-bromo-2- (trifluoromethyl)benzaldehyde (5.00 g, 19.76 mmol, 1 eq) in THF (25 mL) was then added and the resulting mixture was stirred at 0 °C for another 30 min. The reaction mixture was quenched by sat. NH4CI solution (40 mL) at 20 °C and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SOr, fdtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (silica gel, petroleum ether: ethyl acetate = 10: 1 to 0: 1) to afford the title compound (3.51 g, 13.98 mmol, 70.75% yield) as a colorless oil.1H NMR (400 MHz, DMSO-de) δ 7.91 - 7.86 (m, 2H), 7.82 - 7.78 (m, 1H), 6.98 - 6.88 (m, 1H), 5.98 (d, J= 17.2 Hz, 1H), 5.56 (d, J= 11.0 Hz, 1H).Step 2: S-(4-bromo-2-(trifluoromethyl)phenethyl)-N-(tert-butoxycarbonyl)-L- homocysteinate:

[0202] To a solution of compound 2 (1.00 g, 3.98 mmol, 1 eq) in MeOH (1.8 mL) and H2O (0.18 mL) was added tert-butyl (tert-butoxycarbonyl)-L-homocysteinate (929 mg, 3.19 mmol, 0.8 eq) and AIBN (196 mg, 1.20 mmol, 0.3 eq) at 20°C under Ar. The reaction mixture was stirred at 60 °C for 12 h. The reaction mixture was filtered, and the filtrate was condensed under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex luna C18 100*40 mm*3 pm; mobile phase: [H2O (0.2% FA)-MeCN]; gradient:75%-98% B over 10.0 min) to afford the title compound (530 mg, 850.03 pmol, 21.34% yield, 87% purity) as a light-yellow oil.1H NMR (400 MHz, CDCh-<7) δ 7.76 (d, J = 1.6 Hz, 1H), 7.61 (dd, J= 1.5, 8.2 Hz, 1H), 7.24 (s, 1H), 5.15 - 5.04 (m, 1H), 4.28 (br d, J = 2.7 Hz, 1H), 3.03 - 2.97 (m, 2H), 2.76 - 2.69 (m, 2H), 2.64 - 2.56 (m, 2H), 2.14 - 2.06 (m, 1H), 1.93 - 1.82 (m, 1H), 1.47 (s, 9H), 1.44 (s, 9H).Step 3: tert-butyl (2S)-4-(2-(4-bromo-2-(trifluoromethyl)phenyl)ethylsulfonimidoyl)-2-((tert- butoxycarbonyl)amino)butanoate:

[0203] To a solution of compound 3 (3.52 g, 6.49 mmol, 1 eq) in i-PrOH (70 mL) was added [acetoxy (phenyl) -iodanyl] acetate (8.36 g, 26.0 mmol, 4 eq) and ammonia; carbamic acid (4.05 g, 51.9 mmol, 8 eq). The reaction mixture was stirred at 25 °C for 12 h. The reaction mixture was poured into water (20 mL) and extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine (10 mL), dried over Na2SOr, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford the title compound (3.41 g, 5.53 mmol, 85.22% yield) as a lightyellow oil. ‘HNMR (400 MHz, CDCI3-d) δ 7.80 (d, J= 1.8 Hz, 1H), 7.65 (dd, J= 1.7, 8.2 Hz, 1H), 7.31 (d, J= 8.2 Hz, 1H), 5.23 (br s, 1H), 4.29 (br d, J= 2.0 Hz, 1H), 3.34 - 3.03 (m, 6H), 2.47 - 2.34 (m, 1H), 2.19 - 2.10 (m, 1H), 1.48 (s, 9H), 1.44 (s, 9H).Step 4: tert-butyl (2S)-2-((tert-butoxycarbonyl)amino)-4-(2-(3-(trifluoromethyl)-[l,r- biphenyl]-4-yl)ethylsulfonimidoyl)butanoate:

[0204] To a solution of phenyl boronic acid (159 mg, 1.31 mmol, 1.5 eq), compound 4 (500 mg, 872 pmol, 1 eq) and Na2CO3(231 mg, 2.18 mmol, 2.5 eq) in t-BuOH (5 mL) and H2O (1.5 mL) was added Pd(dppf)C12.CH2Ch (142 mg, 174 pmol, 0.2 eq) under N2. The resulting mixture was stirred at 90 °C for 2 h. The reaction mixture was poured into water (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4. filtered, and concentrated under reduced pressure. The residue was purified by prep-TLC (silica gel, petroleum ether: ethyl acetate = 1:2, Ri=0.4) to afford the title compound (420 mg, 735.99 pmol, 84.41% yield) as a light-yellow oil. 'HNMR (400 MHz, CDCI3-d) δ 7.87 (s, 1H), 7.74 (d, J= 6.9 Hz, 1H), 7.59 - 7.55 (m, 2H), 7.55 - 7.45 (m, 3H), 7.44 - 7.38 (m, 1H), 5.35 - 5.23 (m, 1H), 4.37 - 4.26 (m, 1H), 3.61 - 3.20 (m, 6H), 2.52 - 2.39 (m, 1H), 2.25 - 2.13 (m, 1H), 1.49 (s, 9H), 1.44 (s, 9H).Step 5: (2S)-2-amino-4-(2-(3-(trifluoromethyl)-[l,r-biphenyl]-4-yl)ethylsulfonimidoyl) butanoic acid:

[0205] Compound 5 (106 mg, 185.75 pmol, 1 eq) in HCl / dioxane (2 mL, 4M) was stirred at 25 °C for 4 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 100*30 mm*3 pm; mobile phase: [H2O (0.2% FA)-MeCN]; gradient: 20%-50% B over 8.0 min) to afford the title compound (32.65 mg, 75.29 pmol, 40.53% yield, 95.57% purity) as a white solid. LCMS: Rt = 2.040 min, (ES+) m / z (M+H)+= 415.1.1H NMR (400 MHz, MeOD-d4) δ 7.94- 7.86 (m, 2H), 7.66 (br d, J= 7.6 Hz, 3H), 7.50 (t, J= 7.5 Hz, 2H), 7.44 - 7.38 (m, 1H), 3.79 - 3.71 (m, 1H), 3.54 - 3.43 (m, 3H), 3.42 - 3.36 (m, 3H), 2.51 - 2.33 (m, 2H).Step 6: (2S)-2-((tert-butoxycarbonyl)amino)-4-(2-(3-(trifluoromethyl)-[l, 1 '-biphenyl] -4- yl) ethylsulf onimidoyl)butanoic acid:

[0206] To a solution of Compound 6 (331 mg, 734 pmol, 1 eq, HC1) in dioxane (0.66 mL) and H2O (3.3 mL) was added BOC2O (192 mg, 881 pmol, 202 μL, 1.2 eq) and Na2CO3(233 mg, 2.20 mmol, 3 eq) at 20 °C. The reaction mixture was stirred at 20°C for 12 h. The reaction mixture was adjusted to pH = 5 by aqueous HC1 (1 M) at 0 °C. The reaction mixture was quenched by addition water (10 mL) at 20 °C and extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex luna C18 100*40 mm*3 pm; mobile phase: [H2O (0.2% FA)-MeCN]; gradient: 40%-80% B over 10.0 min) to afford the title compound (377 mg, 718.02 pmol, 97.81% yield) as a white solid.1HNMR (400 MHz, DMSO-d6) δ 7.96 - 7.90 (m, 2H), 7.76- 7.67 (m, 3H), 7.53 - 7.48 (m, 2H), 7.45 - 7.40 (m, 1H), 7.21 (br d, J= 7.3 Hz, 1H), 3.29 - 3.13 (m, 6H), 3.11 - 3.02 (m, 1H), 2.22 - 2.11 (m, 1H), 2.08 - 1.99 (m, 1H), 1.38 (s, 9H).Step 7: tert-butyl ((4S)-l-oxido-3-oxo-l-(2-(3-(trifluoromethyl)-[l,l'-biphenyl]-4-yl)ethyl)- 3, 4, 5, 6-tetrahydro-ll6, 2-thiazin-4-yl) carbamate:

[0207] To a solution of compound 7 (180 mg, 350 pmol, 1 eq) and TEA (212 mg, 2.10 mmol, 292 μL, 6 eq) in DCM (0.36 mL) was added T4P (756 mg, 1.05 mmol, 50% purity, 3eq) at 0°C. The reaction mixture was stirred at 20 °C for 2 h. The reaction mixture was quenched by water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SOr, fdtered, and concentrated under reduced pressure. The residue was purified by prep-TLC (silica gel, petroleum ether: ethyl acetate = 1:2, Rf= 0.3) to afford the title compound (165 mg, 331 pmol, 94.52% yield) as a light-yellow oil.1H NMR (400 MHz, DMSO-d6) δ 8.02 - 7.93 (m, 2H), 7.78 - 7.69 (m, 3H), 7.54 - 7.47 (m, 2H), 7.46 - 7.40 (m, 1H), 7.04 (br dd, J= 4.0, 8.3 Hz, 1H), 4.15 - 3.98 (m, 2H), 3.84 - 3.62 (m, 3H), 3.32 - 3.24 (m, 2H), 2.43 - 2.21 (m, 2H),1.39 (s, 9H).Step 8: (4S)-4-amino-l-(2-(3-(trifluoromethyl)-[l,l'-biphenyl]-4-yl)ethyl)-5,6-dihydro-116, 2 -thiazin- 3 ( 4H)-one 1 -oxide :

[0208] A solution of compound 8 (165 mg, 332 pmol, 1 eq) in DCM (1.65 mL) and TFA (0.33 mL) was stirred at 20 °C for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex luna C18 100*40 mm*3 pm; mobile phase: [H2O (0.2% FA)-MeCN]; gradient: 35%-65% B over 10.0 min) to afford the title compound (59.46 mg, 142.60 pmol, 42.91% yield, 95.07% purity) as a white solid. LCMS: Rt = 2.170 min, (ES+) m / z (M+H)+= 397. 1. ' H NMR (400 MHz, MeOD-d4) 5 = 7.94 (s, 1H), 7.90 (br d, J= 7.9 Hz, 1H), 7.69 - 7.63 (m, 3H), 7.53 - 7.47 (m, 2H), 7.45 -7.39 (m, 1H), 4.37 - 4.27 (m, 0.5H), 4.26 - 4.07 (m, 1H), 3.99 - 3.71 (m, 3.5H), 3.55 - 3.39 (m, 2H), 2.76 - 2.38 (m, 2H).Example 15: Synthesis of (4S)-4-amino-l-(2-(2',4'-dichloro-3-(trifluoromethyl)-[l,l'- biphenyl]-4-yl)ethyl)-5,6-dihydro-116,2-thiazin-3(4H)-one 1-oxide (Compound 115)

[0209] A mixture of compound 1 (500 mg, 872 pmol, 1 eq), (2,4- dichlorophenyl)boronic acid (250 mg, 1.31 mmol, 1.5 eq), Na2CO3(231 mg, 2.18 mmol, 2.5 eq) and Pd(dppf)Ch.CH2C12 (142 mg, 174 pmol, 0.2 eq) in t-BuOH (3 mL) and H2O (1 mL) was degassed with N2. The mixture was stirred at 90 °C for 3 h. The reaction mixture was diluted with H2O (15 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic phase was washed with brine (30 mL), dried with anhydrous Na2SO4. fdtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford the title compound (330 mg, 515.99 pmol, 59.18% yield) as a yellow solid. ' H NMR (400 MHz, MeOD-A) δ 7.77 - 7.57 (m, 4H), 7.46 - 7.34 (m, 2H), 4.19 - 4.06 (m, 1H), 3.50 - 3.34 (m, 4H), 3.25 (br dd, J= 5.8, 11.7 Hz, 2H), 2.43 - 2.26 (m, 1H), 2.22 - 2.07 (m, 1H), 1.49 (s, 9H), 1.45 (s, 9H).Step 2: (2S)-2-amino-4-(2-(2',4'-dichloro-3-(trifluoromethyl)-[l,l '-biphenyl]-4- yl) ethylsulf onimidoyl)butanoic acid:

[0210] A solution of compound 3 (330 mg, 516 pmol, 1 eq) in HCl / dioxane (4 mL, 4M) was stirred at 25 °C for 16 h. The mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex luna C18 100*40 mm*3 pm; mobile phase: [H2O(0.2% FA)-MeCN];gradient:25%-55% B over 10.0 min) to afford the title compound (170 mg, 266 pmol, 51.52% yield) as a white solid. LCMS: Rt = 2.319 min.,(ES ) m / z (M+H)+= 483.0.1H NMR (400 MHz, MeOD-d4) δ 7.77 - 7.59 (m, 4H), 7.41 (s, 2H), 3.73 (t, J= 6.1 Hz, 1H), 3.51 - 3.35 (m, 6H), 2.49 - 2.33 (m, 2H).Step 3: (2S)-2-((tert-butoxycarbonyl)amino)-4-(2-(2',4'-dichloro-3-(trifluoromethyl)-[l,r- biphenyl ]-4-yl)ethylsulfonimidoyl)butanoic acid:

[0211] A mixture of Compound 4 (100 mg, 207 pmol, 1 eq), BOC2O (63.2 mg, 290 pmol, 66.5 μL, 1.4 eq) and Na2CO3(65.8 mg, 621 pmol, 3 eq) in dioxane (0.5 mL) and H2O (2.5 mL) was stirred at 25 °C for 8 h. The reaction mixture was diluted with H2O (10 mL) and extracted with Ethyl acetate (10 mL x 3). The combined organic phases were washed with brine (10 mL), dried with anhydrous Na2SOr, filtered, and concentrated under reduced pressure to afford the title compound (100 mg, 171 pmol, 82.8% yield) as a yellow solid.Step 4: tert-butyl ((4S)-l-(2-(2',4'-dichloro-3-(trifluoromethyl)-[l,l'-biphenyl]-4-yl)ethyl)-l- oxido-3-oxo-3,4,5, 6-tetrahydro-ll6,2-thiazin-4-yl)carbamate:

[0212] To a solution of compound 5 (100 mg, 171 pmol, 1 eq) in DCM (1 mL) was added T4P (247 mg, 343 pmol, 50% purity, 2 eq) and TEA (86.7 mg, 857 pmol, 119 μL, 5 eq) at 0°C. The mixture was stirred at 15 °C for 1 h. The residue was diluted with H2O (10 mL) and extracted with DCM (10 mL x 3). The combined organic phases were washed with brine (5 mL), dried with anhydrous Na2SOr, filtered, and concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2, Petroleum ether / Ethyl acetate = 1:2) to afford the title compound (60 mg, 106 pmol, 61.9% yield) as a white solid.1H NMR (400 MHz, CDCI3-d) δ 7.74 (br s, 1H), 7.63 (br d, J= 7.6 Hz, 1H), 7.56 - 7.47 (m, 2H), 7.39 - 7.33 (m, 1H), 7.29 - 7.27 (m, 1H), 5.96 - 5.60 (m, 1H), 4.28 (br d, J= 11.0 Hz, 0.5H), 4.08 (br d, J= 7.7 Hz, 0.5H), 3.78 - 3.30 (m, 6H), 3.05 - 2.88 (m, 1H), 2.52 - 2.34 (m, 0.5H), 2.05 - 1.93 (m, 0.5H), 1.46 (s, 9H).Step 5: (4S)-4-amino-l-(2-(2',4'-dichloro-3-(trifluoromethyl)-[l,r-biphenyl]-4-yl)ethyl)- 5, 6-dihydro-ll6,2-thiazin-3(4H)-one 1-oxide:

[0213] A solution of compound 6 (60 mg, 106 pmol, 1 eq) in DCM (2.5 mL) and TFA (0.5 mL) was degassed with N2. The mixture was stirred at 15 °C for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18 150*40 mm* 10 pm; mobile phase: [H2O (lOmM NH4HCO3)-MeCN]; gradient: 20%-70% B over 8.0 min) to afford the title compound (34 mg, 73.07 pmol, 68.86% yield) as a white solid. LCMS: Rt = 2.393 min., (ES+) m / z (M+H)+= 465.0.1H NMR (400 MHz, MeOD-d4) δ 7.79 - 7.58 (m, 4H), 7.49 - 7.35 (m, 2H), 4.10 (br d, J= 14.7 Hz, 1H), 3.86 - 3.67 (m, 3H), 3.63 - 3.40 (m, 4H), 2.60 - 2.12 (m, 2H).Example 16: Synthesis of (4S)-4-amino-l-(3-(5-(2,4-dichlorophenyl)pyrazin-2-yl)- 4,4,4-trifluoro-3-hydroxybutyl)-5,6-dihydro-116,2-thiazin-3(4H)-one 1-oxide (Compound 116)

[0214] To a solution of compound 1 (200 mg, 312 pmol, 1 eq) in i-PrOH (2 mL) was added PIDA (402 mg, 1.25 mmol, 4 eq) and ammonia; carbamic acid (195 mg, 2.50 mmol, 8 eq) at 25°C, the mixture was stirred at 25 °C for 12 h. The reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (3 mL x 3). The combined organic phases were washed with brine (3 mL), dried with anhydrous Na2SO4. filtered and the filtrate was concentrated in vacuum. The residue was purified by prep-TLC (Petroleum ether: Ethyl acetate = 1:3, product Rr = 0.5) to afford the title compound (180 mg, 219.79 pmol, 70.39% yield, 82% purity) as a yellow oil.1H NMR (400 MHz, CDCI3-d) δ 9.19 - 9.10 (m, 1H), 8.99 (s, 1H), 7.67 (d, J= 8.4 Hz, 1H), 7.57 (d, J= 2.0 Hz, 1H), 7.44 (dd, J= 2.0, 8.4 Hz, 1H), 5.33 - 5.12 (m, 1H), 4.38 - 4.19 (m, 1H), 3.28 - 2.74 (m, 6H), 2.44 - 2.30 (m, 1H), 2.18 - 2.07 (m, 1H), 1.50 - 1.43 (m, 18H).Step 2: (2S)-2-amino-4-( 3-(5-(2, 4-dichlorophenyl)pyrazin-2-yl)-4, 4, 4-trifluoro-3- hydroxybutylsulfonimidoyl)butanoic acid:

[0215] Compound 2 (180 mg, 268 pmol, 1 eq) in HCl / dioxane (2 mL, 4 M) was stirred at 20 °C for 0.5 h. The mixture was concentrated under vacuum to afford the title compound (170 mg, crude, HC1) as a yellow solid. ' H NMR (400 MHz, MeOD-A) δ 9.23 - 8.94 (m, 2H), 7.83 - 7.65 (m, 2H), 7.54 (dd, J= 2.0, 8.4 Hz, 1H), 4.25 (br d, J= 4.2 Hz, 1H), 4.21 - 3.82 (m, 3H), 3.79 - 3.69 (m, 0.5H), 3.60 (br s, 0.5H), 3.27 - 3.17 (m, 1H), 2.83 - 2.69 (m, 1H), 2.67 - 2.38 (m, 2H).Step 3: (2S)-2-((tert-butoxycarbonyl)amino)-4-(3-(5-(2, 4-dichlorophenyl)pyrazin-2-yl)- 4, 4, 4-trifluoro-3-hydroxybutylsulfonimidoyl)butanoic acid:

[0216] To a solution of Compound 3 (170 mg, 308 pmol, 1 eq, HC1) in dioxane (2 mL) and H2O (10 mL) was added BOC2O (87.4 mg, 401 pmol, 1.3 eq) and Na2CO3(98.0 mg, 924 pmol, 3 eq) at 25 °C, the mixture was stirred at 25 °C for 4 h. The reaction mixture was acidified to pH =3 with HC1 (I M) and then extracted with ethyl acetate (5 mL x 3). The combined organic phases were washed with brine (5 mL), dried with anhydrous Na2SOr, filtered and the filtrate was concentrated in vacuum to afford the title compound (160 mg, crude) as a yellow oil.1H NMR (400 MHz, MeOD-d6) δ 9.16 - 8.92 (m, 2H), 7.78 - 7.65 (m, 2H), 7.53 (br d, J= 8.2 Hz, 1H), 4.26 - 3.94 (m, 1H), 3.29 - 3.02 (m, 4H), 2.99 - 2.73 (m, 1H), 2.69 - 2.49 (m, 1H), 2.37 - 2.04 (m, 2H), 1.43 (br s, 9H).Step 4: tert-butyl ((4S)-l-(3-(5-(2,4-dichlorophenyl)pyrazin-2-yl)-4,4,4-trifluoro-3- hydroxybutyl)-l-oxido-3-oxo-3,4,5,6-tetrahydro-ll6,2-thiazin-4-yl)carbamate:

[0217] To a solution of compound 4 (140 mg, 227 pmol, 1 eq) and TEA (138 mg, 1.36 mmol, 189.97 μL, 6 eq) in DCM (3 mL) was added T4P (492 mg, 682 pmol, 50% purity, 3 eq) at 0 °C. The resulting mixture was stirred at 15 °C for 1 h. The reaction mixture was poured into water (8 mL) and extracted with DCM (8 mL x 2). The combined organic layers were washed with brine (8 mL), dried over Na2SOr, filtered, and concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2, Petroleum ether: Ethyl acetate = 1: 5) to afford the title compound (64 mg, 107.12 pmol, 47.09% yield) as a yellow oil.1H NMR (400 MHz, CDCI3-d) δ 9.08 - 8.98 (m, 2H), 7.68 (d, J= 8.4 Hz, 1H), 7.58 (d, J= 1.8 Hz, 1H), 7.46 (br d, J= 8.4 Hz, 1H), 5.95 - 5.85 (m, 1H), 5.84 - 5.54 (m, 1H), 4.32 - 3.97 (m, 1H), 3.93 - 3.48 (m, 3H), 3.27 - 3.10 (m, 1H), 2.98 - 2.78 (m, 3H), 2.47 - 1.96 (m, 1H), 1.45 (s, 9H).Step 5: (4S)-4-amino-l-(3-(5-(2,4-dichlorophenyl)pyrazin-2-yl)-4,4,4-trifluoro-3- hydroxybutyl)-5, 6-dihydro-ll6,2-thiazin-3(4H)-one 1 -oxide:

[0218] To a solution of compound 5 (64 mg, 107 pmol, 1 eq) in DCM (0.5 mL) was added TFA (154 mg, 1.35 mmol, 0.1 mL, 12.57 eq) at 25°C, the mixture was stirred at 25°C for 1 h. The mixture was concentrated under vacuum to afford a yellow residue. The residue was purified by prep- HPLC (column: Phenomenex Luna C18 100*30 mm *3 pm;mobile phase: [H2O(0.2% FA)-MeCN]; gradient: 10%-50% B over 8.0 min), and then purified by prep- HPLC (column: Waters Xbridge Prep OBD C18 150* 40 mm* 10 pm; mobile phase: [H2O (10 mM NH4HCO3) -MeCN]; gradient: 35%-55% B over 8.0 min) to afford the title compound (7.01 mg, 13.83 pmol, 12.91% yield, 98.11% purity) as a white solid. LCMS: Rt = 2.040 min, (ES+) m / z (M+H)+= 497.0. ' H NMR (400 MHz, MeOD-d4) δ 9.10 (s, 1H), 9.05 - 8.98 (m, 1H), 7.73 - 7.65 (m, 2H), 7.60 - 7.46 (m, 1H), 4.12 - 3.57 (m, 2H), 3.56 - 3.48 (m, 1H), 3.45 - 3.34 (m, 1H), 3.28 - 3.12 (m, 2H), 2.78 - 2.54 (m, 1H), 2.52 - 1.97 (m, 2H).Example 17: Synthesis of (4S)-4-amino-l-(2-(2',4'-dichloro-4-(trifluoromethyl)-[l,l'- biphenyl]-3-yl)ethyl)-5,6-dihydro-116,2-thiazin-3(4H)-one 1-oxide (Compound 117)

[0219] A mixture of compound 1 (300 mg, 523 pmol, 1 eq), compound 2 (149 mg, 784 pmol, 1.5 eq) and Na2CO3(139 mg, 1.31 mmol, 2.5 eq) in t-BuOH (3 mL) and H2O (1 mL) was degassed with N2. Pd(dppf)C12.CH2C12 (85.4 mg, 104 pmol, 0.2 eq) was then added. The mixture was stirred at 90 °C for 2 h under N2. The reaction mixture was poured into water (25 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2, Petroleum ether / Ethylacetate = 1: 1) to afford the title compound (0.22 g, 343 pmol, 65.7% yield) as a colorless oil. 'HNMR (400 MHz, CDCI3-d) 3 7.81 (d, J= 6.8 Hz, 1H), 7.58 - 7.29 (m, 5H), 5.29 (br dd, J = 3.4, 4.7 Hz, 1H), 4.37 - 4.26 (m, 1H), 3.59 - 3.15 (m, 6H), 2.50 - 2.35 (m, 1H), 2.29 - 2.12 (m, 1H), 1.50 - 1.42 (m, 18H).Step 2: (2S)-2-amino-4-(2-(2', 4 '-dichloro-4-( trifluoromethyl)- [1, 1 '-biphenyl ]-3- yl) ethylsulf onimidoyl)butanoic acid:

[0220] A solution of compound 3 (0.22 g, 343 pmol, 1 eq) in HCl / dioxane (10 mL, 4M) was stirred at 30 °C for 8 h. The reaction mixture concentrated under reduced pressure to afford the crude product (150 mg).Step 3: (2S)-2-((tert-butoxycarbonyl)amino)-4-(2-(2',4'-dichloro-4-(trifluoromethyl)-[l,r- biphenyl ]-3-yl)ethylsulfonimidoyl)butanoic acid:

[0221] To a solution of compound 4 (0.1 g, 192 pmol, 1 eq, HC1) in H2O (1.5 mL) and dioxane (0.3 mL) was added BOC2O (54.5 mg, 250 pmol, 57.4 μL, 1.3 eq) and Na2CO3(61.1 mg, 577 pmol, 3 eq). The mixture was stirred at 25 °C for 16 h. The reaction mixture was poured into water (25 mL), adjusted to pH ~4 with citric acid and extracted with ethyl acetate (20 mL x 2). The combined organic layers were dried overNa2SO4, fdtered, and concentrated under reduced pressure to afford the title compound (0.1 g, crude) as a colorless oil.Step 4: tert-butyl ((4S)-l-(2-(2',4'-dichloro-4-(trifluoromethyl)-[l,l'-biphenyl]-3-yl)ethyl)-l- oxido-3-oxo-3, 4, 5, 6-tetrahydro-ll6, 2-thiazin-4-yl)carbamate :

[0222] To a solution of compound 5 (100 mg, 171 pmol, 1 eq) in DCM (3 mL) was added T4P (370 mg, 514 pmol, 50% purity, 3 eq) and TEA (104 mg, 1.03 mmol, 143 μL, 6 eq) at 0 °C. The mixture was stirred at 25 °C for 1 h. The reaction mixture was poured into water (25 mL) and extracted with dichloromethane (20 mL x 2). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, fdtered, and concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2, Petroleum ether / Ethyl acetate = 1: 1) to afford the title compound (0.07 g, 123 pmol, 72.2% yield) as a colorless oil. 'HNMR (400 MHz, CDCI3-d) 3 7.77 (dd, J= 2.8, 8.2 Hz, 1H), 7.60 - 7.43 (m, 3H), 7.37 (dd, J= 1.8, 8.3 Hz, 2H), 7.25 (s, 1H), 5.85 - 5.65 (m, 1H), 4.33 - 4.04 (m, 1H), 3.63 - 3.38 (m, 6H), 3.08 - 2.84 (m, 1H), 2.57 - 2.28 (m, 0.5H), 2.02 - 1.91 (m, 0.5H), 1.46 (s, 9H).Step 5: (4S)-4-amino-l-(2-(2',4'-dichloro-4-(trifluoromethyl)-[l,r-biphenyl]-3-yl)ethyl)-5,6- dihydro-116, 2-thiazin-3 ( 4H)-one 1 -oxide:

[0223] A solution of compound 6 (70 mg, 123 pmol, 1 eq) in TFA (1 mL) and DCM (5 mL) was stirred at 25 °C for 1 h. The reaction mixture concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Waters Xbridge BEH C18100*30mm* lOum; mobile phase: [ELOQOmM NH4HC03)-MeCN];gradient:30%-60% B over 8.0 min), to afford the title compound (27 mg, 57.39 pmol, 46.35% yield) as a white solid. LCMS: Rt = 2.321 min., (ES+) m / z (M+H)+=465.0.1H NMR (400 MHz, MeOD-A) 37.81 (d, J = 8.1 Hz, 1H), 7.68 - 7.58 (m, 2H), 7.54 (d, J= 8.1 Hz, 1H), 7.49 - 7.37 (m, 2H), 4.12 - 4.04 (m, 0.5H), 3.84 - 3.66 (m, 3H), 3.59 - 3.50 (m, 1H), 3.49 - 3.38 (m, 2.5H), 2.52 - 2.07 (m, 2H).Example 18: Synthesis of (lR,4S)-4-amino-l-((S)-3-(2',4'-dichloro-[l,l'-biphenyl]-4- yl)-4,4,4-trifluoro-3-hydroxybutyl)-5,6-dihydro-116,2-thiazin-3(4H)-one 1-oxide and (lR,4S)-4-amino-l-((R)-3-(2',4'-dichloro-[l,l'-biphenyl]-4-yl)-4,4,4-trifluoro-3- hydroxybutyl)-5,6-dihydro-116,2-thiazin-3(4H)-one 1-oxide (Compounds 118 and 119)

[0224] A mixture of l-(4-bromophenyl)-2,2,2-trifluoro-ethanone (15.0 g, 59.3 mmol, 9.01 mL, 1 eq), (2,4-dichlorophenyl)boronic acid (14.7 g, 77.1 mmol, 1.3 eq) , K2CO3 (16.4 g, 119 mmol, 2 eq) and Pd(PPh3)4 (6.85 g, 5.93 mmol, 0.1 eq) in i-PrOH (150 mL) was degassed with N2. The mixture was stirred at 100 °C for 3hr. The reaction mixture wasdiluted with H2O (200 mL) and extracted with DCM (200 mL x 3). The combined organic phases were washed with brine (50 mL), dried with anhydrous Na2SO4. filtered, and concentrated under reduced pressure. The residue was purified by silica gel column to afford the title compound (16.0 g, 50.1 mmol, 84.57% yield) as a white solid.1H NMR (400 MHz, MeOD-A) δ 7.69 (d, J= 8.3 Hz, 2H), 7.58 (d, J= 1.8 Hz, 1H), 7.52 - 7.46 (m, 2H), 7.43 - 7.35 (m, 2H).Step 2: 2-(2',4'-dichloro-[l,l '-biphenyl]-4-yl)-2-(trifluoromethyl)oxirane (Compound 2):

[0225] To a solution of trimethylsulfoxonium iodide (1.52 g, 6.89 mmol, 1.1 eq) in DMSO (15 mL) was added t-BuOK (844 mg, 7.52 mmol, 1.2 eq) at 20 °C. The mixture was stirred at 20 °C for 10 min. Compound 1 (2.00 g, 6.27 mmol, 1 eq) was then added dropwise at 0 °C. The mixture was stirred at 0 °C for 10 min. The reaction mixture was diluted with water (130 mL) and extracted with Ethyl acetate (100 mL x 2). The combined organic layers were washed with brine 20 mL, dried over Na2SOr, fdtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiC>2, Petroleum ether / Ethyl acetate = 100 / 0) to afford the title compound (1.68 g, 5.04 mmol, 53.67% yield) as a white solid.1H NMR (400 MHz, MeOD-d4) δ 7.66 (d, J= 8.2 Hz, 2H), 7.62 (s, 1H), 7.53 (d, J= 7.9 Hz, 2H), 7.48 - 7.38 (m, 2H), 3.52 (d, J= 4.6 Hz, 1H), 3.09 (dd, J= 1.7, 3.3 Hz, 1H).Step 3: (2S)-2-((tert-butoxycarbonyl)amino)-4-( (R)-( 3-(2\ 4 '-dichloro- [1, 1 '-biphenyl ]-4-yl)-4.4.4-trifluoro-3-hydroxybutyl)sulfinyl)butanoic acid (Compound 3):

[0226] To a solution of compound 2A (1.4 g, 5.3 mmol, 1 eq) in THF (40 mL) was added LDA (2 M, 11 mL, 4 eq) at -65 °C dropwise. The mixture was stirred at -65 °C for 15 min. Compound 2 (1.76 g, 5.3 mmol, 1 eq) in THF (20 mL) was then added dropwise at -65 °C. The resulting mixture was stirred at -65 °C for 1 h. The mixture was quenched by NH4Q (30 mL) and extracted with ethyl acetate (45 mL x 2). The combined organic phase was washed with brine (10 mL), dried with anhydrous Na2SOr, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford the title compound (800 mg, 1.34 mmol, 28.7% yield) as a yellow solid.1H NMR (400 MHz, MeOD-A) δ 7.70 (br d, J= 8.0 Hz, 2H), 7.57 (s, 1H), 7.49 (br dd, J= 1.8, 8.4 Hz, 2H), 7.40 (br s, 2H), 4.13 (br s, 1H), 3.99 - 3.84 (m, 1H), 2.95 - 2.64 (m, 4H), 2.60 - 2.38 (m, 2H), 2.19 (br d, J = 4.1 Hz, 1H), 2.06 - 1.90 (m, 1H), 1.43 (s, 9H).Step 4: (S)-2-((tert-butoxycarbonyl)amino)-4-( (R, 3S)-3-(2', 4 '-dichloro-[l, 1 '-biphenyl ]-4-yl)-4.4.4-trifluoro-3-hydroxybutylsulfonimidoyl)butanoic acid and (S)-2-((tert-butoxycarbonyl)amino)-4-( (R, 3R)-3-(2', 4 '-dichloro- [1, 1 '-biphenyl] -4-yl) -4, 4, 4-trifluoro-3- hydroxybutylsulfonimidoyl)butanoic acid (Compound 4-P1 and Compound 4-P2):

[0227] To a solution of compound 3 (700 mg, 1.17 mmol, 1 eq) in i-PrOH (28 mL) was added [acetoxy (phenyl) -iodanyl] acetate (1.51 g, 4.68 mmol, 4 eq) and ammonium carbamate (731 mg, 9.36 mmol, 8 eq). The mixture was stirred at 20 °C for 12 h. The reaction mixture was concentrated under reduced pressure. The reaction mixture was diluted with H2O (10 mL) and extracted with DCM (5 mL x 3). The combined organic phase was washed with brine (5 mL), dried with anhydrous Na2SOr, fdtered, and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Waters Xbridge BEH C18 250*50 mm* 10 pm; mobile phase: [H2O (lOmM NH4HCO3)-MeCN]; gradient: 15%- 55% B over 10.0 min) to afford compound 4 (470 mg, yield 57%, purity 98.93 %) as a white solid. 200 mg of compound 4 was further separated by SFC (column: DAICEL CHIRALCEL OX (250mm*30 mm, 10 pm); mobile phase: [CO2-MeOH (0.1% NH3H2O)]; B%:30%, isocratic elution mode) to afford compound 4-P1 (65 mg, 105.95 pmol, 9.06% yield) as a white solid.1H NMR (400 MHz, MeOD-A) δ 7.68 (br d, J= 7.9 Hz, 2H), 7.55 (s, 1H), 7.47 (d, J= 8.3 Hz, 2H), 7.37 (s, 2H), 4.20 - 4.04 (m, 1H), 3.24 - 3.03 (m, 3H), 2.83 - 2.64 (m, 2H), 2.62 - 2.43 (m, 1H), 2.26 - 1.98 (m, 2H), 1.41 (s, 9H). Compound 4-P2 (80 mg, 130.41 pmol, 11.15% yield) as a white solid.1H NMR (400 MHz, MeOD-d6) δ 7.71 (d, J= 8.3 Hz, 2H), 7.58 (s, 1H), 7.51 (d, J= 8.3 Hz, 2H), 7.41 (s, 2H), 4.18 - 4.08 (m, 1H), 3.26 - 3.09 (m, 3H), 2.85 - 2.69 (m, 2H), 2.66 - 2.51 (m, 1H), 2.31 - 2.15 (m, 1H), 2.10 - 1.93 (m, 1H), 1.43 (s, 9H).Step 5: tert-butyl ((lR,4S)-l-((S)-3-(2',4'-dichloro-[l,l'-biphenyl]-4-yl)-4,4,4-trifluoro-3- hydroxybutyl)-l-oxido-3-oxo-3, 4, 5, 6-tetrahydro-ll6, 2-thiazin-4-yl)carbamate or tert-butyl ((1R, 4S)-l-( (R)-3-(2 ', 4 '-dichloro- [1, 1 '-biphenyl / -4-yl) -4, 4, 4-trifluoro-3-hydroxybutyl)-l - oxido-3-oxo-3, 4,5, 6-tetrahydro-ll6,2-thiazin-4-yl)carbamate (Compound 5-P1):

[0228] To a solution of compound 4-P1 (65 mg, 106 pmol, 1 eq) in DCM (1 mL) was added TEA (53.6 mg, 523 pmol, 73.7 μL, 5 eq) and T4P (153 mg, 212 pmol, 50% purity, 2 eq). The mixture was stirred at 20 °C for 1 h. The reaction mixture was diluted with H2O (1 mL) and the layers were separated. The organic layer was concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2, Petroleum ether: Ethyl acetate =1: 1) to afford title compound (60 mg, 100.76 pmol, 58.87% yield) as a yellow oil.1H NMR (400 MHz, MeOD-d4) δ 7.75 (d, J= 8.2 Hz, 2H), 7.62 (d, J= 1.8 Hz, 1H), 7.55 (d, J= 8.4 Hz, 2H), 7.47 - 7.31 (m, 2H), 4.20 - 4.00 (m, 2H), 3.69 - 3.52 (m, 2H), 3.18 - 3.05 (m, 1H), 2.97- 2.79 (m, 1H), 2.67 (dt, J= 3.8, 12.7 Hz, 1H), 2.46 (br dd, J = 5.1, 14.4 Hz, 1H), 2.26 (br dd, J= 4.1, 10.1 Hz, 1H), 1.46 (s, 9H).Step 6: tert-butyl ((lR,4S)-l-((R)-3-(2',4'-dichloro-[l,l '-biphenyl]-4-yl)-4,4,4-trifluoro-3- hydroxybutyl)-l-oxido-3-oxo-3, 4,5, 6-tetrahydro-ll6,2-thiazin-4-yl)carbamate or tert-butyl ((1R, 4S)-l-( (S)-3-(2',4 '-dichloro- [1, 1 '-biphenyl ]-4-yl)-4, 4, 4-trifluoro-3-hydroxybutyl)-l - oxido-3-oxo-3, 4,5, 6-tetrahydro-ll6,2-thiazin-4-yl)carbamate (Compound 5-P2):

[0229] To a solution of compound 4-P2 (120 mg, 196 pmol, 1 eq) in DCM (1 mL) was added TEA (99.0 mg, 978 pmol, 136 μL, 5 eq) and T4P (282 mg, 391 pmol, 50% purity, 2 eq) at 0°C. The mixture was stirred at 20 °C for 1 r. The reaction mixture was diluted by H2O (3 mL) and the layers were separated. The organic layer was concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2, Petroleum ether: Ethyl acetate =1: 1) to afford the title compound (80 mg, 134.35 pmol, 68.68% yield) as a yellow oil.1H NMR (400 MHz, MeOD-A) δ 7.76 (d, J= 8.3 Hz, 2H), 7.62 (d, J= 1.8 Hz, 1H), 7.56 (d, J= 8.4 Hz, 2H), 7.48 - 7.35 (m, 2H), 4.27 - 3.96 (m, 2H), 3.66 - 3.48 (m, 2H), 3.21 - 3.04 (m, 1H), 2.92 - 2.71 (m, 2H), 2.52 - 2.34 (m, 1H), 2.33 - 2.15 (m, 1H), 1.47 (s, 9H).Step 7: (lR,4S)-4-amino-l-((S)-3-(2',4'-dichloro-[l,l '-biphenyl]-4-yl)-4,4,4-trifluoro-3- hydroxybutyl)-5, 6-dihydro-ll6,2-thiazin-3(4H)-one 1-oxide or (lR,4S)-4-amino-l-((R)-3- (2', 4 '-dichloro- [1, 1 '-biphenyl ]-4-yl)-4, 4, 4-trifluoro-3-hydroxybutyl)-5, 6-dihydro-ll6, 2- thiazin-3(4H)-one 1-oxide:

[0230] A solution of compound 5 -Pl (60 mg, 101 pmol, 1 eq) in DCM (5 mL) and TFA (1 mL) was stirred at 20 °C for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex luna C18 100*40 mm*3 pm; mobile phase: [H2O (0.2% FA)-MeCN]; gradient: 25%-55% B over 8.0 min) to afford the title compound (34.91 mg, 70.13 pmol, 69.60% yield) as a white solid. LCMS: Rt = 2.327 min., (ES+) m / z (M+H)+= 495.0.1H NMR (400 MHz, MeOD-A) δ 8.36 (br s, 1H), 7.71 (d, J = 8.2 Hz, 2H), 7.59 (d, J= 1.9 Hz, 1H), 7.54 - 7.47 (m, 2H), 7.46 - 7.31 (m, 2H), 4.17 (td, J = 4.5, 14.7 Hz, 1H), 3.94 (dd, J= 4.5, 11.9 Hz, 1H), 3.69 - 3.57 (m, 1H), 3.55 - 3.45 (m, 1H), 3.18 - 3.02 (m, 1H), 2.88 (dt, J= 4.5, 12.9 Hz, 1H), 2.65 (ddd, J= 4.0, 12.2, 13.6 Hz, 1H), 2.51 (qd, J= 4.6, 13.8 Hz, 1H), 2.28 - 2.13 (m, 1H).Step 8: (lR4S)-4-amino-l-((R)-3-(2',4'-dichloro-[l,l '-biphenyl]-4-yl)-4,4,4-trifluoro-3- hydroxybutyl)-5,6-dihydro-ll6,2-thiazin-3(4H)-one 1-oxide or (lR,4S)-4-amino-l-((S)-3-(2 ' 4 '-dichloro- [1, 1 '-biphenyl ]-4-yl)-4, 4, 4-trifluoro-3-hydroxybutyl)-5, 6-dihydro-ll6, 2- thiazin-3(4H)-one 1-oxide:

[0231] A solution of compound 5-P2 (80 mg, 134 pmol, 1 eq) in DCM (5 mL) and TFA (1 mL) was stirred at 20 °C for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex luna C18 100*40mm*3 pm; mobile phase: [H2O (0.2% FA)-MeCN]; gradient: 25%-55% B over 8.0 min) to afford the title compound (48.52 mg, 97.78 pmol, 72.78% yield) as a white solid. LCMS: Rt = 2.339 min., (ES+) m / z (M+H)+=495.0.1H NMR (400 MHz, MeOD-A) δ 8.38 (s, 1H), 7.74 (d, J= 8.3 Hz, 2H), 7.61 (d, J= 2.0 Hz, 1H), 7.55 (d, J= 8.3 Hz, 2H), 7.48 - 7.33 (m, 2H), 4.16 (td, J= 4.4, 14.9 Hz, 1H), 3.95 (dd, J= 4.6, 11.8 Hz, 1H), 3.68 - 3.55 (m, 1H), 3.54 - 3.45 (m, 1H), 3.24 - 3.09 (m, 1H), 3.00 - 2.66 (m, 2H), 2.57 - 2.45 (m, 1H), 2.28 - 2.11 (m, 1H).Example 19: Synthesis of (4S)-4-amino-l-oxo-l-[4,4,4-trifluoro-3-hydroxy-3-(5- phenylisothiazol-3-yl)butyl]-lthia-2-azacyclohexen-3-one (Compound 120)Step 1: methyl (Z)-2-amino-4-oxo-4-phenylbut-2-enoate:

[0232] A mixture of methyl 2,4-dioxo-4-phenyl-butanoate (2.70 g, 13.1 mmol, 1 eq), NHrOAc (8.07 g, 105 mmol, 8 eq) in MeOH (40 mL) was stirred at 15 °C for 16 h. The mixture was concentrated under reduced pressure. The residue was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). the combined organic phases were dried over Na2SO4, fdtered, and concentrated under reduced pressure to afford the title compound (2.56 g, crude) as brown oil. 'HNMR (400 MHz, CDCI3-d) δ 9.65 - 9.21 (m, 1H), 8.05 - 7.88 (m, 2H), 7.59 - 7.37 (m, 3H), 6.67 (s, 1H), 6.20 - 5.81 (m, 1H), 3.95 (s, 3H).Step 2: methyl 5-phenylisothiazole-3-carboxylate:

[0233] A mixture of compound 2 (2.56 g, 12.5 mmol, 1 eq) and P2S5 (2.22 g, 9.98 mmol, 0.8 eq) in THF (30 mL) was stirred at 15 °C for 16 h. The mixture was concentrated under reduced pressure. The residue was diluted with ethyl acetate (20 mL) and then fdtered through celite. The fdtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography to afford the title compound (1.5 g, 6.84 mmol, 54.8% yield) as brown solid. ‘HNMR (400 MHz, CDCI3-d) δ 7.99 (s, 1H), 7.69 - 7.59 (m, 2H), 7.51 - 7.45 (m, 3H), 4.01 (s, 3H).Step 3: 5-phenylisothiazole-3-carboxylic acid:

[0234] A mixture of compound 3 (1.5 g, 6.84 mmol, leq) and LiOHLLO (574 mg, 13.7 mmol, 2 eq) in THF (3 mL) and H2O (1 mL) was stirred at 15 °C for 2 h. Volatiles were removed under vacuum. The residue was adjusted to pH = 2~3 with IM HC1 and extracted with ethyl acetate (5 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SOr, filtered, and concentrated under reduced pressure to afford the title compound (1.1 g, 5.36 mmol, 78.35% yield) as brown solid.1H NMR (400 MHz, CDCI3-d) 5 8.02 (s, 1H), 7.69 - 7.60 (m, 2H), 7.53 - 7.45 (m, 3H).Step 4: N-methoxy-N-methyl-5-phenylisothiazole-3-carboxamide:

[0235] To a solution of compound 4 (1.05 g, 5.12 mmol, 1 eq), N-methoxymethanamine (1.50 g, 15.4 mmol, 3 eq, HC1) and TEA (3.11 g, 30.7 mmol, 4.27 mL, 6 eq) in DCM (10 mL) was added T4P (7.37 g, 10.2 mmol, 50% purity, 2 eq) at 0°C. The mixture was stirred at 15 °C for 2 h. The mixture was poured into water (10 mL) and extracted with DCM (10 mL x 2), the combined organic phases were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column to afford the title compound (0.8 g, 3.22 mmol, 53.33% yield) as yellow solid.1HNMR (400 MHz, CDCI3-d) δ 7.82 (br s, 1H), 7.67 - 7.59 (m, 2H), 7.51 - 7.40 (m, 3H), 3.85 (s, 3H), 3.64 - 3.38 (m, 3H).Step 5: tert-butyl (2S)-2-(tert-butoxycarbonylamino)-4-[3-oxo-3-(5-phenylisothicizol-3- yl)propyl Jsulfanyl-butanoate:

[0236] To a solution of compound 5 (0.7 g, 2.8 mmol, 1 eq) in THF (5 mL) was added bromo(vinyl)magnesium (1 M, 5.6 mL, 2 eq) dropwise at -65 °C. The mixture was stirred at -65 °C for 0.5 h. TEA (427 mg, 4.22 mmol, 588 μL, 3 eq) and tert-butyl (tert- butoxycarbonyl)-L-homocysteinate (410 mg, 1.41 mmol, 1 eq) were then added. The resulting mixture was stirred at -65 °C for Ih. The reaction mixture was quenched by NHrCl (10 mL) at 0 °C, and then diluted with H2O (10 mL). The mixture was extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (15 mL), dried over Na2SO4, fdtered, and concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2, Petroleum ether: Ethyl acetate = 3: 1) to afford the title compound (0.8 g, 1.36 mmol, 56.01% yield, 86% purity) as a white solid.1H NMR (400 MHz, CDCI3-d) 5 7.94 (s, IH), 7.67 - 7.57 (m, 2H), 7.53 - 7.38 (m, 3H), 5.13 (br d, J = 7.5 Hz, IH), 4.29 (br d, J = 4.8 Hz, IH), 3.47 (t, J = 7.1 Hz, 2H), 2.95 (t, J = 7.3 Hz, 2H), 2.68 - 2.57 (m, 2H), 2.13 (br d, J = 6.6 Hz, IH), 1.97 - 1.86 (m, IH), 1.47 (d, J = 11.7 Hz, 18H).Step 6: tert-butyl (2S)-2-(tert-butoxycarbonylamino)-4-[4,4,4-trifluoro-3-hydroxy-3-(5- phenylisothiazol-3-yl)butyl]sulfanyl-butanoate:

[0237] To a solution of compound 7 (0.8 g, 1.58 mmol, 1 eq) in THF (8 mL) was added TMSCF3 (2.25 g, 15.8 mmol, 10 eq) and then TBAF (82.6 mg, 316 pmol, 0.2 eq) at 15°C. The mixture was stirred at 15 °C for 10 min. More TBAF (1 M, 789 μL. 2 eq) was added and the resulting mixture was stirred at 15 °C for 1 h. The reaction mixture was poured into water (10 mL) and extracted with EtOAc (lOmL x 2). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, fdtered, and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Waters Xbridge BEH Cl 8 100*25 mm* 10 pm; mobile phase: [H2O (lOmM NH4HCO3)-MeCN]; gradient: 55%-85% B over 8.0 min) to afford the title compound (0.11 g, 179.30 pmol, 11.36% yield) as a white solid.1H NMR (400 MHz, CDCI3-d) δ 7.63 (ddd, J= 2.0, 5.3, 7.3 Hz, 2H), 7.53 - 7.40 (m, 4H), 5.10 (br s, IH), 4.87 (br d, J= 10.1 Hz, IH), 4.25 (br d, J= 5.1 Hz, IH), 2.75 - 2.60 (m, IH), 2.59 - 2.49 (m, 2H), 2.47 - 2.36 (m, 2H), 2.30 - 2.17 (m, IH), 2.04 (br dd, J= 5.4, 7.9 Hz, IH), 1.91 - 1.77 (m, IH), 1.47 - 1.42 (m, 18H).Step 7: tert-butyl (2S)-2-(tert-butoxycarbonylamino)-4-[[4,4,4-trifluoro-3-hydroxy-3-(5- phenylisothiazol-3-yl)butyl ] sulfonimidoyl Jbutanocite:

[0238] To a solution of compound 8 (72.0 mg, 125 pmol, 1 eq) in isopropanol (3 mL) was added [acetoxy(phenyl)-iodanyl] acetate (161 mg, 499 pmol, 4 eq) and ammonium carbamate (78.0 mg, 999 pmol, 8 eq). The mixture was stirred at 25 °C for 12 h. The residue was quenched water (10 mL) and extracted with ethyl acetate (10 mL x 3). the combined organic layers were washed with brine (10 mL), dried over Na2SOr, fdtered, and concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2, Petroleum ether: Ethyl acetate = 1: 1) to afford the title compound (70.0 mg, 96.76 pmol, 77.50% yield, 84% purity) as a colorless oil. ' H NMR (400 MHz, CDCI3-d) δ 7.68 - 7.57 (m, 3H), 7.52 - 7.39 (m, 3H), 5.31 - 5.13 (m, 1H), 4.41 - 4.17 (m, 1H), 3.35 - 3.20 (m, 2H), 3.19 - 2.97 (m, 2H), 2.93 - 2.56 (m, 2H), 2.48 - 2.27 (m, 1H), 2.19 - 2.07 (m, 1H), 1.52 - 1.41 (m, 18H).Step 8: (2S)-2-amino-4-[[4, 4, 4-trifluoro-3-hydroxy-3-(5-phenylisothiazol-3- yl)butyl ] sulfonimidoyl Jbutcmoic acid:

[0239] A solution of compound 9: (70.0 mg, 96.76 pmol, 1 eq) in HCl / dioxane (1 mL) was stirred at 25 °C for 12 h. The reaction mixture was concentrated under reduced pressure to afford the title compound (80 mg, crude) as a colorless oil.Step 9: (2S)-2-(tert-butoxycarbonylamino)-4-[[4, 4, 4-trifluoro-3-hydroxy-3-(5- phenylisothiazol-3-yl)butyl ] sulfonimidoyl Jbutanoic acid:

[0240] To a solution of compound 10 (80.0 mg, 177 pmol, 1 eq) in dioxane (0.2 mL) and H2O (1 mL) was added BOC2O (50.3 mg, 230 pmol, 1.3 eq) and Na2CO3(56.3 mg, 532 pmol, 3 eq). The mixture was stirred at 25 °C for 2 h. The reaction mixture was diluted with H2O (5 mL), adjusted to pH = 3-4 with IM HC1, and extracted with ethyl acetate (5mL x 3). The combined organic layers were washed with brine (15 mL), dried over Na2SOr, fdtered, and concentrated under reduced pressure to afford the title compound (82.0 mg, 136.77 pmol, 77.18% yield, 92% purity) as a white solid.1H NMR (400 MHz, CDCI3-d) δ 7.65 - 7.54 (m, 3H), 7.51 - 7.38 (m, 3H), 5.71 - 5.44 (m, 1H), 4.52 - 4.30 (m, 1H), 3.51 - 3.26 (m, 3H), 3.21 - 3.05 (m, 1H), 2.93 - 2.59 (m, 2H), 2.43 - 2.18 (m, 2H), 1.48 - 1.39 (m, 9H).Step 10: tert-butyl N-[(4S)-1, 3-dioxo-l-[4, 4, 4-trifluoro-3-hydroxy-3-(5-phenylisothiazol-3- yl)butyl ]-l thia-2-azacyclohexen-4-yl ] carbamate :

[0241] To a solution of compound 11 (70.0 mg, 127 pmol, 1 eq) in DCM (2 mL) was added T4P (183 mg, 254 pmol, 50% purity, 2 eq) and TEA (77.1 mg, 761 pmol, 106 μL, 6 eq). The mixture was stirred at 25 °C for 1 h. The mixture was diluted with water 5 mL and extracted with DCM (5 mL x 3). The combined organic layers were washed with brine 10 mL, dried over Na2SOr, fdtered, and concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2, Petroleum ether: Ethyl acetate = 1: 1) to afford the title compound (40.0 mg, 67.47 pmol, 53.16% yield, 90% purity) as a white solid.1H NMR (400 MHz, CDCI3-d) δ 7.65 - 7.59 (m, 2H), 7.53 - 7.44 (m, 4H), 5.62 (br s, 1H), 5.77 (br s, 1H), 5.28 - 4.83 (m, 1H), 4.26 - 4.18 (m, 0.5H), 4.07 - 3.98 (m, 0.5H), 3.93 - 3.39 (m, 3H), 3.08 (br dd, J= 5.3, 9.1 Hz, 1H), 2.92 (br d, J= 3.9 Hz, 1H), 2.87 - 2.60 (m, 2H), 2.46 - 2.29 (m, 0.5H), 2.03 - 1.89 (m, 0.5H), 1.51 - 1.37 (m, 9H).Step 11: (4S)-4-amino-l-oxo-l-[4,4,4-trifluoro-3-hydroxy-3-(5-pherrylisothiazol-3-yl)butyl]- 1 thia-2-azacyclohexen-3-one:

[0242] A solution of compound 12 (40.0 mg, 74.9 pmol, 1 eq) in TLA (0.2 mL) and DCM (1 mL) was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex luna Cl 8 100*40 mm*3 pm; mobile phase: [H2O (0.2% LA)-MeCN]; gradient: 10%-50% B over 8.0 min) to afford the title compound (8.6 mg, 18.26 pmol, 24.36% yield, 98.96% purity) as a light pink solid. LCMS: Rt = 2.078 min, (ES+) m / z (M+H)+= 434.0. ' H NMR (400 MHz, MeOD-A) δ 8.43 (s, 1H), 7.80 (s, 1H), 7.71 (dd, J = 1.3, 7.7 Hz, 2H), 7.54 - 7.44 (m, 3H), 4.31 - 3.89 (m, 1H), 3.89 - 3.53 (m, 3H), 3.44 - 3.34 (m, 1H), 3.12 - 2.93 (m, 1H), 2.76 - 2.11 (m, 3H).Example 20: Synthesis of (4S)-4-amino-l-(4,4,4-trifluoro-3-hydroxy-3-(pyrazin-2- yl)butyl)-5,6-dihydro-116,2-thiazin-3(4H)-one 1-oxide (Compound 121)

[0243] To a solution of pyrazine-2-carboxylic acid (9.3 g, 74.9 mmol, 1 eq), N,O- dimethylhydroxylamine (14.6 g, 149 mmol, 2 eq, HC1) and TEA (45.5 g, 449 mmol, 62.6 mL, 6 eq) in DCM (93 mL) was added T4P (108 g, 149 mmol, 50% purity, 2 eq) at 0 °C, the mixture was stirred at 0 °C for 0.5 h. The reaction mixture was quenched with water (200 mL) and extracted with DCM (100 mL x 3). The combined organic phases were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography afford the title compound (12.3 g, 73.6 mmol, 98.2% yield) as a colorless oil.1H NMR (400 MHz, CDCI3-d) δ 8.91 (br s, 1H), 8.66 (d, J= 2.4 Hz, 1H), 8.62 - 8.56 (m, 1H), 3.74 (br s, 3H), 3.42 (s, 3H).Step 2: tert-butyl N-(tert-butoxycarbonyl)-S-(3-oxo-3-(pyrazin-2-yl)propyl)-L- homocysteinate:

[0244] To a solution of compound 2 (1 g, 5.98 mmol, 1 eq) in THF (20 mL) was added bromo(vinyl)magnesium (1 M, 17.9 mL, 3 eq) at -65 °C under N2, the mixture was stirred at -65°C for 0.5 h. tert-butyl (tert-butoxycarbonyl)-L-homocysteinate (1.22 g, 4.17 mmol, 0.7 eq) in THF (10 mL) and TEA (1.81 g, 17.9 mmol, 2.49 mL, 3 eq) were then added. The mixture was allowed to stir at -65 °C for another 1 h. The reaction was quenched by NH4Q solution (100 mL), and the mixture was extracted by diethyl ether (100 mL x 3). The combined organic phases were dried over Na2SOr, fdtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford the titlecompound (1.59 g, 3.74 mmol, 15.7% yield) as a yellow oil. H NMR (400 MHz, CDCI3-d) 5 9.24 (d, J= 1.2 Hz, 1H), 8.77 (d, J= 2.4 Hz, 1H), 8.68 - 8.63 (m, 1H), 5.13 (br d, J= 6.8 Hz, 1H), 4.28 (br d, J= 4.4 Hz, 1H), 3.55 - 3.45 (m, 2H), 2.94 (t, J= 7.2 Hz, 2H), 2.70 - 2.54 (m, 2H), 2.19 - 2.06 (m, 1H), 1.97 - 1.84 (m, 1H), 1.52 - 1.38 (m, 18H).Step 3: tert-butyl N-(tert-butoxycarbonyl)-S-(4, 4, 4-trifluoro-3-hydroxy-3-(pyrazin-2- yl)butyl)-L-homocysteinate:

[0245] To a solution of compound 4 (1.59 g, 3.74 mmol, 1 eq) and TMSCF3 (5.31 g, 37.4 mmol, 10 eq) in THF (60 mL) was added TBAF (1 M, 374 μL, 0.1 eq) at 0 °C. The mixture was stirred at 25 °C for 1 h. Another batch of TBAF (1 M, 3.74 mL, 1 eq) was added at 0 °C. The reaction was stirred at 0-25 °C for another 2 h. The reaction mixture was quenched by water (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford the title compound (670 mg, 1.35 mmol, 36.2% yield) as a yellow oil. H NMR (400 MHz, CDCI3-d) δ 8.92 (s, 1H), 8.71 (5, 1H), 8.61 (5, 1H), 5.57 (br s, 1H), 5.10 (br d, J= 6.8 Hz, 1H), 4.24 (br d, J = 3.2 Hz, 1H), 2.68 - 2.38 (m, 4H), 2.25 - 2.09 (m, 1H), 2.04 - 1.94 (m, 1H), 1.88 - 1.73 (m, 1H), 1.46 (d, J= 6.0 Hz, 18H).Step 4: tert-butyl (2S)-2-((tert-butoxycarbonyl)amino)-4-(4,4,4-trifluoro-3-hydroxy-3- (pyrazin-2-yl)butylsulfonimidoyl)butanoate:

[0246] To a solution of compound 5 (470 mg, 948 pmol. 1 eq) in i-PrOH (10 mL) was added PhI(OAc)2 (916 mg, 2.85 mmol, 3 eq) and ammonium acetate (366 mg, 4.74 mmol, 5 eq). The mixture was stirred at 15 °C for 24 h. The reaction mixture was quenched by water (20 mL), and then extracted with DCM (30 mL x 2), the combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford the title compound (375 mg, 712 pmol, 75.1% yield) as a yellow solid. H NMR (400 MHz, CDCI3-d) δ 9.08 (br d, J= 10.0 Hz, 1H), 8.69 (dd, J= 2.4, 6.8 Hz, 1H), 8.60 (d, J= 1.6 Hz, 1H), 5.35 - 5.13 (m, 1H), 4.38 - 4.18 (m, 1H), 3.33 - 2.66 (m, 6H), 2.49 - 2.23 (m, 1H), 2.19 - 1.94 (m, 1H), 1.54 - 1.39 (m, 18H).Step 5: (2S)-2-amino-4-(4,4,4-trifluoro-3-hydroxy-3-(pyrazin-2- yl)butylsulfonimidoyl)butanoic acid:

[0247] A solution of compound 6 (300 mg, 569.73 pmol, 1 eq) in HCl / dioxane (15 mL) was stirred at 25 °C for 16 h. The mixture was concentrated under reduced pressure to afford 250 mg of crude product. 100 mg of crude product was purified by prep-HPLC (column: Waters Xbridge BEH C18 100*30 mm* 10 pm; mobile phase: [H2O (lOmM NH4HCO3)- MeCN]; gradient: l%-35% B over 12.0 min) to afford the title compound (31.57 mg, 85.24 pmol, 14.96% yield, 100% purity) as a white solid. LCMS: Rt = 1.433 min, (ES+) m / z (M+H)+= 371.1.1H NMR (400 MHz, MeOD-A) δ 9.01 (s, 1H), 8.72 - 8.68 (m, 1H), 8.65 (d, J= 2.4 Hz, 1H), 3.70 - 3.59 (m, 1H), 3.44 - 3.35 (m, 1H), 3.28 - 2.99 (m, 3H), 2.89 - 2.76 (m, 1H), 2.67 - 2.49 (m, 1H), 2.35 - 2.18 (m, 2H).Step 6: (2S)-2-((tert-butoxycarbonyl)amino)-4-(4, 4, 4-trifluoro-3-hydroxy-3-(pyrazin-2- yl)butylsulfonimidoyl)butanoic acid:

[0248] A mixture of Compound 6A (150 mg, 250 pmol, 1 eq, 3HC1), Na2CO3(79.5 mg, 750 pmol, 3 eq) and (Boc)2O (65.5 mg, 300 pmol, 68.9 μL, 1.2 eq) in H2O (3 mL) and dioxane (0.6 mL) was stirred at 25 °C for 12 h. The mixture was adjusted to pH = 3 by IM HC1 and then extracted with EtOAc (3 mL x 5). The combined organic layers were washed with brine (2 mL), dried over Na2SO4. filtered, and concentrated under reduced pressure to afford the title compound (90 mg, 191 pmol, 47.2% yield) as a white solid.1H NMR (400 MHz, DMSO-t / e) δ 8.97 (d, J= 2.0 Hz, 1H), 8.77 - 8.67 (m, 2H), 6.73 - 6.48 (m, 1H), 3.77 (br dd, J= 1.6, 6.0 Hz, 1H), 3.13 - 2.85 (m, 3H), 2.83 - 2.71 (m, 1H), 2.68 - 2.54 (m, 1H), 2.47 - 2.39 (m, 1H), 2.07 - 1.83 (m, 2H), 1.37 (s, 9H).Step 7: tert-butyl ((4S)-l-oxido-3-oxo-l-(4,4,4-trifluoro-3-hydroxy-3-(pyrazin-2-yl)butyl)- 3, 4, 5, 6-tetrahydro-ll6, 2-thiazin-4-yl) carbamate:

[0249] To a solution of compound 7 (60 mg, 127 pmol, 1 eq) and TEA (77.4 mg, 765 pmol, 106 μL, 6 eq) in DCM (1 mL) was added T4P (276 mg, 383 pmol, 50% purity, 3 eq) at 0 °C. The resulting mixture was stirred at 15 °C for 1 h. The reaction mixture was poured into water (5 mL) and extracted with DCM (5 mL x 2). The combined organic layers were washed with brine (6 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2, Petroleum ether: Ethyl acetate = 1: 5) to afford the title compound (52 mg, 115 pmol, 90. 1% yield) as a yellow oil.Step 8: (4S)-4-amino-l-(4,4,4-trifluoro-3-hydroxy-3-(pyrazin-2-yl)butyl)-5,6-dihydro-ll6,2- thiazin-3(4H)-one 1-oxide:

[0250] To a solution of compound 8 (52 mg, 115 pmol, 1 eq) in DCM (5 mL) was added TFA (1 mL) and the mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Waters Xbridge 150*25 mm 10 pm; mobile phase: [H2O (lOmM NHdTCChj-MeCN]; gradient: l%-30% B over 9.0 min) to afford the title compound (33.68 mg, 91.42 pmol, 79.55% yield, 95.641% purity) as a white solid. LCMS: Rt = 1.773 min., (ES+) m / z (M+H)+=353.0.1H NMR (400 MHz, D2O) δ 8.99 (s, 1H), 8.75 - 8.65 (m, 2H), 4.07 - 3.47 (m, 4H), 3.30 - 3.18 (m, 1H), 3.03 - 2.90 (m, 1H), 2.79 - 2.64 (m, 1H), 2.55 - 2.42 (m, 1H), 2.37 - 2.04 (m, 1H).Example 21: (S)-2-amino-4-((S)-2-(l-(hydroxymethyl)cyclobutyl)ethylsulfonimidoyl)butanoic acid or (lS,4S)-4-amino-l-(2-(l-(hydroxymethyl)cyclobutyl)ethyl)-5,6-dihydro-116,2-thiazin-3(4H)-one 1-oxide(Compound 122)

[0251] A mixture of compound 1 (prepared as described in W02024030960A3, 1 eq) in HCl / dioxane (4 M) was stirred at 20 °C for 2 hours. The mixture was concentrated under reduced pressure at 40 °C to afford the title compound (39.01% yield, HC1) as a white solid, which was used in the next step directly.Step 2: (S)-2-((tert-butoxycarbonyl)amino)-4-((S)-2-(l- (hydroxymethyl)cyclobutyl)ethylsulfonimidoyl)butanoic acid:

[0252] To a mixture of crude compound 2 (1 eq) in H2O (0.14 M) and dioxane (0.7 M) was added Na2CO3(3 eq) and BOC2O (1.3 eq) in one portion at 20 °C. The mixture was stirred at 20 °C for 12 h and extracted with EtOAc. The aqueous phase was adjusted to pH = 6 with 0.5 N HC1 solution and extracted with EtOAc (100 mL x 10). The combined organicphase was washed with brine, dried with anhydrous Na2SCri. filtered and concentrated in vacuum to afford the title compound (56.83% yield) as a yellow solid.1H NMR (400 MHz, MeOD) 34.29-4.25 (m, 1H), 3.53 (s, 2H), 3.32-3.13 (m, 4H), 2.48-2.38 (m, 1H), 2.25 - 2.13 (m, 1H), 2.04 - 1.82 (m, 8H), 1.47 (s, 9H).Step 3: tert-butyl ((IS, 4S)-l-(2-(l-(hydroxymethyl)cyclobutyl)ethyl)-l-oxido-3-oxo-3, 4,5,6- tetrahydro-ll6,2-thiazin-4-yl)carbamate:

[0253] To a mixture of compound 3 (1 eq) in DCM (0.05 M) was added TEA (2 eq) and TrP (0.5 eq) in one portion at 0 °C. The mixture was stirred at 20 °C for 3 hours and then poured into saturated aqueous NaHCO3solution. The aqueous phase was extracted with DCM and the combined organic phase was washed with brine, dried with anhydrous Na2SO4, fdtered and concentrated under vacuum to afford the title compound (98.44% yield) as a yellow solid.1H NMR (400 MHz, CDCh-ri) 3 5.78 (br s, 1H), 4.18-4.15 (m, 1H), 3.75- 3.72 (m, 1H), 3.55 (s, 2H), 3.40 (m, 1H), 3.27-3.23 (m, 2H), 2.78 (m, 1H), 2.05 - 1.77 (m, 9H), 1.75 (s, 9H).Step 4: (IS, 4S)-4-amino-l-(2-(l-(hydroxymethyl)cyclobutyl)ethyl)-5, 6-dihydro-ll6, 2-thiazin- 3(4H)-one 1-oxide:

[0254] To a mixture of compound 4 (1 eq) in DCM (0.3 M) was added TFA (1.3 M) in one portion at 20 °C. The mixture was stirred for 2 hours and then concentrated under reduced pressure at 40 °C. The residue was purified by prep-HPLC (column: Phenomenex Gemini C18 (250 x 50mm x 10 um); mobile phase: [H2O (lOmM NH4HCO3)-MeCN]; gradient: 0-25% B over 20.0 min) to afford the title compound as a white solid. LCMS: Rt = 2.761 min., (ES+) m / z (M+H)+=261.1. *HNMR (400 MHz, D2O) 3 4.07-4.03 (m, 1H), 3.63-3.40 (m, 6H), 2.43 - 2.42 (m, 1H), 2.15 - 2.08 (m, 1H), 1.97 - 1.95 (m, 2H), 1.81-1.72 (m, 6H).Example 22: (lS,4S)-4-amino-l-((S)-4,4,4-trifluoro-3-phenylbutyl)-5,6-dihydro-116,2- thiazin-3(4H)-one 1-oxide (Compound 123)Step 1 : (S)-2-((tert-butoxycarbonyl)amino)-4-( (S, 3S)-4, 4, 4-trifluoro-3- phenylbutylsulfonimidoyl)butanoic acid:

[0255] A mixture of compound 1 (70 mg, 199 pmol, 1 eq), BOC2O (65.0 mg, 298 pmol, 68.5 μL, 1.5 eq) and Na2CO3(63.2 mg, 596 pmol, 3 eq) in H2O (2 mL) and dioxane (0.4 mL) was degassed and purged 3 times with N2, and then the mixture was stirred at 25 °C for 12 h under N2 atmosphere. The reaction mixture was adjusted to pH = 3 with 10% aq. citric acid and extracted with EtOAc (3 mL x 5). The combined organic layers were washed with brine (3 mL), dried over Na2SO4. fdtered, and concentrated under reduced pressure to give the title compound (89 mg, 197 pmol, 99.0% yield) as a yellow oil.Step 2: tert-butyl ((lS,4S)-l-oxido-3-oxo-l-((S)-4,4,4-trifluoro-3-phenylbutyl)-3,4,5,6- tetrahydro-ll6,2-thiazin-4-yl)carbamate:

[0256] To a solution of compound 2 (89.0 mg, 197 pmol, 1 eq) and TEA (99.5 mg, 983 pmol, 137 μL, 5 eq) in DCM (1 mL) was added T4P (283 mg, 393 pmol, 50% purity, 2 eq) at 0 °C under N2. The resulting mixture was stirred at 15 °C for 1 h under N2 and then poured into water (3 mL) and extracted with DCM (3 mL x 2). The combined organic layers were washed with brine (3 mL), dried over Na2SO4. fdtered, and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO2, Petroleum ether / EtOAc = 1: 2) to afford the title compound (50 mg, 115 pmol, 58.5% yield) as a white solid.1H NMR (400 MHz, MeOD-A) δ 7.46 - 7.31 (m, 5H), 4.09 (dd, J= 4.8, 10.8 Hz, 1H), 4.05 - 3.92 (m, 1H), 3.76 (ddd, J= 4.4, 9.2, 11.2 Hz, 1H), 3.62 - 3.45 (m, 1H), 3.38 (br dd, J = 4.8, 10.0 Hz, 1H), 3.21 - 3.13 (m, 1H), 2.72 - 2.59 (m, 1H), 2.55 - 2.35 (m, 2H), 2.29 - 2.12 (m, 1H), 1.44 (s, 9H).Step 3: (lS,4S)-4-amino-l-((S)-4,4,4-trifluoro-3-phenylbutyl)-5, 6-dihydro-ll6,2-thiazin- 3(4H)-one 1-oxide:

[0257] To a solution of compound 3 (50 mg, 115 pmol, 1 eq) in DCM (1 mL) was added TLA (0.2 mL) at 25 °C. The resulting mixture was stirred for 1 h and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge BEH C18 (100*30mm* lOum); mobile phase: [H2O (lOmM NH4HCO3)- MeCN]; gradient: 10-60% B over 8.0 min) to afford the title compound (16.66 mg, 49.8 pmol, 43.3% yield, 100% purity) as a white solid. LCMS: Rt = 1.667 min, (ES+) m / z (M+H)+= 335.1.1H NMR (400 MHz, MeOD-Ai) δ 7.47 - 7.34 (m, 5H), 3.99 (td, J= 4.8,14.8 Hz, 1H), 3.84 - 3.69 (m, 1H), 3.53 - 3.35 (m, 3H), 3.16 (ddd, J= 4.8, 10.0, 14.4 Hz, 1H), 2.65 (dddd, J= 4.4, 6.0, 10.0, 14.0 Hz, 1H), 2.53 - 2.33 (m, 2H), 2.10 - 1.93 (m, 1H).Example 23: (lR,4S)-4-amino-l-((S)-4,4,4-trifluoro-3-methoxy-3-phenylbutyl)-5,6- dihydro-116,2-thiazin-3(4H)-one 1-oxide (Compound 124)

[0258] To a solution of compound 1 (see Example 8, 400 mg, 854 pmol, 1 eq) in DCM (5 mL) was added tert-butyl 2,2,2-trichloroethanimidate (746 mg, 3.42 mmol, 611 μL, 4 eq) at 0 °C. The mixture was stirred at 40 °C for 12 h, then poured into water (25 mL) and extracted with DCM (20 mL x 2). The combined organic layers were washed with brine (20 mL), dried over Na2SOr, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / EtOAc = 65:35) to afford the title compound (256 mg, 488.00 pmol, 57. 16% yield) as a white solid. 1H NMR (400 MHz, CDCI3-d) δ ppm 1.45 (d, J= 14.26 Hz, 18 H) 1.92 - 2.04 (m, 1 H) 2.22 - 2.43 (m, 1 H) 2.64 - 2.79 (m, 1 H) 2.84 - 3.07 (m, 4 H) 3.10 - 3.26 (m, 1 H) 4.20 - 4.36 (m, 1 H) δ.17 (br d, J= 5.13 Hz, 1 H) 7.33 - 7.49 (m, 3 H) 7.61 (br d, J= 125 Hz, 2 H).Step 2: tert-butyl (S)-2-((tert-butoxycarbonyl)amino)-4-((R,3S)-4,4,4-trifluoro-3-methoxy-3- phenylbutylsulfonimidoyl)butanoate:

[0259] To a solution of compound 2 (256 mg, 488 pmol, 1 eq) in DMF (2 mL) was added Mel (76.19 mg, 537 pmol, 33.4 μL, 1.1 eq) and CS2CO3 (477 mg, 1.46 mmol, 3 eq). The resulting mixture was stirred at 20 °C for 12 h, diluted with water (20 mL), andextracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine 30 mL and NHrCI 30 mL, dried over Na2SOr. filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO2, Petroleum ether / EtOAc = 3: 1) to afford crude compound (200 mg). The crude material (200 mg) was purified by prep-HPLC (column: Waters Xbridge BEH C18 (100*25mm* 10 um); mobile phase: [H2O (10 mM NH4HCO3)-MeCN]; gradient: 45-75% B over 8.0 min) to afford the title compound (110 mg, 204.23 pmol, 41.85% yield) as a white solid.1H NMR (400 MHz, CDCI3-d) δ 1.37 (s, 9 H) 1.40 (s, 9 H) 1.91 - 2.05 (m, 1 H) 2.20 - 2.35 (m, 1 H) 2.40 - 2.54 (m, 1 H) 2.69 (ddd, J= 14.36, 12.04, 4.83 Hz, 1 H) 2.88 - 3.16 (m, 4 H) 3.34 (d, J= 0.72 Hz, 3 H) 4.19 (br s, 1 H) δ.13 (br d, J= 2.03 Hz, 1 H) 7.30 - 7.39 (m, 3 H) 7.40 - 7.48 (m, 2 H).Step 3: (S)-2-amino-4-((R3S)-4,4,4-trifluoro-3-methoxy-3- phenylbutylsulfonimidoyl)butanoic acid:

[0260] A solution of compound 3 (110 mg, 204 pmol, 1 eq) in HCl / dioxane (3 mL) (4M) was stirred at 25 °C for 12 h. The reaction mixture was concentrated under reduced pressure to give a residue (126 mg). A portion of the residue (30 mg) was purified by prep- HPLC (column: Phenomenex Luna C18 (100*30 mm*3 um); mobile phase: [H2O (0.2% LA)-MeCN]; gradient: 5-40% B over 12.0 min) to afford the title compound (13.97 mg, 36.53 pmol, 17.89% yield, 100% purity) as a white solid. LCMS: Rt = 1.899 min, (ES+) m / z (M+H)+= 383.1. ‘HNMR (400 MHz, MeOD-A) δ 2.25 (dd, J= 4.50, 1.50 Hz, 2 H) 2.66 (br s, 1 H) 2.84 - 2.97 (m, 1 H) 3.01 - 3.15 (m, 1 H) 3.17 - 3.28 (m, 1 H) 3.37 - 3.50 (m, 5 H) 3.63 - 3.80 (m, 1 H) 7.40 - 7.53 (m, 3 H) 7.60 (br d, J= 7.38 Hz, 2 H).Step 4: (S)-2-( ( tert-butoxycarbonyl)amino)-4-( (R, 3S)-4, 4, 4-trifluoro-3-methoxy-3- phenylbutylsulfonimidoyl)butanoic acid:

[0261] To a solution of compound 4 (96 mg, 229 pmol, 1 eq, HC1) in dioxane ( 1 mL) and H2O (5 mL) was added BOC2O (65.0 mg, 298 pmol, 68.5 μL, 1.3 eq) and Na2CO3(72.9 mg, 688 pmol, 3 eq). The mixture was stirred at 20 °C for 2 h and then adjusted to pH ~5 with citric acid and extracted with EtOAc (10 mL x 2). The combined organic layers were dried over Na2SO4. filtered and concentrated under reduced pressure to afford the title compound (130 mg, crude) as a white solid.Step 5: tert-butyl ((lR,4S)-l-oxido-3-oxo-l-((S)-4,4,4-trifluoro-3-methoxy-3-phenylbutyl)- 3, 4, 5, 6-tetrahydro-ll6, 2-thiazin-4-yl)carbamate :

[0262] To a solution of compound 5 (110 mg, 228 pmol, 1 eq) in DCM (4 mL) was added TrP (263 mg, 364.76 pmol, 50% purity, 1.6 eq) and TEA (115 mg, 1.14 mmol, 159 μL, 5 eq) at 0 °C. The mixture was warmed to 20 °C and stirred for 1 h. The reaction mixture was diluted with water (15 mL) and extracted with DCM (10 mL x 2). The combined organic layers were washed with brine 5 mL, dried over Na2SOr, fdtered and concentrated under reduced pressure to give a residue. The residue was purified by prep- TLC (SiO2, Petroleum ether: EtOAc = 1:1) to afford the title compound (55 mg, 118.41 pmol, 51.94% yield as a yellow oil. ' H NMR (400 MHz, MeOD-A) δ 1.37 - 1.52 (m, 9 H) 2.23 - 2.52 (m, 2 H) 2.80 (br d, J=4.89 Hz, 1 H) 2.94 - 3.06 (m, 1 H) 3.36 - 3.45 (m, 4 H) 3.52 - 3.72 (m, 2 H) 3.92 - 4.23 (m, 2 H) 7.34 - 7.50 (m, 3 H) 7.58 (br d, J=1.39 Hz, 2 H).Step 6: (lR,4S)-4-amino-l-((S)-4,4,4-trifluoro-3-methoxy-3-phenylbutyl)-5, 6-dihydro-ll6,2- thiazin-3(4H)-one 1-oxide:

[0263] A solution of compound 6 (55 mg, 118 pmol, 1 eq) in DCM (10 mL) and TFA (2 mL) was stirred at 20 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 (100*30 mm*3 um); mobile phase: [H2O (0.2% FA)-MeCN]; gradient: 5-45% B over 12.0 min) to afford the title compound (22.81 mg, 62.60 pmol, 52.87% yield, 100% purity, FA salt ) as a white solid. LCMS: Rt = 1.969 min, (ES+) m / z (M+H)+= 365.0.1H NMR (400 MHz, MeOD-d6) δ 2.16 - 2.55 (m, 1 H) 2.56 - 2.78 (m, 2 H) 2.95 - 3.07 (m, 1 H) 3.44 - 3.51 (m, 4 H) 3.53 - 3.72 (m, 2 H) 3.83 - 4.25 (m, 2 H) 7.40 - 7.53 (m, 3 H) 7.59 (br d, J= 7.38 Hz, 2 H) 8.37 (br s, 1 H).Example 24: (4S)-4-amino-l-(4,4,4-trifluoro-3-methoxy-3-(pyrazin-2-yl)butyl)-5,6- dihydro-lX6,2-thiazin-3(4H)-one 1-oxide (Compound 125)

[0264] A mixture of compound 1 (80.0 mg, 190 pmol, 1 eq), (Boc)2O (62.2 mg, 285 pmol, 65.5 μL, 1.5 eq) and Na2CO3(60.4 mg, 570 pmol, 3 eq) in dioxane (0.4 mL) and H2O (2 mL) was stirred at 25 °C for 12 h. The reaction mixture was quenched by addition water (5 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to afford the title compound (60.0 mg, crude) as a yellow oil.1H NMR (400 MHz, MeOD-A) δ 8.95 (s, 1H), 8.72 (d, J= 1.5 Hz, 1H), 8.66 (d, J= 2.4 Hz, 1H), 4.33 - 4.22 (m, 1H), 3.59 (s, 3H), 3.29 - 2.83 (m, 6H), 2.44 - 2.24 (m, 1H), 2.22 - 2.04 (m, 1H), 1.45 (s, 9H).Step 2: tert-butyl ((4S)-l-oxido-3-oxo-l-(4,4,4-trifluoro-3-methoxy-3-(pyrazin-2-yl)butyl)- 3, 4, 5, 6-ieirahydro-l / :'.2-thiazin-4-yl)carbamate:

[0265] A mixture of compound 2 (60.0 mg, 123 pmol, 1 eq), T4P (133 mg, 371 pmol, 3 eq) and TEA (75.1 mg, 743 pmol, 103 μL, 6 eq) in DCM (0.6 mL) was stirred at 25 °C for 2 h. The reaction mixture was quenched by addition water (10 mL) and extracted with dichloromethane (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (40.0 mg, crude) as a yellow oil.Step 3: ( 4S)-4-amino-l-( 4, 4, 4-trifluoro-3-methoxy-3-(pyrazin-2-yl)butyl)-5, 6-dihydro-l X6, 2- thiazin-3(4H)-one 1 -oxide:

[0266] A mixture of compound 3 (40.0 mg, 77.1 pmol, 1 eq) in TFA (0.5 mL) and DCM (2.5 mL) was stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge BEH C18 (100*30 mm* 10 um); mobile phase: [H2O (10 mM NH4HCC>3)-MeCN]; gradient: 1-40% B over 8.0 min) to afford the title compound (11.28 mg, 30.1 pmol, 39.0% yield, 97.8% purit) as a white solid. LCMS: Rt = 1.941 min, (ES+) m / z (M+H)+= 367.1.1H NMR (400 MHz, MeOD-J4) δ 8.94 (s, 1H), 8.73 - 8.69 (m, 1H), 8.67 (d, J= 2.4 Hz, 1H), 4.15 - 3.65 (m, 2H), 3.57 (br d, J= 5.0 Hz, 3H), 3.54 - 3.34 (m, 3H), 3.11 - 2.96 (m, 2H), 2.51 - 2.07 (m, 2H).Example 25: (4S)-4-amino-l-(4,4,4-trifluoro-3-hydroxy-3-(pyridin-2-yl)butyl)-5,6- dihydro-116,2-thiazin-3(4H)-one 1-oxide (Compound 126)

[0267] To a solution of compound 1 (prepared as described in W02024030960A3, 170 mg, 419 pmol, 1 eq, HC1) in dioxane (0.4 mL) and H2O (2 mL) was added BOC2O (110 mg, 503 pmol, 115 μL, 1.2 eq) and Na2CO3(133 mg, 1.26 mmol, 3 eq) a t 25 °C under N2, then the reaction mixture was stirred at 25 °C for 12 h. The reaction mixture was adjusted to pH = 5 by addition of aqueous citric acid (1 M) at 0 °C. Water (10 mL) was added at 20 °C and the mixture was extracted with EtOAc (10 mLx3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4. fdtered and concentrated under reduced pressure to give the title compound (138 mg, 294 pmol, 70. 17% yield) as a light yellow oil.Step 2: tert-butyl ((4S)-l-oxido-3-oxo-l-(4,4,4-trifluoro-3-hydroxy-3-(pyridin-2-yl)butyl)- 3, 4, 5, 6-tetrahydro-ll6, 2-thiazin-4-yl)carbamate :

[0268] To a solution of compound 2 (100 mg, 213 pmol, 1 eq) in DCM (1 mL) was added T4P (307 mg, 426 pmol, 50% purity, 2 eq) and TEA (64.7 mg, 639 pmol, 88.9 μL, 3 eq) at 0 °C, then the reaction mixture was stirred at 20 °C for 2 h. The reaction mixture was quenched by addition of water (10 mL) at 20 °C and extracted with EtOAc (10 mLx3). The combined organic layers were washed with brine (30 mL), dried over Na2SOr, fdtered and concentrated under reduced pressure to give a residue. The residue was purified by prep- TLC (silica gel, petroleum ether / EtOAc = 1 : 1, Rr = 0.5) to afford the title compound (51 mg, 102 pmol, 48.10% yield, 90.7% purity) as a yellow oil.Step 3: (4S)-4-amino-l-(4,4,4-trifluoro-3-hydroxy-3-(pyridin-2-yl)butyl)-5, 6-dihydro-ll6,2- thiazin-3(4H)-one 1 -oxide:

[0269] To a solution of compound 3 (50 mg, 111 pmol, 1 eq) in DCM (0.5 mL) was added TFA (0.1 mL) at 20 °C and then the reaction mixture was stirred at 20 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residuewas purified by prep-HPLC (column: Phenomenex luna C18 (100*40mm*5 um); mobile phase: [H2O (0.2% LA)-MeCN]; gradient: 5-40% B over 8.0 min) to afford the title compound (23.45 mg, 59.01 pmol, 53.28% yield, 100% purity, PA salt) as a white solid. LCMS: Rt = 1.414 min, (ES+) m / z (M+H)+= 352.0.1H NMR (400 MHz, MeOD-d4) δ 8.65 (br d, J= 4.0 Hz, 1H), 8.43 (s, 1H), 7.98 - 7.91 (m, 1H), 7.82 (d, J= 7.9 Hz, 1H), 7.51 - 7.44 (m, 1H), 4.26 - 3.93 (m, 1H), 3.92 - 3.42 (m, 3H), 3.20 - 2.95 (m, 2H), 2.75 - 2.15 (m, 3H).Example 26: (4S)-4-amino-l-(4,4,4-trifluoro-3-hydroxy-3-(isothiazol-3-yl)butyl)-5,6- dihydro-116,2-thiazin-3(4H)-one 1-oxide (Compound 127)

[0270] To a solution of compound 1 (90 mg, 219 pmol, 1 eq, HC1) in H2O (2.5 mL) was added Na2CO3(69.5 mg, 655 pmol, 3 eq) and BOC2O (71.5 mg, 327 pmol, 75.3 μL, 1.5 eq) under N2 and the mixture was stirred at 25 °C for 3 h. The solution was adjusted to pH ~4 with citric acid and extracted with EtOAc (20 mL x 2). The combined organic layers were dried over Na2SOr, filtered and concentrated under reduced pressure to obtain the title compound (100 mg, crude).Step 2: tert-butyl ((4S)-l-oxido-3-oxo-l-(4,4,4-trifluoro-3-hydroxy-3-(isothiazol-3-yl)butyl)- 3,4,5, 6-tetrahydro-ll6,2-thiazin-4-yl)carbamate:

[0271] To a solution of compound 2 (0.1 g, 210 pmol, 1 eq) and TEA (148 mg, 1.47 mmol, 204 μL, 7 eq) in DCM (2 mL) was added T4P (242 mg, 336 pmol, 50% purity, 1.6 eq) dropwise at 0 °C under N2 and the mixture was stirred at 25 °C for 1 h. The reaction mixture was poured into water (25 mL) and extracted with dichloromethane (10 mL x 2). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiC>2, Petroleum ether / EtOAc = 1: 1) to afford the title compound (40 mg, 87.4pmol, 41.58% yield) as a colorless oil. ‘HNMR (400 MHz, CDCI3-d) 3 8.95 - 8.76 (m, 1H), 7.44 . 7.34 (m, 1H), 5.90 - 5.55 (m, 1H), 4.34 - 3.79 (m, 1H), 3.65 - 3.35 (m, 3H), 3.07 - 2.62 (m, 4H), 2.47 - 1.88 (m, 1H), 1.49 - 1.42 (m, 9H).Step 3: (4S)-4-amino-l-(4, 4, 4-trifluoro-3-hydroxy-3-(isothiazol-3-yl)butyl)-5, 6-dihydro- 116, 2 -thiazin- 3 ( 4H)-one 1 -oxide :

[0272] A solution of compound 3 (40 mg, 87.4 pmol, 1 eq) in DCM (1 mL) and TFA (0.1 mL) was stirred at 25 °C for 1 h under N2. The reaction mixture concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Waters Xbridge BEH C18 (100*30mm* 10 urn); mobile phase: [H2O (10 mM NH4HCO3)-MeCN]; gradient: 1- 25% B over 8.0 min) to afford the title compound (20.5 mg, 57.36 pmol, 65.61% yield, 100% purity) as a white solid. LCMS: Rt = 1.812 min., (ES+) m / z (M+H)+= 358.0.1H NMR (400 MHz, D2O) 3 9.02 (dd, J= 1.3, 4.8 Hz, 1H), 7.57 (d, J= 4.6 Hz, 1H), 4.16 - 3.96 (m, 0.5H), 3.83 - 3.69 (m, 1H), 3.65 - 3.55 (m, 2H), 3.46 (td, J= 4.3, 11.9 Hz, 0.5H), 3.32 - 3.16 (m, 1H), 2.97 - 2.81 (m, 1H), 2.77 - 2.57 (m, 1H), 2.55 - 2.00 (m, 2H).Example 27: (R)-4-((lR,4S)-4-amino-l-oxido-3-oxo-3,4,5,6-tetrahydro-116,2-thiazin-l- yl)-l,l,l-trifluorobutan-2-yl 6,6,6-trifluorohexanoate (Compound 128)

[0273] To a solution of 6,6,6-trifluorohexanoic acid (46 mg, 270 pmol, 1 eq) in DCM (0.5 mL) was added oxalyl dichloride (68.6 mg, 541 pmol, 47.3 μL, 2 eq) and DMF (988 pg, 13.5 pmol, 1.04 μL, 0.05 eq) at 0 °C under N2. The resulting mixture was stirred at 15 °C for 1 h under N2. The reaction mixture was concentrated under reduced pressure to afford the title compound (50.9 mg, 269.92 pmol, 99.83% yield) as a yellow oil.Step 2: (R)-4-((lR,4S)-4-((tert-hutoxycarhonyl)amino)-l-oxido-3-oxo-3,4,5, 6-tetrahydro- 116, 2-thiazin-l-yl)-l, l,l-trifluorobutan-2-yl 6, 6, 6-trifluorohexanoate :

[0274] To a solution of compound 3 (50.0 mg, 134 pmol, 1 eq) and pyridine (84.5 mg, 1.07 mmol, 86.2 μL, 8 eq) in DCM (1 mL) was added compound 2 (50.4 mg, 267 pmol, 2 eq) at 0 °C under N2. The resulting mixture was stirred at 15 °C for 1 h under N2. The reaction mixture was poured into water (5 mL) and extracted with DCM (5 mL x 2). The combined organic layers were washed with brine (5 mL), dried over Na2SOr, fdtered and concentrated under reduced pressure to give a residue. The residue was purified by prep- TLC (SiC>2, Petroleum ether / EtOAc = 1:3) to give the title compound (130 mg, 246.92 pmol, 92.44% yield) as a yellow oil. ' H NMR (400 MHz, MeOD-tri) δ = 5.63 (ddd, J= 3.6, 6.4, 9.6 Hz, 1H), 4.22 - 3.98 (m, 2H), 3.63 - 3.55 (m, 2H), 2.58 - 2.41 (m, 4H), 2.38 - 2.31 (m, 2H), 2.22 - 2.15 (m, 2H), 1.83 - 1.56 (m, 6H), 1.45 (s, 9H).Step 3: (R)-4-((lR, 4S)-4-amino-l-oxido-3-oxo-3, 4,5, 6-tetrahydro-ll6,2-thiazin-l-yl)-l, 1,1- trifluorobutan-2-yl 6, 6, 6-trifluorohexanocite:

[0275] To a solution of compound 4 (130 mg, 247 pmol, 1 eq) in DCM (3 mL) was added TFA (0.6 mL) at 20 °C and the resulting mixture was stirred for 1 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge BEH C18 (100*30 mm* 10 um); mobile phase: [H2O (10 mM NH4HCO3)-MeCN]; gradient: 15-45% B over 8.0 min) to afford the title compound (67.85 mg, 159.13 pmol, 64.45% yield, 100% purity) as a white solid. LCMS: Rt = 2.105 min, (ES+) m / z (M+H)+= 427.1.1H NMR (400 MHz, MeOD-tri) δ = 5.69 - 5.53 (m, 1H), 4.07 (td, J= 4.8, 14.8 Hz, 1H), 3.65 - 3.44 (m, 4H), 2.61 - 2.49 (m, 2H), 2.48 - 2.30 (m, 3H), 2.26 - 2.06 (m, 3H), 1.79 - 1.68 (m, 2H), 1.67 - 1.56 (m, 2H).Example 28: (lR,4S)-4-(diphenylphosphorylamino)-l-oxo-l-[(3R)-4,4,4-trifluoro-3- hydroxy-butyl]-lthia-2-azacyclohexen-3-one (Compound 129)

[0276] To a solution of compound 1 (30.0 mg, 109 pmol, 1 eq) in DCM (0.3 mL) was added TEA (55.3 mg, 547 pmol, 76.1 μL, 5 eq), followed by compound 1A (31.1 mg, 131pmol, 24.7 μL, 1.2 eq) dropwise at 0 °C and the mixture was stirred at 25 °C for 3 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 (100*30 mm*3 um); mobile phase: [H2O (0.2% FA)-MeCN]; gradient: 30-60% B over 8.0 min). The product fractions were further purified by re-crystallization from EtOAc (1 mL) at 25 °C to afford the title compound (2. 1 mg, 4.43 pmol, 4.05% yield) as a white solid. LCMS: Rt = 2.035 min, (ES+) m / z (M+H)+= 475.0.1H NMR (400 MHz, MeOD-A) δ 8.00 (br dd, J= 7.4, 12.1 Hz, 2H), 7.88 (br dd, J= 7.3, 12.1 Hz, 2H), 7.64 - 7.45 (m, 6H), 4.18 - 4.01 (m, 2H), 3.89 (dt, J= 4.4, 10.6 Hz, 1H), 3.63 - 3.52 (m, 3H), 2.65 - 2.52 (m, 1H), 2.43 - 2.20 (m, 2H), 2.17 - 2.03 (m, 1H).Example 29: (S)-4-((lR,4S)-4-amino-l-oxido-3-oxo-3,4,5,6-tetrahydro-116,2-thiazin-l- yl)-l,l,l-trifluoro-2-phenylbutan-2-yl 6,6,6-trifluorohexanoate (Compound 130)

[0277] To a solution of compound 1 (prepared as described in W02024030960A3, 150 mg, 407 pmol, 1 eq) in dioxane (0.5 mL) and H2O (2.5 mL) was added Na2CO3(129 mg, 1.22 mmol, 3 eq) and (Boc)2O (116 mg, 529 pmol, 122 μL, 1.3 eq) and the resulting mixture was stirred at 15 °C for 1 h. The mixture was washed with petroleum ether and the aqueous layer was diluted with water (10 mL), adjusted to pH = 4 with citric acid, and then extracted with DCM (10 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford the title compound (180 mg, 384 pmol, 94.4% yield) as a colorless oil.1H NMR (400 MHz, CDCI3-d) δ 7.57 (br d, J= 7.1Hz, 2H), 7.42 (br d, J= 7.7 Hz, 3H), 5.42 - 4.38 (m, 2H), 3.29 - 3.02 (m, 3H), 2.98 - 2.82 (m, 1H), 2.82 - 2.71 (m, 2H), 2.44 - 2.30 (m, 1H), 2.27 - 2.13 (m, 1H), 1.45 (s, 9H).Step 2: tert-butyl ((lR,4S)-l-oxido-3-oxo-l-((S)-4,4,4-trifluoro-3-hydroxy-3-phenylbutyl)- 3,4,5, 6-tetrahydro-ll6,2-thiazin-4-yl)carbamate:

[0278] To a solution of compound 2 (180 mg, 384 pmol, 1 eq) in DCM (2 mL) was added TEA (156 mg, 1.54 mmol, 214 μL, 4 eq) and T4P (554 mg, 768 pmol, 50% purity, 2 eq) at 0 °C and the resulting mixture was stirred at 15 °C for 1 h. The mixture was poured into water (10 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were dried over Na2SOr, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2, Petroleum ether / EtOAc = 1:2) to afford the title compound (160 mg, 355 pmol, 92% yield) as a white solid.1H NMR (400 MHz, MeOD-d4) δ 7.63 (d, J = 7.5 Hz, 2H), 7.43 (br d, J= 7.6 Hz, 3H), 4.12 - 4.05 (m, 1H), 4.02 - 3.92 (m, 1H), 3.54 (ddd, J = 5.2, 11.8, 14.5 Hz, 1H), 3.46 - 3.37 (m, 1H), 3.02 (br s, 1H), 2.76 (dd, J= 4.3, 12.4 Hz, 1H), 2.72 - 2.62 (m, 1H), 2.40 (qd, J= 4.8, 14.4 Hz, 1H), 2.26 - 2.11 (m, 1H), 1.43 (s, 9H).Step 3: (S)-4-((lR,4S)-4-((tert-butoxycarbonyl)amino)-l-oxido-3-oxo-3,4,5, 6-tetrahydro- 116, 2-thiazin-l-yl)-l, l,l-trifluoro-2-phenylbutan-2-yl 6, 6, 6-trifluorohexanoate:

[0279] To a solution of compound 3 (80 mg, 178 pmol, 1 eq) in DCM (1 mL) and DML (0.1 mL) was added DMAP (2.17 mg, 17.8 pmol, 0.1 eq), DIPEA (68.9 mg, 533 pmol, 92.8 μL, 3 eq) and compound 2A (100 mg, 533 pmol, 3 eq) at 0 °C. The mixture was stirred at 15 °C for 16 h under N2 atmosphere. The mixture was poured into water (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over Na2SO4. fdtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex luna C18 (30*2 mm*3 um); mobile phase: [H2O (0.02% FA)- MeCN]; gradient: 30-70% B over 12.0 min) to afford the title compound (14 mg, 23.2 pmol, 13.1% yield) as a white solid.1H NMR (400 MHz, MeOD-d4) δ 7.55 - 7.38 (m, 5H), 4.20 - 3.93 (m, 2H), 3.73 (br dd, J = 5.4, 12.6 Hz, 1H), 3.55 (br d, J= 14.3 Hz, 2H), 3.34 (br d, J = 3.3 Hz, 1H), 3.29 - 3.21 (m, 1H), 2.67 (t, J= 7.3 Hz, 2H), 2.53 - 2.42 (m, 1H), 2.37 - 2.11 (m, 3H), 1.79 - 1.69 (m, 2H), 1.68 - 1.59 (m, 2H), 1.45 (s, 9H)Step 4: (S)-4-((lR, 4S)-4-amino-l-oxido-3-oxo-3, 4, 5, 6-tetrahydro-ll6, 2-thiazin-l-yl)-l, 1, 1- trifluoro-2-phenylbutan-2-yl 6, 6, 6-trifluorohexanoate:

[0280] To a solution of compound 4 (12 mg, 19.9 pmol, 1 eq) in DCM (1 mL) and TFA (0. 1 mL) was degassed and purged 3 times with N2 and then the mixture was stirred at 25 °C for 1 h under N2 atmosphere. The mixture was concentrated under reduced pressure to give crude product. The residue was purified by prep-HPLC (column: Waters Xbridge BEH Cl 8 (100*30 mm* 10 um); mobile phase: [H2O (10 mM NH4HCO3)-MeCN]; gradient: 20-55% B over 15.0 min) to afford the title compound (8 mg, 15.1 pmol, 76% yield, 95% purity) as a white solid. LCMS: Rt = 2.900 min, (ES+) m / z (M+H)+= 503.1.1H NMR (400 MHz, MeOD-di) δ 7.55 - 7.40 (m, 5H), 4.03 (br d, J= 14.6 Hz, 1H), 3.77 - 3.64 (m, 1H), 3.59 - 3.46 (m, 3H), 3.33 (br s, 1H), 3.28 (br d, J= 6.0 Hz, 1H), 2.67 (dt, J= 1.7, 7.2 Hz, 2H), 2.47 - 2.36 (m, 1H), 2.26 - 2.05 (m, 3H), 1.79 - 1.69 (m, 2H), 1.64 (br d, J= 7.4 Hz, 2H).Example 30: (lR,4S)-4-amino-l-oxo-l-[(3S)-3,4,4,4-tetrafluorobutyl]-lthia-2- azacyclohexen-3-one (Compound 131)

[0281] To a solution of compound 1 (200 mg, 534 pmol, 1 eq) in THF (2 mL) was added N-ethyl-JV-(trifluoro-sulfanyl)ethanamine (344 mg, 2.14 mmol, 282 μL, 4 eq) and the mixture was stirred at 50 °C for 5 h under N2. The reaction was quenched by addition of H2O (5 mL), and the mixture was extracted with EtOAc (5mL x 3). The combined organic layers were washed with brine (5mL x 2), dried over anhydrous Na2SOr, fdtered and the fdtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters XBridge (150*25 mm 10 um); mobile phase: [H2O (0.2% FA)-MeCN]; gradient: 20-50% B over 9.0 min) to afford the title compound (15 mg, 39.9 pmol, 7.46% yield) as a white solid. ' H NMR (400 MHz, CDCI3-d) δ = 5.79 (br s, 1H), 5.12 - 4.85 (m, 1H), 4.30 - 4.05 (m, 1H), 3.77 (ddt, J= 3.1, 5.8, 14.9 Hz, 1H), 3.58 (ddd, J= 5.9, 12.2, 14.5 Hz, 1H), 3.47 (t, J = 7.4 Hz, 2H), 3.05 - 2.85 (m, 1H), 2.72 - 2.36 (m, 1H), 2.15 - 1.89 (m, 1H), 1.46 (s, 9H).Step 2: (lR,4S)-4-amino-l-oxo-l-[(3S)-3,4,4,4-tetrafluorobutyl]-lthia-2-azacyclohexen-3- one:

[0282] To a solution of compound 2 (15.0 mg, 39.9 pmol, 1 eq) in DCM (1 mL) was added TFA (0.1 mL) and the mixture was stirred at 25 °C for 0.25 h under N2. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Waters Xbridge BEH C18 (100*30 mm* 10 um); mobile phase: [H2O (10 mM NH4HCO3)-MeCN]; gradient: 1-25% B over 12.0 min) to give the title compound (1.93 mg, 6.82 pmol, 17. 11% yield, 97.59% purity) as a white solid. LCMS: Rt = 0.231 min, (ES+) m / z (M+H)+= 277.0. ' H NMR (400 MHz, MeOD-A) δ = 5.35 - 5. 10 (m, 1H), 4. 11 (td, J = 4.6, 14.6 Hz, 1H), 3.68 (td, J= 6.1, 9.0 Hz, 2H), 3.60 - 3.46 (m, 2H), 2.53 - 2.32 (m, 3H), 2.21 - 2.07 (m, 1H).Example 31: (R)-4-((lR, 4S)-4-amino-l-oxido-3-oxo-3, 4, 5, 6-tetrahydro-l, 2-thiazin-l- yl)-l, 1, 1-trifluorobutan -2-yl 2- (2-ethoxyethoxy) acetate (Compound 132)Step 1: (R)-4-((lR, 4S)-4-((tert- butoxycarbonyl) amino)-l-oxido-3-oxo-3, 4, 5, 6- tetrahydro-1, 2-thiazin-l-yl)-l, 1, l-trifluorobutan-2-yl 2-(2-ethoxyethoxy) acetate:

[0283] A mixture of compound 1 (150 mg, 400 pmol, 1 eq), compound 1A (62.3 mg, 420 pmol, 1.05 eq), EDCI (115 mg, 601 pmol, 1.5 eq) and DMAP (49.1 mg, 400 pmol, 1 eq) in DCM (2 mL) was degassed and purged 3 times with N2 and then the mixture was stirred at 20 °C for 1 h under N2 atmosphere. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by prep-TLC (Petroleum ether / EtOAc = 2: 1, Ri= 0.6) to afford the title compound (150 mg, 297.31 pmol, 74.20% yield) as a colorless oil.1H NMR (400 MHz, CDCI3) δ = 5.80 (br s, 1H), 5.58 - 5.43 (m, 1H), 4.31 (d, J= 2.6 Hz, 2H), 4.27 - 4.18 (m, 1H), 3.84 - 3.71 (m, 3H), 3.68 - 3.61 (m, 2H), 3.55 (q, J= 7.0 Hz, 3H), 3.36 (t, J= 7.9 Hz, 2H), 3.00 - 2.87 (m, 1H), 2.60 - 2.40 (m, 2H), 2.11 - 1.95 (m, 1H), 1.46 (s, 9H), 1.23 (t, J= 7.1 Hz, 3H).Step 2: (R)-4-((lR, 4S) -4-amino-l-oxido-3-oxo-3, 4, 5, 6 -tetrahydro- 1 , 2-thiazin-l-yl) -1, 1, 1- trifluorobutan -2-yl 2 - (2-ethoxyethoxy) acetate:

[0284] To a solution of compound 2 (150 mg, 297 pmol, 1 eq) in DCM (1 mL) was added TFA (460 mg, 4.04 mmol, 13.6 eq) and the mixture was stirred at 20 °C for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Xselect CSH C18 (100*30 mm*5 um); mobile phase: [H2O (0.2% FA) - ((1: 1) MeCN / THF)]; gradient: 1-35% B over 12.0 min) to afford the title compound (82 mg, 158.17 pmol, 53.20% yield, 100% purity, TFA) as a white solid. LCMS: Rt = 2.218 min, (ES+) m / z (M+H)+= 405.1.1H NMR (400 MHz, D2O) δ = 5.71 (ddd, J= 4.3, 6.3, 8.1 Hz, 1H), 4.38 (s, 2H), 4.28 (td, J= 4.1, 15.2 Hz, 1H), 4.15 (dd, J= 4.6, 12.3 Hz, 1H), 3.79 - 3.71 (m, 5H), 3.68 - 3.64 (m, 2H), 3.58 (q, J= 7.1 Hz, 2H), 2.74 - 2.62 (m, 1H), 2.58 - 2.34 (m, 3H), 1.17 (t, J= 7.1 Hz, 3H).Example 32: (4S)-4-amino-l-(4,4,4-trifluoro-3-hydroxy-3-(isoquinolin-3-yl)butyl)-5,6- dihydro-116,2-thiazin-3(4H)-one 1-oxide (Compound 133)Step 1: 2,2,2-trifluoro-l-(isoquinolin-3-yl)ethan-l-one:

[0285] To a solution of compound 1 (4 g, 21.4 mmol, 1 eq) in THF (40 mL) was added TMSCF3 (15.2 g, 107 mmol, 5 eq) and TBAF (1 M, 2.14 mL, 0.1 eq) at -15 °C and the mixture was stirred at -15 °C for 0.5 h before TBAF (1 M, 21.4 mL, 1 eq) was added. The resulting mixture was stirred at -15 °C for 2 h. The reaction mixture was diluted with H2O(50 mL) and extracted with EtOAc (50 mL X 3). The combined organic phase was washed with brine (30 mL), dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO2, Petroleum ether / EtOAc = 3: 1) to afford the title compound (1.5 g, 6.66 mmol, 31.2% yield) as a yellow oil.1H NMR (400 MHz, MeOD-d4) δ 9.34 - 9.24 (m, 1H), 8.25 - 8.20 (m, 1H), 8.17 (d, J = 8.2 Hz, 1H), 8.04 (d, J= 7.9 Hz, 1H), 7.88 - 7.72 (m, 2H).Step 2: 1 ,1 , l-trifluoro-2-(isoquinolin-3-yl)but-3-en-2-ol:

[0286] To a solution of compound 2 (500 mg, 2.22 mmol, 1 eq) in THF (10 mL) was added vinyl magnesium bromide (1 M, 6.66 mL, 3 eq) at -65 °C and the mixture was stirred at -65 °C for 1 h. The reaction mixture was quenched with saturated aqueous NH4C1 (50 mL) and extracted with EtOAc (50 mL X 3). The combined organic phase was washed with brine (10 mL), dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO2, Petroleum ether / EtOAc = 5 : 1) to afford the title compound (300 mg, 1.18 mmol, 53.35% yield) as a white solid.1H NMR (400 MHz, MeOD-J4) δ 9.33 - 9.13 (m, 1H), 8.21 - 8.09 (m, 2H), 7.99 (br d, J= 8.2 Hz, 1H), 7.81 (t, J= 7.2 Hz, 1H), 7.76 - 7.66 (m, 1H), 6.70 (dd, J= 10.8, 17.1 Hz, 1H), 5.73 (d, J= 17.1 Hz, 1H), 5.48 (d, J= 10.9 Hz, 1H).Step 3: methyl N-(tert-butoxycarbonyl)-S-(4,4,4-trifluoro-3-hydroxy-3-(isoquinolin-3- yl)butyl)-L-homocysteinate:

[0287] A mixture of compound 3 (290 mg, 1.15 mmol, 1 eq), compound 3 A (428 mg, 1.72 mmol, 1.5 eq) and AIBN (56.4 mg, 344 pmol, 0.3 eq) in MeOH (1 mL) and H2O (0.1 mL) was degassed and purged three times with N2, and then the mixture was stirred at 80 °C for 16 h under N2 atmosphere. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (20 mL X 3). The combined organic phase was washed with brine (10 mL), dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO2, Petroleum ether / EtOAc = 5: 1) to afford the title compound (560 mg, 1.11 mmol, 97.3% yield) as a white solid.1H NMR (400 MHz, MeOD-J4) δ 9.28 (s, 1H), 8.18 (d, J= 2.4 Hz, 1H), 8.15 - 8.11 (m, 1H), 8.02 - 7.97 (m, 1H), 7.85 - 7.79 (m, 1H), 7.78 - 7.69 (m, 1H), 4.27 - 4.18 (m, 1H), 3.66 - 3.60 (m, 3H), 2.92 - 2.78 (m, 1H), 2.62 - 2.44 (m, 3H), 2.34 (br d, J= 12.2 Hz, 1H), 2.09 - 2.03 (m, 1H), 1.96 - 1.73 (m, 2H), 1.41 (s, 9H)Step 4: methyl (2S)-2-((tert-butoxycarbonyl)amino)-4-(4,4,4-trifluoro-3-hydroxy-3- (isoquinolin-3-yl)butylsulfonimidoyl)butanoate:

[0288] A mixture of compound 4 (560 mg, 1.11 mmol, 1 eq), ammonium carbamate (696 mg, 8.91 mmol, 8 eq) and PIDA (1.44 g, 4.46 mmol, 4 eq) in i-PrOH (7 mL) was degassed and purged three times with N2, and then the mixture was stirred at 15 °C for 3 h under N2 atmosphere. The reaction mixture was concentrated under reduced pressure and the residue was diluted with H2O (10 mL) and extracted with DCM (10 mL X 3). The combined organic phase was washed with brine (5 mL), dried with anhydrous Na2SO4, fdtered, and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO2, Petroleum ether / EtOAc = 2: 1) to afford the title compound (400 mg, 750 pmol, 67.3% yield) as a colorless oil. ' H NMR (400 MHz, MeOD-d4) δ 9.30 (s, 1H), 8.22 (s, 1H), 8.14 (d, J= 8.1 Hz, 1H), 8.01 (d, J = 8.2 Hz, 1H), 7.83 (t, J= 7.6 Hz, 1H), 7.77 - 7.70 (m, 1H), 4.29 - 4.19 (m, 1H), 3.71 (d, = 1.8 Hz, 3H), 3.17 (br s, 4H), 2.79 - 2.55 (m, 2H), 2.29 - 2.16 (m, 1H), 2.07 - 2.01 (m, 1H), 1.42 (s, 9H)Step 5: (2S)-2-((tert-butoxycarbonyl)amino)-4-(4,4,4-trifluoro-3-hydroxy-3-(isoquinolin-3- yl)butylsulfonimidoyl)butanoic acid:

[0289] A solution of compound 5 (300 mg, 562 pmol, 1 eq) and LiOH.H2O (28.3 mg, 675 pmol, 1.2 eq) in THF (1 mL), MeOH (1 mL), H2O (1 mL) was stirred at 15 °C for 4 h. The organic solvent was removed under vacuum and the aqueous mixture was cooled to 0 °C and adjusted to pH = 5 by careful addition of 1 N HC1. The mixture was extracted with EtOAc (10 mL X 7) and the combined organic layer was dried over Na2SO4, fdtered, and concentrated to afford the title compound (290 mg, 558 pmol, 99.3% yield) as a colorless oil.1H NMR (400 MHz, MeOD-J4) δ 9.31 (s, 1H), 8.22 (d, J= 2.5 Hz, 1H), 8.14 (d, J= 8.3 Hz, 1H), 8.01 (d, J= 8.3 Hz, 1H), 7.89 - 7.79 (m, 1H), 7.75 (d, J= 7.4 Hz, 1H), 4.25 - 4.14 (m, 1H), 3.24 - 3.04 (m, 4H), 2.79 - 2.54 (m, 2H), 2.23 (br dd, J= 4.6, 8.6 Hz, 1H), 2.09 - 2.01 (m, 1H), 1.43 (d, J= 1.9 Hz, 9H).Step 6: tert-butyl N-[(4S)-l,3-dioxo-l-[4,4,4-trifluoro-3-hydroxy-3-(3-isoquinolyl)butyl]- 1 thia-2-azacyclohexen-4-yl ] carbamate :

[0290] A solution of compound 6 (290 mg, 559 pmol, 1 eq) in DCM (3 mL) was added TEA (282 mg, 2.79 mmol, 388 μL, 5 eq) and T4P (804 mg, 1. 12 mmol, 50% purity, 2 eq) at 0 °C. The mixture was stirred at 15 °C for 1 h. The residue was diluted with H2O (10 mL) and extracted with DCM (10 mL X 3). The combined organic phase was washed with brine(5 mL), dried with anhydrous Na2SO4. filtered, and concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2, Petroleum ether / EtOAc = 1: 1) to afford the title compound (180 mg, 359 pmol, 64.3% yield) as a colorless oil.1H NMR (400 MHz, MeOD-d4) δ 9.31 (s, 1H), 8.27 - 8.21 (m, 1H), 8.15 (d, J= 8.2 Hz, 1H), 8.01 (d, J= 8.2 Hz, 1H), 7.87 - 7.80 (m, 1H), 7.76 (d, J= 7.2 Hz, 1H), 4.07 - 3.98 (m, 1H), 3.91 - 3.71 (m, 1H), 3.68 - 3.40 (m, 2H), 3.22 - 2.99 (m, 2H), 2.80 - 2.61 (m, 1H), 2.43 (tt, J= 4.9, 9.4 Hz, 1H), 1.44 - 1.40 (m, 9H)Step 7: ( 4S)-4-amino-l -oxo-1 -[4, 4, 4-trifluoro-3-hydroxy-3-(3-isoquinolyl)butyl ]-l thia-2- azacyclohexen- 3-one :

[0291] A solution of compound 7 (180 mg, 359 pmol, 1 eq) in DCM (2.5 mL) and TFA (0.5 mL) was stirred at 15 °C for 1 h under N2 atmosphere and then the mixture was concentrated. The residue was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18, (150*40 mm, 10 pm); mobile phase: [H2O (lOmM NH4HCO3)-MeCN]; gradient: 10- 60% B over 8.0 min) to afford the title compound (80 mg, 199 pmol, 55.5% yield) as a white solid. LCMS: Rt = 2.364 min., (ES+) m / z (M+H)+= 402.1. ‘HNMR (400 MHz, MeOD-d4) δ 9.31 (s, 1H), 8.24 - 8.21 (m, 1H), 8.14 (d, J= 8.1 Hz, 1H), 8.01 (d, J= 8.2 Hz, 1H), 7.83 (s, 1H), 7.76 (d, J= 7.3 Hz, 1H), 4.07 - 4.00 (m, 0.5H), 3.77 - 3.59 (m, 1H), 3.53 - 3.41 (m, 2H), 3.37 (br d, J= 6.7 Hz, 0.5H), 3.21 - 2.98 (m, 2H), 2.50 - 2.47 (m, 1H), 2.50 - 1.92 (m, 2H).Example 33: (4S)-4-amino-l-(3-(benzo[d]isothiazol-3-yl)-4,4,4-trifluoro-3- hydroxybutyl)-5,6-dihydro-116,2-thiazin-3(4H)-one 1-oxide (Compound 134)Step 1 : N-methoxy-N-methylbenzo[d]isothiazole-3-carboxamide:

[0292] To a solution of compound 1 (25 g, 140 mmol, 1 eq) in DCM (125 mL) was added TEA (56.5 g, 558 mmol, 77.7 mL, 4 eq) at 0 °C under N2 and the mixture was stirred for 30 min at 0 °C before adding compound 1A (21.8 g, 223 mmol, 1.6 eq). After stirring another 30 min at 0 °C, TiP (111 g, 153 mmol, 50% purity, 1.1 eq) was then added dropwise and the mixture was stirred for 1 h at 0 °C. The reaction mixture was diluted with water (200 mL) and the resulting mixture was extracted with dichloromethane (150 mLx3). The combined organic phases were washed with brine (200 mL), dried with anhydrous Na2SOr, fdtered, and concentrated under vacuum to afford a yellow residue. The residue was purified by column chromatography (SiO2, Petroleum ether / EtOAc = 98:2 to 9: 1) to afford the title compound (28 g, 126 mmol, 90.30% yield) as a yellow oil.1H NMR (400 MHz, CDCI3-d) δ 8.00 (br s, 1H), 7.96 (d, J= 8.0 Hz, 1H), 7.59 - 7.55 (m, 2H), 7.51 - 7.48 (m, 2H), 3.96 (s, 1H), 3.58 (s, 1H).Step 2: l-(benzo[d]isothiazol-3-yl)-2,2,2-trifluoroethan-l-one:

[0293] To a solution of compound 2 (5 g, 22.5 mmol, 1 eq) in THF (50 mL) was added TMSCF3 (16 g, 113 mmol, 5 eq) and TBAF (I M, 2.25 mL, 0. 1 eq) at 0 °C under N2 and the mixture was stirred at 0 °C for 1 h before adding TBAF (1 M, 22.5 mL, 1 eq) at 0 °C. The mixture was stirred at 0 °C for 1 h under N2 atmosphere. The reaction mixture was diluted with H2O (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic solvent was dried over Na2SOr, fdtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / EtOAc = 1:0 to 25: 1) to afford the title compound (4.1 g, 16.9 mmol, 74.9% yield, 95% purity) as a colorless oil.1H NMR (400 MHz, CDCI3-d) δ 8.84 - 8.65 (m, 1H), 8.06 - 7.95 (m, 1H), 7.67 - 7.51 (m, 2H).Step 3: 2-(benzo[d]isothiazol-3-yl)-l, l,l-trifluorobut-3-en-2-ol:

[0294] To a solution of compound 3 A (1 M, 14.7 mL, 2 eq) in THF (8 mL) at -70 °C was added a solution of compound 3 (1.7 g, 7.35 mmol, 1 eq) in THF (19 mL) dropwise at - 70 °C over a period of 30 min under N2. The mixture was stirred at -70 °C for 1 h under N2 atmosphere. The reaction mixture was diluted with H2O (40 mL) and extracted with EtOAc (60 mL x 3). The combined organic layer was dried over Na2SO4. filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / EtOAc = 1:0 to 25: 1) to give compound 4 (1.2 g, 4.40 mmol, 59.80% yield, 95% purity) as a colorless oil.1H NMR (400 MHz, CDCI3-d) 5 8.25 (dd, J= 0.8, 8.4 Hz, 1H), 7.97 (d, J= 8.2 Hz, 1H), 7.58 (dt, J= 1.0, 7.6 Hz, 1H), 7.52 - 7.45 (m, 1H), 6.66 (dd, J= 10.8, 17.0 Hz, 1H), 5.84 (d, J= 17.0 Hz, 1H), 5.60 (d, J= 10.8 Hz, 1H), 5.24 (s, 1H).Step 4: tert-butyl S-(3-(benzo[d]isothiazol-3-yl)-4,4,4-trifluoro-3-hydroxybutyl)-N-(tert- butoxycarbonyl)-L-homocysteinate:

[0295] A solution of compound 4 (2 g, 7.71 mmol, 1 eq), compound 4A (3.37 g, 11.6 mmol, 1.5 eq) and AIBN (633 mg, 3.86 mmol, 0.5 eq) in H2O (0.1 mL) and MeOH (0.3 mL) was degassed and purged three times with Ar, and then the mixture was stirred at 80 °C for 12 h under Ar atmosphere. The reaction mixture was diluted with H2O (150 mL) and extracted with EtOAc (60 mL x 4). The combined organic solvent was dried over Na2SO4. fdtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / EtOAc = 1:0 to 18: 1) to afford the titlecompound (4.1 g, 7.07 mmol, 91.7% yield, 95% purity) as a yellow oil.1H NMR (400 MHz, CDCW) δ 8.31 (br d, J= 7.3 Hz, 1H), 7.98 (d, J= 8.1 Hz, 1H), 7.62 - 7.56 (m, 1H), 7.55 - 7.47 (m, 1H), 5.43 - 5.35 (m, 1H), 5.09 (br d, J= 8.7 Hz, 1H), 4.22 (br s, 1H), 2.94 - 2.78 (m, 1H), 2.68 - 2.42 (m, 4H), 2.19 (br dd, J= 5.9, 10.8 Hz, 1H), 2.01 - 1.92 (m, 1H), 1.86 - 1.75 (m, 1H), 1.46 - 1.43 (m, 18H).Step 5: tert-butyl (2S)-4-(3-(benzo[d]isothiazol-3-yl)-4,4,4-trifluoro-3- hydroxybutylsulfonimidoyl)-2-((tert-butoxycarbonyl)amino)butarioate:

[0296] A solution of compound 5 (4.1 g, 7.45 mmol, 1 eq), PIDA (6 g, 18.6 mmol, 2.5 eq) and ammonium carbamate (2.91 g, 37.2 mmol, 5 eq) in i-PrOH (41 mL) was degassed and purged three times with N2, and then the mixture was stirred at 25 °C for 3 h under N2 atmosphere. The reaction mixture was diluted with H2O (150 mL) and extracted with EtOAc (60 mL x 4). the combined organic solvent was dried over Na2SO4. filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / EtOAc = 1:0 to 3: 1) to afford the title compound (3.4 g, 5.67 mmol, 76.2% yield, 97% purity) as a white solid.1H NMR (400 MHz, CDCI3-d) 5 8.68 - 8.53 (m, 1H), 8.01 - 7.86 (m, 1H), 7.61 - 7.42 (m, 2H), 5.31 - 5.10 (m, 1H), 4.36 - 4.18 (m, 1H), 3.48 - 3.30 (m, 1H), 3.22 (td, J= 6.1, 15.1 Hz, 2H), 3.15 - 3.06 (m, 1H), 2.97 - 2.70 (m, 1H), 2.44 - 2.24 (m, 1H), 2.15 - 2.07 (m, 1H), 1.51 - 1.40 (m, 18H).Step 6: (2S)-2-amino-4-( 3-(benzo[d]isothiazol-3-yl)-4, 4, 4-trifluoro-3- hydroxybutylsulfonimidoyl)butanoic acid:

[0297] A solution of compound 6 (3.4 g, 5.85 mmol, 1 eq) in HCl / dioxane (34 mL, 4M) was degassed and purged three times with N2, and then the mixture was stirred at 25 °C for 8 h under N2 atmosphere. The mixture was concentrated under reduced pressure to afford the title compound (2.7 g, 5.55 mmol, 95.00% yield, HC1 salt) as a white solid.1H NMR (400 MHz, MeOD-A) δ 8.68 - 8.60 (m, 1H), 8.09 (d, J= 8.2 Hz, 1H), 7.64 - 7.58 (m, 1H), 7.50 (s, 1H), 4.31 - 4.08 (m, 3H), 4.04 - 3.78 (m, 2H), 3.51 - 3.39 (m, 1H), 2.83 - 2.72 (m, 1H), 2.65 - 2.45 (m, 2H).Step 7: (2S)-4-(3-(benzo[d]isothiazol-3-yl)-4, 4, 4-trifluoro-3-hydroxybutylsulfonimidoyl)-2- ( ( tert-butoxycarbonyl)amino)butanoic acid:

[0298] To a solution of compound 7 (2.7 g, 5.85 mmol, 1 eq, HC1) and Na2CO3(1.86 g, 17.5 mmol, 3 eq) in dioxane (5 mL) and H2O (25 mL) was added (Boc)2O (1.91 g, 8.77 mmol, 2.01 mL, 1.5 eq). The mixture was stirred at 25 °C for 3 h and the mixture wasadjusted to pH = 5 with citric acid. The reaction mixture was diluted with H2O (150 mL) and extracted with EtOAc (60 mL x 4). The combined organic solvent was dried over Na2SO4, filtered, and concentrated under reduced pressure to afford the title compound (3.4 g, 5.67 mmol, 76.2% yield, 97% purity) as a white solid.Step 8: tert-butyl ((4S)-l-(3-(benzo[d]isothiazol-3-yl)-4,4,4-trifluoro-3-hydroxybutyl)-l- oxido-3-oxo-3, 4, 5, 6-tetrahydro-ll6, 2-thiazin-4-yl) carbamate:

[0299] To a solution of compound 8 (3 g, 5.71 mmol, 1 eq) in DCM (31 mL) was added T4P (8.23 g, 11.4 mmol, 50% purity, 2 eq) and TEA (2.31 g, 22.8 mmol, 3.18 mL, 4 eq) at 0 °C. The mixture was stirred at 25 °C for 1 h under N2 atmosphere. The reaction mixture was diluted with H2O (150 mL) and extracted with EtOAc (60 mL x 3). The combined organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / EtOAc = 1:0 to 1:2) to afford the title compound (2.2 g, 4.33 mmol, 75.9% yield) as a white solid.1H NMR (400 MHz, MeOD-tri) δ 8.65 (br d, J= 8.3 Hz, 1H), 8.06 (d, J= 7.9 Hz, 1H), 7.58 (t, J= 7.6 Hz, 1H), 7.48 (d, J= 8.2 Hz, 1H), 4.21 - 4.11 (m, 1H), 3.98 - 3.78 (m, 1H), 3.76 - 3.41 (m, 3H), 2.79 - 2.60 (m, 1H), 2.35 - 2.20 (m, 1H), 2.52 - 2.20 (m, 1H), 1.47 - 1.39 (m, 9H).Step 9: (4S)-4-amino-l-(3-(benzo[d]isothiazol-3-yl)-4, 4, 4-trifluoro-3-hydroxybutyl)-5, 6- dihydro-116, 2-thiazin-3 ( 4H)-one 1 -oxide:A solution of compound 9 (2.2 g, 4.33 mmol, 1 eq) in DCM (20 mL) and TLA (4 mL) was stirred at 25 °C for 1 h under N2 atmosphere. The mixture was then slowly added to saturated aqueous sodium carbonate solution, maintaining pH ~ 10, then stirred for 30 min. The mixture was extracted with DCM and the organic phase was concentrated. The resultant residue was purified by prep-HPLC (column: WePure Biotech XP tC18 250*70* 10 pm; mobile phase: [H2O (10 mM NH4HCO3-MeCN]; gradient: 15-50% B over 20.0 min) to afford the title compound (1.4 g, 3.40 mmol, 78.5% yield, 99% purity) as a white solid.LCMS: Rt = 2.415 min, (ES+) m / z (M+H)+= 408.0. 'HNMR (400 MHz, MeOD-tri) δ 8.65 (br d, J= 8.3 Hz, 1H), 8.07 (d, J= 8.2 Hz, 1H), 7.58 (t, J= 7.5 Hz, 1H), 7.53 - 7.38 (m, 1H), 4.20 - 4.02 (m, 0.5H), 3.73 (br dd, J= 4.4, 6.2 Hz, 1H), 3.58 - 3.38 (m, 4H), 3.36 (br d, J = 4.8 Hz, 0.5H), 2.78 - 2.58 (m, 1H), 2.52 - 1.94 (m, 2H).Example 34: (lR,4S)-4-amino-l-((R)-3-(benzo[d]isothiazol-3-yl)-4,4,4-trifluoro-3- hydroxybutyl)-5,6-dihydro-116,2-thiazin-3(4H)-one 1-oxide (isomer Pl), (lS,4S)-4-amino-l-((R)-3-(benzo[d]isothiazol-3-yl)-4,4,4-trifluoro-3-hydroxybutyl)-5,6-dihydro- 116,2-thiazin-3(4H)-one 1-oxide (isomer P2), (lR,4S)-4-amino-l-((S)-3- (benzo[d]isothiazol-3-yl)-4,4,4-trifluoro-3-hydroxybutyl)-5,6-dihydro-116,2-thiazin- 3(4H)-one 1-oxide (isomer P3) and (lS,4S)-4-amino-l-((S)-3-(benzo[d]isothiazol-3-yl)- 4,4,4-trifluoro-3-hydroxybutyl)-5,6-dihydro-116,2-thiazin-3(4H)-one 1-oxide (isomer P4) (Compound 135, 136, 137, & 138)Step 1: SFC Separation of (4S)-4-amino-l-(3-(benzo[d]isothiazol-3-yl)-4,4,4-trifluoro-3- hydroxybutyl)-5, 6-dihydro-ll6,2-thiazin-3(4H)-one 1-oxide:

[0300] (4S)-4-amino-l-(3-(benzo[d]isothiazol-3-yl)-4,4,4-trifluoro-3-hydroxybutyl)-5,6- dihydro- 116, 2-thiazin-3(4H)-one 1-oxide (200 mg) was separated by prep-SFC (column: DAICEL CHIRALPAK IG (250 mm*30mm,10um); mobile phase: [CCh-MeOH (0.1% NH3H2O)]; gradient: 20-45% B over 17.0 min) and (column: DAICEL CHIRALPAK AD (250 mm*30 mm, 10 um); mobile phase: [CCh-EtOH (0.1% NH3H2O)]; gradient: 30% B, isocratic elution mode). The stereochemistry of each of the separated compounds was tentatively assigned notated by their peak elution order. Isomer Pl (30 mg, SFC purity: 81%), isomer P2 (20 mg, SFC purity: 79%), isomer P3 (33 mg, SFC purity: 91%) and isomer P4 (39 mg, SFC purity: 90%) were obtained as white solids.Step 2: (1R, 4S)-4-amino-l-((R)-3-(benzo[d]isothiazol-3-yl)-4, 4, 4-trifluoro-3-hydroxybutyl)- 5 f -dihydro-116, 2-thiazin-3(4H)-one 1-oxide (Isomer Pl):

[0301] Isomer Pl (30 mg, SFC purity: 81%) was repurified by prep-SFC (column: DAICEL CHIRALPAK AD (250 mm*30 mm, 10 um); mobile phase: [CCh-EtOH (0.1% NH3H2O)]; gradient: 30% B, isocratic elution mode) to give the title compound (12.18 mg, SFC purity: 99.55%) as a white solid. LCMS: Rt = 2.417 min., (ES+) m / z (M+H)+= 408.1.1H NMR (400 MHz, MeOD-d4) δ 8.65 (d, J= 8.5 Hz, 1H), 8.07 (d, J= 8.2 Hz, 1H), 7.63 - 7.55 (m, 1H), 7.52 - 7.42 (m, 1H), 4.09 (td, J= 4.8, 14.6 Hz, 1H), 3.59 - 3.47 (m, 3H), 3.46 - 3.33 (m, 2H), 2.66 (ddd, J= 4.2, 12.1, 13.3 Hz, 1H), 2.44 (qd,J= 4.8, 14.3 Hz, 1H), 2.15- 2.06 (m, 1H).Step 3: (IS, 4S)-4-amino-l-((R)-3-(benzo[d]isothiazol-3-yl)-4, 4, 4-trifluoro-3-hydroxybutyl)- 5,6-dihydro-ll6,2-thiazin-3(4H)-one 1-oxide (Isomer P2):Isomer P2 (20 mg, SFC purity: 79%) was repurified by prep-SFC (column: DAICEL CHIRALPAK AD (250 mm*30 mm, 10 um); mobile phase: [CCh-EtOH (0.1% NH3H2O)]; gradient: 30% B, isocratic elution mode) to give the title compound (7 mg, SFC purity: 96.29%) as a white solid. LCMS: Rt = 2.438 min., (ES+) m / z (M+H)+= 408.1. ‘HNMR (400 MHz, MeOD-d4) δ 8.69 - 8.63 (m, 1H), 8.07 (d, J= 8.2 Hz, 1H), 7.62 - 7.55 (m, 1H), 7.53 - 7.42 (m, 1H), 4.14 (td, J= 4.5, 14.6 Hz, 1H), 3.57 - 3.41 (m, 4H), 3.34 (br s, 1H), 2.72 (ddd, J= 5.9, 10.5, 13.4 Hz, 1H), 2.48 - 2.36 (m, 1H), 2.11 - 1.96 (m, 1H).Step 4: (lR,4S)-4-amino-l-((S)-3-(benzo[d]isothiazol-3-yl)-4,4,4-trifluoro-3-hydroxybutyl)- 5,6-dihydro-ll6,2-thiazin-3(4H)-one 1-oxide (isomer P3) and (lS,4S)-4-amino-l-((S)-3- (benzo[d]isothiazol-3-yl)-4, 4, 4-trifluoro-3-hydroxybutyl)-5, 6-dihydro-ll6, 2-thiazin-3(4H)- one 1-oxide (isomer P4):

[0302] (4S)-4-amino-l-(3-(benzo[d]isothiazol-3-yl)-4,4,4-trifluoro-3-hydroxybutyl)-5,6- dihydro-116, 2-thiazin-3(4H)-one 1-oxide (200 mg) was purified by prep-SFC (column: DAICEL CHIRALPAK IG (250*30 mm, 10 um); mobile phase: [CCh-MeOH (0.1% NH3H2O)]; gradient: 20-45% B over 18.0 min). The stereochemistry of each of the separated compounds was tentatively assigned and notated by their peak elution order. Isomer P3 (29 mg, SFC purity: 91.04%) was obtained as a white solid. LCMS: Rt = 2.428 min., (ES+) m / z (M+H)+= 408.1.1H NMR (400 MHz, MeOD-Ai) δ 8.65 (d, J= 8.3 Hz, 1H), 8.07 (d, J= 8.2 Hz, 1H), 7.58 (t, J= 7.6 Hz, 1H), 7.51 - 7.44 (m, 1H), 3.76 - 3.70 (m, 1H), 3.57 - 3.38 (m, 3H), 3.37 - 3.32 (m, 1H), 3.27 (br d, J= 5.4 Hz, 1H), 2.79 - 2.60 (m, 1H), 2.54 - 2.27 (m, 2H). Isomer P4 (42 mg, SFC purity: 94.13%) was obtained as a white solid. LCMS: Rt = 2.427 min., (ES+) m / z (M+H)+= 408.1.1H NMR (400 MHz, MeOD-d4) δ 8.65 (d, J= 8.5 Hz, 1H), 8.07 (d, J= 8.2 Hz, 1H), 7.62 - 7.55 (m, 1H), 7.48 (s, 1H), 3.82 (dt, J= 4.1, 13.6 Hz, 1H), 3.66 (td, J= 3.6, 13.5 Hz, 1H), 3.58 - 3.39 (m, 3H), 3.38 - 3.33 (m, 1H), 2.71 - 2.59 (m, 1H), 2.52 - 2.43 (m, 1H), 2.41-2.29 (m, 1H).Example 35: Synthesis of (4S)-4-amino-l-(4,4,4-trifluoro-3-hydroxy-3-(thiazol-2- yl)butyl)-5,6-dihydro-116,2-thiazin-3(4H)-one 1-oxide (Compound 139)Step 1: 2,2,2-trifluoro-l-(thiazol-2-yl)ethan-l-oneTo a solution of thiazole (10 g, 117 mmol, 1 eq) in toluene (100 mL) was added TFAA (29.6 g, 141 mmol, 19.6 mL, 1.2 eq) at -20 °C. The mixture was stirred at -20 °C for 10 min and TEA (14.3 g, 141 mmol, 19.6 mL, 1.2 eq) was added and the resulting mixture was stirred at 15 °C for 12 h. The reaction mixture was purified by distillation under reduced pressure to give the title compound (7 g, 38.6 mmol, 32.9% yield) as a yellow oil.1H NMR (400 MHz, CDCW) δ 8.24 (d, J= 2.8 Hz, 1H), 7.93 (d, J= 2.8 Hz, 1H).Step 2: 1 ,1 ,l-trifluoro-2-(thiazol-2-yl)but-3-en-2-ol:

[0303] To a solution of compound 2 (7 g, 38.6 mmol, 1 eq) in THF (70 mL) was added dropwise vinyl magnesium bromide (I M, 116 mL, 3 eq) at 0-5 °C for 30 min. The resulting mixture was stirred at 15 °C for 1 h. The reaction mixture was poured into aq. NHrCl (100 mL) at 0 °C and extracted with EtOAc (100 mL x 2). The combined organic layers were washed with brine (150 mL), dried over Na2SOr, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / EtOAc = 1:0 to 6:4) to give the title compound (826 mg, 3.95 mmol, 10.22% yield) as a yellow oil.1H NMR (400 MHz, CDCI3-d) δ 7.83 (d, J= 3.2 Hz, 1H),7.51 (d, J = 3.2 Hz, 1H), 6.33 (dd, J= 10.4, 16.8 Hz, 1H), 5.85 (d, J= 16.8 Hz, 1H), 5.57 (d, J= 10.8 Hz, 1H).Step 3: tert-butyl N-(tert-butoxycarbonyl)-S-(4,4,4-trifluoro-3-hydroxy-3-(thiazol-2- yl)butyl)-L-homocysteinate:

[0304] A mixture of compound 3 (725 mg, 3.47 mmol, 2 eq), compound 4 (505 mg, 1.73 mmol, 1 eq) and AIBN (227 mg, 1.39 mmol, 0.8 eq) in MeOH (0.3 mL) and H2O (0.3 mL) was degassed and purged three times with Ar, and then the mixture was stirred at 110 °C for 48 h under Ar atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / EtOAc = 1 : 0 to 6 : 4) to give the title compound (160 mg, 319 pmol, 18.4% yield) as a yellow oil.Step 4: tert-butyl (2S)-2-((tert-butoxycarbonyl)amino)-4-(4,4,4-trifluoro-3-hydroxy-3- (thiazol-2-yl)butylsulfonimidoyl)butanoate:

[0305] A mixture of compound 5 (160 mg, 320 pmol, 1 eq), ammonium carbamate (199 mg, 2.56 mmol, 8 eq) and PhI(OAc)2 (412 mg, 1.28 mmol, 4 eq) in i-PrOH (2 mL) was stirred at 25 °C for 12 h. The reaction mixture was concentrated under reduced pressure. The residue was added water (30 mL) and extracted with EtOAc (30 mL x 2). The combined organic layers were washed with brine (30 mL), dried over Na2SOr, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep- TLC (SiO2, Petroleum ether: EtOAc = 1: 1) to give the title compound (72 mg, 135 pmol, 42.4% yield) as a yellow oil. ' H NMR (400 MHz, CDCI3-d) δ 7.87 - 7.84 (m, 1H), 7.51 - 7.47 (m, 1H), 5.43 - 5.23 (m, 1H), 4.36 - 4.21 (m, 1H), 3.56 - 3.16 (m, 4H), 3.12 - 2.70 (m, 2H), 2.47 - 2.28 (m, 1H), 2.22 - 2.03 (m, 1H), 1.50 (s, 9H), 1.46 (s, 9H).Step 5: (2S)-2-amino-4-(4, 4, 4-trifluoro-3-hydroxy-3-(thiazol-2- yl)butylsulfonimidoyl)butanoic acid:

[0306] Compound 6 (72 mg, 135 pmol, 1 eq) in HCl / dioxane (3 mL, 4 M) was stirred at 25 °C for 12 h. The reaction mixture was concentrated under reduced pressure to give the title compound (55 mg, 135 pmol, 98.6% yield, HC1) as a yellow solid.1H NMR (400 MHz, MeOD-d4) δ 7.90 (d, J= 3.2 Hz, 1H), 7.75 (d, J= 3.2 Hz, 1H), 4.24 - 4.15 (m, 1H), 3.77 - 3.67 (m, 2H), 3.62 - 3.50 (m, 2H), 3.10 - 2.92 (m, 1H), 2.73 - 2.58 (m, 1H), 2.55 - 2.30 (m, 2H).Step 6: (2S)-2-((tert-butoxycarbonyl)amino)-4-(4,4,4-trifluoro-3-hydroxy-3-(thiazol-2- yl)butylsulfonimidoyl)butanoic acid:

[0307] To a solution of compound 7 (55 mg, 134 pmol, 1 eq, HC1) in dioxane (0.1 mL) and H2O (0.5 mL) was added BOC2O (37.9 mg, 174 pmol, 39.9 μL, 1.3 eq) and Na2CO3(42.5 mg, 401 pmol, 3 eq) at 25 °C under N2. The resulting mixture was stirred at 25 °C for 12 h under N2. The reaction mixture was poured into water (2 mL) and extracted with petroleum ether (2 mL x 3). The aqueous phase was adjusted to pH = 3 with IM HC1 and then extracted with EtOAc (2 mL x 5). The combined organic layers were washed with brine (2 mL), dried over Na2SOr. fdtered and concentrated under reduced pressure to give the title compound (63 mg, 132 pmol, 99.2% yield) as a yellow oil.1H NMR (400 MHz, MeOD-d4) δ 7.88 (dd, J= 1.6, 3.2 Hz, 1H), 7.70 (t, J= 2.8 Hz, 1H), 4.21 (br d, J= 3.6 Hz, 1H), 3.21 - 3.14 (m, 3H), 2.95 - 2.82 (m, 2H), 2.67 - 2.54 (m, 1H), 2.31 - 2.22 (m, 1H), 2.13 - 2.02 (m, 1H), 1.45 (s, 9H).Step 7: tert-butyl ((4S)-l-oxido-3-oxo-l-(4,4,4-trifluoro-3-hydroxy-3-(thiazol-2-yl)butyl)- 3,4,5, 6-tetrahydro-ll6,2-thiazin-4-yl)carbamate:

[0308] To a solution of compound 8 (63 mg, 132 pmol, 1 eq) and TEA (80.4 mg, 795 pmol, 111 μL, 6 eq) in DCM (2 mL) was added T4P (286 mg, 397 pmol, 50% purity, 3 eq) at 0 °C under N2. The resulting mixture was stirred at 15 °C for 1 h under N2. The reaction mixture was poured into water (5 mL) and extracted with DCM (5 mL x 2). The combined organic layers were washed with brine (5 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO2, Petroleum ether: EtOAc = 1: 5) to afford the title compound (45 mg, 98.4 pmol, 74.2% yield) as a yellow oil. ‘HNMR (400 MHz, MeOD-d4) δ 7.89 (d, J= 3.2 Hz, 1H), 7.71 (d, J = 3.2 Hz, 1H), 4.17 - 4.07 (m, 1H), 3.75 - 3.44 (m, 3H), 3.20 - 3.11 (m, 1H), 3.07 - 2.92 (m, 1H), 2.69 - 2.54 (m, 1H), 2.53 - 2.22 (m, 2H), 1.45 (d, J= 2.0 Hz, 9H).Step 8: ( 4S)-4-amino-l-(4, 4, 4-trifluoro-3-hydroxy-3-( thiazol-2-yl)butyl)-5, 6-dihydro-ll6, 2- thiazin-3(4H)-one 1 -oxide:

[0309] A mixture of compound 9 (45 mg, 98.4 pmol, 1 eq) in DCM (2.5 mL) and TFA (0.5 mL) was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge 150*25mm* 10 pm; mobile phase: [H2O (0.2% FA)-MeCN]; gradient: 1 %-30% B over 9.0 min) to afford the title compound (22.23 mg, 61.7 pmol, 56% yield, 99.1% purity,FA salt) as a white solid. LCMS: Rt = 1.784 min, (ES+) m / z (M+H)+= 358.0.1H NMR (400 MHz, MeOD-d4) δ 8.40 (br s, 1H), 7.89 (d, J= 3.2 Hz, 1H), 7.73 (d, J= 2.8 Hz, 1H), 4.28 - 3.48 (m, 4H), 3.28 - 3.12 (m, 1H), 3.08 - 2.93 (m, 1H), 2.77 - 2.18 (m, 3H).Example 36: (4S)-4-amino-l-(4,4,4-trifluoro-3-hydroxy-3-(5-(4-(2-hydroxypropan-2- yl)phenoxy)pyridin-2-yl)butyl)-5,6-dihydro-lX6,2-thiazin-3(4H)-one 1-oxide (Compound 140)Step 1: 5-(4-(2-hydroxypropan-2-yl)phenoxy)picolinaldehyde'.

[0310] A mixture of compound 1 (3.10 g, 24.7 mmol, 1 eq), compound 1A (3.77 g, 24.7 mmol, 1 eq) and K2CO3 (6.85 g, 49.5 mmol, 2.0 eq) in DMF (31 mL) was degassed andpurged 3 times with N2, and then the mixture was stirred at 60 °C for 4 h under N2 atmosphere. The reaction mixture was quenched by addition H2O (50 mL) at 0 °C and extracted with EtOAc (25 mL x 3). The combined organic layers were washed with brine (25 mL x 2), dried over Na2SOr, fdtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiC>2, Petroleum ether / EtOAc = 10 / 1 to 2 / 1) to afford the title compound (4.60 g, 16.7 mmol, 67.5% yield, 93.6% purity) as a light yellow oil.1H NMR (400 MHz, CDCI3-d) δ 10.00 (s, 1H), 8.49 (d, J = 2.7 Hz, 1H), 7.93 (d, J= 8.7 Hz, 1H), 7.56 (d, J= 8.7 Hz, 2H), 7.37 - 7.29 (m, 1H), 7.06 (d, J= 8.8 Hz, 2H), 1.62 (s, 6H).Step 2: l-(5-(4-(2-hydroxypropan-2-yl)phenoxy)pyridin-2-yl)prop-2-en-l-ol:

[0311] To a solution of compound 2 (1.15 g, 4.47 mmol, 1 eq) in THE (19.5 mL) was slowly added a solution of vinyl magnesium bromide (1 M, 13.4 mL, 3 eq) at -65 °C under N2. The mixture was stirred at 20 °C for 12 h under N2 atmosphere. The reaction mixture was quenched with water (100 mL) at 0 °C and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL x 2), dried overNa2SO4, filtered and concentrated under reduced pressure. Four reactions were set up in parallel and the combined crude material was purified by column chromatography (SiO2, Petroleum ether / EtOAc = 5 / 1 to 1 / 1) to afford the title compound (3.10 g, 10.5 mmol, 58.8% yield, 96.8% purity) as a white solid.1H NMR (400 MHz, CDCI3-d) δ 8.34 (d, J= 2.5 Hz, 1H), 7.51 (d, J= 8.7 Hz, 2H), 7.38 - 7.32 (m, 1H), 7.29 (s, 1H), 7.01 (d, J= 8.7 Hz, 2H), 6.00 (ddd, J= 6.7, 10.2, 17.0 Hz, 1H), 5.47 (d, J= 17.0 Hz, 1H), 5.32 - 5.15 (m, 2H), 4.37 (br s, 1H), 1.62 (s, 6H).Step 3: 1 -(5-(4-(2-hydroxypropan-2-yl)phenoxy)pyridin-2-yl)prop-2-en-l -one :

[0312] To a solution of compound 3 (1.00 g, 3.50 mmol, 1 eq) in DCM (15 mL) was added MnCh (6.09 g, 70.0 mmol, 20 eq) at 20 °C and the mixture was stirred for 1 h. The reaction mixture was suspended in dichloromethane and filtered. The filtrate was concentrated under vacuum to give the title compound (920 mg, 3.18 mmol, 90.6% yield, 97.8% purity), which was used in the next step without further purification.1H NMR (400 MHz, CDCI3-d) δ 8.43 (d, J= 2.7 Hz, 1H), 8.12 (d, J= 8.8 Hz, 1H), 7.86 (dd, J= 10.5, 17.4 Hz, 1H), 7.60 - 7.51 (m, 2H), 7.33 (dd, J= 2.8, 8.7 Hz, 1H), 7.11 - 7.01 (m, 2H), 6.59 (dd, J = 2.0, 17.4 Hz, 1H), 5.91 (dd, J= 2.0, 10.5 Hz, 1H), 1.62 (s, 6H).Step 4: 1, 1, l-trifluoro-2-(5-(4-(2-hydroxypropan-2-yl)phenoxy)pyridin-2-yl)but-3-en-2-ol:

[0313] To a solution of compound 4 (920 mg, 3.25 mmol, 1 eq) in THF (13.8 mL) was added TMSCF3 (4.62 g, 32.4 mmol, 10 eq) and TBAF (169 mg, 649 pmol, 0.2 eq) at 0 °C. The mixture was stirred at 25 °C for 1 h under N2 and then another portion of TBAF (2.55 g, 9.74 mmol, 3 eq) was added dropwise at 0 °C. The resulting mixture was stirred at 25 °C for 3 h. The reaction mixture was quenched with water (15 mL) at 0 °C and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, fdtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO2, Petroleum ether / EtOAc = 3: 1) to give the title compound (720 mg, 2.03 mmol, 62.4% yield, 99.5% purity) as a yellow oil.1H NMR (400 MHz, CDCW) δ 8.31 (d, J= 2.4 Hz, 1H), 7.58 - 7.51 (m, 2H), 7.50 - 7.45 (m, 1H), 7.43 - 7.36 (m, 1H), 7.08 - 6.97 (m, 2H), 6.37 - 6.23 (m, 2H), 5.82 (d, J= 16.8 Hz, 1H), 5.47 (d, J = 10.6 Hz, 1H), 1.61 (s, 6H).Step 5: tert-butyl N-(tert-butoxycarbonyl)-S-(4,4,4-trifluoro-3-hydroxy-3-(5-(4-(2- hydroxypropan-2-yl)phenoxy)pyridin-2-yl)butyl)-L-homocysteinate:

[0314] To a solution of compound 5 (720 mg, 2.04 mmol, 1 eq) in MeOH / H2O (5: 1, 3.6 mL) was added AIBN (1.00 g, 6.11 mmol, 3.0 eq) and compound 4A (1.78 g, 6.11 mmol, 3 eq) at 60 °C. The mixture was stirred at 60 °C for 8 h, diluted with water (15 mL), and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL x 2), dried over Na2SOr, fdtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / EtOAc = 5: 1 to 2 / 1) to give the title compound (760 mg, 1.06 mmol, 52.0% yield, 90.0% purity) as a yellow oil.1H NMR (400 MHz, CDCI3-d) δ 8.32 (d, J= 2. 1 Hz, 1H), 7.57 - 7.51 (m, 2H), 7.49 - 7.36 (m, 2H), 7.10 - 7.00 (m, 2H), 5.08 (br d, J= 3.5 Hz, 1H), 4.23 (br s, 1H), 2.61 - 2.44 (m, 4H), 2.35 - 2.24 (m, 1H), 2.11 - 2.05 (m, 1H), 2.04 - 1.97 (m, 1H), 1.88 - 1.75 (m, 2H), 1.62 (s, 6H), 1.47 - 1.43 (m, 18H).Step 6: tert-butyl (2S)-2-((tert-butoxycarbonyl)amino)-4-(4,4,4-trifluoro-3-hydroxy-3-(5-(4- (2-hydroxypropan-2-yl)phenoxy)pyridin-2-yl)butylsulfonimidoyl)butanoate:

[0315] To a solution of compound 6 (640 mg, 992 pmol, 1 eq) in i-PrOH (6.4 mL) was added PhI(OAc)2 (959 mg, 2.98 mmol, 3 eq) and ammonium carbamate (387 mg, 4.96 mmol, 5 eq) at 25 °C and the mixture was stirred for 40 min. The reaction mixture was diluted with H2O (15 mL) and extracted with EtOAc (6 mL x 3). The combined organic layers were washed with brine (6 mL x 2), dried over Na2SOr. filtered and concentratedunder reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / EtOAc = 5: 1 to 0: 1) to afford the title compound (270 mg, 332 pmol, 33.4% yield, 83.2% purity) as a yellow oil.1H NMR (400 MHz, CDCh- d) 5 8.33 (d, J= 2.0 Hz, 1H), 7.59 - 7.51 (m, 3H), 7.45 - 7.35 (m, 1H), 7.06 (d, J= 8.7 Hz, 2H), 6.51 - 6.15 (m, 1H), 5.23 (br d, J= 6.2 Hz, 1H), 4.26 (br d, J= 0.7 Hz, 1H), 3.25 - 2.95 (m, 3H), 2.74 - 2.62 (m, 3H), 2.42 - 2.27 (m, 1H), 2.10 - 2.03 (m, 1H), 1.87 - 1.75 (m, 1H), 1.62 (s, 6H), 1.46 (dd, J= 2.0, 13.4 Hz, 18H).Step 7: (2S)-2-amino-4-(4, 4, 4-trifluoro-3-hydroxy-3-(5-(4-(2-hydroxypropan-2- yl)phenoxy)pyridin-2-yl)butylsulfonimidoyl)butanoic acid:

[0316] A mixture of compound 7 (230 mg, 340 pmol, 1 eq) and HCl / dioxane (4 M, 340 μL, 4 eq) in DCM (2.3 mL) was stirred at 25 °C for 1 h under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue. The reaction mixture was diluted with H2O (1 mL) at 20°C and adjusted to pH = 7 by aqueous NaHCO3at 0 °C. The residue was purified by prep-HPLC (column: WePure Biotech XP tC18 (150*40*7 um); mobile phase: [H2O (10 mM NH4HCO3-MeCN]; gradient: 5-35% B over 8.0 min) to afford the title compound (49.05 mg, 89.51 pmol, 26.30% yield, 94.81% purity) as a white solid. LCMS: Rt = 2.232 min, (ES+) m / z (M+H)+= 520.2.1H NMR (400 MHz, MeOD-d4) δ 8.35 (d, J= 2.1 Hz, 1H), 7.75 (d, J= 8.7 Hz, 1H), 7.60 - 7.51 (m, 2H), 7.48 - 7.40 (m, 1H), 7.10 - 7.01 (m, 2H), 3.74 - 3.63 (m, 1H), 3.44 - 3.34 (m, 1H), 3.28 - 3.10 (m, 2H), 3.02 - 2.88 (m, 1H), 2.87 - 2.73 (m, 1H), 2.63 - 2.46 (m, 1H), 2.39 - 2.23 (m, 2H), 1.55 (s, 6H).Step 8: (2S)-2-((tert-butoxycarbonyl)amino)-4-(4,4,4-trifluoro-3-hydroxy-3-(5-(4-(2- hydroxypropan-2-yl)phenoxy)pyridin-2-yl)butylsulfonimidoyl)butanoic acid:

[0317] A mixture of compound 8 (300 mg, 577 pmol, 1 eq), Na2CO3(183 mg, 1.73 mmol, 3.0 eq), and BOC2O (138 mg, 635 pmol, 145 μL, 1.1 eq) in dioxane / H2O (5: 1, 6 mL) was degassed and purged 3 times with N2, and then the mixture was stirred at 25 °C for 12 h under N2 atmosphere. The reaction mixture was adjusted to pH = 4 by addition of aqueous citric acid at 0 °C. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (7 mL x 3). The combined organic layers were washed with brine (7 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (300 mg, 435 pmol, 75.4% yield, 90.0% purity) as a colorless oil.1H NMR (400 MHz, CDC1-J) δ 8.32 (br s, 1H), 7.62 - 7.47 (m, 3H), 7.39 (ddd, J= 2.8, 5.2, 8.3 Hz, 1H), 7.04 (d,J= 8.6 Hz, 2H), 5.99 - 5.32 (m, 1H), 4.43 - 4.24 (m, 1H), 3.34 - 3.08 (m, 3H), 2.86 - 2.58 (m, 3H), 2.41 - 2.09 (m, 2H), 1.60 (s, 6H), 1.42 (s, 9H).Step 9: tert-butyl ((4S)-l-oxido-3-oxo-l-(4,4,4-trifluoro-3-hydroxy-3-(5-(4-(2- hydroxypropan-2-yl)phenoxy)pyridin-2-yl)butyl)-3, 4, 5, 6-ieirahydro-l / :'.2-thiazin-4- yl)carbcimcite:

[0318] To a solution of compound 9 (300 mg, 484 pmol, 1 eq) in DCM (3 mL) was added T4P (697 mg, 968 pmol, 50% purity, 2 eq) and TEA (244 mg, 2.42 mmol, 336 μL, 5 eq) at 0 °C. The mixture was stirred at 20 °C for 2 h, diluted with H2O (10 mL), and extracted with dichloromethane (7 mL x 3). The combined organic layers were washed with brine (7 mL x 2), dried over Na2SOr, fdtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO2, Petroleum ether / EtOAc = 2: 1) to afford the title compound (180 mg, 297 pmol, 61.4% yield, 99.4% purity) as a colorless oil. ' H NMR (400 MHz, CDCI3-d) δ 8.39 - 8.28 (m, 1H), 7.57 (d, J= 8.6 Hz, 2H), 7.52 - 7.37 (m, 2H), 7.11 - 7.02 (m, 2H), 6.41 - 6.14 (m, 1H), 5.89 - 5.59 (m, 1H), 4.21 (ddd, J= 4.2, 8.2, 12.0 Hz, 0.5H), 4.09 - 3.95 (m, 0.5H), 3.89 - 3.53 (m, 1H), 3.52 - 3.29 (m, 2H), 3.05 - 2.84 (m, 2H), 2.80 - 2.54 (m, 2H), 2.46 - 2.29 (m, 0.5H), 2.03 - 1.88 (m, 0.5H), 1.62 (s, 6H), 1.52 - 1.38 (m, 9H).Step 10: (4S)-4-amino-l-(4, 4, 4-trifluoro-3-hydroxy-3-(5-(4-(2-hydroxypropan-2- yl)phenoxy)pyridin-2-yl)butyl)-5, 6-dihydro-l / :: 2-thiazin-3(4H)-one 1 -oxide:

[0319] To a solution of compound 10 (180 mg, 299 pmol, 1 eq) in DCM (1.8 mL) was added HCl / dioxane (4 M, 299 μL, 4 eq) at 25 °C and the mixture was stirred for 1 h. The reaction mixture was concentrated under reduced pressure to give a residue. The reaction mixture was diluted with H2O (2 mL) and adjusted to pH = 7 by addition of aqueous NaHCO3at 0 °C. The mixture was concentrated, and the residue was purified by prep- HPLC (column: WePure Biotech XPt C18 (150*40*7 um); mobile phase: [H2O (10 mMNH4HCO3-MeCN]; gradient: 20-60% B over 8.0 min) to afford the title compound (50.90 mg, 100.92 pmol, 33.73% yield, 99.44% purity) as a white solid. LCMS: Rt = 2.467 min, (ES+) m / z (M-H)+= 500.1.1H NMR (400 MHz, MeOD-d4) δ 8.34 (d, J= 2.6 Hz, 1H), 7.80 - 7.72 (m, 1H), 7.62 - 7.52 (m, 2H), 7.44 (dd, J= 2.8, 8.8 Hz, 1H), 7.06 (d, J= 8.6 Hz, 2H), 4.11 - 3.70 (m, 1H), 3.69 - 3.36 (m, 3H), 3.17 - 2.93 (m, 2H), 2.69 - 2.51 (m, 1H), 2.50 - 2.05 (m, 2H), 1.55 (s, 6H).Example 37: (4S)-4-amino-l-(3-(6-chlorobenzo[d]isoxazol-3-yl)-4,4,4-trifluoro-3- hydroxybutyl)-5,6-dihydro-116,2-thiazin-3(4H)-one 1-oxide (Compound 141)Step 1 : 6-chloro-N-methoxy-N-methylbenzo[d]isoxazole-3-carboxamide:

[0320] To a solution of compound 1 (4.5 g, 22.7 mmol, 1 eq) and compound 1A (4.44 g, 45.5 mmol, 2 eq) in DCM (90 mL) was added TEA (13.8 g, 136 mmol, 19 mL, 6 eq) at 0 °C under N2. T4P (32.8 g, 45.5 mmol, 50% purity, 2 eq) was added dropwise at 0 °C and the mixture was stirred at 25 °C for 1.5 h. The reaction mixture was poured into water (55 mL) and extracted with dichloromethane (50 mL x 2). The combined organic layers were dried over Na2SO4, fdtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / EtOAc = 95:5) to afford the title compound (4.51 g, 18.74 mmol, 82.29% yield) as a colorless oil.1H NMR (400 MHz, CDCI3-d) 3 8.02 - 7.87 (m, 1H), 7.67 (d, J= 1.2 Hz, 1H), 7.39 (dd, J= 1.4, 8.5 Hz, 1H), 3.87 (s, 3H), 3.62 - 3.34 (m, 3H).Step 2: l-(6-chlorobenzo[d]isoxazol-3-yl)prop-2-en-l-one

[0321] Two reactions were set up in parallel. To a solution of compound 2 (1 g, 4. 16 mmol, 1 eq) in THF (15 mL) was added compound 2A (1 M, 12.47 mL, 3 eq) at -65 °C under N2 over 30 min and the mixture was stirred at -65 °C for another 30 min. The reaction mixture was used directly in the next step without work-up.Step 3: tert-butyl N-(tert-butoxycarbonyl)-S-(3-(6-chlorobenzo[d]isoxazol-3-yl)-3- oxopropyl)-L-homocysteinate:

[0322] To a solution of compound 3 (1.73 g, 8.33 mmol, 1 eq) in THF (30 mL) was added dropwise a solution of compound 3A (2.43 g, 8.33 mmol, 1 eq) in THF (3 mL) and TEA (2.53 g, 25 mmol, 3.48 mL, 3 eq) at -65 °C under N2 and the mixture was stirred at -65 °C for 1 h under N2. The reaction was quenched by addition of saturated aqueous NH4Q (20 mL) at 0 °C, and then the mixture was diluted with H2O (10 mL) and extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, fdtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / EtOAc = 92:8) to afford the title compound (3 g, 6.01 mmol, 72. 15% yield) as a colorless oil.1H NMR (400 MHz, CDCI3-d) 8 8.15 (d, J= 8.4 Hz, 1H), 7.69 (d, J= 1.2 Hz, 1H), 7.43 (dd, J= 1.6, 8.4 Hz, 1H), 5.18 - 5.07 (m, 1H), 4.29 (br d, J= 4.8 Hz, 1H), 3.50 (t, J= 7.0 Hz, 2H), 2.99 (t, J = 7.0 Hz, 2H), 2.68 - 2.59 (m, 2H), 2.21 - 2.07 (m, 1H), 1.97 - 1.85 (m, 1H), 1.50 - 1.41 (m, 18H).Step 4: tert-butyl N-(tert-butoxycarbonyl)-S-(3-(6-chlorobenzo[d]isoxazol-3-yl)-4,4,4- trifluoro-3-hydroxybutyl)-L-homocysteinate:

[0323] To a solution of Compound 4 (250 mg, 500 pmol, 1 eq) ) in THF (1 mL) was added TMSCF3 (712 mg, 5.01 mmol, 10 eq) and TBAF (1 M, 50.1 μL, 0.1 eq) at -30 °C under N2 and the mixture was stirred between -30 to 10 °C for 3 h. TBAF (I M, 500 μL, 1 eq) was then added at -30 °C and the mixture was stirred between -30 to 10 °C for Ih. The reaction mixture was poured into water (25 mL) and extracted with EtOAc (10 mL x 2). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, fdtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO2, Petroleum ether / EtOAc = 4: 1) to afford the title compound (40 mg, 70.29 pmol, 14.03% yield) as a colorless oil.1H NMR (400 MHz, CDCI3-d) 8 7.92 (d, J= 8.7 Hz,1H), 7.64 (s, 1H), 7.35 (br d, J= 8.7 Hz, 1H), 5.36 - 4.86 (m, 2H), 4.44 - 4.17 (m, 1H), 2.79 - 2.46 (m, 5H), 2.12 - 1.95 (m, 1H), 1.95 - 1.81 (m, 1H), 1.49 - 1.41 (m, 18H).Step 5: tert-butyl (2S)-2-((tert-butoxycarbonyl)amino)-4-(3-(6-chlorobenzo[d]isoxazol-3-yl)- 4, 4, 4-trifluoro-3-hydroxybutylsulfonimidoyl)butanoate:

[0324] To a solution of Compound 5 (40 mg, 70.2 pmol, 1 eq) in i-PrOH (3 mL) was added PIDA (90.5 mg, 281 pmol, 4 eq) and ammonium carbamate (43.9 mg, 562 pmol, 8 eq). The mixture was stirred at 25 °C for 16 h. The reaction mixture was poured into water (15 mL) and extracted with dichloromethane (10 mL x 2). The combined organic layers were dried over Na2SOr, fdtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO2, Petroleum ether / EtOAc = 1 : 1) to afford the title compound (25 mg, 41.66 pmol, 59.27% yield) as a colorless oil.1H NMR (400 MHz, CHLOROFORM-d) δ = 8.03 (br d, J = 8.4 Hz, 1H), 7.62 (s, 1H), 7.39 - 7.32 (m, 1H), 5.36 - 5.12 (m, 1H), 4.43 - 4.20 (m, 1H), 3.62 - 3.52 (m, 1H), 3.48 - 3.13 (m, 3H), 3.09 - 2.75 (m, 1H), 2.56 - 2.27 (m, 1H), 2.21 - 2.02 (m, 1H), 1.54 - 1.36 (m, 18H).Step 6: (2S)-2-amino-4-(3-(6-chlorobenzo[d]isoxazol-3-yl)-4,4,4-trifluoro-3- hydroxybutylsulfonimidoyl)butanoic acid:

[0325] A solution of compound 6 (25 mg, 41.6 pmol, 1 eq) in HCl / dioxane (5 mL, 4 mL) was stirred at 25 °C for 16 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge BEH C18 (100*30 mm* 10 um); mobile phase: [H2O (10 mM NH4HCO3)-MeCN]; gradient: 5-35% B over 8.0 min) to afford the title compound (11 mg, 24.78 pmol, 59.49% yield, 100% purity) as a white solid. LCMS: Rt = 2.028 min., (ES+) m / z (M+H)+= 444.0.1H NMR (400 MHz, D2O) δ = 7.99 (d, J= 8.6 Hz, 1H), 7.81 (s, 1H), 7.47 (dd, J= 1.6, 8.7 Hz, 1H), 3.88 - 3.80 (m, 1H), 3.51 - 3.22 (m, 5H), 2.94 (dt, J= 4.1, 13.1 Hz, 1H), 2.79 - 2.69 (m, 1H), 2.35 - 2.25 (m, 2H)Step 7: (2S)-2-((tert-butoxycarbonyl)amino)-4-(3-(6-chlorobenzo[d]isoxazol-3-yl)-4, 4, 4- trifluoro-3-hydroxybutylsulfonimidoyl)butanoic acid:

[0326] To a solution of compound 7 (0.2 g, 358 pmol, 1 eq) in H2O (5 mL) and dioxane (1 mL) was added Na2CO3(114 mg, 1.08 mmol, 3 eq) and BOC2O (125 mg, 573 pmol, 131 μL, 1.6 eq) under N2 and the mixture was st...

Claims

CLAIMSWhat is claimed is:

1. A compound represented by Formula I:or a pharmaceutically acceptable salt and / or a stereoisomer thereof, wherein:R1is selected from the group consisting of Ci-Cioalkyl, C2-Cioalkenyl, C2-Cioalkynyl, 5-6 membered monocyclic heteroaryl, and 8-10 membered bicyclic heteroaryl; wherein R1may optionally be substituted with one more substituents each independently selected from R11;R11is independently selected for each occurrence from the group consisting of halogen, deuterium, hydroxyl, -CN, -NO2, -NRaRb, oxo, -C(=O)NRaRb, -NRa(C=O)Rb, - O(C=O)NRaRb, -NRa(C=O)ORb, -NRa(C=O)NRaRb, -(C=O)C1-C6alkyl, -(C=O)OC1-C6alkyl, -0(C=0)Ci-C2oalkyl, -0(C=0)Ci-C2ohaloalkyl, -0(C=0)Ci-C2oheteroalkyl, -O(C=O)OCi- Cealkyl, -SH, -SC1-C6alkyl, -S(O)C1-C6alkyl, -S(O)2Ci-C6alkyl, -S(O)2NRaRb, -NRaS(O)2Ci- Cealkyl, C1-C6alkyl, C1-C6alkoxy, C3-C6cycloalkyl. -Z -phenyl, -Z -naphthyl, -Z-(5-6 membered monocyclic heteroaryl), -Z-(8-10 membered bicyclic heteroaryl), -Z-(4-7 membered heterocyclyl), (phenyl)-Z-(phenyl), (phenyl)-Z-(5-6 membered heteroaryl), (5-6 membered heteroaryl)-Z-(phenyl), and (5-6 membered heteroaryl)-Z-(5-6 membered heteroaryl); wherein each alkyl, cycloalkyl, phenyl, heterocyclyl, and heteroaryl may optionally be substituted with one or more substituents each independently selected from R12; or two geminal R11groups, together with the carbon atom to which they are attached, may be joined together to form a Ca-Cecycloalkyl or a 4-7 membered heterocyclyl optionally substituted with one or more substituents each independently selected from the group consisting of halogen, deuterium, hydroxyl, -NRaRb, -CF3, C1-C6alkyl, and C1-C6alkoxy;Z is selected from the group consisting of a bond, -O-, -C=C-, -CH2O-, -OCH2-, - O(CO)-, -C(O)O-, -NRa, -S-, -S(O), -S(O)2, and -HC=CH-;R12is independently selected for each occurrence from the group consisting of halogen, deuterium, hydroxyl, -CN, -NO2, -NRaRb, oxo, C1-C6alkyl, C1-C6alkoxy, C3- Cecycloalkyl, -C(=O)NRaRb, -NRa(C=O)Rb, -O(C=O)NRaRb, -NRa(C=O)ORb, - NRa(C=O)NRaRb, -(C=O)C1-C6alkyl, -(C=O)OC1-C6alkyl, -O(C=O)OC1-C6alkyl, -SH, -SCi- Cealkyl, -S(O)C1-C6alkyl, -S(O)2C1-C6alkyl, -S(O)2NRaRb, and -NRaS(O)2C1-C6alkyl; wherein each alkyl, alkoxy, and cycloalkyl may optionally be substituted with one or more substituents each independently selected from the group consisting of halogen, hydroxyl, and Ci-Csalkoxy;R2is independently selected for each occurrence from the group consisting of halogen, hydroxyl, -CF3, -OCF3, C1-C6alkyl, and C1-C6alkoxy;R3is selected from the group consisting of hydrogen, C1-C6alkyl, -C(O)C1-C6alkyl, and -C(O)OC1-C6alkyl, -S(O)2C1-C6alkyl, and -P(O)(phenyl)2;Raand Rbare each independently selected for each occurrence from the group consisting of hydrogen and C1-C6alkyl, wherein C1-C6alkyl may optionally be substituted with one or more substituents each independently selected from the group consisting of halogen, deuterium, hydroxyl, and C1-C6alkoxy; orRaand Rb, together with the nitrogen to which they are attached, may be joined together to form a 4-7 membered heterocyclyl optionally substituted by one or more substituents each independently selected from the group consisting of halogen, deuterium, hydroxyl, -NRaRb, C1-C6alkyl, and C1-C6alkoxy; and p is 0, 1, 2, 3, or 4.

2. The compound of claim 1, wherein R3is hydrogen or -C(O)O-tert-butyl.

3. The compound of claim 1 or 2, wherein p is 0, 1, or 2.

4. The compound of any one of claims 1-6, wherein R12is selected from the group consisting of halogen, deuterium, hydroxyl, oxo, -CN, -NRaRb, -O(C=O)Ci-C6alkyl, -(C=O)OCi- Cealkyl, C1-C6alkyl, C1-C6alkoxy, and Q-Cecycloalkyl: wherein each alkyl, alkoxy, and cycloalkyl may optionally be substituted with one or more substituents each independently selected from the group consisting of halogen, hydroxyl, and Ci-Csalkoxy.

5. The compound of any one of claims 1-4, wherein the compound is represented by:

6. The compound of any one of claims 1-5, wherein R1iswherein:R13is selected from the group consisting of hydrogen, halogen, hydroxyl, -OCH3, - OCF3, C2-C6alkoxy, and -O(C=O)C1-C6alkyl;R14is selected from the group consisting of -Z -phenyl, -Z-(5-6 membered monocyclic heteroaryl), -Z-(5-6 membered monocyclic heterocyclyl), -Z-(8-10 membered bicyclic heteroaryl), (phenyl)-Z-(phenyl), (5-6 membered heteroaryl)-Z-(phenyl), (5-6 membered heteroaryl)-Z-(phenyl) and -O(C=O)Ci-C6alkyl; wherein each phenyl and heteroaryl may optionally be substituted with one or more substituents each independently selected from the group consisting of halogen, hydroxyl, -C1-C6alkyl, C1-C6alkoxy, and -0(C=0)CH3; wherein -C1-C6alkyl, and C1-C6alkoxy may optionally be substituted with one or more halogens or hydroxyl; and wherein any aforementioned -O(C=O)Ci-C6alkyl may optionally be substituted with one or more halogens.

7. The compound of any one of claims 1-6, wherein the compound is not (4.S)-4-amino- l - (3.3-dimcthylbutyl)-5.6-dihydro- IZ6.2-thiazin-3(4 / / )-onc 1-oxide, (4.S)-4-amino- l-(4.4.4- trifluorobutyl)-5,6-dihydro-lX6,2-thiazin-3(4H)-one 1-oxide, or (4.S)-4-amino- l -((.S)-4.4.4- trifluoro-3 -hydroxybutyl)-5 ,6-dihydro- lX6,2-thiazin-3 (4H)-one 1 -oxide .

8. The compound of any one of claims 1-7, wherein R13is selected from the group consisting of hydroxyl, -OCH3, halogen, hydrogen, and -O(C=O)Ci-C6alkyl optionally with one or more halogens.

9. The compound of any one of claims 1-8, wherein Z is selected from the group consisting of a bond, -O-, -C=C-, -OCH2-, and -O(CO)-.

10. The compound of any one of claims 1-8, wherein R14is selected from the group consisting ofX and Y and Z are each independently selected from N and CR’, wherein R’ is selected independently for each occurrence from the group consisting of hydrogen, halogen, and C1-C6alkyl; andR15is independently selected for each occurrence from the group consisting of halogen, hydroxyl, -CH3, -CH(CH3)2, -C(CH3)2OH, -0(C0)CH3, -CF3, -OCH3, and -OCF3.

11. The compound of any one of claims 1-10, wherein R14is selected from the group consisting of12. The compound of any one of claims 1-5, wherein R1is selected from the group consisting ofwherein R15is independently selected for each occurrence from the group consisting of hydrogen, halogen, hydroxyl, -CH3, -CF3, -OCH3, and -OCF3.

13. The compound of claim 12, wherein R1is selected from the group consisting of14. A compound represented by Formula II:or a pharmaceutically acceptable salt and / or a stereoisomer thereof, wherein:R1is selected from the group consisting ofR13is selected from the group consisting of hydrogen, halogen, hydroxyl, -OCH3, - OCF3, and C2-Cealkoxy;R14is selected from the group consisting ofX and Y and Z are each independently selected from N and CR’, wherein R’ is selected independently for each occurrence from the group consisting of hydrogen, halogen, and C1-C6alkyl; andR15is independently selected for each occurrence from the group consisting of halogen, hydroxyl, -CH3, -CH(CH3)2, -C(CH3)2OH, -0(C0)CH3, -CF3, -OCH3, and -OCF3.

15. The compound of claim 14, wherein R14is selected from the group consisting of16. The compound of claim 14, wherein R1is selected from the group consisting of17. A compound selected from the group consisting of:or a pharmaceutically acceptable salt and / or a stereoisomer thereof.

18. A pharmaceutical composition comprising a compound of any one of claims 1-17, or a pharmaceutically acceptable salt and / or a stereoisomer thereof, and a pharmaceutically acceptable excipient.

19. A method of treating a cancer in a patient in need thereof, comprising administering to the patient an effective amount of a compound of any one of claims 1-17, or the pharmaceutical composition of claim 18.

20. The method of claim 19, wherein the cancer is selected from the group consisting of a carcinoma, a sarcoma, or a melanoma.

21. The method of claim 19 or 20, wherein the cancer is selected from the group consisting of clear cell renal carcinoma, a nonclear cell renal carcinoma, and a liver carcinoma.

22. A method of treating an inflammatory disease, a fibrosis, or a kidney disorder in a patient in need thereof, comprising administering to the patient an effective amount of a compound of any one of claims 1-17, or the pharmaceutical composition of claim 18.

23. The method of claim 22, wherein the fibrosis is liver fibrosis.

24. A method of modulating ferroptosis in a patient in need thereof, comprising administering to the patient an effective amount of a compound of any one of claims 1-17, or the pharmaceutical composition of claim 18.

25. The method of claim 24, wherein modulating ferroptosis comprises inducing ferroptosis.

26. The method of claim 24 or 25, wherein the patient is suffering from a cancer.

27. The method of any one of claims 24-26, wherein the patient is suffering from clear cell renal carcinoma, a nonclear cell renal carcinoma, and a liver carcinoma.

28. The method of any one of claims 24-26, wherein the patient is suffering from an inflammatory disease, a fibrosis, or a kidney disorder.

29. A method of inducing weight loss, fat loss, or both, in a patient in need thereof, comprising administering to the patient an effective amount of a compound of any one of claims 1-17, or the pharmaceutical composition of claim 18.

30. A method of treating a patient suffering from one or more suffering from one or more of the conditions selected from the group consisting of obesity, metabolic syndrome, elevated blood glucose, a diabetes, diabetes type 2, diabetes type 3, insulin resistance, high blood pressure, a cardiovascular disease, a coronary artery disease, a cerebrovascular disease, a stroke, a rheumatic heart disease, an arteriosclerosis, an atherosclerosis, a liver disease, a fatty liver disease, nonalcoholic fatty liver disease (NAFLD), and nonalcoholic steatohepatitis (NASH), comprising administering to the patient an effective amount of a compound of any one of claims 1-17, or the pharmaceutical composition of claim 18.

31. The method of claim 29 or 30, wherein the patient is obese or overweight.

32. A method of treating obesity in a patient in need thereof, comprising administering to the patient an effective amount of a compound of any one of claims 1-17, or the pharmaceutical composition of claim 18.

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