Macrocyclic inhibitors of ATP citrate lyase

Abstract

The application relates to macrocyclic compounds of formula (I) which act as inhibitors of ATP citrate lyase (ACLY) useful for the treatment of conditions, diseases, and disorders associated with aberrant levels of lipids such as liver diseases, type-2 diabetes, inflammation, chronic kidney disease, autoimmunity and cancer.

Description

MACROCYCLIC INHIBITORS OF ATP CITRATE LYASE CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of and priority to U.S. Patent Application No.63 / 595,012, filed on November 1, 2023, the entire contents of which are incorporated by reference herein. BACKGROUND

[0002] A combination of human genetic factors, overnutrition, and a sedentary lifestyle promote derangements in cholesterol and triglyceride metabolism. These derangements can manifest as one or more risk factors associated with increased probability of developing a number of life-threatening metabolic and / or cardiovascular diseases. The importance of maintaining cholesterol homeostasis in humans is strongly supported by both epidemiologic cohort studies and meta-analyses of multiple Mendelian and statin randomized trials that clearly demonstrate an association between elevated plasma levels of low-density lipoprotein cholesterol (LDL-C) (hypercholesterolemia) and atherosclerotic cardiovascular disease (ASCVD) risk. (Ference et al. (2017) Low-density lipoproteins cause atherosclerotic cardiovascular disease.1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel., Eur. Heart J., 38, 2459–2472; Silverman et al., (2016) Association between lowering LDL- C and cardiovascular risk reduction among different therapeutic interventions: a systematic review and meta-analysis., JAMA, 316, 1289–1297).

[0003] While an association between ASCVD and circulating triglyceride levels is less clear (Helgadottir et al., (2016), Variants with large effects on blood lipids and the role of cholesterol and triglycerides in coronary disease., Nat. Genet., 48, 634–639; Miller et al., (2011), Triglycerides and cardiovascular disease: a scientific statement from the American Heart Association., Circulation, 123, 2292–2333), aberrations in triglyceride metabolism also manifest as other metabolic ASCVD risk factors including insulin resistance, type 2 diabetes, and nonalcoholic fatty liver disease (NAFLD). (Cohen et al., (2011), Human fatty liver disease: old questions and new insights., Science, 332, 1519–1523; Armstrong et al., (2014), Extrahepatic complications of nonalcoholic fatty liver disease., Hepatology 59, 1174-1197). Moreover, NAFLD poses an independent health challenge as one of the most common causes of chronic liver disease and hepatocellular carcinoma, leading causes of liver-related morbidity and mortality in the Western world. (Loomba and Sanyal, (2013), The global NAFLD epidemic., Nat. Rev. Gastroenterol. Hepatol., 10, 686–690).

[0004] Neither ASCVD nor NAFLD (also known as metabolic dysfunction-associated fatty liver disease (MAFLD)) is adequately addressed by currently available treatment options. Many patients are not effectively treated for lipid disorders with the current standard of care, ASCVD remains the leading cause of death and disability in the Western world. (Mendis, (2010), The contribution of the Framingham Heart Study to the prevention of cardiovascular disease: a global perspective., Prog. Cardiovasc. Dis., 53, 10–14). As such, new therapeutic strategies that target cholesterol and triglyceride metabolism are required. ATP-citrate lyase (ACLY) is an enzyme uniquely positioned at the intersection of nutrient catabolism, and cholesterol and fatty acid biosynthesis, a metabolic nexus shown to be dysregulated in multiple disease states. Significant evidence supports that ACLY-derived acetyl-coenzyme A (CoA) serves not only as carbon precursor for cholesterol and fatty acid biosynthesis, but also as a key metabolic checkpoint used by multiple cell types to sense nutrient availability and coordinate metabolic adaptions with multiple effector functions. Thus, there is an unmet need to develop new therapeutic agents that modulate (e.g., inhibit) ACLY activity to treat metabolic and / or cardiovascular diseases. SUMMARY

[0005] Provided herein are compounds designed to function as modulators (e.g., inhibitors) of ATP citrate lyase (ACLY). Such compounds can be useful as therapeutic agents for treating conditions, diseases, and disorders associated with aberrant metabolism, such as NAFLD or MAFLD, nonalcoholic steatohepatitis (NASH) or metabolic dysfunction- associated steatohepatitis (MASH), type-2 diabetes, chronic kidney disease, inflammation, autoimmunity, and cancer.

[0006] In one aspect, provided herein are compounds of formula (I)or a stereoisomer and / or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0007] In another aspect, provided herein are compounds of formula (Ia)or a stereoisomer and / or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0008] In another aspect, provided herein are compounds of formula (Ib), or a stereoisomer and / or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0009] In another aspect, provided herein are compounds of formula (Ic)or a stereoisomer and / or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0010] In another aspect, provided herein are compounds of formula (Id), or a stereoisomer and / or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0011] In another aspect, provided herein are compounds of formula (Ie)or a stereoisomer and / or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0012] In certain embodiments, the compounds of formula (I), formula (Ia), formula (Ib), formula (Ic), formula (Id), or formula (Ie) are selected from the compounds of Table 1 or a stereoisomer and / or a pharmaceutically acceptable salt thereof.

[0013] In another aspect, provided herein are pharmaceutical compositions comprising a compound disclosed herein or a stereoisomer and / or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

[0014] A compound of formula (I), formula (Ia), formula (Ib), formula (Ic), formula (Id), or formula (Ie), or a stereoisomer and / or a pharmaceutically acceptable salt thereof; or a pharmaceutical composition of the invention can be used in treating the various conditions, diseases, and disorders described herein. For example, the methods of treatment can include inhibiting ACLY, inhibiting cholesterol synthesis, and / or suppressing fatty acid biosynthesis. In some embodiments, the condition, disease, or disorder can be a liver condition, disease, or disorder such as NAFLD / MAFLD or NASH / MASH and the methods include treating the liver condition, disease, or disorder such as NAFLD / MAFLD or NASH / MASH. In some embodiments, the condition, disease, or disorder can be type-2 diabetes and the methods include treating type-2 diabetes. In some embodiments, the condition, disease, or disorder can be inflammation and the methods include treating inflammation. In some embodiments, the condition, disease, or disorder is chronic kidney disease, and the methods include treating chronic kidney disease. In some embodiments, the condition, disease, or disorder isautoimmunity, and the methods include treating autoimmunity. In some embodiments, the condition, disease, or disorder is cancer, and the methods include treating cancer. DETAILED DESCRIPTION

[0015] As generally described herein, the disclosure provides compounds of formula (I), formula (Ia), formula (Ib), formula (Ic), formula (Id), and formula (Ie), or a stereoisomer and / or a pharmaceutically acceptable salt thereof, and pharmaceutical compositions containing the same. The compounds and compositions described herein function as modulators (e.g., inhibitors) of ACLY. The disclosure also provides methods of using the compounds and compositions disclosed herein to treat a variety of conditions, diseases, and disorders associated with aberrant metabolism. Such conditions, diseases, and disorders include, but are not limited to NAFLD / MAFLD, NASH / MASH, type-2 diabetes, chronic kidney disease, inflammation, autoimmunity, and cancer. Definitions

[0016] To facilitate an understanding of the present invention, a number of terms and phrases are defined below.

[0017] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The abbreviations used herein have their conventional meaning within the chemical and biological arts. The chemical structures and formulae set forth herein are constructed according to the standard rules of chemical valency known in the chemical arts.

[0018] Throughout the description, where compositions and kits are described as having, including, or comprising specific components, or where processes and methods are described as having, including, or comprising specific steps, it is contemplated that, additionally, there are compositions and kits of the present invention that consist essentially of, or consist of, the recited components, and that there are processes and methods according to the present invention that consist essentially of, or consist of, the recited processing steps.

[0019] In the application, where an element or component is said to be included in and / or selected from a list of recited elements or components, it should be understood that the element or component can be any one of the recited elements or components, or the element or component can be selected from a group consisting of two or more of the recited elements or components.

[0020] Further, it should be understood that elements and / or features of a composition or a method described herein can be combined in a variety of ways without departing from the spirit and scope of the present invention, whether explicit or implicit herein. For example, where reference is made to a particular compound, that compound can be used in various embodiments of compositions of the present invention and / or in methods of the present invention, unless otherwise understood from the context. In other words, within this application, embodiments have been described and depicted in a way that enables a clear and concise application to be written and drawn, but it is intended and will be appreciated that embodiments may be variously combined or separated without parting from the present teachings and invention(s). For example, it will be appreciated that all features described and depicted herein can be applicable to all aspects of the invention(s) described and depicted herein.

[0021] The articles “a” and “an” are used in this disclosure to refer to one or more than one (i.e., to at least one) of the grammatical object of the article, unless the context is inappropriate. By way of example, “an element” means one element or more than one element. By way of further example “an analogue” means one analogue or more than one analogue.

[0022] The term “and / or” is used in this disclosure to mean either “and” or “or” unless indicated otherwise.

[0023] It should be understood that the expression “at least one of” includes individually each of the recited objects after the expression and the various combinations of two or more of the recited objects unless otherwise understood from the context and use. The expression “and / or” in connection with three or more recited objects should be understood to have the same meaning unless otherwise understood from the context.

[0024] The use of the term “include,” “includes,” “including,” “have,” “has,” “having,” “contain,” “contains,” or “containing,” including grammatical equivalents thereof, should be understood generally as open-ended and non-limiting, for example, not excluding additional unrecited elements or steps, unless otherwise specifically stated or understood from the context.

[0025] Where the use of the term “about” is before a quantitative value, the present invention also includes the specific quantitative value itself, unless specifically stated otherwise. As used herein, the term “about” refers to a ±10%, ±5%, ±3%, ±2%, or ±1% variation from the nominal value unless otherwise indicated or inferred from the context.

[0026] Where a molecular weight is provided and not an absolute value, for example, of a polymer, then the molecular weight should be understood to be an average molecule weight, unless otherwise stated or understood from the context.

[0027] It should be understood that the order of steps or order for performing certain actions is immaterial so long as the present invention remain operable. Moreover, two or more steps or actions may be conducted simultaneously.

[0028] At various places in the present specification, variable or parameters are disclosed in groups or in ranges. It is specifically intended that the description include each and every individual subcombination of the members of such groups and ranges. For example, “C1–6 alkyl” is intended to encompass, C1, C2, C3, C4, C5, C6, C1–6, C1–5, C1–4, C1–3, C1–2, C2–6, C2–5, C2–4, C2–3, C3–6, C3–5, C3–4, C4–6, C4–5, and C5–6 alkyl. By way of another example, an integer in the range of 0 to 40 is specifically intended to individually disclose 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, and 40, and an integer in the range of 1 to 20 is specifically intended to individually disclose 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20. Additional examples include that the phrase “optionally substituted with 1-5 substituents” is specifically intended to individually disclose a chemical group that can include 0, 1, 2, 3, 4, 5, 0-5, 0-4, 0-3, 0-2, 0-1, 1-5, 1-4, 1-3, 1-2, 2-5, 2-4, 2-3, 3-5, 3-4, and 4-5 substituents.

[0029] The use of any and all examples, or exemplary language herein, for example, “such as” or “including,” is intended merely to illustrate better the present invention and does not pose a limitation on the scope of the invention unless claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the present invention. Chemical Definitions

[0030] Definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March’s Advanced Organic Chemistry, 5thEdition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers,Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3rdEdition, Cambridge University Press, Cambridge, 1987.

[0031] The compounds of the disclosure can contain one or more chiral centers and / or double bonds and therefore, can exist as stereoisomers, such as geometric isomers, and enantiomers or diastereomers. The term “stereoisomers,” when used herein, consists of all geometric isomers, enantiomers and / or diastereomers of the compound. For example, when a compound is shown with specific chiral center(s), the compound depicted without such chirality at that and other chiral centers of the compound are within the scope of the present disclosure, i.e., the compound depicted in two-dimensions with “flat” or “straight” bonds rather than in three dimensions, for example, with solid or dashed wedge bonds.

[0032] More specifically, a compound described herein (e.g., a compound of formula (I), formula (Ia), formula (Ib), formula (Ic), formula (Id), or formula (Ie)) can comprise one or more asymmetric centers, and thus can exist in various isomeric forms, e.g., enantiomers and / or diastereomers. For example, the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses. See, for example, Carreira and Kvaerno, Classics in Stereoselective Synthesis, (Wiley-VCH: Weinheim, 2009); Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw–Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions p.268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). The disclosure additionally encompasses compounds described herein as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

[0033] As used herein a pure enantiomeric compound is substantially free from other enantiomers or stereoisomers of the compound (i.e., in enantiomeric excess). In other words, an “S” form of the compound is substantially free from the “R” form of the compound and is, thus, in enantiomeric excess of the “R” form. The term “enantiomerically pure” or “pure enantiomer” denotes that the compound comprises more than 75% by weight, more than 80% by weight, more than 85% by weight, more than 90% by weight, more than 91% by weight, more than 92% by weight, more than 93% by weight, more than 94% by weight, more than95% by weight, more than 96% by weight, more than 97% by weight, more than 98% by weight, more than 98.5% by weight, more than 99% by weight, more than 99.2% by weight, more than 99.5% by weight, more than 99.6% by weight, more than 99.7% by weight, more than 99.8% by weight or more than 99.9% by weight, of the enantiomer. In certain embodiments, the weights are based upon total weight of all enantiomers or stereoisomers of the compound.

[0034] Geometric isomers, resulting from the arrangement of substituents around a carbon- carbon double bond or arrangement of substituents around a cycloalkyl or heterocycloalkyl, can also exist in the compounds of the present disclosure. 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 “” configuration, where the terms are used in accordance with IUPAC standards. Unless otherwise specified, structures depicting double bonds encompass both the “and “Z” isomers.

[0035] Substituents around a carbon-carbon 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. The arrangement of substituents around a carbocyclic ring can also be designated as “cis” or “trans.” 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.”

[0036] A compound described herein may also comprise one or more isotopic substitutions. For example, H may be in any isotopic form, including1H,2H (D or deuterium), and3H (T or tritium); C may be in any isotopic form, including12C,13C, and14C; O may be in any isotopic form, including16O and18O; and F may be in any isotopic form, including18F and19F. Other examples of isotopes that can be incorporated into compounds described herein include isotopes of nitrogen, phosphorus, and chlorine, such as15N,31P,32P,35S, and36Cl, respectively. As an example of an isotopic compound, a compound described herein can have one or more H atoms replaced with deuterium.

[0037] The terms described herein are intended to have the meanings presented and can be useful in understanding the description and intended scope of the present disclosure. When describing the disclosure, which may include a compound disclosed herein or a stereoisomer and / or a pharmaceutically acceptable salt thereof, pharmaceutical compositions containingsuch compounds and methods of using such compounds and compositions, the defined terms, if present, have their ascribed meanings unless otherwise indicated.

[0038] Unless otherwise stated, the term “substituted” is to be defined as set out herein. It should be further understood that the terms “groups” and “radicals” can be considered interchangeable when used herein.

[0039] As used herein, “alkyl” refers to a radical (e.g., a monovalent or divalent radical) of a straight–chain or branched saturated hydrocarbon group, e.g., having 1 to 20 carbon atoms (“C1–20alkyl”) such as a straight-chain or branched group of 1-6, 1-4, or 1-3 carbon atoms, referred to herein as C1-C6 alkyl, C1-C4 alkyl, and C1-C3 alkyl, respectively. For example, “C1- C6alkyl” refers to a straight-chain or branched saturated hydrocarbon containing 1-6 carbon atoms. Examples of a C1-C6 alkyl group include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, and neopentyl. In another example, “C1-C4 alkyl” refers to a straight-chain or branched saturated hydrocarbon containing 1-4 carbon atoms. Examples of a C1-C4alkyl group include, but are not limited to, methyl, ethyl, propyl, butyl, isopropyl, isobutyl, sec-butyl and tert-butyl. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-1-propyl, 2- methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 3-methyl-2-butyl, 2,2-dimethyl-1- propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-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, and hexyl.

[0040] As used herein, “carbocyclyl” or “carbocyclic” refers to a radical (e.g., a monovalent or divalent radical) of a non–aromatic cyclic hydrocarbon group having from 3 to 10 ring carbon atoms (“C3–10carbocyclyl”) and zero heteroatoms in the non–aromatic ring system. In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms (“C3–8 carbocyclyl”); 3 to 7 ring carbon atoms (“C3-7carbocyclyl”); 3 to 6 ring carbon atoms (“C3–6carbocyclyl”); or 5 to 10 ring carbon atoms (“C5–10 carbocyclyl”). Exemplary C3–6carbocyclyl groups include, without limitation, cyclopropyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. Exemplary C3–8carbocyclyl groups include, without limitation, the aforementioned C3–6carbocyclyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), and the like. Exemplary C3–10carbocyclyl groups include, without limitation, the aforementioned C3–8carbocyclyl groups as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10),cyclodecenyl (C10), octahydro–1H–indenyl (C9), decahydronaphthalenyl (C10), spiro[4.5]decanyl (C10), and the like. As the foregoing examples illustrate, in certain embodiments, the carbocyclyl group is either monocyclic (“monocyclic carbocyclyl”) or contain a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic carbocyclyl”). In certain embodiments, the carbocyclyl group, as defined above, can be saturated or can be partially unsaturated.

[0041] As used herein, “cycloalkyl” refers to a monovalent saturated cyclic, bicyclic, or bridged cyclic (e.g., adamantyl) hydrocarbon group of 3-12, 3-8, 3-6, 4-8, or 4-6 carbons, referred to herein, e.g., as "C3-6 cycloalkyl," derived from a cycloalkane. Exemplary cycloalkyl groups include, but are not limited to, cyclohexanes such as cyclohexyl and cyclohexenyl, cyclopentanes such as cyclopentyl and cyclopentenyl, cyclobutanes such cyclobutyl, and cyclopropanes such as cyclopropyl.

[0042] As used herein, “heteroatom” refers to an atom of any element other than carbon or hydrogen and includes, for example, nitrogen (N), oxygen (O), silicon (Si), sulfur (S), phosphorus (P), and selenium (Se).

[0043] As used herein, “heterocyclyl” or “heterocyclic” refer to a radical (e.g., a monovalent or divalent radical) of a 3– to 10–membered non–aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“3–10 membered heterocyclyl”). In some embodiments, a heterocyclyl is 5- to 10-membered (“5-10 membered heterocyclyl”). In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. A heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”), and can be saturated or can be partially unsaturated. Heterocyclyl bicyclic ring systems can include one or more heteroatoms in one or both rings. “Heterocyclyl” also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system. The terms “heterocycle,” “heterocyclyl,” “heterocyclyl ring,” “heterocyclic group,” “heterocyclic moiety,” and “heterocyclic radical,” may be used interchangeably.

[0044] As used herein, “aryl” refers to a radical of a monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 electrons shared in a cyclic array) having 6–10 ring carbon atoms and zero heteroatoms provided in the aromatic ring system. Non-limiting examples of aryl groups include phenyl and naphthyl.

[0045] As used herein, “heteroaryl” refers to a radical (e.g., a monovalent or divalent radical) of a 5–14 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 electrons shared in a cyclic array) having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system(“5–10 membered heteroaryl”). In certain embodiments, each heteroatom is independently selected from nitrogen, oxygen and sulfur. In heteroaryl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings. “Heteroaryl” also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused (aryl / heteroaryl) ring system. Bicyclic heteroaryl groups wherein one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and the like) the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2–indolyl) or the ring that does not contain a heteroatom (e.g., 5–indolyl). Other non-limiting examples of heteroaryl groups include pyridyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, and isoquinolinyl.

[0046] As used herein, “hetero” can be used to describe a compound or a group present on a compound where one or more carbon atoms in the compound or group have been replaced by a heteroatom. Hetero may be applied to any of the hydrocarbyl groups described above such as alkyl, e.g., heteroalkyl; carbocyclyl, e.g., heterocyclyl; aryl, e.g., heteroaryl; and the like having from 1 to 5, and particularly from 1 to 3 heteroatoms.

[0047] As used herein, “carbonyl” refers to the radical -C(O)- or C=O.

[0048] As used herein, “cyano” refers to -CN.

[0049] As used herein, “hydroxy” and “hydroxyl” refer to the radical -OH.

[0050] As used herein, “oxo” refers to the radical =O (double bonded oxygen).

[0051] As used herein, “halo” and “halogen” refer to an atom selected from fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), and iodine (iodo, -I). In certain embodiments, the halo group is bromo, fluoro, or chloro.

[0052] As used herein, “alkoxy” refers to an alkyl group which is attached to another moiety via an oxygen atom (–O(alkyl)). Alkoxy groups can have 1-6 or 2-6 carbon atoms and are referred to herein as C1-C6 alkoxy and C2-C6 alkoxy, respectively. Exemplary alkoxy groups include, but are not limited to, methoxy, ethoxy, propyloxy, isopropoxy, and tert- butoxy.

[0053] As used herein, “haloalkyl” refers to an alkyl group as defined herein substituted with one or more halogen atoms where the halogens are independently selected from fluorine, chlorine, bromine, and iodine. In some embodiments, a haloalkyl has 1 to 6 carbon atoms (“C1-6haloalkyl”).

[0054] As used herein, “haloalkoxy” refers to a haloalkyl group which is attached to another moiety via an oxygen atom such as, e.g., but are not limited to –OCHCF2 or –OCF3. In some embodiments, a haloalkoxy has 1 to 6 carbon atoms (“C1-6haloalkoxy”).

[0055] As generally used herein, “substituted,” whether preceded by the term “optionally” or not, means that at least one hydrogen present on a group (e.g., a carbon or nitrogen atom) is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction. Unless otherwise indicated, a “substituted” group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position.

[0056] Nitrogen atoms can be substituted or unsubstituted as valency permits, and include primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents include, but are not limited to, hydrogen, –OH, –ORaa, –N(Rcc)2, –CN, – C(=O)Raa, –C(=O)N(Rcc)2, –CO2Raa, –SO2Raa, –C(=NRbb)Raa, –C(=NRcc)ORaa, – C(=NRcc)N(Rcc)2, –SO2N(Rcc)2, –SO2Rcc, –SO2ORcc, –SORaa, –C(=S)N(Rcc)2, –C(=O)SRcc, – C(=S)SRcc, –P(=O)2Raa, –P(=O)(Raa)2, –P(=O)2N(Rcc)2, –P(=O)(NRcc)2, C1–10 alkyl, C1–10 perhaloalkyl, C2–10alkenyl, C2–10alkynyl, C3–10carbocyclyl, 3–14 membered heterocyclyl, C6–14 aryl, and 5–14 membered heteroaryl, or two Rccgroups attached to a nitrogen atom are joined to form a 3–14 membered heterocyclyl or 5–14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups, and wherein Raa, Rbb, Rccand Rddare as defined herein.

[0057] Each instance of Raais, independently, selected from C1-10alkyl, C1-10perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl, or two Raagroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups.

[0058] Each instance of Rbbis, independently, selected from hydrogen, -OH, -ORaa, - N(Rcc)2, -CN, -C(=O)Raa, -C(=O)N(Rcc)2, -CO2Raa, -SO2Raa, -C(=NRcc)ORaa, - C(=NRcc)N(Rcc)2, -SO2N(Rcc)2, -SO2Rcc, -SO2ORcc, -SORaa, -C(=S)N(Rcc)2, -C(=O)SRcc, - C(=S)SRcc, -P(=O)2Raa, -P(=O)(Raa)2, -P(=O)2N(Rcc)2, -P(=O)(NRcc)2, C1-10alkyl, C1-10perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14aryl, and 5-14 membered heteroaryl, or two Rbbgroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups.

[0059] Each instance of Rccis, independently, selected from hydrogen, C1-10alkyl, C1-10perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6- 14 aryl, and 5-14 membered heteroaryl, or two Rccgroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups.

[0060] Each instance of Rddis, independently, selected from halogen, -CN, -NO2, -N3, - SO2H, -SO3H, -OH, -ORee, -ON(Rff)2, -N(Rff)2, -N(Rff)3+X- , -N(ORee)Rff, -SH, -SRee, -SSRee, -C(=O)Ree, -CO2H, -CO2Ree, -OC(=O)Ree, -OCO2Ree, -C(=O)N(Rff)2, -OC(=O)N(Rff)2, - NRffC(=O)Ree, -NRffCO2Ree, -NRffC(=O)N(Rff)2, -C(=NRff)ORee, -OC(=NRff)Ree, - OC(=NRff)ORee, -C(=NRff)N(Rff)2, -OC(=NRff)N(Rff)2, -NRffC(=NRff)N(Rff)2, -NRffSO2Ree, - SO2N(Rff)2, -SO2Ree, -SO2ORee, -OSO2Ree, -S(=O)Ree, -Si(Ree)3, -OSi(Ree)3, -C(=S)N(Rff)2, - C(=O)SRee, -C(=S)SRee, -SC(=S)SRee, -P(=O)2Ree, -P(=O)(Ree)2, -OP(=O)(Ree)2, - OP(=O)(ORee)2, C1-6alkyl, C1-6perhaloalkyl, C2-6alkenyl, C2-6alkynyl, C3-10carbocyclyl, 3- 10 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgggroups, or two geminal Rddsubstituents can be joined to form =O or =S.

[0061] Each instance of Reeis, independently, selected from C1-6 alkyl, C1-6 perhaloalkyl, C2-6alkenyl, C2-6alkynyl, C3-10carbocyclyl, C6-10aryl, 3-10 membered heterocyclyl, and 3-10membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgggroups.

[0062] Each instance of Rffis, independently, selected from hydrogen, C1-6 alkyl, C1-6 perhaloalkyl, C2-6alkenyl, C2-6alkynyl, C3-10carbocyclyl, 3-10 membered heterocyclyl, C6-10aryl and 5-10 membered heteroaryl, or two Rffgroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgggroups.

[0063] Each instance of Rggis, independently, halogen, -CN, -NO2, -N3, -SO2H, -SO3H, - OH, -OC1-6alkyl, -ON(C1-6alkyl)2, -N(C1-6alkyl)2, -N(C1-6alkyl)3+X-, -NH(C1-6alkyl)2+X-, - NH2(C1-6 alkyl)+X-, -NH3+X-, -N(OC1-6 alkyl)(C1-6 alkyl), -N(OH)(C1-6 alkyl), -NH(OH), -SH, -SC1-6alkyl, -SS(C1-6alkyl), -C(=O)(C1-6alkyl), -CO2H, -CO2(C1-6alkyl), -OC(=O)(C1-6alkyl), -OCO2(C1-6 alkyl), -C(=O)NH2, -C(=O)N(C1-6 alkyl)2, -OC(=O)NH(C1-6 alkyl), - NHC(=O)(C1-6alkyl), -N(C1-6alkyl)C(=O)(C1-6alkyl), - NHCO2(C1-6alkyl), -NHC(=O)N(C1-6 alkyl)2, -NHC(=O)NH(C1-6 alkyl), -NHC(=O)NH2, -C(=NH)O(C1-6 alkyl), -OC(=NH)(C1-6 alkyl), -OC(=NH)OC1-6 alkyl, -C(=NH)N(C1-6 alkyl)2, -C(=NH)NH(C1-6 alkyl), - C(=NH)NH2, -OC(=NH)N(C1-6 alkyl)2, -OC(NH)NH(C1-6 alkyl), -OC(NH)NH2, - NHC(NH)N(C1-6 alkyl)2, -NHC(=NH)NH2, -NHSO2(C1-6 alkyl), -SO2N(C1-6 alkyl)2, - SO2NH(C1-6alkyl), -SO2NH2, -SO2C1-6alkyl, -SO2OC1-6alkyl, -OSO2C1-6alkyl, -SOC1-6alkyl, -Si(C1-6 alkyl)3, -OSi(C1-6 alkyl)3, -C(=S)N(C1-6 alkyl)2, C(=S)NH(C1-6 alkyl), C(=S)NH2, -C(=O)S(C1-6alkyl), -C(=S)SC1-6alkyl, -SC(=S)SC1-6alkyl, -P(=O)2(C1-6alkyl), - P(=O)(C1-6 alkyl)2, -OP(=O)(C1-6 alkyl)2, -OP(=O)(OC1-6 alkyl)2, C1-6 alkyl, C1-6 perhaloalkyl, C2-6alkenyl, C2-6alkynyl, C3-10carbocyclyl, C6-10aryl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl; or two geminal Rggsubstituents can be joined to form =O or =S.

[0064] X- is a counterion. A "counterion" or "anionic counterion" is a negatively charged group associated with a cationic quaternary amino group in order to maintain electronic neutrality. Exemplary counterions include halide ions (e.g., F , CI", Br", Γ), NO3-, ClO4-, OH-, H2PO4-, HSO4-, sulfonate ions (e.g., methansulfonate, trifluoromethanesulfonate, p- toluenesulfonate, benzenesulfonate, 10-camphor sulfonate, naphthalene-2-sulfonate, naphthalene-l-sulfonic acid-5-sulfonate, ethan-l-sulfonic acid-2-sulfonate, and the like), and carboxylate ions (e.g., acetate, ethanoate, propanoate, benzoate, glycerate, lactate, tartrate, glycolate, and the like).

[0065] These and other exemplary substituents are described in more detail in the Detailed Description, Examples, and Claims. The invention is not intended to be limited in any manner by the above exemplary listing of substituents.

[0066] As used herein, “compound” refers to the compound itself and its pharmaceutically acceptable salts, hydrates, esters and N-oxides including its various stereoisomers and its isotopically-labelled forms, unless otherwise understood from the context of the description or expressly limited to one particular form of the compound, i.e., the compound itself, a specific stereoisomer and / or isotopically-labelled compound, or a pharmaceutically acceptable salt, a hydrate, an ester, or an N-oxide thereof. It should be understood that a compound can refer to a pharmaceutically acceptable salt, or a hydrate, an ester or an N- oxide of a stereoisomer of the compound and / or an isotopically-labelled compound.

[0067] Further, if a variable is not accompanied by a definition, then the variable is defined as found elsewhere in the disclosure unless understood to be different from the context. In addition, the definition of each variable and / or substituent, for example, C1-C6alkyl, R2, Rb, w and the like, when it occurs more than once in any structure or compound, can be independent of its definition elsewhere in the same structure or compound.

[0068] Definitions of the variables and / or substituents in formulae and / or compounds herein encompass multiple chemical groups. The present disclosure includes embodiments where, for example, i) the definition of a variable and / or substituent is a single chemical group selected from those chemical groups set forth herein, ii) the definition is a collection of two or more of the chemical groups selected from those set forth herein, and iii) the compound is defined by a combination of variables and / or substituents in which the variables and / or substituents are defined by (i) or (ii). Other definitions

[0069] As used herein, “pharmaceutically acceptable” and “pharmacologically acceptable,” refer to compounds, molecular entities, compositions, materials, and / or dosage forms 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, general safety and purity standards as required by FDA Office of Biologics standards.

[0070] As used herein, “pharmaceutically acceptable carrier” and “pharmaceutically acceptable excipient,” refer to any and all solvents, dispersion media, coatings, isotonic and absorption delaying agents, and the like, that are compatible with pharmaceuticaladministration. Pharmaceutical acceptable carriers can include phosphate buffered saline solution, water, emulsions (e.g., such as an oil / water or water / oil emulsions), and various types of wetting agents. The compositions also can include stabilizers and preservatives.

[0071] As used herein, “pharmaceutically acceptable salt” refers to any salt of an acidic or a basic group that may be present in a compound of the present disclosure, which salt is compatible with pharmaceutical administration. As is known to those of skill in the art, “salts” of the compounds of the present disclosure may be derived from inorganic or organic acids and bases. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al., describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66:1–19. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2–hydroxy–ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2– naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3–phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p–toluenesulfonate, undecanoate, valerate salts, and the like. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(C1–4alkyl)4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

[0072] As used herein, a “subject” to which administration is contemplated includes, but is not limited to, humans (i.e., a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle–aged adult or senior adult)) and / or a non-human animal, e.g., a mammal such as primates (e.g., cynomolgusmonkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In certain embodiments, the subject is a human. In certain embodiments, the subject is a non- human animal. The terms “human,” “patient,” and “subject” are used interchangeably herein.

[0073] As used herein, and unless otherwise specified, the terms “treat,” “treating” and “treatment” contemplate an action that occurs while a subject is suffering from the specified disease, disorder or condition, which reduces the severity of the disease, disorder or condition, or retards or slows the progression of the disease, disorder or condition (“therapeutic treatment”), and also contemplates an action that occurs before a subject begins to suffer from the specified disease, disorder or condition (“prophylactic treatment”).

[0074] As used herein, “effective amount” or “therapeutically-effective amount” refers to the amount of a compound (e.g., bempedoic acid), a combination of compounds (e.g., bempedoic acid and ezetimibe), a pharmaceutical composition (e.g., a pharmaceutical composition of the present disclosure), or a fixed-dose combination (e.g., a fixed-dose combination of the present disclosure) sufficient to effect beneficial or desired results. An effective amount can be administered in one or more administrations, applications or dosages and is not intended to be limited to a particular formulation or administration route.

[0075] As used herein, “disease,” “disorder,” “condition,” or “illness,” can be used interchangeably unless otherwise underacted or understood from the context, refers to a state of being or health status of a patient or subject capable of being treated with a compound, pharmaceutical composition, or method provided herein. In some embodiments, the compounds and methods described herein comprise reduction or elimination of one or more symptoms of the disease, disorder, or condition, or illness e.g., through administration of the compound of formula (I), formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (Ie), or a stereoisomer and / or a pharmaceutically acceptable salt thereof.

[0076] As used herein, “administering” means oral administration, administration as a suppository, topical contact, intravenous, parenteral, intraperitoneal, intramuscular, intralesional, intrathecal, intracranial, intranasal or subcutaneous administration, or the implantation of a slow-release device, e.g., a mini-osmotic pump, to a subject. Administration is by any route, including parenteral and transmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or transdermal). Parenteral administration includes, e.g., intravenous, intramuscular, intra-arterial, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial. Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, etc. By “co- administer” it is meant that a composition described herein is administered at the same time,just prior to, or just after the administration of one or more additional therapies (e.g., anti- cancer agent, chemotherapeutic, or treatment for a neurodegenerative disease). The compound of the invention can be administered alone or can be co-administered to the patient. Co-administration is meant to include simultaneous or sequential administration of the compound individually or in combination (more than one compound or agent). Thus, the preparations can also be combined, when desired, with other active substances (e.g., to reduce metabolic degradation).

[0077] As used herein, “liver disorder” refers generally to a disease, a disorder, and / or a condition affecting the liver, and may have a wide range of severity encompassing, for example, simple accumulation of fat in the hepatocytes (steatosis), macrovesicular steatosis, periportal and lobular inflammation (steatohepatitis), cirrhosis, fibrosis, liver cancers, and liver failure.

[0078] As used herein, “fatty liver disease” (“FLD”), which is also called “fatty liver,” refers to a disease leading to liver injury caused by abnormal fat accumulation in liver cells. FLD may arise from a number of sources, including excessive alcohol consumption and metabolic disorders, such as those associated with insulin resistance, obesity, and hypertension.

[0079] As used herein, “non-alcoholic fatty liver disease” (“NAFLD”) and “metabolic dysfunction-associated fatty liver disease” (“MAFLD”) are used interchangeably and refer to the spectrum of disorders resulting from an accumulation of fat in liver cells in individuals with no history of excessive alcohol consumption. In the mildest form, NAFLD / MAFLD refers to hepatic steatosis.

[0080] As used herein, “drug-induced liver disease” or “toxic liver injury” refers to a disease or a condition in which an active agent has caused injury to the liver.

[0081] As used herein, “alcoholic liver disease,” also called “alcoholic liver injury,” refers to a disease caused by fat accumulation in liver cells, caused at least in part by alcohol ingestion. Examples include, but are not limited to, diseases such as alcoholic simple fatty liver, alcoholic steatohepatitis (“ASH”), alcoholic hepatic fibrosis, alcoholic cirrhosis, alcoholic fatty liver disease, and the like. It should be noted that alcoholic steatohepatitis is also called alcoholic fatty hepatitis and includes alcoholic hepatic fibrosis.

[0082] As used herein, “fatty liver of pregnancy” refers to acute fatty liver conditions that can arise during pregnancy and can be life-threatening.

[0083] As used herein, “altering lipid metabolism” refers to an observable (measurable) change in at least one aspect of lipid metabolism, including, but not limited to, total bloodlipid content, blood HDL cholesterol, blood LDL cholesterol, blood VLDL cholesterol, blood triglyceride, blood Lp(a), blood apo A-I, blood apo E and blood non-esterified fatty acids.

[0084] As used herein, “altering glucose metabolism” refers to an observable (measurable) change in at least one aspect of glucose metabolism, including, but not limited to, total blood glucose content, blood insulin, the blood insulin to blood glucose ratio, insulin sensitivity, and oxygen consumption.

[0085] Various aspects of the disclosure are set forth herein under headings and / or in sections for clarity; however, it is understood that all aspects, embodiments, or features of the disclosure described in one particular section are not to be limited to that particular section but rather can apply to any aspect, embodiment, or feature of the present disclosure. Compounds

[0086] Disclosed herein, in one aspect, are compounds of formula (I):or a stereoisomer and / or a pharmaceutically acceptable salt thereof, wherein: Ring A is phenyl or 9-membered bicyclic heteroaryl; Ring B is phenyl or 5-6 membered heteroaryl; Ring C is selected from the group consisting of phenyl, 9-membered bicyclic heterocyclyl, 9-membered bicyclic carbocyclyl, and 5-6 membered heteroaryl; R1is independently, for each occurrence, selected from the group consisting of halogen, hydroxyl, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, and 6-membered heterocyclyl; R2is independently, for each occurrence, selected from the group consisting of halogen, hydroxyl, cyano, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C1-6haloalkoxy, -O-C3-6cycloalkyl, and 4-6 membered heterocyclyl, wherein the 4-6 membered heterocyclyl is optionally substituted with one or more substituents independently selected from R2A; oroptionally two R2may be taken together, along with the ring to which they are attached, to form a 9-membered bicyclic carbocyclyl, a 9-membered bicyclic heterocyclyl, or a 9-membered bicyclic heteroaryl; R3is independently, for each occurrence, selected from the group consisting of cyano, halogen, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, and -C(O)N(RA)(RB), wherein the C1-6alkyl is optionally substituted with one or more substituents independently selected from C1-6alkoxy; L1is *-S(O)2N(RC)-**, wherein * denotes the point of attachment to Ring A and ** denotes the point of attachment to Ring B; L2is selected from the group consisting of #-C(O)O-##, #-C(O)-(C1-6alkyl)-##, #- C(O)O-(C1-6alkyl)-##, #-C(O)O-(C1-6alkyl)-O-##, #-C(O)O-(C1-6haloalkyl)-##, and C1-6alkyl, wherein # denotes the point of attachment to Ring A and ## denotes the point of attachment to Ring C; R2Ais halogen or C1-6alkoxy; RAis hydrogen or C1-6alkyl; RBis hydrogen or C1-6alkyl; RCis hydrogen or C1-3alkyl; n is 2 or 3; o is 0, 1, or 2; and p is 0, 1, or 2.

[0087] In some embodiments, Ring A is phenyl, indazolyl, or benzo[d]isoxazolyl.^

[0088] In some embodiments, Ring, wherein Δ denotes the point of attachment to L1 and ΔΔ denotes thepoint of attachment to L2. In some embodiments, Ring, wherein Δ denotes the point of attachment to L1and ΔΔ denotes the point of attachment to L2. In some embodiments, Ring As, wherein Δ denotes the point ofattachment to L1and ΔΔ denotes the point of attachment to L2. In some embodiments, Ringwherein Δ denotes the point of attachment to L1and ΔΔ denotes the point of attachment to L2.

[0089] In some embodiments, L1is *-S(O)2N(H)-**, wherein * denotes the point of attachment to Ring A and ** denotes the point of attachment to Ring B.

[0090] In another aspect, provided herein are compounds of formula (Ia):or a stereoisomer and / or a pharmaceutically acceptable salt thereof, wherein: Ring B is phenyl or 5-6 membered heteroaryl; Ring C is selected from the group consisting of phenyl, 9-membered bicyclic heterocyclyl, 9-membered bicyclic carbocyclyl, and 5-6 membered heteroaryl; R1is independently, for each occurrence, selected from the group consisting of halogen, hydroxyl, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, and 6-membered heterocyclyl; R2is independently, for each occurrence, selected from the group consisting of halogen, hydroxyl, cyano, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C1-6haloalkoxy, -O-C3-6cycloalkyl, and 4-6 membered heterocyclyl, wherein the 4-6 membered heterocyclyl is optionally substituted with one or more substituents independently selected from R2A; oroptionally two R2may be taken together, along with the ring to which they are attached, to form a 9-membered bicyclic carbocyclyl, a 9-membered bicyclic heterocyclyl, or a 9-membered bicyclic heteroaryl; R3is independently, for each occurrence, selected from the group consisting of cyano, halogen, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, and -C(O)N(RA)(RB), wherein the C1-6alkyl is optionally substituted with one or more substituents independently selected from C1-6alkoxy; L2is selected from the group consisting of #-C(O)O-##, #-C(O)-(C1-6alkyl)-##, #- C(O)O-(C1-6alkyl)-##, #-C(O)O-(C1-6alkyl)-O-##, #-C(O)O-(C1-6haloalkyl)-##, and C1-6alkyl, wherein # denotes the point of attachment to Ring A and ## denotes the point of attachment to Ring C; R2Ais halogen or C1-6alkoxy; RAis hydrogen or C1-6alkyl; RBis hydrogen or C1-6alkyl; n is 2 or 3; o is 1 or 2; and p is 0, 1, or 2.

[0091] In some embodiments, n is 2.

[0092] In some embodiments, n is 3.

[0093] In some embodiments, R1is, independently, for each occurrence, selected from the group consisting of bromo, chloro, fluoro, hydroxyl, -CH3, -CF3, cyclopropyl,, .

[0094] In some embodiments, n is 2 and R1is, independently, for each occurrence, selected from the group consisting of bromo, chloro, hydroxyl, -CF3, cyclopropyl,, an .

[0095] In some embodiments, n is 2 and R1is, independently, for each occurrence, bromo, chloro, or hydroxyl.

[0096] In some embodiments, n is 2 and R1is, independently, for each occurrence, bromo or hydroxyl.

[0097] In some embodiments, n is 2 and R1is, independently, for each occurrence, chloro or hydroxyl.

[0098] In some embodiments, n is 3 and R1is independently, for each occurrence, chloro, fluoro, hydroxyl, and CH3.

[0099] In another aspect, provided herein are compounds of formula (Ib):or a stereoisomer and / or a pharmaceutically acceptable salt thereof, wherein: Ring B is phenyl or 5-6 membered heteroaryl; Ring C is phenyl, 9-membered bicyclic heterocyclyl, 9-membered bicyclic carbocyclyl, C3-6cycloalkyl, or 5-6 membered heteroaryl; R2is independently, for each occurrence, selected from the group consisting of halogen, hydroxyl, cyano, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C1-6haloalkoxy, -O-C3-6cycloalkyl, and 4-6 membered heterocyclyl, wherein the 4-6 membered heterocyclyl is optionally substituted with one or more substituents independently selected from R2A; or optionally two R2may be taken together, along with the ring to which they are attached, to form a 9-membered bicyclic carbocyclyl, a 9-membered bicyclic heterocyclyl, or a 9-membered bicyclic heteroaryl; R3is independently, for each occurrence, selected from the group consisting of cyano, halogen, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, and -C(O)N(RA)(RB), whereinthe C1-6alkyl is optionally substituted with one or more substituents independently selected from C1-6alkoxy; R4is selected from the group consisting of halogen, C1-6haloalkyl, C3-6cycloalkyl, and 6-membered heterocyclyl; R5is hydrogen or halogen; L2is selected from the group consisting of #-C(O)O-##, #-C(O)-(C1-6alkyl)-##, #- C(O)O-(C1-6alkyl)-##, #-C(O)O-(C1-6alkyl)-O-##, #-C(O)O-(C1-6haloalkyl)-##, and C1-6alkyl, wherein # denotes the point of attachment to Ring A and ## denotes the point of attachment to Ring C; R2Ais halogen or C1-6alkoxy; RAis hydrogen or C1-6alkyl; RBis hydrogen or C1-6alkyl; o is 1 or 2; and p is 0, 1, or 2.

[0100] In some embodiments, Ring B is phenyl, thiophenyl, or pyridinyl.

[0101] In some embodiments, Ring B is selected from the group consisting of, , , ,, wherein ● denotes the point of attachment to L1and ●● denotes the point of attachment to Ring C.

[0102] In some embodiments, o is 1.

[0103] In some embodiments, o is 2.

[0104] In some embodiments, R2is, independently, for each occurrence, selected from the group consisting of chloro, fluoro, cyano, hydroxyl, -CH3, -CF3, -O-CH3, -O-CH2CH3, -O-CHF2, -O-CF3, cyclopropyl, -O-cyclopropyl, morpholinyl,whereinoptionally substituted with one or more substituents independently selected from fluoro and -O-CH3.

[0105] In some embodiments, R2is, independently, for each occurrence, selected from the group consisting of chloro, fluoro, cyano, hydroxyl, -CH3, -CF3, -O-CH3, -O-CH2CH3, -O- CHF2, -O-CF3, cyclopropyl, -O-cyclopropyl, morpholinyl,,.

[0106] In some embodiments, R2is selected from the group consisting of chloro, fluoro, CF3, and -O-CH3.

[0107] In some embodiments, o is 1 and R2is selected from the group cyano, chloro, fluoro, hydroxyl, -CF3, -O-CF3, -O-CHF2, cyclopropyl, -O-cyclopropyl, -O-CH3, -O- CH2CH3, morpholinyl,, .

[0108] In some embodiments, o is 1 and R2is chloro.

[0109] In some embodiments, o is 1 and R2is -O-CH3.

[0110] In some embodiments, two R2groups on different carbon atoms are taken together, along with the atoms to which they are attached, to form a 5 membered carbocyclyl, a 5- membered heterocyclyl, or a 5-membered heteroaryl.

[0111] In some embodiments, o is 0.

[0112] In another aspect, provided herein are compounds of formula (Ic):or a stereoisomer and / or a pharmaceutically acceptable salt thereof, wherein: Ring C is selected from the group consisting of phenyl, 9-membered bicyclic heterocyclyl, 9-membered bicyclic carbocyclyl, and 5-6 membered heteroaryl; R3is independently, for each occurrence, selected from the group consisting of cyano, halogen, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, and -C(O)N(RA)(RB), wherein the C1-6alkyl is optionally substituted with one or more substituents independently selected from C1-6alkoxy; R4is selected from the group consisting of halogen, C1-6haloalkyl, C3-6cycloalkyl, and 6-membered heterocyclyl; R5is hydrogen or halogen; X1is CR6or N; X2 is CR7or N; X3is CR8or N; R6is selected from the group consisting of hydrogen, cyano, halogen, hydroxyl, C1-6alkoxy, C1-6haloalkyl, C1-6haloalkoxy, C3-6cycloalkyl, and 4-6 membered heterocyclyl, wherein the 4-6 membered heterocyclyl is optionally substituted with one or more substituents independently selected from halogen; R7is selected from the group consisting of hydrogen, cyano, halogen, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -O-C3-6cycloalkyl, and 4-6 membered heterocyclyl, wherein the 4- 6 membered heterocyclyl is optionally substituted with C1-6alkoxy; orR6and R7may be taken together, along with the ring to which they are attached, to form a 9-membered bicyclic heteroaryl or a 9-membered bicyclic heterocyclyl; R8is hydrogen or halogen; or R7and R8may be taken together, along with the ring to which they are attached, to form a 9-membered bicyclic carbocyclyl; L2is selected from the group consisting of #-C(O)O-##, #-C(O)-(C1-6alkyl)-##, #- C(O)O-(C1-6alkyl)-##, #-C(O)O-(C1-6alkyl)-O-##, #-C(O)O-(C1-6haloalkyl)-##, and C1-6alkyl, wherein # denotes the point of attachment to Ring A and ## denotes the point of attachment to Ring C; RAis hydrogen or C1-6alkyl; RBis hydrogen or C1-6alkyl; and p is 0, 1, or 2.

[0113] In some embodiments, Ring C is selected from the group consisting of cyclopropyl, phenyl, pyridinyl, thiazolyl, pyrimidinyl, pyrazolyl, isoxazolyl,,.

[0114] In some embodiments, Ring C is selected from the group consisting of, wherein □ denotes the point of attachment to Ring B and □□ denotes the point of attachment to L2.

[0115] In some embodiments, Ring,, wherein □ denotes the point of attachment to Ring B and □□ denotes the point of attachment to L2.

[0116] In some embodiments, p is 1.

[0117] In some embodiments, p is 2.

[0118] In some embodiments, R3is, independently, for each occurrence, selected from the group consisting of cyano, bromo, fluoro, -CH3, -CHF2, -CF3, -O-CH3, -O-CHF2, -CH2CH2- O-CH3, -C(O)NH2, and -CH2CHF2.

[0119] In some embodiments, R3is, independently, for each occurrence, selected from the group consisting of cyano, fluoro, CF3, O-CH3, and -O-CHF2.

[0120] In some embodiments, p is 1 and R3is selected from the group consisting of cyano, bromo, fluoro, -CH3, -CHF2, -CF3, -O-CH3, -O-CHF2, -CH2CH2-O-CH3, -C(O)NH2, and - CH2CHF2.

[0121] In some embodiments, p is 1 and R3is selected from the group consisting of cyano, fluoro, CF3, -O-CH3, and -O-CHF2.

[0122] In certain embodiments, p is 2 and R3is fluoro.

[0123] In some embodiments, p is 0.

[0124] In another aspect, provided herein are compounds of formula (Id):or a stereoisomer and / or a pharmaceutically acceptable salt thereof, wherein: R4is selected from the group consisting of halogen, C1-6haloalkyl, C3-6cycloalkyl, and 6-membered heterocyclyl; R5is hydrogen or halogen; X1 is CR6or N; X2is CR7or N; X3 is CR8or N; X4is CH or N; X5 is CR9or N; X6is CR10or N; X7 is CR11or N; R6is selected from the group consisting of hydrogen, cyano, halogen, hydroxyl, C1-6alkoxy, C1-6haloalkyl, C1-6haloalkoxy, C3-6cycloalkyl, and 4-6 membered heterocyclyl, wherein the 4-6 membered heterocyclyl is optionally substituted with one or more substituents independently selected from halogen; R7is selected from the group consisting of hydrogen, cyano, halogen, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -O-C3-6cycloalkyl, and 4-6 membered heterocyclyl, wherein the 4- 6 membered heterocyclyl is optionally substituted with C1-6alkoxy; or R6and R7may be taken together, along with the ring to which they are attached, to form a 9-membered bicyclic heteroaryl or a 9-membered bicyclic heterocyclyl; R8is hydrogen or halogen; or R7and R8may be taken together, along with the ring to which they are attached, to form a 9-membered bicyclic carbocyclyl;R9is selected from the group consisting of hydrogen, cyano, halogen, C1-6haloalkyl, - C(O)N(RA)(RB), and C1-6alkoxy; R10is selected from the group consisting of hydrogen, halogen, C1-6haloalkyl, C1-6haloalkoxy, and C1-6alkoxy; R11is hydrogen, halogen, or C1-6alkyl; and L2is selected from the group consisting of #-C(O)O-##, #-C(O)-(C1-6alkyl)-##, #- C(O)O-(C1-6alkyl)-##, #-C(O)O-(C1-6alkyl)-O-##, #-C(O)O-(C1-6haloalkyl)-##, and C1-6alkyl, wherein # denotes the point of attachment to Ring A and ## denotes the point of attachment to Ring C; RAis hydrogen or C1-6alkyl; and RBis hydrogen or C1-6alkyl.

[0125] In some embodiments, L2is selected from the group consisting of #-C(O)O-##, #- C(O)O-CH2-##, #-C(O)O-C(CH3)(H)-##, #-C(O)O-C(CH2F)(H)-##, #-C(O)O-(CH2)2-##, #- C(O)O-(CH2)2-O-##, -(CH2)2-, -(CH2)3-, and #-C(O)-(CH2)3-##, wherein # denotes the point of attachment to Ring A and ## denotes the point of attachment to Ring C. In some embodiments, L2is #-C(O)O-CH2-## or #-C(O)O-(CH2)2-##, wherein # denotes the point of attachment to Ring A and ## denotes the point of attachment to Ring C. In some embodiments, L2is #-C(O)O-CH2-##, wherein # denotes the point of attachment to Ring A and ## denotes the point of attachment to Ring C.

[0126] In another aspect, provided herein are compounds of formula (Ie):e or a stereoisomer and / or a pharmaceutically acceptable salt thereof, wherein:R4is selected from the group consisting of halogen, C1-6haloalkyl, C3-6cycloalkyl, and 6-membered heterocyclyl; R5is hydrogen or halogen; X1is CR6or N; X2 is CR7or N; X3is CR8or N; X4 is CH or N; X5is CR9or N; X6 is CR10or N; X7is CR11or N; R6is selected from the group consisting of hydrogen, cyano, halogen, hydroxyl, C1-6alkoxy, C1-6haloalkyl, C1-6haloalkoxy, C3-6cycloalkyl, and 4-6 membered heterocyclyl, wherein the 4-6 membered heterocyclyl is optionally substituted with one or more substituents independently selected from halogen; R7is selected from the group consisting of hydrogen, cyano, halogen, C1-6alkyl, C1- 6haloalkyl, C3-6cycloalkyl, -O-C3-6cycloalkyl, and 4-6 membered heterocyclyl, wherein the 4- 6 membered heterocyclyl is optionally substituted with C1-6alkoxy; or R6and R7may be taken together, along with the ring to which they are attached, to form a 9-membered bicyclic heteroaryl or a 9-membered bicyclic heterocyclyl; R8is hydrogen or halogen; or R7and R8may be taken together, along with the ring to which they are attached, to form a 9-membered bicyclic carbocyclyl; R9is selected from the group consisting of hydrogen, cyano, halogen, C1-6haloalkyl, - C(O)N(RA)(RB), and C1-6alkoxy; R10is selected from the group consisting of hydrogen, halogen, C1-6haloalkyl, C1-6haloalkoxy, and C1-6alkoxy; R11is hydrogen, halogen, or C1-6alkyl; RAis hydrogen or C1-6alkyl; and RBis hydrogen or C1-6alkyl.

[0127] In some embodiments, R4is selected from the group consisting of bromo, chloro, fluoro, -CF3, cyclopropyl,.

[0128] In some embodiments, R4is bromo or chloro.

[0129] In some embodiments, R4is bromo.

[0130] In some embodiments, R4is chloro.

[0131] In some embodiments, R5is hydrogen or fluoro.

[0132] In some embodiments, R5is hydrogen.

[0133] In some embodiments, R5is fluoro.

[0134] In some embodiments, R4is bromo or chloro and R5is hydrogen.

[0135] In some embodiments, R4is bromo and R5is hydrogen. R4is chloro and R5is hydrogen.

[0136] In some embodiments, X1is CR6, X2is CR7, and X3is CR8.

[0137] In some embodiments, X1 is CR6, X2 is N, and X3 is CR8.

[0138] In some embodiments, X1is N, X2is CR7, and X3is CR8.

[0139] In some embodiments, R6is selected from the group consisting of hydrogen, cyano, chloro, fluoro, hydroxyl, -CF3, -O-CH3, -O-CH2-CH3, -O-CHF2, -O-CF3, cyclopropyl, and.

[0140] In some embodiments, R6is selected from the group consisting of chloro, fluoro, CF3, and -O-CH3.

[0141] In some embodiments, R7is selected from the group consisting of hydrogen, cyano, chloro, fluoro, -CH3, -CF3, cyclopropyl, -O-cyclopropyl, morpholinyl, and.

[0142] In some embodiments, R7is hydrogen or fluoro.

[0143] In some embodiments, R7is hydrogen.

[0144] In some embodiments, R7is fluoro.

[0145] In some embodiments, R8is hydrogen or fluoro.

[0146] In some embodiments, R8is hydrogen.

[0147] In some embodiments, R8is fluoro.

[0148] In certain embodiments, R6is selected from the group consisting of chloro, fluoro, CF3, and -O-CH3; R7is hydrogen or fluoro; and R8is hydrogen or fluoro.

[0149] In some embodiments, R6and R7are taken together, along with the atoms to which they are attached, to form a 5 membered heteroaryl or a 5 membered heterocyclyl.

[0150] In some embodiments, R7and R8may be taken together, along with the atoms to which they are attached, to form a 5-6 membered carbocyclyl.

[0151] In some embodiments, X1is CR6, X2is CR7, and X3is CR8, wherein R6is selected from the group consisting of chloro, fluoro, CF3, and -O-CH3; R7is hydrogen or fluoro; and R8is hydrogen or fluoro.

[0152] In some embodiments, X4 is CH, X5 is CR9, X6 is CR10, and X7 is CR11.

[0153] In some embodiments, X4 is CH, X5 is CR9, X6 is CR10, and X7 is CH.

[0154] In some embodiments, X4 is CH, X5 is N, X6 is CR10, and X7 is CR11.

[0155] In some embodiments, X4 is CH, X5 is CR9, X6 is N, and X7 is CR11.

[0156] In some embodiments, X4is CH, X5is CR9, X6is CR10, and X7is N.

[0157] In some embodiments, X4 is N, X5 is CR9, X6 is N, and X7 is CR11.

[0158] In some embodiments, R9is selected from the group consisting of hydrogen, cyano, bromo, fluoro, -CF3, -O-CH3, and -C(O)NH2.

[0159] In some embodiments, R9is fluoro, cyano, or -O-CH3.

[0160] In some embodiments, R10is selected from the group consisting of hydrogen, fluoro, -CHF2, -CF3, -O-CH3, and -O-CHF2.

[0161] In some embodiments, R10is selected from the group consisting of hydrogen, fluoro, CF3, -O-CHF2, and -O-CH3.

[0162] In some embodiments, R11is hydrogen, fluoro, or CH3.

[0163] In some embodiments, R11is hydrogen.

[0164] In some embodiments, R9is fluoro, cyano, or -O-CH3; R10is selected from the group consisting of hydrogen, fluoro, CF3, -O-CHF2, and -O-CH3; and R11is hydrogen.

[0165] In some embodiments, X4 is CH, X5 is CR9, X6 is CH, and X7 is CH, wherein R9is cyano or fluoro.

[0166] In some embodiments, X4 is CH, X5 is N, X6 is CR10, and X7 is CH, wherein R10is fluoro, CF3, -O-CHF2, and -O-CH3.

[0167] In some embodiments, X4 is CH, X5 is CR9, X6 is N, and X7 is CH, wherein R9is - O-CH3.

[0168] In some embodiments, the compound of formula (I), formula (Ia), formula (Ib), formula (Ic), formula (Id), or formula (Ie) is not a compound selected from the group consisting of: ,,,, , ,, .

[0169] In another aspect, provided herein is a compound selected from the group consisting of: 13-chloro-19,21-difluoro-14-hydroxy-16,16-dioxo-5-(trifluoromethyl)-9-oxa-16λ6-thia-4,17- diazatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2,4,6,11(23),12,14,18(22),19-nonaen-10- one; 13-chloro-4-fluoro-14-hydroxy-16,16-dioxo-20-(trifluoromethyl)-9-oxa-16λ6-thia-17- azatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2(7),3,5,11(23),12,14,18(22),19-nonaen-10- one;13-chloro-19,21-difluoro-14-hydroxy-16,16-dioxo-9-oxa-16λ6-thia-4,17- diazatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2(7),3,5,11,13,15(23),18(22),19-nonaen-10- one; 13-chloro-4-fluoro-14-hydroxy-16,16-dioxo-9-oxa-16λ6-thia-17,20- diazatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2(7),3,5,11,13,15(23),18(22),19-nonaen-10- one; 13-chloro-4-fluoro-14-hydroxy-19-methoxy-16,16-dioxo-9-oxa-16λ6-thia-17,20- diazatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2(7),3,5,11,13,15(23),18(22),19-nonaen-10- one; 13-chloro-19-cyclopropyl-4-fluoro-14-hydroxy-16,16-dioxo-9-oxa-16λ6-thia-17- azatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2(7),3,5,11,13,15(23),18(22),19-nonaen-10- one; 13-chloro-6,19-difluoro-14-hydroxy-16,16-dioxo-9-oxa-16λ6-thia-17- azatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2(7),3,5,11,13,15(23),18(22),19-nonaen-10- one; 13-chloro-4,20-difluoro-14-hydroxy-19-methoxy-16,16-dioxo-9-oxa-16λ6-thia-17- azatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2(7),3,5,11,13,15(23),18(22),19-nonaen-10- one; 13-chloro-19,21-difluoro-14-hydroxy-16,16-dioxo-9-oxa-16λ6-thia-5,17- diazatetracyclo[16.3.1.111,15.02,7]tricosa-1(22),2,4,6,11,13,15(23),18,20-nonaen-10-one; 13-chloro-5,19,21-trifluoro-14-hydroxy-16,16-dioxo-9-oxa-16λ6-thia-6,17- diazatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2(7),3,5,11,13,15(23),18(22),19-nonaen-10- one; 13-chloro-5,19,21-trifluoro-14-hydroxy-16,16-dioxo-9-oxa-16λ6-thia-4,17- diazatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2(7),3,5,11,13,15(23),18(22),19-nonaen-10- one; 13-chloro-5-fluoro-14-hydroxy-19-methoxy-16,16-dioxo-9-oxa-16λ6-thia-6,17- diazatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2(7),3,5,11,13,15(23),18(22),19-nonaen-10- one; 13-chloro-5-fluoro-14-hydroxy-19-methoxy-16,16-dioxo-9-oxa-16λ6-thia-4,17- diazatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2(7),3,5,11,13,15(23),18(22),19-nonaen-10- one;13-chloro-19,21-difluoro-14-hydroxy-5-methoxy-16,16-dioxo-9-oxa-16λ6-thia-4,17- diazatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2(7),3,5,11,13,15(23),18(22),19-nonaen-10- one; 13-chloro-4-fluoro-14-hydroxy-19-methoxy-16,16-dioxo-9-oxa-16λ6-thia-5,17- diazatetracyclo[16.3.1.111,15.02,7]tricosa-1(22),2(7),3,5,11,13,15(23),18,20-nonaen-10-one; 13,19-dichloro-14-hydroxy-5-methoxy-16,16-dioxo-9-oxa-16λ6-thia-4,17- diazatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2,4,6,11,13,15(23),18(22),19-nonaen-10- one; 13-chloro-4-fluoro-14-hydroxy-19-methoxy-20-methyl-16,16-dioxo-9-oxa-16λ6-thia-17- azatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2,4,6,11,13,15(23),18(22),19-nonaen-10-one; 13,19-dichloro-5-fluoro-14-hydroxy-16,16-dioxo-9-oxa-16λ6-thia-4,17- diazatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2(7),3,5,11,13,15(23),18(22),19-nonaen-10- one; 13-chloro-19-(3,3-difluoroazetidin-1-yl)-5-fluoro-14-hydroxy-16,16-dioxo-9-oxa-16λ6-thia- 4,17-diazatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2(7),3,5,11,13,15(23),18(22),19- nonaen-10-one; 13-chloro-5,19,20-trifluoro-14-hydroxy-16,16-dioxo-9-oxa-16λ6-thia-17- azatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2,4,6,11,13,15(23),18(22),19-nonaen-10-one; 13-chloro-4-fluoro-14-hydroxy-19-methoxy-16,16-dioxo-9-oxa-16λ6-thia-17- azatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2,4,6,11,13,15(23),18(22),19-nonaen-10-one; 13-chloro-20,21-difluoro-14-hydroxy-16,16-dioxo-9-oxa-16λ6-thia-17- azatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2,4,6,11(23),12,14,18(22),19-nonaen-10-one; 13-chloro-21-fluoro-14-hydroxy-16,16-dioxo-9-oxa-16λ6-thia-17- azatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2(7),3,5,11,13,15(23),18(22),19-nonaen-10- one; 13-chloro-4,5-difluoro-14-hydroxy-19-methoxy-16,16-dioxo-9-oxa-16λ6-thia-17- azatetracyclo[16.3.1.111,15.02,7]tricosa-1(22),2(7),3,5,11,13,15(23),18,20-nonaen-10-one; 13-chloro-5,19,21-trifluoro-14-hydroxy-16,16-dioxo-9-oxa-16λ6-thia-17- azatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2,4,6,11(23),12,14,18(22),19-nonaen-10-one; 13-chloro-4,19,21-trifluoro-14-hydroxy-6-methyl-16,16-dioxo-9-oxa-16λ6-thia-17- azatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2(7),3,5,11(23),12,14,18(22),19-nonaen-10- one; 13-chloro-19,21-difluoro-14-hydroxy-16,16-dioxo-5-(trifluoromethyl)-9-oxa-16λ6-thia-17- azatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2,4,6,11,13,15(23),18(22),19-nonaen-10-one;13-chloro-19,21-difluoro-14-hydroxy-16,16-dioxo-4-(trifluoromethyl)-9-oxa-16λ6-thia-17- azatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2,4,6,11,13,15(23),18(22),19-nonaen-10-one; 4-bromo-13-chloro-19,21-difluoro-14-hydroxy-16,16-dioxo-9-oxa-16λ6-thia-17- azatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2,4,6,11,13,15(23),18(22),19-nonaen-10-one; 13-chloro-20-cyclopropyl-5-fluoro-14-hydroxy-16,16-dioxo-9-oxa-16λ6-thia-17- azatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2(7),3,5,11,13,15(23),18(22),19-nonaen-10- one; 13-chloro-4-fluoro-14-hydroxy-16,16-dioxo-19-(trifluoromethoxy)-9-oxa-16λ6-thia-17- azatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2,4,6,11(23),12,14,18(22),19-nonaen-10-one; 13-bromo-20-fluoro-14-hydroxy-19-methoxy-16,16-dioxo-5-(trifluoromethyl)-9-oxa-16λ6- thia-4,17-diazatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2(7),3,5,11,13,15(23),18(22),19- nonaen-10-one; 13-bromo-4-fluoro-14-hydroxy-19-methoxy-16,16-dioxo-9-oxa-16λ6-thia-17,20- diazatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2(7),3,5,11(23),12,14,18(22),19-nonaen-10- one; 13-bromo-14-hydroxy-19-methoxy-10,16,16-trioxo-9-oxa-16λ6-thia-17,20- diazatetracyclo[16.3.1.111,15.02,7]tricosa-1(22),2(7),3,5,11,13,15(23),18,20-nonaene-4- carbonitrile; 13-bromo-14-hydroxy-19-methoxy-16,16-dioxo-5-(trifluoromethyl)-9-oxa-16λ6-thia- 4,17,20-triazatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2(7),3,5,11,13,15(23),18(22),19- nonaen-10-one; 13-bromo-19,21-difluoro-14-hydroxy-16,16-dioxo-5-(trifluoromethyl)-9-oxa-16λ6-thia-17- azatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2(7),3,5,11,13,15(23),18(22),19-nonaen-10- one; 13-bromo-14-hydroxy-19-methoxy-10,16,16-trioxo-9-oxa-16λ6-thia-17- azatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2(7),3,5,11,13,15(23),18(22),19-nonaene-4- carbonitrile; 13-bromo-19,21-difluoro-14-hydroxy-16,16-dioxo-5-(trifluoromethyl)-9-oxa-16λ6-thia-4,17- diazatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2(7),3,5,11,13,15(23),18(22),19-nonaen-10- one; 13-bromo-20-fluoro-14-hydroxy-19-methoxy-10,16,16-trioxo-9-oxa-16λ6-thia-17- azatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2(7),3,5,11,13,15(23),18(22),19-nonaene-4- carbonitrile;13-bromo-14-hydroxy-19-methoxy-16,16-dioxo-5-(trifluoromethyl)-9-oxa-16λ6-thia-4,17- diazatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2(7),3,5,11,13,15(23),18(22),19-nonaen-10- one; 13-bromo-21-fluoro-14-hydroxy-19-methoxy-16,16-dioxo-5-(trifluoromethyl)-9-oxa-16λ6- thia-4,17-diazatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2(7),3,5,11,13,15(23),18(22),19- nonaen-10-one; 13-bromo-19,21-difluoro-14-hydroxy-16,16-dioxo-5-(trifluoromethyl)-9-oxa-16λ6-thia-6,17- diazatetracyclo[16.3.1.111,15.02,7]tricosa-1(22),2(7),3,5,11,13,15(23),18,20-nonaen-10-one; 13-bromo-21-fluoro-14-hydroxy-19-methoxy-10,16,16-trioxo-9-oxa-16λ6-thia-17- azatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2(7),3,5,11,13,15(23),18(22),19-nonaene-4- carbonitrile; 13-bromo-14-hydroxy-19-methoxy-20-methyl-16,16-dioxo-5-(trifluoromethyl)-9-oxa-16λ6- thia-4,17-diazatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2(7),3,5,11,13,15(23),18(22),19- nonaen-10-one; 13-bromo-20-chloro-14-hydroxy-19-methoxy-16,16-dioxo-5-(trifluoromethyl)-9-oxa-16λ6- thia-4,17-diazatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2,4,6,11(23),12,14,18(22),19- nonaen-10-one; 13-bromo-14-hydroxy-19-methoxy-20-methyl-10,16,16-trioxo-9-oxa-16λ6-thia-17- azatetracyclo[16.3.1.111,15.02,7]tricosa-1(22),2(7),3,5,11,13,15(23),18,20-nonaene-4- carbonitrile; 13-bromo-5-fluoro-14-hydroxy-19-methoxy-16,16-dioxo-9-oxa-16λ6-thia-4,17- diazatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2(7),3,5,11,13,15(23),18(22),19-nonaen-10- one; 13-bromo-19,21-difluoro-14-hydroxy-5-methoxy-16,16-dioxo-9-oxa-16λ6-thia-4,17- diazatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2,4,6,11(23),12,14,18(22),19-nonaen-10- one; 13-bromo-19,21-difluoro-14-hydroxy-4-methoxy-16,16-dioxo-9-oxa-16λ6-thia-5,17- diazatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2,4,6,11(23),12,14,18(22),19-nonaen-10- one; 13-bromo-14-hydroxy-5,19-dimethoxy-16,16-dioxo-9-oxa-16λ6-thia-4,17- diazatetracyclo[16.3.1.111,15.02,7]tricosa-1(22),2(7),3,5,11,13,15(23),18,20-nonaen-10-one; 13-bromo-20-fluoro-14-hydroxy-5,19-dimethoxy-16,16-dioxo-9-oxa-16λ6-thia-4,17- diazatetracyclo[16.3.1.111,15.02,7]tricosa-1(22),2(7),3,5,11,13,15(23),18,20-nonaen-10-one;13-bromo-21-fluoro-14-hydroxy-4,19-dimethoxy-16,16-dioxo-9-oxa-16λ6-thia-5,17- diazatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2(7),3,5,11,13,15(23),18(22),19-nonaen-10- one; 13-bromo-20-fluoro-14-hydroxy-4,19-dimethoxy-16,16-dioxo-9-oxa-16λ6-thia-5,17- diazatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2(7),3,5,11,13,15(23),18(22),19-nonaen-10- one; 13-bromo-19,21-difluoro-14-hydroxy-5-methoxy-16,16-dioxo-9-oxa-16λ6-thia-6,17- diazatetracyclo[16.3.1.111,15.02,7]tricosa-1(22),2(7),3,5,11,13,15(23),18,20-nonaen-10-one; 13-bromo-14-hydroxy-5,19-dimethoxy-20-methyl-16,16-dioxo-9-oxa-16λ6-thia-4,17- diazatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2(7),3,5,11,13,15(23),18(22),19-nonaen-10- one; 13-bromo-14-hydroxy-5-methoxy-16,16-dioxo-19-(trifluoromethoxy)-9-oxa-16λ6-thia-4,17- diazatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2(7),3,5,11,13,15(23),18(22),19-nonaen-10- one; 13-bromo-19-chloro-14-hydroxy-4-methoxy-16,16-dioxo-9-oxa-16λ6-thia-5,17- diazatetracyclo[16.3.1.111,15.02,7]tricosa-1(22),2(7),3,5,11,13,15(23),18,20-nonaen-10-one; 13-bromo-20-chloro-14-hydroxy-4,19-dimethoxy-16,16-dioxo-9-oxa-16λ6-thia-5,17- diazatetracyclo[16.3.1.111,15.02,7]tricosa-1(22),2(7),3,5,11,13,15(23),18,20-nonaen-10-one; 13-bromo-14-hydroxy-4,19-dimethoxy-16,16-dioxo-9-oxa-16λ6-thia-5,17,20- triazatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2(7),3,5,11,13,15(23),18(22),19-nonaen-10- one; 13-bromo-21-fluoro-14-hydroxy-5,19-dimethoxy-16,16-dioxo-9-oxa-16λ6-thia-4,17- diazatetracyclo[16.3.1.111,15.02,7]tricosa-1(22),2,4,6,11(23),12,14,18,20-nonaen-10-one; 13-bromo-5-(difluoromethoxy)-14-hydroxy-19-methoxy-16,16-dioxo-9-oxa-16λ6-thia- 4,17,20-triazatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2(7),3,5,11,13,15(23),18(22),19- nonaen-10-one; 13-bromo-5-(difluoromethoxy)-21-fluoro-14-hydroxy-19-methoxy-16,16-dioxo-9-oxa-16λ6- thia-4,17-diazatetracyclo[16.3.1.111,15.02,7]tricosa-1(22),2(7),3,5,11,13,15(23),18,20- nonaen-10-one; 12-bromo-4-(difluoromethyl)-13-hydroxy-18-methoxy-15,15-dioxo-8-oxa-15λ6-thia- 4,5,16,19-tetrazatetracyclo[15.3.1.110,14.02,6]docosa-1(20),2,5,10(22),11,13,17(21),18- octaen-9-one;12-bromo-4-(2,2-difluoroethyl)-18,20-difluoro-13-hydroxy-15,15-dioxo-8-oxa-15λ6-thia- 4,5,16-triazatetracyclo[15.3.1.110,14.02,6]docosa-1(20),2,5,10(22),11,13,17(21),18-octaen- 9-one; 12-bromo-5-(2,2-difluoroethyl)-18,20-difluoro-13-hydroxy-15,15-dioxo-8-oxa-15λ6-thia- 4,5,16-triazatetracyclo[15.3.1.110,14.02,6]docosa-1(20),2(6),3,10(22),11,13,17(21),18- octaen-9-one; 13-bromo-20-fluoro-14-hydroxy-19-methoxy-10,16,16-trioxo-9-oxa-16λ6-thia-5,17- diazatetracyclo[16.3.1.111,15.02,7]tricosa-1(22),2(7),3,5,11,13,15(23),18,20-nonaene-4- carbonitrile; 13-bromo-20-fluoro-14-hydroxy-19-methoxy-10,16,16-trioxo-9-oxa-16λ6-thia-5,17- diazatetracyclo[16.3.1.111,15.02,7]tricosa-1(22),2(7),3,5,11,13,15(23),18,20-nonaene-4- carboxamide; 13-bromo-4,19,21-trifluoro-14-hydroxy-16,16-dioxo-9-oxa-16λ6-thia-17- azatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2,4,6,11,13,15(23),18(22),19-nonaen-10-one; 13-bromo-14-hydroxy-19-methoxy-16,16-dioxo-5-(trifluoromethyl)-9-oxa-16λ6-thia-17- azatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2(7),3,5,11,13,15(23),18(22),19-nonaen-10- one; 13-bromo-14-hydroxy-19-methoxy-16,16-dioxo-4-(trifluoromethyl)-9-oxa-16λ6-thia-17- azatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2(7),3,5,11,13,15(23),18(22),19-nonaen-10- one; 13-chloro-19,21-difluoro-14-hydroxy-16,16-dioxo-4-(trifluoromethyl)-9-oxa-16λ6-thia- 3,5,17-triazatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2(7),3,5,11,13,15(23),18(22),19- nonaen-10-one; 13-chloro-14-hydroxy-5-methoxy-16,16-dioxo-19-(trifluoromethyl)-9-oxa-16λ6-thia- 4,17,20-triazatetracyclo[16.3.1.111,15.02,7]tricosa-1(22),2(7),3,5,11,13,15(23),18,20- nonaen-10-one; 12-chloro-18,20-difluoro-13-hydroxy-15,15-dioxo-8-oxa-5,15λ6-dithia-3,16- diazatetracyclo[15.3.1.110,14.02,6]docosa-1(20),2(6),3,10,12,14(22),17(21),18-octaen-9-one; 12-chloro-18,20-difluoro-13-hydroxy-4-methyl-15,15-dioxo-8-oxa-3,15λ6-dithia-5,16- diazatetracyclo[15.3.1.110,14.02,6]docosa-1(20),2(6),4,10,12,14(22),17(21),18-octaen-9-one; 12-chloro-18,20-difluoro-13-hydroxy-15,15-dioxo-8-oxa-3,15λ6-dithia-5,16- diazatetracyclo[15.3.1.110,14.02,6]docosa-1(20),2(6),4,10,12,14(22),17(21),18-octaen-9-one; 12-chloro-18,20-difluoro-13-hydroxy-15,15-dioxo-4,8-dioxa-15λ6-thia-5,16- diazatetracyclo[15.3.1.110,14.02,6]docosa-1(21),2,5,10,12,14(22),17,19-octaen-9-one;12-chloro-19-fluoro-13-hydroxy-18-methoxy-15,15-dioxo-4-(trifluoromethyl)-8-oxa-3,15λ6- dithia-5,16-diazatetracyclo[15.3.1.110,14.02,6]docosa-1(21),2(6),4,10(22),11,13,17,19- octaen-9-one; 13-chloro-5-(difluoromethoxy)-19,21-difluoro-14-hydroxy-16,16-dioxo-9-oxa-16λ6-thia- 4,17-diazatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2(7),3,5,11,13,15(23),18(22),19- nonaen-10-one; 13-chloro-5,20-difluoro-14-hydroxy-19-methoxy-16,16-dioxo-9-oxa-16λ6-thia-4,17- diazatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2(7),3,5,11,13,15(23),18(22),19-nonaen-10- one; 13-chloro-5,21-difluoro-14-hydroxy-19-methoxy-16,16-dioxo-9-oxa-16λ6-thia-4,17- diazatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2(7),3,5,11,13,15(23),18(22),19-nonaen-10- one; 13-chloro-19-ethoxy-5-fluoro-14-hydroxy-16,16-dioxo-9-oxa-16λ6-thia-4,17- diazatetracyclo[16.3.1.111,15.02,7]tricosa-1(22),2(7),3,5,11(23),12,14,18,20-nonaen-10-one; 13-chloro-5-fluoro-14-hydroxy-19-methoxy-20-methyl-16,16-dioxo-9-oxa-16λ6-thia-4,17- diazatetracyclo[16.3.1.111,15.02,7]tricosa-1(22),2(7),3,5,11,13,15(23),18,20-nonaen-10-one; 5,19-dichloro-11-fluoro-20-hydroxy-2,2-dioxo-15-oxa-2λ6,6-dithia-3,10- diazatetracyclo[15.3.1.14,7.08,13]docosa-1(21),4,7(22),8,10,12,17,19-octaen-16-one; 5,19-dichloro-20-hydroxy-11-methoxy-2,2-dioxo-15-oxa-2λ6,6-dithia-3,10- diazatetracyclo[15.3.1.14,7.08,13]docosa-1(21),4,7(22),8,10,12,17,19-octaen-16-one; 13-chloro-4-fluoro-14-hydroxy-16,16-dioxo-9-oxa-16λ6-thia-17,19- diazatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2(7),3,5,11,13,15(23),18(22),19-nonaen-10- one; 13-chloro-5-fluoro-14-hydroxy-10,16,16-trioxo-9-oxa-16λ6-thia-4,17- diazatetracyclo[16.3.1.111,15.02,7]tricosa-1(22),2(7),3,5,11,13,15(23),18,20-nonaene-19- carbonitrile; 13-chloro-4-fluoro-14-hydroxy-16,16-dioxo-19-(trifluoromethyl)-9-oxa-16λ6-thia-17- azatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2,4,6,11(23),12,14,18(22),19-nonaen-10-one; 12-chloro-18,20-difluoro-13-hydroxy-4-methyl-15,15-dioxo-8-oxa-15λ6-thia-4,5,16- triazatetracyclo[15.3.1.110,14.02,6]docosa-1(20),2,5,10,12,14(22),17(21),18-octaen-9-one; 12-chloro-18,20-difluoro-13-hydroxy-15,15-dioxo-4-(trifluoromethyl)-8-oxa-3,15λ6-dithia- 5,16-diazatetracyclo[15.3.1.110,14.02,6]docosa-1(21),2(6),4,10,12,14(22),17,19-octaen-9- one;13-bromo-5,19,21-trifluoro-14-hydroxy-16,16-dioxo-9-oxa-16λ6-thia-6,17- diazatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2(7),3,5,11,13,15(23),18(22),19-nonaen-10- one; 13-bromo-5-fluoro-14-hydroxy-19-methoxy-16,16-dioxo-9-oxa-16λ6-thia-6,17- diazatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2(7),3,5,11,13,15(23),18(22),19-nonaen-10- one; 13-bromo-5-(difluoromethoxy)-20-fluoro-14-hydroxy-19-methoxy-16,16-dioxo-9-oxa-16λ6- thia-4,17-diazatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2(7),3,5,11,13,15(23),18(22),19- nonaen-10-one; 12-bromo-18,20-difluoro-13-hydroxy-4-methyl-15,15-dioxo-8-oxa-15λ6-thia-4,5,16- triazatetracyclo[15.3.1.110,14.02,6]docosa-1(20),2,5,10(22),11,13,17(21),18-octaen-9-one; 12-bromo-13-hydroxy-18-methoxy-4-methyl-15,15-dioxo-8-oxa-15λ6-thia-4,5,16- triazatetracyclo[15.3.1.110,14.02,6]docosa-1(20),2,5,10(22),11,13,17(21),18-octaen-9-one; 12-bromo-4-(difluoromethyl)-18,20-difluoro-13-hydroxy-15,15-dioxo-8-oxa-15λ6-thia- 4,5,16-triazatetracyclo[15.3.1.110,14.02,6]docosa-1(20),2,5,10(22),11,13,17(21),18-octaen- 9-one; 12-bromo-18,20-difluoro-13-hydroxy-4-(2-methoxyethyl)-15,15-dioxo-8-oxa-15λ6-thia- 4,5,16-triazatetracyclo[15.3.1.110,14.02,6]docosa-1(21),2,5,10,12,14(22),17,19-octaen-9- one; 19-bromo-5-chloro-20-hydroxy-10-methoxy-2,2-dioxo-15-oxa-2λ6,6-dithia-3,11- diazatetracyclo[15.3.1.14,7.08,13]docosa-1(21),4,7(22),8,10,12,17,19-octaen-16-one; 19-bromo-5-chloro-20-hydroxy-2,2-dioxo-11-(trifluoromethyl)-15-oxa-2λ6,6-dithia-3,10- diazatetracyclo[15.3.1.14,7.08,13]docosa-1(21),4,7(22),8,10,12,17,19-octaen-16-one; 19-bromo-20-hydroxy-2,2-dioxo-11-(trifluoromethyl)-15-oxa-2λ6,6-dithia-3,10- diazatetracyclo[15.3.1.14,7.08,13]docosa-1(21),4,7(22),8,10,12,17,19-octaen-16-one; 19-bromo-11-fluoro-20-hydroxy-2,2-dioxo-15-oxa-2λ6,5-dithia-3,10- diazatetracyclo[15.3.1.14,7.08,13]docosa-1(21),4(22),6,8,10,12,17,19-octaen-16-one; 12-bromo-18,20-difluoro-13-hydroxy-5-methyl-15,15-dioxo-8-oxa-15λ6-thia-4,5,16- triazatetracyclo[15.3.1.110,14.02,6]docosa-1(20),2(6),3,10,12,14(22),17(21),18-octaen-9- one; 13-cyclopropyl-4,19,21-trifluoro-14-hydroxy-16,16-dioxo-9-oxa-16λ6-thia-17- azatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2,4,6,11(23),12,14,18(22),19-nonaen-10-one;13-(3,6-dihydro-2H-pyran-4-yl)-4,19,21-trifluoro-14-hydroxy-16,16-dioxo-9-oxa-16λ6-thia- 17-azatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2,4,6,11(23),12,14,18(22),19-nonaen-10- one; 4,19,21-trifluoro-14-hydroxy-16,16-dioxo-13-tetrahydropyran-4-yl-9-oxa-16λ6-thia-17- azatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2,4,6,11(23),12,14,18(22),19-nonaen-10-one; 13-bromo-19-chloro-21-fluoro-14-hydroxy-4-methoxy-16,16-dioxo-9-oxa-16λ6-thia-5,17- diazatetracyclo[16.3.1.111,15.02,7]tricosa-1(22),2(7),3,5,11,13,15(23),18,20-nonaen-10-one; 19-bromo-5-chloro-20-hydroxy-2,2,16-trioxo-15-oxa-2λ6,6-dithia-3- azatetracyclo[15.3.1.14,7.08,13]docosa-1(21),4,7(22),8,10,12,17,19-octaene-10-carbonitrile; 13-bromo-14-hydroxy-10,16,16-trioxo-19-(trifluoromethyl)-9-oxa-16λ6-thia-17- azatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2(7),3,5,11,13,15(23),18(22),19-nonaene-4- carbonitrile; 13-bromo-4-fluoro-14-hydroxy-10,16,16-trioxo-9-oxa-16λ6-thia-17- azatetracyclo[16.3.1.111,15.02,7]tricosa-1(22),2,4,6,11(23),12,14,18,20-nonaene-19- carbonitrile; 12-bromo-18-chloro-13-hydroxy-15,15-dioxo-4-(trifluoromethyl)-8-oxa-3,15λ6-dithia-5,16- diazatetracyclo[15.3.1.110,14.02,6]docosa-1(21),2(6),4,10,12,14(22),17,19-octaen-9-one; 13-bromo-19-chloro-14-hydroxy-10,16,16-trioxo-9-oxa-16λ6-thia-17- azatetracyclo[16.3.1.111,15.02,7]tricosa-1(22),2(7),3,5,11,13,15(23),18,20-nonaene-4- carbonitrile; 13-bromo-14-hydroxy-4-methoxy-16,16-dioxo-19-(trifluoromethyl)-9-oxa-16λ6-thia-5,17- diazatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2,4,6,11(23),12,14,18(22),19-nonaen-10- one; 13-bromo-19-(difluoromethoxy)-14-hydroxy-5-methoxy-16,16-dioxo-9-oxa-16λ6-thia- 4,17,20-triazatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2(7),3,5,11,13,15(23),18(22),19- nonaen-10-one; 13-bromo-19-chloro-14-hydroxy-5-methoxy-16,16-dioxo-9-oxa-16λ6-thia-4,17- diazatetracyclo[16.3.1.111,15.02,7]tricosa-1(22),2,4,6,11(23),12,14,18,20-nonaen-10-one; 13-bromo-19-chloro-21-fluoro-14-hydroxy-5-methoxy-16,16-dioxo-9-oxa-16λ6-thia-4,17- diazatetracyclo[16.3.1.111,15.02,7]tricosa-1(22),2,4,6,11(23),12,14,18,20-nonaen-10-one; 13-bromo-19-cyclopropyl-14-hydroxy-16,16-dioxo-5-(trifluoromethyl)-9-oxa-16λ6-thia- 4,17-diazatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2,4,6,11(23),12,14,18(22),19-nonaen- 10-one;13-bromo-14-hydroxy-4-methoxy-10,16,16-trioxo-9-oxa-16λ6-thia-5,17- diazatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2(7),3,5,11,13,15(23),18(22),19-nonaene- 19-carbonitrile; 13-bromo-14-hydroxy-10,16,16-trioxo-19-(trifluoromethoxy)-9-oxa-16λ6-thia-17- azatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2(7),3,5,11,13,15(23),18(22),19-nonaene-4- carbonitrile; 13-bromo-20-fluoro-14-hydroxy-5-methoxy-10,16,16-trioxo-9-oxa-16λ6-thia-4,17- diazatetracyclo[16.3.1.111,15.02,7]tricosa-1(22),2(7),3,5,11,13,15(23),18,20-nonaene-19- carbonitrile; 13-bromo-19-cyclopropyl-14-hydroxy-10,16,16-trioxo-9-oxa-16λ6-thia-17- azatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2,4,6,11(23),12,14,18(22),19-nonaene-4- carbonitrile; 13-bromo-5-(difluoromethyl)-19,21-difluoro-14-hydroxy-16,16-dioxo-9-oxa-16λ6-thia-4,17- diazatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2(7),3,5,11(23),12,14,18(22),19-nonaen-10- one; 13-bromo-19-chloro-21-fluoro-14-hydroxy-16,16-dioxo-5-(trifluoromethyl)-9-oxa-16λ6-thia- 4,17-diazatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2(7),3,5,11(23),12,14,18(22),19- nonaen-10-one; 13-bromo-20-chloro-14-hydroxy-19-methoxy-10,16,16-trioxo-9-oxa-16λ6-thia-17- azatetracyclo[16.3.1.111,15.02,7]tricosa-1(22),2,4,6,11(23),12,14,18,20-nonaene-4- carbonitrile; 4,13-dibromo-14-hydroxy-16,16-dioxo-19-(trifluoromethyl)-9-oxa-16λ6-thia-17- azatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2(7),3,5,11,13,15(23),18(22),19-nonaen-10- one; 12-bromo-4-(difluoromethyl)-19-fluoro-13-hydroxy-18-methoxy-15,15-dioxo-8-oxa-15λ6- thia-4,5,16-triazatetracyclo[15.3.1.110,14.02,6]docosa-1(20),2,5,10(22),11,13,17(21),18- octaen-9-one; 13-bromo-14-hydroxy-10,16,16-trioxo-19-(trifluoromethyl)-9-oxa-16λ6-thia-17,20- diazatetracyclo[16.3.1.111,15.02,7]tricosa-1(22),2(7),3,5,11,13,15(23),18,20-nonaene-4- carbonitrile; 14-chloro-4,20,22-trifluoro-15-hydroxy-17,17-dioxo-10-oxa-17λ6-thia-18- azatetracyclo[17.3.1.112,16.02,7]tetracosa-1(22),2(7),3,5,12,14,16(24),19(23),20-nonaen-11- one;14-chloro-4,20,21-trifluoro-15-hydroxy-17,17-dioxo-10-oxa-17λ6-thia-18- azatetracyclo[17.3.1.112,16.02,7]tetracosa-1(22),2(7),3,5,12,14,16(24),19(23),20-nonaen-11- one; 14-chloro-4-fluoro-15-hydroxy-20-methoxy-17,17-dioxo-10-oxa-17λ6-thia-18- azatetracyclo[17.3.1.112,16.02,7]tetracosa-1(22),2(7),3,5,12(24),13,15,19(23),20-nonaen-11- one; 14-chloro-4,22-difluoro-15-hydroxy-20-methoxy-17,17-dioxo-10-oxa-17λ6-thia-18- azatetracyclo[17.3.1.112,16.02,7]tetracosa-1(22),2,4,6,12,14,16(24),19(23),20-nonaen-11- one; 14-chloro-4-fluoro-15-hydroxy-17,17-dioxo-10-oxa-17λ6-thia-18,22,23- triazapentacyclo[17.6.1.112,16.02,7.020,24]heptacosa-1(26),2(7),3,5,12,14,16(27),19,21,24- decaen-11-one; 14-chloro-4-fluoro-15-hydroxy-11,17,17-trioxo-10-oxa-17λ6-thia-18- azatetracyclo[17.3.1.112,16.02,7]tetracosa-1(22),2,4,6,12,14,16(24),19(23),20-nonaene-21- carbonitrile; 14-chloro-5-fluoro-15-hydroxy-20-methoxy-17,17-dioxo-10-oxa-17λ6-thia-4,18- diazatetracyclo[17.3.1.112,16.02,7]tetracosa-1(23),2(7),3,5,12(24),13,15,19,21-nonaen-11- one; 14-chloro-20-cyclopropyl-5-fluoro-15-hydroxy-17,17-dioxo-10-oxa-17λ6-thia-4,18- diazatetracyclo[17.3.1.112,16.02,7]tetracosa-1(23),2(7),3,5,12(24),13,15,19,21-nonaen-11- one; 14-chloro-5,20,22-trifluoro-15-hydroxy-17,17-dioxo-10-oxa-17λ6-thia-4,18- diazatetracyclo[17.3.1.112,16.02,7]tetracosa-1(23),2(7),3,5,12(24),13,15,19,21-nonaen-11- one; 14-chloro-5-fluoro-15-hydroxy-17,17-dioxo-20-(trifluoromethoxy)-10-oxa-17λ6-thia-4,18- diazatetracyclo[17.3.1.112,16.02,7]tetracosa-1(23),2(7),3,5,12(24),13,15,19,21-nonaen-11- one; 14-bromo-4,20,22-trifluoro-15-hydroxy-17,17-dioxo-10-oxa-17λ6-thia-18- azatetracyclo[17.3.1.112,16.02,7]tetracosa-1(22),2(7),3,5,12,14,16(24),19(23),20-nonaen-11- one; 14-chloro-20,22-difluoro-15-hydroxy-4-methoxy-17,17-dioxo-10-oxa-17λ6-thia-18- azatetracyclo[17.3.1.112,16.02,7]tetracosa-1(22),2,4,6,12,14,16(24),19(23),20-nonaen-11- one;14-chloro-21-cyclopropyl-5-fluoro-15-hydroxy-17,17-dioxo-10-oxa-17λ6-thia-18- azatetracyclo[17.3.1.112,16.02,7]tetracosa-1(22),2,4,6,12,14,16(24),19(23),20-nonaen-11- one; 11-chloro-3,5-difluoro-10-hydroxy-8,8-dioxo-15-oxa-8λ6-thia-7- azapentacyclo[14.6.1.12,6.19,13.019,23]pentacosa-1(23),2,4,6(25),9(24),10,12,19,21- nonaen-14-one; 14-chloro-21-(cyclopropoxy)-4-fluoro-15-hydroxy-17,17-dioxo-10-oxa-17λ6-thia-18- azatetracyclo[17.3.1.112,16.02,7]tetracosa-1(23),2(7),3,5,12,14,16(24),19,21-nonaen-11-one; 14-chloro-4-fluoro-15-hydroxy-21-(3-methoxyazetidin-1-yl)-17,17-dioxo-10-oxa-17λ6-thia- 18-azatetracyclo[17.3.1.112,16.02,7]tetracosa-1(23),2(7),3,5,12,14,16(24),19,21-nonaen-11- one; 14-chloro-4-fluoro-15-hydroxy-21-morpholino-17,17-dioxo-10-oxa-17λ6-thia-18- azatetracyclo[17.3.1.112,16.02,7]tetracosa-1(23),2(7),3,5,12,14,16(24),19,21-nonaen-11-one; 14-chloro-4-fluoro-15-hydroxy-17,17-dioxo-10,21-dioxa-17λ6-thia-18- azapentacyclo[17.6.1.112,16.02,7.020,24]heptacosa-1(26),2(7),3,5,12,14,16(27),19,24- nonaen-11-one; 14-chloro-5-fluoro-15-hydroxy-17,17-dioxo-10-oxa-17λ6-thia-18- azapentacyclo[17.6.1.112,16.02,7.021,25]heptacosa-1(25),2,4,6,12,14,16(27),19(26),20- nonaen-11-one; 4-bromo-14-chloro-15-hydroxy-20-methoxy-17,17-dioxo-10-oxa-17λ6-thia-18- azatetracyclo[17.3.1.112,16.02,7]tetracosa-1(22),2(7),3,5,12,14,16(24),19(23),20-nonaen-11- one; 13-bromo-19,21-difluoro-14-hydroxy-4-methyl-16,16-dioxo-9-oxa-3,16λ6-dithia-5,17- diazatetracyclo[16.3.1.111,15.02,6]tricosa-1(22),2(6),4,11,13,15(23),18,20-octaen-10-one; 14-chloro-4-fluoro-15-hydroxy-17,17-dioxo-20-(trifluoromethyl)-10-oxa-17λ6-thia-18- azatetracyclo[17.3.1.112,16.02,7]tetracosa-1(23),2(7),3,5,12,14,16(24),19,21-nonaen-11-one; 14-chloro-5-fluoro-15-hydroxy-17,17-dioxo-20-(trifluoromethyl)-10-oxa-17λ6-thia-4,18- diazatetracyclo[17.3.1.112,16.02,7]tetracosa-1(23),2(7),3,5,12,14,16(24),19,21-nonaen-11- one; 5-fluoro-15-hydroxy-20-methoxy-17,17-dioxo-14-(trifluoromethyl)-10-oxa-17λ6-thia-4,18- diazatetracyclo[17.3.1.112,16.02,7]tetracosa-1(22),2(7),3,5,12,14,16(24),19(23),20-nonaen- 11-one;5,14-difluoro-15-hydroxy-20-methoxy-17,17-dioxo-10-oxa-17λ6-thia-4,18- diazatetracyclo[17.3.1.112,16.02,7]tetracosa-1(23),2(7),3,5,12(24),13,15,19,21-nonaen-11- one; 15-chloro-4,21,23-trifluoro-16-hydroxy-18,18-dioxo-8,11-dioxa-18λ6-thia-19- azatetracyclo[18.3.1.113,17.02,7]pentacosa-1(23),2(7),3,5,13,15,17(25),20(24),21-nonaen- 12-one; 15-chloro-22-fluoro-16-hydroxy-18,18-dioxo-8,11-dioxa-18λ6-thia-19- azatetracyclo[18.3.1.113,17.02,7]pentacosa-1(23),2(7),3,5,13,15,17(25),20(24),21-nonaen- 12-one; 4-bromo-15-chloro-16-hydroxy-21-methoxy-18,18-dioxo-8,11-dioxa-18λ6-thia-19- azatetracyclo[18.3.1.113,17.02,7]pentacosa-1(23),2(7),3,5,13,15,17(25),20(24),21-nonaen- 12-one; 15-chloro-5-fluoro-16-hydroxy-21-methoxy-18,18-dioxo-8,11-dioxa-18λ6-thia-4,19- diazatetracyclo[18.3.1.113,17.02,7]pentacosa-1(24),2(7),3,5,13,15,17(25),20,22-nonaen-12- one; 13-chloro-4,19,21-trifluoro-14-hydroxy-8-methyl-16,16-dioxo-9-oxa-16λ6-thia-17- azatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2(7),3,5,11,13,15(23),18(22),19-nonaen-10- one; 12-bromo-18,20-difluoro-13-hydroxy-4,7-dimethyl-15,15-dioxo-8-oxa-15λ6-thia-4,5,16- triazatetracyclo[15.3.1.110,14.02,6]docosa-1(21),2,5,10,12,14(22),17,19-octaen-9-one; 15-chloro-21,23-difluoro-16-hydroxy-18,18-dioxo-11,26-dioxa-18λ6-thia-19- azapentacyclo[18.3.1.16,9.113,17.02,7]hexacosa-1(24),2(7),3,5,13(25),14,16,20,22-nonaen- 12-one; 13-chloro-4-fluoro-8-(fluoromethyl)-14-hydroxy-19-methoxy-16,16-dioxo-9-oxa-16λ6-thia- 17-azatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2,4,6,11(23),12,14,18(22),19-nonaen-10- one; 13-chloro-5-fluoro-14-hydroxy-19-methoxy-8-methyl-16,16-dioxo-9-oxa-16λ6-thia-4,17- diazatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2,4,6,11(23),12,14,18(22),19-nonaen-10- one; 13-bromo-5-fluoro-14-hydroxy-19-methoxy-8-methyl-16,16-dioxo-9-oxa-16λ6-thia-4,17- diazatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2,4,6,11(23),12,14,18(22),19-nonaen-10- one;13-chloro-5,20-difluoro-14-hydroxy-19-methoxy-8-methyl-16,16-dioxo-9-oxa-16λ6-thia- 4,17-diazatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2,4,6,11(23),12,14,18(22),19-nonaen- 10-one; 22-chloro-5,7-difluoro-20-methyl-2,2-dioxo-2λ6-thia-3,19,20- triazapentacyclo[16.5.2.14,8.09,14.021,25]hexacosa- 1(24),4,6,8(26),9(14),10,12,18,21(25),22-decaen-23-ol; 22-chloro-5,7-difluoro-2,2-dioxo-20-oxa-2λ6-thia-3,19- diazapentacyclo[16.5.2.14,8.09,14.021,25]hexacosa- 1(24),4(26),5,7,9(14),10,12,18,21(25),22-decaen-23-ol; 22-chloro-5,7-difluoro-2,2-dioxo-2λ6-thia-3,19,20- triazapentacyclo[16.5.2.14,8.09,14.021,25]hexacosa- 1(24),4(26),5,7,9(14),10,12,18,21(25),22-decaen-23-ol; 14-chloro-13,20,22-trifluoro-15-hydroxy-17,17-dioxo-17λ6-thia-18- azatetracyclo[17.3.1.112,16.02,7]tetracosa-1(22),2(7),3,5,12(24),13,15,19(23),20-nonaen-11- one; 22-chloro-5-methoxy-2,2-dioxo-20-oxa-2λ6-thia-3,19- diazapentacyclo[16.5.2.14,8.09,14.021,25]hexacosa-1(23),4(26),5,7,9(14),10,12,18,21,24- decaen-23-ol; 22-chloro-5,7,12-trifluoro-2,2-dioxo-20-oxa-2λ6-thia-3,11,19- triazapentacyclo[16.5.2.14,8.09,14.021,25]hexacosa-1(23),4(26),5,7,9(14),10,12,18,21,24- decaen-23-ol; 22-chloro-7,12-difluoro-5-methoxy-2,2-dioxo-20-oxa-2λ6-thia-3,19- diazapentacyclo[16.5.2.14,8.09,14.021,25]hexacosa-1(23),4(26),5,7,9(14),10,12,18,21,24- decaen-23-ol; 22-bromo-7,12-difluoro-5-methoxy-2,2-dioxo-20-oxa-2λ6-thia-3,11,19- triazapentacyclo[16.5.2.14,8.09,14.021,25]hexacosa- 1(24),4(26),5,7,9(14),10,12,18,21(25),22-decaen-23-ol; 22-chloro-5,7-difluoro-12-methoxy-2,2-dioxo-20-oxa-2λ6-thia-3,11,19- triazapentacyclo[16.5.2.14,8.09,14.021,25]hexacosa- 1(24),4(26),5,7,9(14),10,12,18,21(25),22-decaen-23-ol; 22-chloro-11-fluoro-5-methoxy-2,2-dioxo-20-oxa-2λ6-thia-3,19- diazapentacyclo[16.5.2.14,8.09,14.021,25]hexacosa- 1(24),4(26),5,7,9(14),10,12,18,21(25),22-decaen-23-ol;21-chloro-7,12-difluoro-5-methoxy-2,2-dioxo-19-oxa-2λ6-thia-3,18- diazapentacyclo[15.5.2.14,8.09,14.020,24]pentacosa-1(22),4(25),5,7,9(14),10,12,17,20,23- decaen-22-ol; 21-chloro-5,7,12-trifluoro-2,2-dioxo-19-oxa-2λ6-thia-3,11,18- triazapentacyclo[15.5.2.14,8.09,14.020,24]pentacosa-1(22),4(25),5,7,9(14),10,12,17,20,23- decaen-22-ol; 11-chloro-3,5-difluoro-10-hydroxy-8,8-dioxo-15-oxa-8λ6-thia-7- azapentacyclo[14.6.1.12,6.19,13.019,23]pentacosa-1(23),2,4,6(25),9(24),10,12,19,21- nonaen-14-one, Enantiomer 1; 11-chloro-3,5-difluoro-10-hydroxy-8,8-dioxo-15-oxa-8λ6-thia-7- azapentacyclo[14.6.1.12,6.19,13.019,23]pentacosa-1(23),2,4,6(25),9(24),10,12,19,21- nonaen-14-one, Enantiomer 2; 13-chloro-4,19,21-trifluoro-14-hydroxy-8-methyl-16,16-dioxo-9-oxa-16λ6-thia-17- azatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2(7),3,5,11,13,15(23),18(22),19-nonaen-10- one, Enantiomer 1; 13-Chloro-4,19,21-trifluoro-14-hydroxy-8-methyl-16,16-dioxo-9-oxa-16λ6-thia-17- azatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2(7),3,5,11,13,15(23),18(22),19-nonaen-10- one, Enantiomer 2; 13-chloro-5-fluoro-14-hydroxy-19-methoxy-8-methyl-16,16-dioxo-9-oxa-16λ6-thia-4,17- diazatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2,4,6,11(23),12,14,18(22),19-nonaen-10- one, Enantiomer 1; 13-chloro-5-fluoro-14-hydroxy-19-methoxy-8-methyl-16,16-dioxo-9-oxa-16λ6-thia-4,17- diazatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2,4,6,11(23),12,14,18(22),19-nonaen-10- one, Enantiomer 2; 13-bromo-5-fluoro-14-hydroxy-19-methoxy-8-methyl-16,16-dioxo-9-oxa-16λ6-thia-4,17- diazatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2,4,6,11(23),12,14,18(22),19-nonaen-10- one, Enantiomer 1; 13-bromo-5-fluoro-14-hydroxy-19-methoxy-8-methyl-16,16-dioxo-9-oxa-16λ6-thia-4,17- diazatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2,4,6,11(23),12,14,18(22),19-nonaen-10- one, Enantiomer 2; 13-chloro-4-fluoro-8-(fluoromethyl)-14-hydroxy-19-methoxy-16,16-dioxo-9-oxa-16λ6-thia- 17-azatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2,4,6,11(23),12,14,18(22),19-nonaen-10- one, Enantiomer 1;13-chloro-4-fluoro-8-(fluoromethyl)-14-hydroxy-19-methoxy-16,16-dioxo-9-oxa-16λ6-thia- 17-azatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2,4,6,11(23),12,14,18(22),19-nonaen-10- one, Enantiomer 2; 12-bromo-18,20-difluoro-13-hydroxy-4,7-dimethyl-15,15-dioxo-8-oxa-15λ6-thia-4,5,16- triazatetracyclo[15.3.1.110,14.02,6]docosa-1(21),2,5,10,12,14(22),17,19-octaen-9-one, Enantiomer 1; 12-bromo-18,20-difluoro-13-hydroxy-4,7-dimethyl-15,15-dioxo-8-oxa-15λ6-thia-4,5,16- triazatetracyclo[15.3.1.110,14.02,6]docosa-1(21),2,5,10,12,14(22),17,19-octaen-9-one, Enantiomer 2; 13-chloro-5,20-difluoro-14-hydroxy-19-methoxy-8-methyl-16,16-dioxo-9-oxa-16λ6-thia- 4,17-diazatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2,4,6,11(23),12,14,18(22),19-nonaen- 10-one, Enantiomer 1; 13-chloro-5,20-difluoro-14-hydroxy-19-methoxy-8-methyl-16,16-dioxo-9-oxa-16λ6-thia- 4,17-diazatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2,4,6,11(23),12,14,18(22),19-nonaen- 10-one, Enantiomer 2; 13-bromo-21-fluoro-14-hydroxy-10,16,16-trioxo-19-(trifluoromethyl)-9-oxa-16λ6-thia-17- azatetracyclo[16.3.1.111,15.02,7]tricosa-1(22),2,4,6,11(23),12,14,18,20-nonaene-4- carbonitrile; 13-bromo-20-fluoro-14-hydroxy-10,16,16-trioxo-19-(trifluoromethyl)-9-oxa-16λ6-thia-17- azatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2,4,6,11(23),12,14,18(22),19-nonaene-4- carbonitrile; 13-bromo-14-hydroxy-4-methoxy-16,16-dioxo-19-(trifluoromethyl)-9-oxa-16λ6-thia-17- azatetracyclo[16.3.1.111,15.02,7]tricosa-1(22),2,4,6,11(23),12,14,18,20-nonaen-10-one; 13-bromo-19-chloro-14-hydroxy-5-methoxy-20-methyl-16,16-dioxo-9-oxa-16λ6-thia-4,17- diazatetracyclo[16.3.1.111,15.02,7]tricosa-1(22),2(7),3,5,11,13,15(23),18,20-nonaen-10-one; 13-bromo-14-hydroxy-5-methoxy-16,16-dioxo-19-(trifluoromethyl)-9-oxa-16λ6-thia-4,17- diazatetracyclo[16.3.1.111,15.02,7]tricosa-1(22),2(7),3,5,11,13,15(23),18,20-nonaen-10-one; 13-bromo-19-chloro-20-fluoro-14-hydroxy-4-methoxy-16,16-dioxo-9-oxa-16λ6-thia-5,17- diazatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2,4,6,11(23),12,14,18(22),19-nonaen-10- one; 13-bromo-14-hydroxy-10,16,16-trioxo-5-(trifluoromethyl)-9-oxa-16λ6-thia-4,17- diazatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2(7),3,5,11,13,15(23),18(22),19-nonaene- 19-carbonitrile;13-bromo-21-fluoro-14-hydroxy-5-methoxy-10,16,16-trioxo-9-oxa-16λ6-thia-4,17- diazatetracyclo[16.3.1.111,15.02,7]tricosa-1(22),2(7),3,5,11,13,15(23),18,20-nonaene-19- carbonitrile; 13-bromo-20-fluoro-14-hydroxy-4,19-dimethoxy-16,16-dioxo-9-oxa-16λ6-thia-17- azatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2(7),3,5,11,13,15(23),18(22),19-nonaen-10- one; 12-bromo-18-chloro-4-(difluoromethyl)-20-fluoro-13-hydroxy-15,15-dioxo-8-oxa-15λ6-thia- 4,5,16-triazatetracyclo[15.3.1.110,14.02,6]docosa-1(20),2,5,10(22),11,13,17(21),18-octaen- 9-one; 13-bromo-20-fluoro-14,19-dihydroxy-16,16-dioxo-5-(trifluoromethyl)-9-oxa-16λ6-thia-4,17- diazatetracyclo[16.3.1.111,15.02,7]tricosa-1(22),2(7),3,5,11,13,15(23),18,20-nonaen-10-one; 13-bromo-20-fluoro-14,19-dihydroxy-10,16,16-trioxo-9-oxa-16λ6-thia-17- azatetracyclo[16.3.1.111,15.02,7]tricosa-1(22),2(7),3,5,11,13,15(23),18,20-nonaene-4- carbonitrile; 12-bromo-4-(difluoromethyl)-13-hydroxy-18-(trifluoromethyl)-15,15-dioxo-8-oxa-15λ6-thia- 4,5,16-triazatetracyclo[15.3.1.1(10,14).0(2,6)]docosa-1(20),2,5,10(22),11,13,17(21),18- octaen-9-one; 12-bromo-18-(difluoromethoxy)-4-(difluoromethyl)-13-hydroxy-15,15-dioxo-8-oxa-15λ6- thia-4,5,16,19-tetrazatetracyclo[15.3.1.1(10,14).0(2,6)]docosa- 1(20),2,5,10(22),11,13,17(21),18-octaen-9-one; 12-bromo-4-(difluoromethyl)-13-hydroxy-18-(trifluoromethyl)-15,15-dioxo-8-oxa-15λ6-thia- 4,5,16,19-tetrazatetracyclo[15.3.1.1(10,14).0(2,6)]docosa-1(20),2,5,10(22),11,13,17(21),18- octaen-9-one; 12-bromo-13-hydroxy-18-methoxy-4-(trifluoromethyl)-15,15-dioxo-8-oxa-15λ6-thia- 4,5,16,19-tetrazatetracyclo[15.3.1.1(10,14).0(2,6)]docosa-1(20),2,5,10(22),11,13,17(21),18- octaen-9-one; 12-bromo-13-hydroxy-18-methoxy-4-(trifluoromethyl)-15,15-dioxo-8-oxa-15λ6-dithia- 5,16,19-triazatetracyclo[15.3.1.1(10,14).0(2,6)]docosa-1(20),2(6),4,10(22),11,13,17(21),18- octaen-9-one; 12-chloro-4-(difluoromethyl)-13-hydroxy-18-methoxy-15,15-dioxo-8-oxa-15λ6-thia- 4,5,16,19-tetrazatetracyclo[15.3.1.1(10,14).0(2,6)]docosa-1(20),2,5,10(22),11,13,17(21),18- octaen-9-one;12-bromo-4-(difluoromethyl)-13-hydroxy-18-(trifluoromethoxy)-15,15-dioxo-8-oxa-15λ6- thia-4,5,16,19-tetrazatetracyclo[15.3.1.1(10,14).0(2,6)]docosa- 1(20),2,5,10(22),11,13,17(21),18-octaen-9-one; 12-bromo-4-(difluoromethyl)-13-hydroxy-18-methoxy-15,15-dioxo-8-oxa-15λ6-thia-4,5,16- triazatetracyclo[15.3.1.1(10,14).0(2,6)]docosa-1(20),2,5,10(22),11,13,17(21),18-octaen-9- one; 12-bromo-18-chloro-4-(difluoromethyl)-13-hydroxy-15,15-dioxo-8-oxa-15λ6-thia-4,5,16- triazatetracyclo[15.3.1.1(10,14).0(2,6)]docosa-1(20),2,5,10(22),11,13,17(21),18-octaen-9- one; 12-bromo-19-chloro-4-(difluoromethyl)-13-hydroxy-18-methoxy-15,15-dioxo-8-oxa-15λ6- thia-4,5,16-triazatetracyclo[15.3.1.1(10,14).0(2,6)]docosa-1(20),2,5,10(22),11,13,17(21),18- octaen-9-one; 12-bromo-18-chloro-4-(difluoromethyl)-19-fluoro-13-hydroxy-15,15-dioxo-8-oxa-15λ6-thia- 4,5,16-triazatetracyclo[15.3.1.1(10,14).0(2,6)]docosa-1(20),2,5,10(22),11,13,17(21),18- octaen-9-one; 13-bromo-19-chloro-5-fluoro-14-hydroxy-16,16-dioxo-9-oxa-16λ6-thia-4,17- diazatetracyclo[16.3.1.1(11,15).0(2,7)]tricosa-1(21),2,4,6,11(23),12,14,18(22),19-nonaen-10- one; 13-bromo-5,20-difluoro-14-hydroxy-19-methoxy-16,16-dioxo-9-oxa-16λ6-thia-4,17- diazatetracyclo[16.3.1.1(11,15).0(2,7)]tricosa-1(21),2,4,6,11(23),12,14,18(22),19-nonaen-10- one; 13-bromo-5-fluoro-14-hydroxy-19-methoxy-16,16-dioxo-9-oxa-16λ6-thia-4,17,20- triazatetracyclo[16.3.1.1(11,15).0(2,7)]tricosa-1(21),2,4,6,11(23),12,14,18(22),19-nonaen-10- one; or a pharmaceutically acceptable salt thereof.

[0170] In some embodiments, the compound of formula (I), formula (Ia), formula (Ib), formula (Ic), formula (Id), or formula (Ie), is one or more compounds selected from Table 1:Table 1. List of compounds.                     Pharmaceutical Compositions and Routes of Administration

[0171] Compounds provided in accordance with the present disclosure are usually administered in the form of pharmaceutical compositions. This invention therefore provides pharmaceutical compositions that contain, as the active ingredient, one or more of the compounds described herein (e.g., a compound of formula (I), formula (Ia), formula (Ib), formula (Ic), formula (Id), or formula (Ie)), or a stereoisomer and / or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, carriers, including inert solid diluents and fillers, diluents, including sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers and adjuvants. The pharmaceutical compositions described herein may be administered alone or in combination with other therapeutic agents. Such compositions are prepared in a manner well known in the pharmaceutical art (see, e.g., Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa.17th Ed. (1985); and Modern Pharmaceutics, Marcel Dekker, Inc.3rd Ed. (G. S. Banker & C. T. Rhodes, Eds.)

[0172] The pharmaceutical compositions described herein may be administered in either single or multiple doses by any of the accepted modes of administration of agents having similar utilities, for example as described in those patents and patent applications incorporated by reference, including rectal, buccal, intranasal and transdermal routes, by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, as an inhalant, or via an impregnated or coated device such as a stent, for example, or an artery-inserted cylindrical polymer.

[0173] One mode for administration is parenteral, particularly by injection. The forms in which the novel compositions of the present disclosure may be incorporated for administration by injection include aqueous or oil suspensions, or emulsions, with sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueous solution, and similar pharmaceutical vehicles. Aqueous solutions in saline are also conventionally used for injection, but less preferred in the context of the present disclosure. Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, and the like (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils may also be employed. The proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.

[0174] Sterile injectable solutions are prepared by incorporating a compound according to the present disclosure in the required amount in the appropriate solvent with various other ingredients as enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum-drying and freeze- drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.

[0175] Oral administration is another route for administration of compounds in accordance with the disclosure. Administration may be via capsule or enteric coated tablets, or the like. In making the pharmaceutical compositions that include at least one compound described herein, the active ingredient is usually diluted by an excipient and / or enclosed within such a carrier that can be in the form of a capsule, sachet, paper, or other container. When the excipient serves as a diluent, it can be in the form of a solid, semi-solid, or liquid material (as above), which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injectable solutions, and sterile packaged powders.

[0176] Some examples of suitable excipients include, but are not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methyl cellulose. The formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl and propylhydroxy- benzoates; sweetening agents; and flavoring agents.

[0177] The compositions of the disclosure can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art. Controlled release drug delivery systems for oral administration include osmotic pump systems and dissolutional systems containing polymer- coated reservoirs or drug-polymer matrix formulations. Examples of controlled release systems are given in U.S. Pat. Nos.3,845,770; 4,326,525; 4,902,514; and 5,616,345. Another formulation for use in the methods of the present disclosure employs transdermal delivery devices ("patches"). Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds of the present disclosure in controlled amounts. The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, e.g., U.S. Pat. Nos.5,023,252, 4,992,445 and 5,001,139. Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.

[0178] The compositions are preferably formulated in a unit dosage form. The term "unit dosage forms" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient (e.g., a tablet, capsule, ampoule). The compounds are generally administered in a pharmaceutically effective amount. It will be understood, however, that the amount of the compound actually administered usually will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered and its relative activity, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.

[0179] For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound of the present disclosure. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient isdispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills, and capsules.

[0180] The tablets or pills of the present disclosure may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action, or to protect from the acid conditions of the stomach. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer that serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.

[0181] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra. Preferably, the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions in preferably pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be inhaled directly from the nebulizing device, or the nebulizing device may be attached to a facemask tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from devices that deliver the formulation in an appropriate manner.

[0182] In some embodiments, a pharmaceutical composition comprises a disclosed compound (e.g., a compound of formula (I), formula (Ia), formula (Ib), formula (Ic), formula (Id) or formula (Ie)), or a stereoisomer and / or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier. Methods of Treatment

[0183] In various embodiments, a compound disclosed herein (e.g., a compound of formula (I), formula (Ia), formula (Ib), formula (Ic), formula (Id) or formula (Ie)), or a stereoisomer thereof and / or a pharmaceutically acceptable salt thereof, including a pharmaceutical composition, may be used for the treatment or prevention of a variety of conditions, diseases, and disorders. The methods of treating a condition, disease, or disorder described herein generally comprise administering to a patient in need thereof, a therapeutically effectiveamount of a compound described herein (e.g., a compound of formula (I), formula (Ia), formula (Ib), formula (Ic), formula (Id) or formula (Ie)) or a stereoisomer and / or a pharmaceutically acceptable salt thereof, to treat the condition, disease, or disorder.

[0184] In typical embodiments, the present disclosure is intended to encompass a compound disclosed herein, or a stereoisomer thereof and / or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure includes an enantiomer, a mixture of enantiomers, a stereoisomer, or mixture of stereoisomers (pure or as a racemic or non- racemic mixture) of a compound described herein (e.g., a compound of formula (I), formula (Ia), formula (Ib), formula (Ic), formula (Id) or formula (Ie)).

[0185] Examples of conditions, diseases, and disorders include, but are not limited to, cardiovascular disease, atrial fibrillation, blood clotting, coronary heart disease, hypercoagulable states, ischemia, myocardial infarction, myopathy, myositis, pulmonary embolism, stroke, peripheral vascular disease, pulmonary hypertension, pulmonary arterial hypertension, dyslipidemia, dyslipoproteinemia, a disorder of glucose metabolism, Alzheimer’s disease, Parkinson’s disease, diabetic nephropathy, diabetic retinopathy, insulin resistance, metabolic syndrome disorders (e.g., Syndrome X), galactosemia, HIV infection, a peroxisome proliferator activated receptor-associated disorder, septicemia, a thrombotic disorder, obesity, pancreatitis, hypertension, renal disease, cancer, inflammation (e.g., liver inflammation), inflammatory muscle diseases (e.g., polymyalgia rheumatica, polymyositis, and fibrositis), impotence, gastrointestinal disease, irritable bowel syndrome, inflammatory bowel disease, inflammatory disorders (e.g., asthma, vasculitis, ulcerative colitis, Crohn’s disease, Kawasaki disease, Wegener’s granulomatosis, (RA), systemic lupus erythematosus (SLE), multiple sclerosis (MS), and autoimmune chronic hepatitis), arthritis (e.g., rheumatoid arthritis, juvenile rheumatoid arthritis, and osteoarthritis), osteoporosis, soft tissue rheumatism (e.g., tendonitis), bursitis, autoimmune disease (e.g., systemic lupus and erythematosus), scleroderma, ankylosing spondylitis, gout, pseudogout, non-insulin dependent diabetes mellitus, diabetes (e.g., type 2), polycystic ovarian disease, hyperlipidemias (e.g., primary hyperlipidemia, familial hypercholesterolemia (FH), Hypercholesterolemia Frederickson Type IIa, Hypercholesterolemia Frederickson Type IIb, familial combined hyperlipidemia (FCH)), lipoprotein lipase deficiencies (e.g., hypertriglyceridemia, hypoalphalipoproteinemia, and hypercholesterolemia), lipoprotein abnormalities associated with diabetes, lipoprotein abnormalities associated with obesity, and lipoprotein abnormalities associated with Alzheimer’s disease. In particular embodiments, themethods include treating and / or preventing hyperlipidemia such as primary hyperlipidemia. In some embodiments, the methods include treating and / or preventing cardiovascular disease.

[0186] In certain embodiments, a compound disclosed herein (e.g., a compound of formula (I), formula (Ia), formula (Ib), formula (Ic), formula (Id) or formula (Ie)), or a stereoisomer and / or a pharmaceutically acceptable salt thereof, including a pharmaceutical composition, may be used for the treatment or prevention of one or more of high levels of low density lipoprotein cholesterol (LDL-C), high levels of apolipoprotein B (apoB), high levels of lipoprotein(a) (Lp(a)), high levels of very low density lipoprotein (VLDL), high levels of non-high density lipid cholesterol (non-HDL-C), high levels of total serum cholesterol (TC), high levels of high sensitivity c-reactive protein (hsCRP), high levels of fibrinogen, high levels of insulin, high levels of glucose, and low levels of high density lipoprotein cholesterol (HDL-C). In other words, methods of the disclosure can include lowering LDL-C, lowering apoB, lowering Lp(a), lowering VLDL, lowering non-HDL-C, lowering TC, and / or lowering hsCRP. Methods of the disclosure can include inhibiting ACLY, inhibiting cholesterol synthesis, and / or suppressing fatty acid biosynthesis. In some embodiments, an effective amount of a compound described herein (e.g., a compound of formula (I), formula (Ia), formula (Ib), formula (Ic), formula (Id) or formula (Ie)), or a stereoisomer and / or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure may be used as an adjunct to diet and maximally tolerated statin therapy to lower LDL-C in adults with heterozygous familial hypercholesterolemia or established atherosclerotic cardiovascular disease. In some embodiments, an effective amount of a compound described herein (e.g., a compound of formula (I), formula (Ia), formula (Ib), formula (Ic), formula (Id) or formula (Ie)), or a stereoisomer and / or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure may be used for the treatment of non-insulin dependent diabetes mellitus without increasing weight gain.

[0187] In certain embodiments, a compound disclosed herein (e.g., a compound of formula (I), formula (Ia), formula (Ib), formula (Ic), formula (Id) or formula (Ie)), or a stereoisomer and / or a pharmaceutically acceptable salt thereof, including a pharmaceutical composition, may be used for the treatment or prevention of a variety of diseases and conditions, which include, but are not limited to aging, Alzheimer’s disease, cancer, cardiovascular disease, diabetic nephropathy, diabetic retinopathy, a disorder of glucose metabolism, dyslipidemia, dyslipoproteinemia, enhancing bile production, hypertension, impotence, inflammation, insulin resistance, lipid elimination in bile, modulating C reactive protein, obesity, oxysterolelimination in bile, pancreatitis, pancreatitius, Parkinson’s disease, a peroxisome proliferator activated receptor-associated disorder, phospholipid elimination in bile, renal disease, rhabdomyolysis, septicemia, sleep apnea, Syndrome X, and a thrombotic disorder.

[0188] In certain embodiments, provided herein is a method of treating a liver disorder selected from the group consisting of steatohepatitis, alcoholic liver disease, fatty liver, liver steatosis, liver cirrhosis, liver fibrosis, and acute fatty liver of pregnancy. In some embodiments, the disorder is steatohepatitis. In some embodiments, the steatohepatitis is NASH / MASH. In some embodiments, the disorder is alcoholic liver disease. In some embodiments, the disorder is fatty liver. In some embodiments, the disorder is liver steatosis, liver cirrhosis, or liver fibrosis. In some embodiments, the disorder is acute fatty liver of pregnancy. In some embodiments, the patient is an adult human.

[0189] In certain embodiments, the present disclosure provides a method for treating or preventing aging, Alzheimer’s disease, cancer, cardiovascular disease, diabetic nephropathy, diabetic retinopathy, a disorder of glucose metabolism, dyslipidemia, dyslipoproteinemia, enhancing bile production, enhancing reverse lipid transport, hypertension, impotence, inflammation, insulin resistance, lipid elimination in bile, modulating C reactive protein, obesity, oxysterol elimination in bile, pancreatitis, pancreatitius, Parkinson’s disease, a peroxisome proliferator activated receptor-associated disorder, phospholipid elimination in bile, renal disease, septicemia, metabolic syndrome disorders (e.g., Syndrome X), or a thrombotic disorder.

[0190] In certain embodiments, the disorder is selected from the group consisting of lipodystrophy, lysosomal acid lipase deficiency, and a glycogen storage disease. In some embodiments, the patient is an adult human.

[0191] In certain embodiments, the disorder is selected from the group consisting of hepatitis C, an infection by human immunodeficiency virus, an alpha 1-antitrypsin deficiency, Bassen-Kornzweig syndrome, hypobetalipoproteinemia, Celiac disease, Wilson’s disease, and Weber-Christian syndrome. In some embodiments, the disorder is hepatitis B. In some embodiments, the disorder is hepatitis C. In some embodiments, the disorder is an infection by human immunodeficiency virus. In some embodiments, the disorder is an alpha 1-antitrypsin deficiency. In some embodiments, the disorder is Bassen-Kornzweig syndrome. In some embodiments, the disorder is hypobetalipoproteinemia. In some embodiments, the disorder is Celiac disease or Wilson’s disease. In some embodiments, the disorder is Weber- Christian syndrome. In some embodiments, the patient is an adult human.

[0192] In certain embodiments, the condition is selected from the group consisting of toxic liver injury, total parenteral nutrition, severe surgical weight loss, environmental toxicity, malnutrition, and starvation. In some embodiments, the condition is toxic liver injury. In some embodiments, the condition is total parenteral nutrition or severe surgical weight loss. In some embodiments, the condition is environmental toxicity. In some embodiments, the condition is malnutrition or starvation. In some embodiments, the patient is an adult human.

[0193] In various embodiments, provided herein are methods of treating NAFLD / MAFLD in a subject in need thereof, the methods generally comprise administering to the subject a therapeutically effect amount of a compound disclosed herein (e.g., a compound of formula (I), formula (Ia), formula (Ib), formula (Ic), formula (Id) or formula (Ie)), or a stereoisomer thereof and / or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein.

[0194] In various embodiments, provided herein are methods of treating NASH / MASH in a subject in need thereof, the methods generally comprise administering to the subject a therapeutically effect amount of a compound disclosed herein (e.g., a compound of formula (I), formula (Ia), formula (Ib), formula (Ic), formula (Id) or formula (Ie)), or a stereoisomer thereof and / or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein.

[0195] In various embodiments, provided herein are methods of treating type-2 diabetes in a subject in need thereof, the methods generally comprise administering to the subject a therapeutically effect amount of a compound disclosed herein (e.g., a compound of formula (I), formula (Ia), formula (Ib), formula (Ic), formula (Id) or formula (Ie)), or a stereoisomer thereof and / or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein.

[0196] In various embodiments, provided herein are methods of treating inflammation in a subject in need thereof, the methods generally comprise administering to the subject a therapeutically effect amount of a compound disclosed herein (e.g., a compound of formula (I), formula (Ia), formula (Ib), formula (Ic), formula (Id) or formula (Ie)), or a stereoisomer thereof and / or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein.

[0197] In various embodiments, provided herein are methods of treating chronic kidney disease in a subject in need thereof, the methods generally comprise administering to the subject a therapeutically effect amount of a compound disclosed herein (e.g., a compound of formula (I), formula (Ia), formula (Ib), formula (Ic), formula (Id) or formula (Ie)), or astereoisomer thereof and / or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein.

[0198] In various embodiments, provided herein are methods of treating autoimmunity in a subject in need thereof, the methods generally comprise administering to the subject a therapeutically effect amount of a compound disclosed herein (e.g., a compound of formula (I), formula (Ia), formula (Ib), formula (Ic), formula (Id) or formula (Ie)), or a stereoisomer thereof and / or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein.

[0199] In various embodiments, provided herein are methods of treating cancer (e.g., a liver cancer) in a subject in need thereof, the methods generally comprise administering to the subject a therapeutically effect amount of a compound disclosed herein (e.g., a compound of formula (I), formula (Ia), formula (Ib), formula (Ic), formula (Id) or formula (Ie)), or a stereoisomer thereof and / or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein.

[0200] In certain embodiments, in order to prolong the effect of a drug, a compound described herein (e.g., a compound of formula (I), formula (Ia), formula (Ib), formula (Ic), formula (Id) or formula (Ie)), or a stereoisomer and / or a pharmaceutically acceptable salt thereof, is administered by subcutaneous or intramuscular injection, or by dissolving or suspending the drug in an oil vehicle.

[0201] In certain embodiments, the actual dosage level of a compound described herein (e.g., a compound of formula (I), formula (Ia), formula (Ib), formula (Ic), formula (Id) or formula (Ie)), or a stereoisomer and / or a pharmaceutically acceptable salt thereof, in the pharmaceutical compositions of the present disclosure may be varied so as to obtain an amount of the compound (e.g., a compound of formula (I), formula (Ia), formula (Ib), formula (Ic), formula (Id) or formula (Ie)), or a stereoisomer and / or a pharmaceutically acceptable salt thereof, which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.

[0202] In certain embodiments, the selected dosage level is dependent upon a variety of factors including the route of administration, the time of administration, the rate of excretion or metabolism of the particular compound being employed, the rate and extent of absorption, the duration of the treatment, other drugs, compounds and / or materials used in combination with the particular compound employed, the age, sex, weight, condition, general health andprior medical history of the patient being treated, and like factors well known in the medical arts.

[0203] In certain embodiments, a physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition as required.

[0204] In certain embodiments, a suitable daily dose of a compound described herein (e.g., a compound of formula (I), formula (Ia), formula (Ib), formula (Ic), formula (Id) or formula (Ie)), or a stereoisomer and / or a pharmaceutically acceptable salt thereof, will be an amount that corresponds to the lowest dose effective to produce a therapeutic effect. In certain embodiments, when a compound described herein (e.g., a compound of formula (I), formula (Ia), formula (Ib), formula (Ic), formula (Id) or formula (Ie)), or a stereoisomer and / or a pharmaceutically acceptable salt thereof, is co-administered with another therapeutic agent, the effective amount may be less than when the compound (e.g., a compound of formula (I), formula (Ia), formula (Ib), formula (Ic), formula (Id) or formula (Ie)), or a stereoisomer and / or a pharmaceutically acceptable salt thereof, is used in isolation.

[0205] In certain embodiments, the effective daily dose of a compound described herein (e.g., a compound of formula (I), formula (Ia), formula (Ib), formula (Ic), formula (Id) or formula (Ie)), or a stereoisomer and / or a pharmaceutically acceptable salt thereof, may be administered as two, three, four, five, six or more sub-doses. In certain embodiments, the two, three, four, five, six or more sub-doses are administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms. In some embodiments, dosing is one administration per day. In some embodiments, a compound described herein (e.g., a compound of formula (I), formula (Ia), formula (Ib), formula (Ic), formula (Id) or formula (Ie)), or a stereoisomer and / or a pharmaceutically acceptable salt thereof, is administered to a patient for 1 day, 5 days, 10 days, 20 days, 30 days, 1 week, 2 weeks, 3 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 1 year, 2 years, 3 years, 4 years, or 5 years. In some embodiments, a compound described herein (e.g., a compound of formula (I), formula (Ia), formula (Ib), formula (Ic), formula (Id) or formula (Ie)), or a stereoisomer and / or a pharmaceutically acceptable salt thereof, is administered to a patient for the duration of the patient’s life span.Combination Therapy

[0206] In various embodiments, a compound disclosed herein (e.g., a compound of formula (I), formula (Ia), formula (Ib), formula (Ic), formula (Id) or formula (Ie)), or a stereoisomer and / or a pharmaceutically acceptable salt thereof, including pharmaceutical compositions of the present disclosure, can be part of a combination therapy. In certain embodiments, the combination therapy comprises a compound described herein (e.g., a compound of formula (I), formula (Ia), formula (Ib), formula (Ic), formula (Id) or formula (Ie)), or a stereoisomer and / or a pharmaceutically acceptable salt thereof; and a second therapeutic agent. In certain embodiments, the combination therapy comprises a pharmaceutical composition comprising an effective amount of a compound described herein (e.g., a compound of formula (I), formula (Ia), formula (Ib), formula (Ic), formula (Id) or formula (Ie)), or a stereoisomer and / or a pharmaceutically acceptable salt thereof; and a second therapeutic agent.

[0207] In some embodiments, the second therapeutic agent is selected from the group comprising a lovastatin, a thiazolidinedione or fibrate, a bile-acid-binding-resin, a niacin, an anti-obesity drug, a hormone, an antiviral agent (e.g., to treat an underlying hepatitis C infection causing liver disease in the patient), an anticancer agent (e.g., to treat hepatocellular carcinoma or other cancer causing liver disease or fatty liver), an antioxidant, a medication that decreases insulin resistance, or a medication that improves lipid metabolism (e.g., treatments for hyperlipidemia), a tyrophostine, a sulfonylurea-based drug, a biguanide, an α- glucosidase inhibitor, an apolipoprotein A-I agonist, apolipoprotein E, a cardiovascular drug, an HDL-raising drug, an HDL enhancer, or a regulator of the apolipoprotein A-I, apolipoprotein A-IV and / or apolipoprotein genes.

[0208] In various embodiments, the second therapeutic agent can be bempedoic acid, a statin and / or ezetimibe.

[0209] In certain embodiments, the second therapeutic agent is bempedoic acid. In certain embodiments, the second therapeutic agent is ezetimibe. In certain embodiments, the second therapeutic agent is a statin. Examples of statins include, but are not limited to, atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin.

[0210] In certain embodiments, administering a pharmaceutical composition of the present disclosure comprising a compound described herein (e.g., a compound of formula (I), formula (Ia), formula (Ib), formula (Ic), formula (Id) or formula (Ie)), or a stereoisomer and / or a pharmaceutically acceptable salt thereof, and a second therapeutic agent is intended to provide a beneficial effect from the co-action of the compound (e.g., a compound of formula (I), formula (Ia), formula (Ib), formula (Ic), formula (Id) or formula (Ie)), or astereoisomer and / or a pharmaceutically acceptable salt thereof, and the second therapeutic agent. In some embodiments, the beneficial effect of the combination therapy may include pharmacokinetic or pharmacodynamic co-action resulting from the combination of the compound (e.g., a compound of formula (I), formula (Ia), formula (Ib), formula (Ic), formula (Id) or formula (Ie)), or a stereoisomer and / or a pharmaceutically acceptable salt thereof, and the second therapeutic agent. Kits

[0211] In various embodiments, the disclosure provides kits for treating a condition, disease or disorder described herein. In some embodiments, a kit comprises: i) instructions for treating a condition, disease or disorder, for example, as described herein, and ii) a compound described herein (e.g., a compound of formula (I), formula (Ia), formula (Ib), formula (Ic), formula (Id) or formula (Ie)), or a stereoisomer and / or a pharmaceutically acceptable salt thereof (e.g., a pharmaceutical composition comprising an effective amount of a compound described herein (e.g., a compound of formula (I), formula (Ia), formula (Ib), formula (Ic), formula (Id) or formula (Ie)), or a stereoisomer and / or a pharmaceutically acceptable salt thereof). In some embodiments, the kit may comprise one or more unit dosage forms containing an amount of a compound described herein (e.g., a compound of formula (I), formula (Ia), formula (Ib), formula (Ic), formula (Id) or formula (Ie)), or a stereoisomer and / or a pharmaceutically acceptable salt thereof, that is effective for treating the condition, disease, or disorder.

[0212] The description herein includes multiple aspects and embodiments of the present disclosure, including methods of making a compound described herein (e.g., a compound of formula (I), formula (Ia), formula (Ib), formula (Ic), formula (Id) or formula (Ie)), or a stereoisomer and / or a pharmaceutically acceptable salt thereof; methods of using a compound described herein (e.g., a compound of formula (I), formula (Ia), formula (Ib), formula (Ic), formula (Id) or formula (Ie)), or a stereoisomer and / or a pharmaceutically acceptable salt thereof; compositions comprising an effective amount of a compound described herein (e.g., a compound of formula (I), formula (Ia), formula (Ib), formula (Ic), formula (Id) or formula (Ie)), or a stereoisomer and / or a pharmaceutically acceptable salt thereof; and kits. The disclosure specifically includes all combinations and permutations of the aspects and embodiments as described herein.Enumerated Embodiments 1. A compound of formula (I)or a stereoisomer and / or a pharmaceutically acceptable salt thereof, wherein: Ring A is phenyl or 9-membered bicyclic heteroaryl; Ring B is phenyl or 5-6 membered heteroaryl; Ring C is selected from the group consisting of phenyl, 9-membered bicyclic heterocyclyl, 9-membered bicyclic carbocyclyl, and 5-6 membered heteroaryl; R1is independently, for each occurrence, selected from the group consisting of halogen, hydroxyl, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, and 6-membered heterocyclyl; R2is independently, for each occurrence, selected from the group consisting of halogen, cyano, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C1-6haloalkoxy, -O-C3-6cycloalkyl, and 4-6 membered heterocyclyl, wherein the 4-6 membered heterocyclyl is optionally substituted with one or more substituents independently selected from R2A; or optionally two R2may be taken together, along with the ring to which they are attached, to form a 9-membered bicyclic carbocyclyl, a 9-membered bicyclic heterocyclyl, or a 9-membered bicyclic heteroaryl; R3is independently, for each occurrence, selected from the group consisting of cyano, halogen, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, and -C(O)N(RA)(RB), wherein the C1-6alkyl is optionally substituted with one or more substituents independently selected from C1-6alkoxy; L1is *-S(O)2N(RC)-**, wherein * denotes the point of attachment to Ring A and ** denotes the point of attachment to Ring B; L2is selected from the group consisting of #-C(O)O-##, #-C(O)-(C1-6alkyl)-##, #- C(O)O-(C1-6alkyl)-##, #-C(O)O-(C1-6alkyl)-O-##, #-C(O)O-(C1-6haloalkyl)-##, and C1-6alkyl,wherein # denotes the point of attachment to Ring A and ## denotes the point of attachment to Ring C; R2Ais halogen or C1-6alkoxy; RAis hydrogen or C1-6alkyl; RBis hydrogen or C1-6alkyl; RCis hydrogen or C1-3alkyl; n is 2 or 3; o is 0, 1, or 2; and p is 0, 1, or 2. 2. The compound of embodiment 1, wherein Ring A is phenyl, indazolyl, or benzo[d]isoxazolyl. 3. The compound of embodiment 1 or 2, wherein Ring,, o , wherein Δ denotes the point ofattachment to L1and ΔΔ denotes the point of attachment to L2. 4. The compound of any one of embodiments 1-3, wherein L1is *-S(O)2N(H)-**, wherein * denotes the point of attachment to Ring A and ** denotes the point of attachment to Ring B. 5. A compound of formula (Ia)or a stereoisomer and / or a pharmaceutically acceptable salt thereof, wherein: Ring B is phenyl or 5-6 membered heteroaryl; Ring C is selected from the group consisting of phenyl, 9-membered bicyclic heterocyclyl, 9-membered bicyclic carbocyclyl, and 5-6 membered heteroaryl; R1is independently, for each occurrence, selected from the group consisting of halogen, hydroxyl, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, and 6-membered heterocyclyl; R2is independently, for each occurrence, selected from the group consisting of halogen, cyano, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C1-6haloalkoxy, -O-C3-6cycloalkyl, and 4-6 membered heterocyclyl, wherein the 4-6 membered heterocyclyl is optionally substituted with one or more substituents independently selected from R2A; or optionally two R2may be taken together, along with the ring to which they are attached, to form a 9-membered bicyclic carbocyclyl, a 9-membered bicyclic heterocyclyl, or a 9-membered bicyclic heteroaryl; R3is independently, for each occurrence, selected from the group consisting of cyano, halogen, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, and -C(O)N(RA)(RB), wherein the C1-6alkyl is optionally substituted with one or more substituents independently selected from C1-6alkoxy; L2is selected from the group consisting of #-C(O)O-##, #-C(O)-(C1-6alkyl)-##, #- C(O)O-(C1-6alkyl)-##, #-C(O)O-(C1-6alkyl)-O-##, #-C(O)O-(C1-6haloalkyl)-##, and C1-6alkyl, wherein # denotes the point of attachment to Ring A and ## denotes the point of attachment to Ring C; R2Ais halogen or C1-6alkoxy;RAis hydrogen or C1-6alkyl; RBis hydrogen or C1-6alkyl; n is 2 or 3; o is 1 or 2; and p is 0, 1, or 2. 6. The compound of any one of embodiments 1-5, wherein n is 2. 7. The compound of any one of embodiments 1-5, wherein n is 3. 8. The compound of any one of embodiments 1-7, wherein R1is, independently, for each occurrence, selected from the group consisting of bromo, chloro, fluoro, hydroxyl, -CH3, - CF3, cyclopropyl,9. A compound of formula (Ib)or a stereoisomer and / or a pharmaceutically acceptable salt thereof, wherein: Ring B is phenyl or 5-6 membered heteroaryl; Ring C is phenyl, 9-membered bicyclic heterocyclyl, 9-membered bicyclic carbocyclyl, C3-6cycloalkyl, or 5-6 membered heteroaryl;R2is independently, for each occurrence, selected from the group consisting of halogen, cyano, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C1-6haloalkoxy, -O-C3-6cycloalkyl, and 4-6 membered heterocyclyl, wherein the 4-6 membered heterocyclyl is optionally substituted with one or more substituents independently selected from R2A; or optionally two R2may be taken together, along with the ring to which they are attached, to form a 9-membered bicyclic carbocyclyl, a 9-membered bicyclic heterocyclyl, or a 9-membered bicyclic heteroaryl; R3is independently, for each occurrence, selected from the group consisting of cyano, halogen, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, and -C(O)N(RA)(RB), wherein the C1-6alkyl is optionally substituted with one or more substituents independently selected from C1-6alkoxy; R4is selected from the group consisting of halogen, C1-6haloalkyl, C3-6cycloalkyl, and 6-membered heterocyclyl; R5is hydrogen or halogen; L2is selected from the group consisting of #-C(O)O-##, #-C(O)-(C1-6alkyl)-##, #- C(O)O-(C1-6alkyl)-##, #-C(O)O-(C1-6alkyl)-O-##, #-C(O)O-(C1-6haloalkyl)-##, and C1-6alkyl, wherein # denotes the point of attachment to Ring A and ## denotes the point of attachment to Ring C; R2Ais halogen or C1-6alkoxy; RAis hydrogen or C1-6alkyl; RBis hydrogen or C1-6alkyl; o is 1 or 2; and p is 0, 1, or 2. 10. The compound of any one of embodiments 1-9, wherein Ring B is phenyl, thiophenyl, or pyridinyl. 11. The compound of any one of embodiments 1-10, wherein Ring B is selected from the group consisting of, , ,, wherein ● denotes the point of attachment to L1and ●● denotes the point of attachment to Ring C. 12. The compound of any one of embodiments 1-11, wherein o is 1. 13. The compound of any one of embodiments 1-11, wherein o is 2. 14. The compound of any one of embodiments 1-13, wherein R2is, independently, for each occurrence, selected from the group consisting of chloro, fluoro, cyano, -CH3, -CF3, -O- CH3, -O-CH2CH3, -O-CHF2, -O-CF3, cyclopropyl, -O-cyclopropyl, morpholinyl, and, optionally substituted with one or more substituents independently selected from fluoro and -O-CH3. 15. The compound of any one of embodiments 1-14, wherein R2is, independently, for each occurrence, selected from the group consisting of chloro, fluoro, cyano, -CH3, -CF3, -O- CH3, -O-CH2CH3, -O-CHF2, -O-CF3, cyclopropyl, -O-cyclopropyl, morpholinyl,, . 16. The compound of any one of embodiments 1-11 and 13, wherein two R2groups on different carbon atoms are taken together, along with the atoms to which they are attached, to form a 5 membered carbocyclyl, a 5-membered heterocyclyl, or a 5-membered heteroaryl. 17. The compound of any one of embodiments 1-11, wherein o is 0.18. A compound of formula (Ic)or a stereoisomer and / or a pharmaceutically acceptable salt thereof, wherein: Ring C is selected from the group consisting of phenyl, 9-membered bicyclic heterocyclyl, 9-membered bicyclic carbocyclyl, and 5-6 membered heteroaryl; R3is independently, for each occurrence, selected from the group consisting of cyano, halogen, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, and -C(O)N(RA)(RB), wherein the C1-6alkyl is optionally substituted with one or more substituents independently selected from C1-6alkoxy; R4is selected from the group consisting of halogen, C1-6haloalkyl, C3-6cycloalkyl, and 6-membered heterocyclyl; R5is hydrogen or halogen; X1is CR6or N; X2 is CR7or N; X3is CR8or N; R6is selected from the group consisting of hydrogen, cyano, halogen, C1-6alkoxy, C1-6haloalkyl, C1-6haloalkoxy, C3-6cycloalkyl, and 4-6 membered heterocyclyl, wherein the 4-6 membered heterocyclyl is optionally substituted with one or more substituents independently selected from halogen; R7is selected from the group consisting of hydrogen, cyano, halogen, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -O-C3-6cycloalkyl, and 4-6 membered heterocyclyl, wherein the 4- 6 membered heterocyclyl is optionally substituted with C1-6alkoxy; orR6and R7may be taken together, along with the ring to which they are attached, to form a 9-membered bicyclic heteroaryl or a 9-membered bicyclic heterocyclyl; R8is hydrogen or halogen; or R7and R8may be taken together, along with the ring to which they are attached, to form a 9-membered bicyclic carbocyclyl; L2is selected from the group consisting of #-C(O)O-##, #-C(O)-(C1-6alkyl)-##, #- C(O)O-(C1-6alkyl)-##, #-C(O)O-(C1-6alkyl)-O-##, #-C(O)O-(C1-6haloalkyl)-##, and C1-6alkyl, wherein # denotes the point of attachment to Ring A and ## denotes the point of attachment to Ring C; RAis hydrogen or C1-6alkyl; RBis hydrogen or C1-6alkyl; and p is 0, 1, or 2. 19. The compound of any one of embodiments 1-18, wherein Ring C is selected from the group consisting of cyclopropyl, phenyl, pyridinyl, thiazolyl, pyrimidinyl, pyrazolyl, isoxazolyl,20. The compound of any one of embodiments 1-19, wherein Ring C is selected from the, , , wherein □ denotes the point of attachment to Ring B and □□denotes the point of attachment to L2. 21. The compound of any one of embodiments 1-20, wherein p is 1. 22. The compound of any one of embodiments 1-20, wherein p is 2. 23. The compound of any one of embodiments 1-22, wherein R3is, independently, for each occurrence, selected from the group consisting of cyano, bromo, fluoro, -CH3, -CHF2, - CF3, -O-CH3, -O-CHF2, -CH2CH2-O-CH3, -C(O)NH2, and -CH2CHF2. 24. The compound of any one of embodiments 1-20, wherein p is 0. 25. A compound of formula (Id)or a stereoisomer and / or a pharmaceutically acceptable salt thereof, wherein: R4is selected from the group consisting of halogen, C1-6haloalkyl, C3-6cycloalkyl, and 6-membered heterocyclyl; R5is hydrogen or halogen; X1 is CR6or N; X2is CR7or N; X3 is CR8or N; X4is CH or N; X5 is CR9or N; X6is CR10or N; X7 is CR11or N; R6is selected from the group consisting of hydrogen, cyano, halogen, C1-6alkoxy, C1-6haloalkyl, C1-6haloalkoxy, C3-6cycloalkyl, and 4-6 membered heterocyclyl, wherein the 4-6 membered heterocyclyl is optionally substituted with one or more substituents independently selected from halogen; R7is selected from the group consisting of hydrogen, cyano, halogen, C1-6alkyl, C1- 6haloalkyl, C3-6cycloalkyl, -O-C3-6cycloalkyl, and 4-6 membered heterocyclyl, wherein the 4- 6 membered heterocyclyl is optionally substituted with C1-6alkoxy; or R6and R7may be taken together, along with the ring to which they are attached, to form a 9-membered bicyclic heteroaryl or a 9-membered bicyclic heterocyclyl; R8is hydrogen or halogen; or R7and R8may be taken together, along with the ring to which they are attached, to form a 9-membered bicyclic carbocyclyl; R9is selected from the group consisting of hydrogen, cyano, halogen, C1-6haloalkyl, - C(O)N(RA)(RB), and C1-6alkoxy; R10is selected from the group consisting of hydrogen, halogen, C1-6haloalkyl, C1-6haloalkoxy, and C1-6alkoxy; R11is hydrogen, halogen, or C1-6alkyl; and L2is selected from the group consisting of #-C(O)O-##, #-C(O)-(C1-6alkyl)-##, #- C(O)O-(C1-6alkyl)-##, #-C(O)O-(C1-6alkyl)-O-##, #-C(O)O-(C1-6haloalkyl)-##, and C1-6alkyl, wherein # denotes the point of attachment to Ring A and ## denotes the point of attachment to Ring C; RAis hydrogen or C1-6alkyl; and RBis hydrogen or C1-6alkyl.26. The compound of any one of embodiments 1-25, wherein L2is selected from the group consisting of #-C(O)O-##, #-C(O)O-CH2-##, #-C(O)O-C(CH3)(H)-##, #-C(O)O- C(CH2F)(H)-##, #-C(O)O-(CH2)2-##, #-C(O)O-(CH2)2-O-##, -(CH2)2-, -(CH2)3-, and #-C(O)- (CH2)3-##, wherein # denotes the point of attachment to Ring A and ## denotes the point of attachment to Ring C. 27. A compound of formula (Ie)or a stereoisomer and / or a pharmaceutically acceptable salt thereof, wherein: R4is selected from the group consisting of halogen, C1-6haloalkyl, C3-6cycloalkyl, and 6-membered heterocyclyl; R5is hydrogen or halogen; X1 is CR6or N; X2is CR7or N; X3 is CR8or N; X4is CH or N; X5 is CR9or N; X6 is CR10or N; X7is CR11or N; R6is selected from the group consisting of hydrogen, cyano, halogen, C1-6alkoxy, C1-6haloalkyl, C1-6haloalkoxy, C3-6cycloalkyl, and 4-6 membered heterocyclyl, wherein the 4-6membered heterocyclyl is optionally substituted with one or more substituents independently selected from halogen; R7is selected from the group consisting of hydrogen, cyano, halogen, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -O-C3-6cycloalkyl, and 4-6 membered heterocyclyl, wherein the 4- 6 membered heterocyclyl is optionally substituted with C1-6alkoxy; or R6and R7may be taken together, along with the ring to which they are attached, to form a 9-membered bicyclic heteroaryl or a 9-membered bicyclic heterocyclyl; R8is hydrogen or halogen; or R7and R8may be taken together, along with the ring to which they are attached, to form a 9-membered bicyclic carbocyclyl; R9is selected from the group consisting of hydrogen, cyano, halogen, C1-6haloalkyl, - C(O)N(RA)(RB), and C1-6alkoxy; R10is selected from the group consisting of hydrogen, halogen, C1-6haloalkyl, C1-6haloalkoxy, and C1-6alkoxy; and R11is hydrogen, halogen, or C1-6alkyl. 28. The compound of any one of embodiments 9-27, wherein R4is selected from the group consisting of bromo, chloro, fluoro, -CF3, cyclopropyl,,. 29. The compound of any one of embodiments 9-28, wherein R5is hydrogen or fluoro. 30. The compound of any one of embodiments 18-29, wherein X1 is CR6, X2 is CR7, and X3is CR8. 31. The compound of any one of embodiments 18-29, wherein X1is CR6, X2is N, and X3is CR8.32. The compound of any one of embodiments 18-29, wherein X1is N, X2is CR7, and X3is CR8. 33. The compound of any one of embodiments 18-31, wherein R6is selected from the group consisting of hydrogen, cyano, chloro, fluoro, -CF3, -O-CH3, -O-CH2-CH3, -O-CHF2, - O-CF3, cyclopropyl,. 34. The compound of any one of embodiments 18-30 and 32, wherein R7is selected from the group consisting of hydrogen, cyano, chloro, fluoro, -CH3, -CF3, cyclopropyl, -O- cyclopropyl, morpholinyl, a. 35. The compound of any one of embodiments 18-34, wherein R8is hydrogen or fluoro. 36. The compound of any one of embodiments 18-30, wherein R6and R7are taken together, along with the atoms to which they are attached, to form a 5 membered heteroaryl or a 5 membered heterocyclyl. 37. The compound of any one of embodiments 18-30, wherein R7and R8may be taken together, along with the atoms to which they are attached, to form a 5-6 membered carbocyclyl. 38. The compound of any one of embodiments 25-37, wherein X4is CH, X5is CR9, X6is CR10, and X7 is CR11. 39. The compound of any one of embodiments 25-37, wherein X4 is CH, X5 is N, X6 is CR10, and X7 is CR11.40. The compound of any one of embodiments 25-37, wherein X4is CH, X5is CR9, X6is N, and X7 is CR11. 41. The compound of any one of embodiments 25-37, wherein X4 is CH, X5 is CR9, X6 is CR10, and X7is N. 42. The compound of any one of embodiments 25-37, wherein X4is N, X5is CR9, X6is N, and X7 is CR11. 43. The compound of any one of embodiments 25-38 and 40-42, wherein R9is selected from the group consisting of hydrogen, cyano, bromo, fluoro, -CF3, -O-CH3, and -C(O)NH2. 44. The compound of any one of embodiments 25-39 and 41, wherein R10is selected from the group consisting of hydrogen, fluoro, -CHF2, -CF3, -O-CH3, and -O-CHF2. 45. The compound of any one of embodiments 25-40 and 42, wherein R11is hydrogen, fluoro, or CH3. 46. The compound of any one of embodiments 1-42, wherein the compound of formula (I) is not a compound selected from the group consisting of:, ,,. 47. A compound selected from any compound set forth in Table 1, or a pharmaceutically acceptable salt thereof. 48. A pharmaceutical composition comprising a compound of any one of embodiments 1- 47; and a pharmaceutically acceptable carrier. 49. A method of inhibiting ACLY in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of embodiments 1-47 or a pharmaceutical composition of embodiment 48. 50. The method of embodiment 49, wherein the subject has a liver condition, disease, or disorder.51. The method of embodiment 49, wherein the liver condition, disease, or disorder is NAFLD or NASH. 52. The method of embodiment 49, wherein the subject has type-2 diabetes. 53. The method of embodiment 49, wherein the subject has inflammation. 54. The method of embodiment 49, wherein the subject has chronic kidney disease. 55. The method of embodiment 49, wherein the subject has autoimmunity. 56. The method of embodiment 49, wherein the subject has cancer. 57. A method of treating NAFLD in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of embodiments 1-47 or a pharmaceutical composition of embodiment 48. 58. A method of treating NASH in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of embodiments 1-47 or a pharmaceutical composition of embodiment 48. 59. A method of treating type-2 diabetes in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of embodiments 1-47 or a pharmaceutical composition of embodiment 48. 60. A method of treating inflammation in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of embodiments 1-47 or a pharmaceutical composition of embodiment 48. 61. A method of treating chronic kidney disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of embodiments 1-47 or a pharmaceutical composition of embodiment 48.62. A method of treating autoimmunity in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of embodiments 1-47 or a pharmaceutical composition of embodiment 48. 63. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of embodiments 1-47 or a pharmaceutical composition of embodiment 48. 64. A method of treating a condition, disease, or disorder as described herein in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of embodiments 1-47 or of the pharmaceutical composition of embodiment 48. EXAMPLES

[0213] The representative examples that follow are intended to help illustrate the disclosure, and are not intended to, nor should they be construed to, limit the scope of the disclosure.

[0214] The compounds provided herein can be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimal reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization.

[0215] Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. The choice of a suitable protecting group for a particular functional group as well as suitable conditions for protection and deprotection are well known in the art. For example, numerous protecting groups, and their introduction and removal, are described in T. W. Greene and P. G. M. Wuts, Protecting Groups in Organic Synthesis, Second Edition, Wiley, New York, 1991, and references cited therein.

[0216] The compounds provided herein may be isolated and purified by known standard procedures. Such procedures include recrystallization, filtration, flash chromatography, trituration, high pressure liquid chromatography (HPLC), or supercritical fluid chromatography (SFC). Note that flash chromatography may either be performed manually orvia an automated system. The compounds provided herein may be characterized by known standard procedures, such as nuclear magnetic resonance spectroscopy (NMR) or liquid chromatography mass spectrometry (LCMS). NMR chemical shifts are reported in part per million (ppm) and are generated using methods well known to those of skill in the art. Analytical Methods

[0217] Method A: UHPLC-MS were performed in reverse phase using a Phenomenex Kinetex-XB C18 column (2.1 mm × 100 mm, 1.7 μm; temperature: 40 °C), with an injection volume of 1 μL at a flow rate of 0.6 mL / min and a gradient of 5 – 100% B over 5.30 min, then 100% B for 0.50 min, where A = 0.1% formic acid in water, and B = 0.1% formic acid in acetonitrile. A second gradient of 100 – 5% B was then applied over 0.02 min and held for 1.18 min. UV spectra were recorded at 215 nm; spectrum range: 200 – 400 nm. ELS data was collected on a Waters ELS detector when reported. Mass spectra were obtained using a Waters SQD, SQD2 or a QDA detector; ionization mode: electrospray positive or negative. Data were integrated and reported using Waters MassLynx and OpenLynx software.

[0218] Method B: UHPLC-MS were performed in reverse phase using a Waters UPLC BEH C18 column (2.1 mm × 100 mm, 1.7 µm; temperature: 55 °C), with an injection volume of 1 μL and at a flow rate of 0.6 mL / min and a gradient of 5 – 100% B over 5.30 min, then 100% B for 0.50 min, where A = 2 mM ammonium bicarbonate in water, buffered to pH 10, and B = acetonitrile. A second gradient of 100 – 5% B was then applied over 0.02 min and held for 1.18 min. UV spectra were recorded at 215 nm; spectrum range: 200 – 400 nm. Mass spectra were obtained using a Waters Quattro Premier XE, QDa or aSQD2; ionization mode: electrospray positive or negative. Data were integrated and reported using Waters MassLynx and OpenLynx software.

[0219] Method C: UHPLC-MS were performed in reverse phase using a Waters UPLC CORTECS C8 column (2.1 mm × 100 mm, 1.6 µm; temperature: 40 °C), with an injection volume of 1 µL at a flow rate of 0.6 mL / min and a gradient of 5 – 100% B over 5.30 min, then 100% B for 0.50 min, where A= 0.1% formic acid in water, and B = 0.1% formic acid in acetonitrile. A second gradient of 100 – 5% B was then applied over 0.02 min and held for 1.18 min. UV spectra were recorded at 215 nm; spectrum range: 200 – 400 nm. ELS data was collected using a Waters ELS detector when reported. Mass spectra were obtained using a Waters SQD, SQD2 or a QDa; ionization mode: electrospray positive or negative. Data were integrated and reported using Waters MassLynx and OpenLynx software.

[0220] Method D: UHPLC-MS were performed in reverse phase system using a Waters UPLC BEH C18 column (2.1 mm × 50 mm, 1.7 µm; temperature: 40 °C), with an injection volume of 1 µL at a flow rate of 0.9 mL / min and a gradient of 5 – 100% B over 1.10 min, then 100% B for 0.25 min, where A = 0.1% formic acid in water, and B = 0.1% formic acid in acetonitrile. A second gradient of 100 – 5% B was then applied over 0.05 min and held for 0.10 min. UV spectra were recorded at 215 nm; spectrum range: 200 – 400 nm. Mass spectra were obtained using a Waters SQD, SQD2 or a QDA detector; ionization mode: electrospray positive or negative. Data were integrated and reported using Waters MassLynx and OpenLynx software.

[0221] Method E: UHPLC-MS were performed in reverse phase using a Phenomenex Kinetex Evo C18 column (2.1 mm × 50 mm, 1.7 µm; temperature 40 °C), with an injection volume of 1 µL at a flow rate of 1.0 mL / min and a gradient of 1 – 100% B over 1.10 min, then 100% B for 0.25 min, where A = water + 0.2% ammonium hydroxide and B = acetonitrile. A second gradient of 100 – 1% B was then applied over 0.05 min and held for 0.40 min. UV spectra were recorded at 215 nm; spectrum range: 200 – 400 nm. Mass spectra were obtained using a Waters QDa or a SQD2; ionization mode: electrospray positive or negative. Data were integrated and reported using Waters MassLynx and OpenLynx software.

[0222] Method F: Analytical (MET / UPLC / 1906) (M12) UHPLC-MS were performed in reverse phase using a Waters UPLC CORTECS C8 column (2.1 mm × 50 mm, 1.6 µm; temperature: 40 °C), with an injection volume of 1 µL at a flow rate of 0.9 mL / min and a gradient of 5 – 100% B over 1.10 min, then 100% B for 0.30 min, where A = 0.1% formic acid in water, and B = 0.1% formic acid in acetonitrile. A second gradient of 100 – 5% B was then applied over 0.02 min and held for 0.28 min. UV spectra were recorded at 215 nm; spectrum range: 200 – 400 nm. ELS data was collected using a Waters ELS detector when reported. Mass spectra were obtained using a Waters SQD2 or a QDa; ionization mode: electrospray positive or negative. Data were integrated and reported using Waters MassLynx and OpenLynx software. Preparative HPLC Methods

[0223] Method P1: LC were performed in reverse phase using a Waters SunfireTM C18 column (30 mm × 100 mm, 5 μm; temperature: room temperature), with an injection volume of 1500 μL at a flow rate of 40 mL / min at 30% B for 1.90 min then a gradient of 30 – 95% B over 9.60 min and held for 1.97 min, where A = 0.1% formic acid in water and B = 0.1%formic acid in acetonitrile. A second gradient of 95 – 30% B was then applied over 0.33 min and held for 1.65 min. UV spectra were recorded at 215 nm.

[0224] Method P2: LC were performed in reverse phase using a Waters SunfireTM C18 column (30 mm × 100 mm, 5 μm; temperature: room temperature), with an injection volume of 1500 μL at a flow rate of 40 mL / min at 10% B for 1.90 min then a gradient of 10 – 95% B over 14.10 min and held for 2.0 min, where A = 0.1% formic acid in water and B = 0.1% formic acid in acetonitrile. A second gradient of 95 – 10% B was then applied over 0.20 min and held for a further 1.25 min. UV spectra were recorded at 215 nm.

[0225] Method P3: LC were performed in reverse phase using a Waters XBridgeTM C18 column (30 mm × 100 mm, 5 μm; temperature: room temperature), with an injection volume of 1500 μL at a flow rate of 40 mL / min at 10% B for 2.00 min then a gradient of 10 – 95% B over 14.00 min and held for 2.00 min, where A = 0.2% ammonium hydroxide in water and B = 0.2% ammonium hydroxide in acetonitrile. A second gradient of 95 – 10% B was then applied over 0.20 min and held for 1.25 min. UV spectra were recorded at 215 nm. Abbreviations aq. aqueous BF3 etherate boron trifluoride diethyl etherate BSA bovine serum albumin CDCl3 deuterated chloroform CHCl3chloroform CO2 carbon dioxide conc. concentrated CV column volumes DAST diethylaminosulfur trifluoride DCC N,N′-dicyclohexylcarbodiimide DCDMH 1,3-dichloro-5,5-dimethyldantoin DCM dichloromethane DIAD diisopropyl azodicarboxylate DIPEA N,N-diisopropylethylamine DMAP 4-(dimethylamino)pyridine DMF N,N-dimethylformamide DMP Dess-Martin periodinane DMSO dimethyl sulfoxideDPPA diphenylphosphoryl azide dppf 1,1'-bis(diphenylphosphino)ferrocene DTT dithiothreitol ESI electrospray ionization Et2O diethyl ether EtOH ethanol EtOAc ethyl acetate FBS fetal bovine serine FCC flash column chromatography HCl hydrogen chloride HEPES 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid HG2 Hoveyda-Grubbs Catalyst®, 2ndgeneration H2O water HPLC high-performance liquid chromatography IPA isopropanol K2CO3 potassium carbonate LCMS liquid chromatography-mass spectrometry LDA lithium diisopropylamide LiHMDS lithium bis(trimethylsilyl)amide M molar mCPBA metachloroperbenzoic acid MeCN acetonitrile MeOH methanol MeMgBr methylmagnesium bromide MgSO4magnesium sulfate N2 nitrogen NaBH4sodium borohydride NaHCO3 sodium bicarbonate Na2CO3sodium carbonate Na2SO4 sodium sulfate Na2S2O3sodium thiosulfate NBS N-bromosuccinimide NH4Cl ammonium hydrochloride NMI 1-methyl-1H-imidazoleNMR nuclear magnetic resonance org organic PBS phosphate-buffered saline Pd palladium Pd / C palladium on carbon Pd2(dba)3tris(dibenzylideneacetone)dipalladium(0) Pd(dppf)Cl2 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) Pt platinum rpm revolutions per minute RM reaction mixture RT retention time r.t. room temperature sat . saturated SCX strong cation exchange cartridge (benzenesulfonic acid-functionalized silica) SFC supercritical fluid chromatography SiO2 silicon dioxide (silica gel for FCC) TBDMSCl tert-butyldimethylsilyl chloride TBME tert-butyl methyl ether TCFH N-[chloro(dimethylamino)methylidene]-N-methylmethanaminium hexafluorophosphate TFA trifluoroacetic acid THF tetrahydrofuran wt% weight percent

[0226] In some embodiments, compounds of the disclosure may be synthesized using the procedure outlined in General Scheme 1: General Scheme 1

[0227] In General Scheme 1, starting material A is reacted with pinacol boronic ester intermediate B using palladium-catalyzed cross coupling conditions (e.g., Pd(dppf)Cl2, K2CO3, dioxane, 100 °C, 18 hours) to yield intermediate C. Rings B and C may be optionally substituted or be 6-membered or 5-membered heteroaromatics. Ring C may optionally be a 9- membered bicycle where X2 is O or C.

[0228] Intermediate C is reacted with sulfonyl chloride intermediate D under basic conditions (e.g., pyridine, 50 °C, 1 hour) to yield intermediate E. Substituent X represents Cl, Br, F or trifluoromethyl. modify length of alcohol to be modular)

[0229] Intermediate E undergoes ester hydrolysis under basic conditions (e.g., NaOH (aq.), THF, r.t., 3 hours) to yield intermediate F. Intermediate F undergoes cyclization using ester coupling conditions (e.g., DCC, DMAP, DCM, r.t., 24 hours; or TCFH, NMI, MeCN, r.t., 2- 18 hours) to yield intermediate G. Finally, intermediate G undergoes ether cleavage (usinge.g., iodocyclohexane, anhydrous DMF, 120 °C, 1-3 hours; or lithium iodide, anhydrous pyridine, 80 °C, 6-18 hours) to yield final product H.

[0230] In some embodiments, compounds of the disclosure may be synthesized using the procedure outlined in General Scheme 2: General Scheme 2

[0231] In General Scheme 2, starting material A is reacted with pinacol boronic ester intermediate B using palladium-catalyzed cross coupling conditions (e.g., Pd(dppf)Cl2, K2CO3, dioxane, 100 °C, 18 hours) to yield intermediate C. Rings B and C may be optionally substituted. R is a silyl protecting group.

[0232] Intermediate C is reacted with sulfonyl chloride intermediate D under basic conditions (e.g., pyridine, 50 °C, 1 hour) to yield intermediate E.

[0233] Intermediate E undergoes ester hydrolysis under basic conditions (e.g., NaOH (aq.), THF, r.t., 3 hours) and acidic deprotection of the silyl group to yield intermediate F. Intermediate F undergoes cyclization using ester coupling conditions (e.g., DCC, DMAP,DCM, r.t., 24 hours; or TCFH, NMI, MeCN, r.t., 2-18 hours) to yield intermediate G. Finally, intermediate G undergoes ether cleavage (using e.g., iodocyclohexane, anhydrous DMF, 120 °C, 1-3 hours; or lithium iodide, anhydrous pyridine, 80 °C, 6-18 hours) to yield final product H.

[0234] In some embodiments, compounds of the disclosure may be synthesized using the procedure outlined in General Scheme 3: General Scheme 3

[0235] In General Scheme 3, starting material A is reacted with pinacol boronic ester intermediate B using palladium-catalyzed cross coupling conditions (e.g., Pd(dppf)Cl2, K2CO3, dioxane, 100 °C, 18 hours) to yield intermediate C. Rings B and C may be optionally substituted.

[0236] Intermediate C is reacted with sulfonyl chloride intermediate D under basic conditions (e.g., pyridine, 50 °C, 1 hour) to yield intermediate E. Substituent X represents Cl, Br, F or trifluoromethyl. modify length of alcohol to be modular)

[0237] Intermediate E is reacted with a Grignard reagent to yield intermediate F wherein n can be 0 or 1. Intermediate F undergoes cyclization via ring closing metathesis and the resulting alkene is reduced with Pd / C to yield intermediate G. Intermediate G is oxidized with DMP to yield Intermediate H. Intermediate H undergoes ether cleavage (using e.g., iodocyclohexane, anhydrous DMF, 120 °C, 1-3 hours; or lithium iodide, anhydrous pyridine, 80 °C, 6-18 hours) to yield final product I-b.

[0238] Alternatively, Intermediate H is reacted with acetoneoxime or N-methylhydrazine to form Intermediate I-a. Intermediate I-a undergoes ether cleavage (using e.g., iodocyclohexane, anhydrous DMF, 120 °C, 1-3 hours; or lithium iodide, anhydrous pyridine, 80 °C, 6-18 hours) to yield final product J. X can be O or N. Example 1 - Synthesis of 13-Chloro-19,21-difluoro-14-hydroxy-16,16-dioxo-5- (trifluoromethyl)-9-oxa-16λ6-thia-4,17-diazatetracyclo[16.3.1.111,15.02,7]tricosa- 1(21),2,4,6,11(23),12,14,18(22),19-nonaen-10-one (Compound 1)

[0239] A mixture of Intermediate 6 (100 mg, 0.16 mmol), lithium iodide (215 mg, 1.61 mmol) and anhydrous pyridine (2 mL) was heated at 90 °C for 3 h 45 min. The reactionmixture was diluted with EtOAc (40 mL), washed with sat. aq. Na2S2O3 (30 ml), 1 M aq. HCl (30 mL) and brine (30 mL), then passed through a phase separator and then concentrated. The crude material was purified by preparative HPLC (Method P1) to afford the title compound as an off-white solid (44 mg, 51% Yield, 97% purity).1H NMR (400 MHz, DMSO) δ 10.21 (br. s, 1H), 8.69 (s, 1H), 8.21 (s, 1H), 7.94 (d, J = 2.2 Hz, 1H), 7.61 – 7.46 (m, 1H), 7.22 (d, J = 2.2 Hz, 1H), 7.18 – 7.05 (m, 1H), 5.61 (d, J = 13.7 Hz, 1H), 5.24 (d, J = 13.6 Hz, 1H). LCMS: m / z = 519.0 / 520.9 [M-H]-, (ESI-), RT = 4.03, Method A Example 2 – Synthesis of 13-Chloro-4-fluoro-14-hydroxy-16,16-dioxo-20- (trifluoromethyl)-9-oxa-16λ6-thia-17-azatetracyclo[16.3.1.111,15.02,7]tricosa- 1(21),2(7),3,5,11(23),12,14,18(22),19-nonaen-10-one (Compound 2)

[0240] Intermediate 7 (93% purity, 240 mg, 0.433 mmol), pyridine (5.4 mL) and lithium iodide (580 mg, 4.33 mmol) were added to a pressure vial. The mixture was heated at 80 °C for 1.5 h and was then allowed to cool to r.t. and concentrated under a stream of nitrogen. The organics were diluted with EtOAc (50 mL), washed with HCl (2 x 50 mL of a 1 M aqueous solution), Na2SO3(30 mL of a saturated aqueous solution) and brine (30 mL), dried over MgSO4, filtered and concentrated in vacuo. The crude material was purified by preparative HPLC (Method P1) to afford the title compound as pale brown solid (71 mg, 32% Yield, 98% purity).1H NMR (500 MHz, DMSO) δ 10.44 (s, 1H), 7.89 (d, J = 2.2 Hz, 1H), 7.81 (s, 1H), 7.63 (dd, J = 8.5, 5.8 Hz, 1H), 7.34 – 7.26 (m, 3H), 7.24 – 7.20 (m, 1H), 7.13 (d, J = 2.2 Hz, 1H), 5.35 (s, 2H). LCMS: m / z = 500.0 / 502.0 [M-H]-, (ESI-), RT = 4.26, Method AExample 3 – Synthesis of 13-Chloro-19,21-difluoro-14-hydroxy-16,16-dioxo-9-oxa-16λ6- thia-4,17-diazatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2(7),3,5,11,13,15(23),18(22),19- nonaen-10-one (Compound 3)

[0241] To a solution of 13-chloro-19,21-difluoro-14-methoxy-16,16-dioxo-9-oxa-16λ6- thia-4,17-diazatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2(7),3,5,11,13,15(23),18(22),19- nonaen-10-one (synthesised using a similar method to intermediate 7, 76% purity, 200 mg, 0.326 mmol) in anhydrous pyridine (28 mL) was added lithium iodide (460 mg, 3.44 mmol). The reaction mixture was heated at 80 °C. After 4.5 h, the reaction was stopped then cooled to r.t. and the pyridine was removed under reduced pressure to give an orange gum. The crude material was purified by preparative HPLC (Method P1) to afford the title compound as white solid (43 mg, 28% Yield, 95% purity).1H NMR (400 MHz, DMSO) δ 10.17 (s, 1H), 8.69 (d, J = 4.9 Hz, 1H), 8.48 (s, 1H), 7.95 (d, J = 2.2 Hz, 1H), 7.62 (d, J = 5.0 Hz, 1H), 7.58 – 7.46 (m, 1H), 7.23 (d, J = 2.2 Hz, 1H), 7.04 – 6.86 (m, 1H), 5.46 (d, J = 13.3 Hz, 1H), 5.18 (d, J = 13.3 Hz, 1H). LCMS: m / z = 451.0 & 453.0 [M-H]-, (ESI-), RT = 3.12, Method AExample 4 – Synthesis of 13-Chloro-4-fluoro-14-hydroxy-16,16-dioxo-9-oxa-16λ6-thia- 17,20-diazatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2(7),3,5,11,13,15(23),18(22),19- nonaen-10-one (Compound 4)

[0242] To a solution of 13-chloro-4-fluoro-14-methoxy-16,16-dioxo-9-oxa-16λ6-thia- 17,20-diazatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2(7),3,5,11,13,15(23),18(22),19- nonaen-10-one (synthesised using a similar method to intermediate 7, 75% purity, 69.0 mg, 0.115 mmol) in anhydrous pyridine (2.0 mL) in a pressure tube was added lithium iodide (109 mg, 0.807 mmol). The reaction mixture was heated at 80 °C for 3 h. The volatiles were removed under reduced pressure. The crude material was purified by preparative HPLC (Method P1) to afford the title compound as white solid (15 mg, 30% Yield, 100% purity).1H NMR (500 MHz, DMSO) δ 10.34 (s, 1H), 8.62 (d, J = 1.9 Hz, 1H), 8.31 (d, J = 2.4 Hz, 1H), 7.90 (d, J = 2.2 Hz, 1H), 7.64 (dd, J = 8.5, 5.8 Hz, 1H), 7.30 (ddd, J = 8.6, 8.5, 2.8 Hz, 1H), 7.23 (dd, J = 9.3, 2.8 Hz, 1H), 7.20 (s, 1H), 7.00 (d, J = 2.2 Hz, 1H), 5.46 – 5.27 (m, 2H). LCMS: m / z = 435 / 437 [M+H]+, (ESI+), RT = 3.47, Method AExample 5 – Synthesis of 13-Chloro-4-fluoro-14-hydroxy-19-methoxy-16,16-dioxo-9- oxa-16λ6-thia-17,20-diazatetracyclo[16.3.1.111,15.02,7]tricosa- 1(21),2(7),3,5,11,13,15(23),18(22),19-nonaen-10-one (Compound 5) C

[0243] To a solution of 13-chloro-4-fluoro-14,19-dimethoxy-16,16-dioxo-9-oxa-16λ6-thia- 17,20-diazatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2(7),3,5,11,13,15(23),18(22),19- nonaen-10-one (synthesised using a similar method to intermediate 7, 95% purity, 110 mg, 0.218 mmol) in anhydrous pyridine (2.0 mL) in a pressure tube was added lithium iodide (109 mg, 0.807 mmol) (108 mg). The reaction mixture was heated at 80 °C for 4 h. After cooling, the volatiles were removed under reduced pressure. The crude material was purified by preparative HPLC (Method P1) to afford the title compound as white solid (55.0 mg, 54% Yield, 99% purity).1H NMR (500 MHz, DMSO) δ 9.73 (s, 1H), 8.13 (d, J = 2.2 Hz, 1H), 7.90 (d, J = 2.2 Hz, 1H), 7.65 – 7.57 (m, 1H), 7.50 (d, J = 2.2 Hz, 1H), 7.32 – 7.24 (m, 3H), 5.68 – 5.55 (m, 1H), 5.27 – 5.09 (m, 1H), 3.55 (s, 3H). LCMS: m / z = 465, 467 [M+H]+, (ESI+), RT = 3.89, Method AExample 6 – Synthesis of 13-Chloro-19-cyclopropyl-4-fluoro-14-hydroxy-16,16-dioxo-9- oxa-16λ6-thia-17-azatetracyclo[16.3.1.111,15.02,7]tricosa- 1(21),2(7),3,5,11,13,15(23),18(22),19-nonaen-10-one (Compound 6) C

[0244] To a solution of 13-chloro-19-cyclopropyl-4-fluoro-14-methoxy-16,16-dioxo-9-oxa- 16λ6-thia-17-azatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2(7),3,5,11,13,15(23),18(22),19- nonaen-10-one (synthesised using a similar method to intermediate 7, 95% purity, 220 mg, 0.428 mmol) in anhydrous pyridine (8 mL) was added lithium iodide (500 mg, 3.74 mmol). The reaction mixture was heated at 80 °C for 3.5 h and was then allowed to cool to r.t.. The organics were diluted with EtOAc (80 mL), then washed with HCl (2 x 100 mL of a 1 M aqueous solution), Na2SO3(40 mL of a saturated aqueous solution), brine (40 mL), dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by FCC (10 g SiO2 cartridge, 0 – 100% EtOAc in DCM) to afford the title compound as off-white solid (55 mg, 26% Yield, 96% purity).1H NMR (500 MHz, DMSO) δ 9.90 (s, 1H), 7.86 (d, J = 2.2 Hz, 1H), 7.58 (dd, J = 8.5, 5.9 Hz, 1H), 7.30 (d, J = 2.2 Hz, 1H), 7.25 (dd, J = 7.8, 2.0 Hz, 1H), 7.25 – 7.20 (m, 1H), 7.11 (dd, J = 9.4, 2.8 Hz, 1H), 6.90 (d, J = 1.9 Hz, 1H), 6.70 (d, J = 8.0 Hz, 1H), 5.42 – 5.33 (m, 1H), 5.28 – 5.18 (m, 1H), 2.20 – 2.14 (m, 1H), 0.92 – 0.83 (m, 2H), 0.67 – 0.59 (m, 1H), 0.18 – 0.06 (m, 1H). LCMS: m / z = 472.1 / 474.2 [M-H]-, (ESI-), RT = 2.71, Method BExample 7 – Synthesis of 13-Chloro-6,19-difluoro-14-hydroxy-16,16-dioxo-9-oxa-16λ6- thia-17-azatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2(7),3,5,11,13,15(23),18(22),19- nonaen-10-one (Compound 7) C

[0245] To a solution of 13-chloro-6,19-difluoro-14-methoxy-16,16-dioxo-9-oxa-16λ6-thia- 17-azatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2(7),3,5,11,13,15(23),18(22),19-nonaen- 10-one (synthesised using a similar method to intermediate 6, 91% purity, 80 mg, 0.156 mmol) in anhydrous pyridine (3.4 mL) was added lithium iodide (23 mg, 0.172 mmol). The reaction mixture was heated at 80 °C for 19 h. The reaction mixture was dissolved in EtOAc (50 mL) and washed with 1 M aq. HCl (50 mL). The aqueous phase was extracted further with EtOAc (2 x 50 mL) and the organics were combined, washed with sat. aq. Na2S2O3(50 mL) and brine (50 mL) and dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude material as a white solid. The crude material was purified by preparative HPLC (Method P1) to afford the title compound as light pink solid (61 mg, 85% Yield, 98% purity).1H NMR (500 MHz, DMSO) δ 10.06 (br. s, 1H), 7.92 (d, J = 2.2 Hz, 1H), 7.52 – 7.46 (m, 1H), 7.46 – 7.41 (m, 1H), 7.33 – 7.25 (m, 2H), 7.15 (d, J = 2.2 Hz, 1H), 7.07 – 7.03 (m, 1H), 6.73 (dd, J = 7.4, 2.3 Hz, 1H), 5.65 (d, J = 13.0 Hz, 1H), 5.20 (d, J = 13.0 Hz, 1H). LCMS: m / z = 450.0 / 452.0 [M-H]-, (ESI-), RT = 4.05, Method AExample 8 – Synthesis of 13-Chloro-4,20-difluoro-14-hydroxy-19-methoxy-16,16-dioxo- 9-oxa-16λ6-thia-17-azatetracyclo[16.3.1.111,15.02,7]tricosa- 1(21),2(7),3,5,11,13,15(23),18(22),19-nonaen-10-one (Compound 8)

[0246] Lithium iodide (137 mg, 1.02 mmol) was added to a stirring solution of 13-chloro- 4,20-difluoro-14,19-dimethoxy-16,16-dioxo-9-oxa-16λ6-thia-17- azatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2(7),3,5,11,13,15(23),18(22),19-nonaen-10- one (synthesised using a similar method to intermediate 7, 89% purity, 274 mg, 0.492 mmol) in anhydrous pyridine (7 mL) in a 20 mL pressure vial at r.t.. The vial was sealed and the mixture stirred at 90 °C for 7 h, allowed to cool to r.t., and left to stand for 3 days. The reaction mixture was diluted with sat. aq. sodium thiosulphate (~30 mL) and 1 M aq. HCl (~30 mL). The mixture became monophasic following addition of HCl and a white precipitate formed. To this suspension was added brine (~30 mL), and the suspension was then extracted with EtOAc (~ 30 mL). The aqueous phase was passed through a phase separator. The precipitate that had collected on the phase separator was washed with EtOAc (~30 mL), the organic phases were combined and concentrated to dryness in vacuo. The residue was purified by reverse phase FCC (12 g C18 cartridge, 0.1% formic acid as modifier, eluting MeCN in H2O: 10%, 2 CV; 10-50%, 2 CV; 50%, 2 CV; 50-65%, 2 CV; 65%, 2 CV; 65-85%, 10 CV; 85-100%, 2 CV; 100%, 4 CV), followed by trituration with water and finally by preparative HPLC (Method P1) to afford the title compound as white solid (22 mg, 0.0452 mmol, 9.2% Yield, 99% purity).1H NMR (500 MHz, DMSO) δ 9.81 (s, 1H), 7.93 (dd, J = 2.2, 1.0 Hz, 1H), 7.61 (dd, J = 8.5, 5.9 Hz, 1H), 7.47 (d, J = 2.1 Hz, 1H), 7.39 (ddd, J = 12.0, 1.4, 1.4 Hz, 1H), 7.27 (ddd, J = 8.5, 8.5, 2.8 Hz, 1H), 7.22 (dd, J = 9.4, 2.8 Hz, 1H), 7.04 (dd, J = 1.6, 1.6 Hz, 1H), 5.50 (d, J = 12.5 Hz, 1H), 5.19 (d, J = 12.6 Hz, 1H), 3.55 (d, J = 1.9 Hz, 3H). LCMS: m / z = 480.3, 482.3 [M-H]-, (ESI-), RT = 4.07, Method AExample 9 – Synthesis of 13-Chloro-19,21-difluoro-14-hydroxy-16,16-dioxo-9-oxa-16λ6- thia-5,17-diazatetracyclo[16.3.1.111,15.02,7]tricosa-1(22),2,4,6,11,13,15(23),18,20- nonaen-10-one (Compound 9)

[0247] To a solution of 13-chloro-19,21-difluoro-14-methoxy-16,16-dioxo-9-oxa-16λ6- thia-5,17-diazatetracyclo[16.3.1.111,15.02,7]tricosa-1(22),2,4,6,11,13,15(23),18,20-nonaen- 10-one (synthesised using a similar method to intermediate 7, 65% purity, 20 mg, 0.0278 mmol) in anhydrous pyridine (1 mL) was added lithium iodide (50 mg, 0.374 mmol). The reaction mixture was heated at 80 °C for 2 h then cooled to r.t and stirred for 1 h, then concentrated. The crude material was purified by preparative HPLC (Method P1) to afford the title compound as white solid (8.0 mg, 62% Yield, 98% purity).1H NMR (500 MHz, DMSO) δ 8.74 (s, 1H), 8.66 (d, J = 4.9 Hz, 1H), 7.84 (s, 1H), 7.49 (dd, J = 9.8, 9.8 Hz, 1H), 7.37 (d, J = 5.0 Hz, 1H), 7.20 (d, J = 2.3 Hz, 1H), 6.93 (dd, J = 7.9, 7.9 Hz, 1H), 5.45 (d, J = 13.0 Hz, 1H), 5.13 (d, J = 12.9 Hz, 1H). LCMS: m / z = 453.0 / 454.8 [M+H]+, (ESI+), RT = 3.29, Method AExample 10 – Synthesis of 13-Chloro-5,19,21-trifluoro-14-hydroxy-16,16-dioxo-9-oxa- 16λ6-thia-6,17-diazatetracyclo[16.3.1.111,15.02,7]tricosa- 1(21),2(7),3,5,11,13,15(23),18(22),19-nonaen-10-one (Compound 10)

[0248] To a solution of 13-chloro-5,19,21-trifluoro-14-methoxy-16,16-dioxo-9-oxa-16λ6- thia-6,17-diazatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2(7),3,5,11,13,15(23),18(22),19- nonaen-10-one (synthesised from intermediate 9, using a similar method to intermediate 7, 99% purity, 120 mg, 0.245 mmol) in anhydrous pyridine (10 mL) was added lithium iodide (300 mg, 2.24 mmol). The reaction mixture was heated at 80 °C for 5.5 h, then stirred at r.t. for 11 h. The organics were diluted with EtOAc (30 mL), washed with HCl (100 mL of a 1 M aqueous solution), then Na2SO3 (30 mL of a saturated aqueous solution) then brine (30 mL), dried over MgSO4, filtered and concentrated in vacuo. The crude material was purified by preparative HPLC (Method P1) to afford the title compound as off-white solid (89 mg, 74% Yield, 96% purity).1H NMR (500 MHz, DMSO) δ 10.19 (br. s, 1H), 8.01 – 7.96 (m, 1H), 7.96 (d, J = 2.2 Hz, 1H), 7.50 – 7.44 (m, 1H), 7.33 (dd, J = 8.3, 2.9 Hz, 1H), 7.27 (d, J = 2.2 Hz, 1H), 7.07 – 7.02 (m, 1H), 5.36 – 5.27 (m, 2H). LCMS: m / z = 469.0 / 470.9 [M-H]-, (ESI-), RT = 3.68, Method AExample 11 – Synthesis of 13-Chloro-5,19,21-trifluoro-14-hydroxy-16,16-dioxo-9-oxa- 16λ6-thia-4,17-diazatetracyclo[16.3.1.111,15.02,7]tricosa- 1(21),2(7),3,5,11,13,15(23),18(22),19-nonaen-10-one (Compound 11)

[0249] To a solution of 13-chloro-5,19,21-trifluoro-14-methoxy-16,16-dioxo-9-oxa-16λ6- thia-4,17-diazatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2(7),3,5,11,13,15(23),18(22),19- nonaen-10-one (synthesised from intermediate 11, using a similar method to intermediate 7, 90% purity, 60 mg, 0.124 mmol) in anhydrous pyridine (4 mL) was added lithium iodide (166 mg, 1.24 mmol). The reaction mixture was heated at 80 °C for 3 h, then at r.t. overnight. The RM was diluted with EtOAc (50 mL) and washed with 1 M aq. HCl (30 mL), sat. aq. Na2S2O3 (30 mL) and brine (30 mL), then passed through a phase separator and then concentrated. The crude material was purified by preparative HPLC (Method P1) to afford the title compound as off-white solid (26 mg, 44% Yield, 99% purity).1H NMR (500 MHz, DMSO) δ 10.14 (br s, 1H), 8.18 (s, 1H), 7.93 (d, J = 2.2 Hz, 1H), 7.53 – 7.44 (m, 2H), 7.22 (d, J = 2.2 Hz, 1H), 7.07 – 6.98 (m, 1H), 5.48 (d, J = 13.5 Hz, 1H), 5.16 (d, J = 13.4 Hz, 1H). LCMS: m / z = 469.3 / 471.3 [M-H]-, (ESI-), RT = 3.69, Method AExample 12 – Synthesis of 13-Chloro-5-fluoro-14-hydroxy-19-methoxy-16,16-dioxo-9- oxa-16λ6-thia-6,17-diazatetracyclo[16.3.1.111,15.02,7]tricosa- 1(21),2(7),3,5,11,13,15(23),18(22),19-nonaen-10-one (Compound 12)

[0250] To a solution of 13-chloro-5-fluoro-14,19-dimethoxy-16,16-dioxo-9-oxa-16λ6-thia- 6,17-diazatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2(7),3,5,11,13,15(23),18(22),19- nonaen-10-one (synthesised from intermediate 9, using a similar method to intermediate 6, 95% purity, 89 mg, 0.186 mmol) in anhydrous pyridine (7.4 mL) was added lithium iodide (30 mg, 0.224 mmol). The reaction mixture was heated at 80 °C for 15 h. The pyridine was removed under reduced pressure and the residue was dissolved in EtOAc (5 mL) and washed with NH4Cl (aq.) (5 mL) and then passed through a phase separator cartridge and concentrated under reduced pressure. The crude material was purified by preparative HPLC (Method P1) to afford the title compound as white solid (70 mg, 81% Yield, 99% purity).1H NMR (400 MHz, DMSO) δ 9.29 (s, 1H), 8.04 – 7.94 (m, 1H), 7.86 (d, J = 2.2 Hz, 1H), 7.37 (d, J = 2.2 Hz, 1H), 7.34 – 7.23 (m, 3H), 6.70 (d, J = 8.3 Hz, 1H), 5.89 (d, J = 13.7 Hz, 1H), 4.88 (d, J = 13.5 Hz, 1H), 3.43 (s, 3H). LCMS: m / z = 463.1 & 465.1 [M-H]-, (ESI-), RT = 3.53, Method AExample 13 – Synthesis of 13-Chloro-5-fluoro-14-hydroxy-19-methoxy-16,16-dioxo-9- oxa-16λ6-thia-4,17-diazatetracyclo[16.3.1.111,15.02,7]tricosa- 1(21),2(7),3,5,11,13,15(23),18(22),19-nonaen-10-one (Compound 13)

[0251] To a solution of 13-chloro-5,19,21-trifluoro-14-methoxy-16,16-dioxo-9-oxa-16λ6- thia-4,17-diazatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2(7),3,5,11,13,15(23),18(22),19- nonaen-10-one (synthesised from intermediate 11, using a similar method to intermediate 7, 52% purity, 150 mg, 0.163 mmol) in anhydrous pyridine (4 mL) was added lithium iodide (43 mg, 0.33 mmol). The reaction mixture was heated at 80 °C for 15 h. The cooled reaction mixture was diluted with EtOAc (50 mL) and washed with 1 M aq. HCl (30 mL), sat. aq. Na2S2O3 (30 mL) and brine (30 mL), then passed through a phase separator and then concentrated. The crude material was purified by preparative HPLC (Method P1) to afford the title compound as off-white solid (57 mg, 73% Yield, 97% purity).1H NMR (500 MHz, DMSO) δ 9.31 (s, 1H), 8.20 (s, 1H), 7.90 – 7.80 (m, 1H), 7.44 (d, J = 1.9 Hz, 1H), 7.35 (d, J = 2.2 Hz, 1H), 7.31 – 7.18 (m, 2H), 6.74 (d, J = 8.4 Hz, 1H), 5.68 (d, J = 13.4 Hz, 1H), 5.15 (d, J = 13.4 Hz, 1H), 3.44 (s, 3H). LCMS: m / z = 463.1 / 465.1 [M-H]-, (ESI-), RT = 3.38, Method AExample 14 - Synthesis of 13-Chloro-19,21-difluoro-14-hydroxy-5-methoxy-16,16-dioxo- 9-oxa-16λ6-thia-4,17-diazatetracyclo[16.3.1.111,15.02,7]tricosa- 1(21),2(7),3,5,11,13,15(23),18(22),19-nonaen-10-one (Compound 14)

[0252] To a solution of intermediate 13, 97% purity, 1653 mg, 3.179 mmol) in anhydrous pyridine (20 mL) was added lithium iodide (1.50 g, 11.2 mmol). The reaction mixture was heated at 90 °C for 6 h. The reaction mixture was cooled to r.t., diluted with EtOAc (20 mL), washed with sat. aq. Na2S2O3(2 x 20 ml), 1 M aq. HCl (4 x 20 mL) and brine (20 mL), then dried over Na2SO4, filtered, and concentrated. The residue was taken into ethanol (~70 mL), sonicated to give a milky white solution, and concentrated to dryness. This was repeated three times, then the solids were dried in a vacuum oven overnight at 60 °C to afford the title product as an off-white solid (1276 mg, 79% Yield, 95% purity).1H NMR (500 MHz, DMSO) δ 10.15 (s, 1H), 8.05 (s, 1H), 7.96 (d, J = 2.2 Hz, 1H), 7.50 – 7.40 (m, 1H), 7.21 (d, J = 2.2 Hz, 1H), 7.08 (s, 1H), 6.93 – 6.85 (m, 1H), 5.41 (d, J = 13.2 Hz, 1H), 5.08 (d, J = 13.1 Hz, 1H), 3.90 (s, 3H). LCMS: m / z = 481.0 / 483.0 [M-H]-, (ESI-), RT = 3.91, Method AExample 15 – Synthesis of 13-Chloro-4-fluoro-14-hydroxy-19-methoxy-16,16-dioxo-9- oxa-16λ6-thia-5,17-diazatetracyclo[16.3.1.111,15.02,7]tricosa- 1(22),2(7),3,5,11,13,15(23),18,20-nonaen-10-one (Compound 15)

[0253] A mixture of 13-chloro-4-fluoro-14,19-dimethoxy-16,16-dioxo-9-oxa-16λ6-thia- 5,17-diazatetracyclo[16.3.1.111,15.02,7]tricosa-1(22),2(7),3,5,11,13,15(23),18,20-nonaen- 10-one (synthesised from intermediate 17, using a similar method to intermediate 13, 69% purity, 26 mg, 0.0375 mmol), lithium iodide (25 mg, 0.19 mmol) and anhydrous pyridine (2 mL) was heated at 90 °C for 2 h. The RM was cooled to r.t., diluted with EtOAc (25 mL), washed with sat. aq. Na2S2O3 (25 ml), 1 M aq. HCl (25 mL) and brine (25 mL), then passed through a phase separator and concentrated. The crude material was purified by preparative HPLC (Method P1) to afford the title compound as an off-white solid (9.0 mg, 51% Yield, 99% purity).1H NMR (500 MHz, DMSO) δ 9.32 (s, 1H), 8.39 (s, 1H), 7.85 (d, J = 2.2 Hz, 1H), 7.36 (dd, J = 8.4, 2.3 Hz, 1H), 7.31 – 7.26 (m, 3H), 6.77 (d, J = 8.5 Hz, 1H), 5.81 – 4.97 (m, 2H), 3.45 (s, 3H). LCMS: m / z = 465.0 / 466.9 [M+H]+, (ESI+), RT = 3.49, Method AExample 16 – Synthesis of 13,19-Dichloro-14-hydroxy-5-methoxy-16,16-dioxo-9-oxa- 16λ6-thia-4,17-diazatetracyclo[16.3.1.111,15.02,7]tricosa- 1(21),2,4,6,11,13,15(23),18(22),19-nonaen-10-one (Compound 16)

[0254] Lithium iodide (105 mg, 0.784 mmol) was added to a stirring solution of 13,19- dichloro-5,14-dimethoxy-16,16-dioxo-9-oxa-16λ6-thia-4,17- diazatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2,4,6,11,13,15(23),18(22),19-nonaen-10-one (synthesised using a similar method to intermediate 13, 148 mg, 0.299 mmol) in anhydrous pyridine (4.0 mL) in a pressure vial. The reaction vessel was sealed, and the mixture stirred at 90 °C for 2 h 30 m. The reaction mixture was allowed to cool to r.t., diluted with EtOAc (~15 mL), and washed sequentially with sat. aq. sodium thiosulphate (~15 mL), 1 M HCl (aq.) (~20 mL), and brine (~15 mL). The organic phase was passed through a phase separator and concentrated to dryness in vacuo. The residue was purified by preparative HPLC (Method P1) to afford the title compound as an off-white solid (49 mg, 100% purity, 34% yield).1H NMR (500 MHz, DMSO) δ 10.03 (s, 1H), 8.09 (s, 1H), 7.91 (d, J = 2.3 Hz, 1H), 7.34 (d, J = 1.2 Hz, 2H), 7.31 (d, J = 2.2 Hz, 1H), 7.21 – 7.15 (m, 1H), 7.08 (s, 1H), 5.63 – 4.98 (m, 2H), 3.91 (s, 3H). LCMS: m / z = 481.0, 483.0 [M+H]+, (ESI+), RT = 1.52, Method BExample 17 – Synthesis of 13-Chloro-4-fluoro-14-hydroxy-19-methoxy-20-methyl-16,16- dioxo-9-oxa-16λ6-thia-17-azatetracyclo[16.3.1.111,15.02,7]tricosa- 1(21),2,4,6,11,13,15(23),18(22),19-nonaen-10-one (Compound 17)

[0255] To a solution of 13-chloro-4-fluoro-14,19-dimethoxy-20-methyl-16,16-dioxo-9- oxa-16λ6-thia-17-azatetracyclo[16.3.1.111,15.02,7]tricosa- 1(21),2(7),3,5,11,13,15(23),18(22),19-nonaen-10-one (synthesised using a similar method to intermediate 7, 98%, 138 mg, 0.275 mmol) in anhydrous pyridine (5 mL) was added lithium iodide (74 mg, 0.553 mmol). The reaction mixture was heated at 80 °C for 1 h. The organics were diluted with EtOAc (30 mL), washed with HCl (2 x 30 mL of a 1 M aqueous solution), Na2SO3(10 mL of a saturated aqueous solution), brine (2 x 20 mL) and then dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by preparative HPLC (Method P1) to afford the title compound as a light pink solid (59 mg, 99% purity, 44% Yield).1H NMR (500 MHz, DMSO) δ 9.48 (s, 1H), 7.89 – 7.83 (m, 1H), 7.59 (dd, J = 8.5, 5.9 Hz, 1H), 7.48 (d, J = 2.2 Hz, 1H), 7.27 – 7.20 (m, 1H), 7.19 – 7.16 (m, 1H), 7.14 (dd, J = 9.4, 2.8 Hz, 1H), 7.00 (d, J = 2.3 Hz, 1H), 5.47 – 5.38 (m, 1H), 5.24 – 5.15 (m, 1H), 3.42 (s, 3H), 2.10 – 2.05 (m, 3H). LCMS: m / z = 476.0 / 478.0 [M-H]-, (ESI-), RT = 4.24, Method AExample 18 – Synthesis of 13,19-Dichloro-5-fluoro-14-hydroxy-16,16-dioxo-9-oxa-16λ6- thia-4,17-diazatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2(7),3,5,11,13,15(23),18(22),19- nonaen-10-one (Compound 18)

[0256] To a solution of 13,19-dichloro-5-fluoro-14-methoxy-16,16-dioxo-9-oxa-16λ6-thia- 4,17-diazatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2(7),3,5,11,13,15(23),18(22),19- nonaen-10-one (synthesised from intermediate 11, using a similar method to intermediate 6, 97%, 60 mg, 0.120 mmol) in anhydrous pyridine (2.1 mL) was added lithium iodide (80 mg, 0.598 mmol). The reaction mixture was heated at 80 °C for 1 h. The organics were diluted with EtOAc (30 mL), washed with HCl (2 x 30 mL of a 1 M aqueous solution), Na2SO3(10 mL of a saturated aqueous solution), brine (2 x 20 mL) and then dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by preparative HPLC (Method P1) to afford the title compound as a light pink solid (21 mg, 95% purity, 35% Yield).1H NMR (500 MHz, DMSO) δ 10.00 (br.s, 1H), 8.19 (s, 1H), 7.90 – 7.85 (m, 1H), 7.49 (d, J = 1.9 Hz, 1H), 7.40 – 7.34 (m, 2H), 7.31 (d, J = 2.3 Hz, 1H), 7.26 – 7.23 (m, 1H), 5.59 – 5.49 (m, 1H), 5.31 – 5.21 (m, 1H). LCMS: m / z = 467.0 / 469.0 [M-H]-, (ESI-), RT = 3.62, Method AExample 19 – Synthesis of 13-Chloro-19-(3,3-difluoroazetidin-1-yl)-5-fluoro-14- hydroxy-16,16-dioxo-9-oxa-16λ6-thia-4,17-diazatetracyclo[16.3.1.111,15.02,7]tricosa- 1(21),2(7),3,5,11,13,15(23),18(22),19-nonaen-10-one (Compound 19)

[0257] To a solution of 13-chloro-19-(3,3-difluoroazetidin-1-yl)-5-fluoro-14-methoxy- 16,16-dioxo-9-oxa-16λ6-thia-4,17-diazatetracyclo[16.3.1.111,15.02,7]tricosa- 1(21),2(7),3,5,11,13,15(23),18(22),19-nonaen-10-one (synthesised from intermediates 11 and 19, using a similar method to intermediate 7, 67% purity, 150 mg, 0.28 mmol) in anhydrous pyridine (3.7 mL) was added lithium iodide (186 mg, 1.39 mmol). The reaction mixture was heated at 80 °C for 16 h. The reaction mixture was dissolved in EtOAc (30 mL) and washed with 1 M aq. HCl (30 mL). The aqueous phase was extracted further with EtOAc (2 x 20 mL) and the organics were combined, washed with sat. aq. Na2S2O3 (30 mL) and brine (30 mL) and dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (Method P1) to afford the title compound as a white solid (8.3 mg, 99% purity, 5.6% Yield).1H NMR (500 MHz, DMSO) δ 9.64 (s, 1H), 7.94 (s, 1H), 7.86 (s, 1H), 7.43 (d, J = 2.0 Hz, 1H), 7.38 (dd, J = 8.3, 2.0 Hz, 1H), 7.21 (d, J = 2.2 Hz, 1H), 6.73 (d, J = 8.4 Hz, 1H), 6.24 (d, J = 2.0 Hz, 1H), 5.68 – 4.99 (m, 2H), 4.67 – 4.30 (m, 4H). LCMS: m / z = 526.0 / 527.9 [M+H]+, (ESI+), RT = 3.94, Method AExample 20 – Synthesis of 13-Chloro-5,19,20-trifluoro-14-hydroxy-16,16-dioxo-9-oxa- 16λ6-thia-17-azatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2,4,6,11,13,15(23),18(22),19- nonaen-10-one (Compound 20) C

[0258] 13-chloro-5,19,20-trifluoro-14-methoxy-16,16-dioxo-9-oxa-16λ6-thia-17- azatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2,4,6,11,13,15(23),18(22),19-nonaen-10-one (synthesised using a similar method to intermediate 7, 80% purity, 220 mg, 0.36 mmol) and iodocyclohexane (0.23 mL, 1.79 mmol) were weighed in a pressure vial and anhydrous DMF (5.5 mL) was added. The reaction mixture was placed at 120 ºC and stirred at that temp for 45 min. The mixture was cooled to r.t. The organics were diluted with EtOAc (40 mL), washed with 1 M HCl (100 mL), Na2SO3 (40 mL of a saturated aqueous solution), then brine (40 mL). The EtOAc layer was passed through phase separator paper and concentrated in vacuo. The residue was purified by FCC (10 g SiO2 cartridge, 0-80% EtOAc in heptane) followed by lyophilisation to afford the title compound as a white solid (111 mg, 96% purity, 62% Yield).1H NMR (400 MHz, DMSO) δ 7.66 (s, 1H), 7.51 – 7.43 (m, 2H), 7.33 – 7.23 (m, 2H), 7.21 (d, J = 2.4 Hz, 1H), 6.83 (d, J = 6.0 Hz, 1H), 5.49 – 5.33 (m, 1H), 5.25 – 5.04 (m, 1H). LCMS: m / z = 468.0 & 470.0 [M-H]-, (ESI-), RT = 4.19, Method AExample 21 – Synthesis of 13-Chloro-4-fluoro-14-hydroxy-19-methoxy-16,16-dioxo-9- oxa-16λ6-thia-17-azatetracyclo[16.3.1.111,15.02,7]tricosa- 1(21),2,4,6,11,13,15(23),18(22),19-nonaen-10-one (Compound 21)

[0259] 13-Chloro-4-fluoro-14,19-dimethoxy-16,16-dioxo-9-oxa-16λ6-thia-17- azatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2,4,6,11,13,15(23),18(22),19-nonaen-10-one (synthesised using a similar method to intermediate 7, 100% purity, 120 mg, 0.25 mmol) and iodocyclohexane (0.042 mL, 0.325 mmol) were weighed in a pressure vial and anhydrous DMF (3.6 mL) was added. The reaction mixture was placed at 120 ºC and stirred for 2 h. The mixture was then purified by preparative HPLC (Method P1) to afford the title compound as a white solid (67 mg, 100% purity, 58% Yield).1H NMR (400 MHz, DMSO) δ 9.30 (s, 1H), 7.86 (d, J = 2.2 Hz, 1H), 7.58 (dd, J = 8.3, 5.9 Hz, 1H), 7.36 (d, J = 2.2 Hz, 1H), 7.32 – 7.16 (m, 4H), 6.73 (d, J = 8.5 Hz, 1H), 5.59 (d, J = 12.7 Hz, 1H), 5.11 (d, J = 12.7 Hz, 1H), 3.44 (s, 3H). LCMS: m / z = 462.1 & 464.1 [M-H]-, (ESI-), RT = 4.04, Method A Example 22 – Synthesis of 13-Chloro-20,21-difluoro-14-hydroxy-16,16-dioxo-9-oxa- 16λ6-thia-17-azatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2,4,6,11(23),12,14,18(22),19- nonaen-10-one (Compound 22)

[0260] Intermediate 20 (95% purity, 130 mg, 0.265 mmol) and iodocyclohexane (285 mg, 1.36 mmol) were combined and the mixture dissolved in anhydrous DMF (3.5 mL). The mixture was heated to 120 ºC and stirred for 2 h. The mixture was allowed to cool to r.t., added to sat. aq. Na2S2O3(50 mL) and extracted with DCM (3 x 50 mL). The combined organic extracts were washed with 1 M aq. HCl (50 mL), then brine (50 mL) and were dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified by preparative HPLC (Method P1) to afford the title compound as a pale yellow solid (73 mg, 98% purity, 60% Yield).1H NMR (500 MHz, DMSO) δ 10.30 (s, 1H), 7.94 (d, J = 2.1 Hz, 1H), 7.60 – 7.56 (m, 1H), 7.51 – 7.46 (m, 2H), 7.35 – 7.30 (m, 1H), 7.29 – 7.22 (m, 1H), 7.16 (d, J = 2.1 Hz, 1H), 6.63 – 6.59 (m, 1H), 5.51 (d, J = 12.8 Hz, 1H), 5.06 (d, J = 12.8 Hz, 1H). LCMS: m / z = 450.0 / 452.0 [M-H]-, (ESI-), RT = 4.20, Method A Example 23 – Synthesis of 13-Chloro-21-fluoro-14-hydroxy-16,16-dioxo-9-oxa-16λ6- thia-17-azatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2(7),3,5,11,13,15(23),18(22),19- nonaen-10-one (Compound 23) C

[0261] To a solution of 13-chloro-21-fluoro-14-methoxy-16,16-dioxo-9-oxa-16λ6-thia-17- azatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2(7),3,5,11,13,15(23),18(22),19-nonaen-10- one (synthesised using a similar method to intermediate 7, 67% purity, 150 mg, 0.224 mmol) in anhydrous DMF (20 mL) was added iodocyclohexane (0.30 mL, 2.32 mmol). The reaction mixture was heated at 120 °C for 3 h. The mixture was allowed to cool to r.t. and added to sat. aq. Na2S2O3 (50 mL) and extracted with DCM (3 x 50 mL). The combined organic extracts were washed with 1 M aq. HCl (50 mL), then brine (50 mL) and were dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified by preparative HPLC (Method P1) to afford the title compound as an off-white solid (72 mg, 97% purity, 72% Yield).1H NMR (500 MHz, DMSO) δ 10.12 (s, 1H), 7.91 (d, J = 2.1 Hz, 1H), 7.57 – 7.53 (m, 1H), 7.50 – 7.46 (m, 1H), 7.46 – 7.43 (m, 1H), 7.34 – 7.27 (m, 2H), 7.22 – 7.16 (m, 1H), 7.12 (d, J = 2.1 Hz, 1H), 6.79 (dd, J = 6.6, 2.7 Hz, 1H), 5.45 (d, J = 12.6 Hz, 1H), 5.07 (d, J = 12.6 Hz, 1H). LCMS: m / z = 432.3 / 434.3 [M-H]-, (ESI-), RT = 4.08, Method A Example 24 – Synthesis of 13-Chloro-4,5-difluoro-14-hydroxy-19-methoxy-16,16-dioxo- 9-oxa-16λ6-thia-17-azatetracyclo[16.3.1.111,15.02,7]tricosa- 1(22),2(7),3,5,11,13,15(23),18,20-nonaen-10-one (Compound 24)

[0262] To a solution of 13-chloro-4,5-difluoro-14,19-dimethoxy-16,16-dioxo-9-oxa-16λ6- thia-17-azatetracyclo[16.3.1.111,15.02,7]tricosa-1(22),2(7),3,5,11,13,15(23),18,20-nonaen- 10-one (synthesised using a similar method to intermediate 7, 93% purity, 135 mg, 0.25 mmol) in anhydrous DMF (3 mL) in a pressure vial was added iodocyclohexane (0.04 mL, 0.33 mmol) . The reaction mixture was heated to 100 °C for 24 h. After cooling, the reaction was quenched by pouring onto sat aq. Na2S2O3 (20 mL). The mixture was extracted with DCM (3 x 10 mL). The combined organic extracts were washed with 1 M aq. HCl (10 mL), then brine (10 mL) and were dried over MgSO4, filtered and concentrated. The residue was purified by preparative HPLC (Method P1) followed by trituration with MeCN to afford the title compound as a beige solid (44 mg, 99% purity, 36% Yield).1H NMR (500 MHz, DMSO) δ 9.31 (s, 1H), 7.86 (d, J = 2.2 Hz, 1H), 7.70 (dd, J = 11.6, 8.2 Hz, 1H), 7.48 (dd, J = 11.2, 8.1 Hz, 1H), 7.35 (d, J = 2.2 Hz, 1H), 7.27 (dd, J = 8.5, 2.2 Hz, 1H), 7.21 (d, J = 2.2 Hz, 1H), 6.71 (d, J = 8.5 Hz, 1H), 5.57 (d, J = 12.8 Hz, 1H), 5.09 (d, J = 12.9 Hz, 1H), 3.43 (s, 3H). LCMS: m / z = 480, 482 [M-H]-, (ESI-), RT = 4.11, Method AExample 25 – Synthesis of 13-Chloro-5,19,21-trifluoro-14-hydroxy-16,16-dioxo-9-oxa- 16λ6-thia-17-azatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2,4,6,11(23),12,14,18(22),19- nonaen-10-one (Compound 25)

[0263] A solution of 13-chloro-5,19,21-trifluoro-14-methoxy-16,16-dioxo-9-oxa-16λ6- thia-17-azatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2,4,6,11(23),12,14,18(22),19-nonaen- 10-one (synthesised using a similar method to intermediate 7, 80% purity, 250 mg, 0.413 mmol) and iodocyclohexane (270 µL, 2.09 mmol) in anhydrous DMF (5 mL) was heated to 120 °C for 1.5 h. The reaction mixture was diluted with EtOAc (20 ml) and washed with sat. Na2SO3 (20 ml), HCl 1 M (20 ml) and brine (20 ml). The combined organic phases were dried over MgSO4and evaporated under vacuum. The residue was dissolved in DMSO / MeCN / water and filtered. The filtrate was purified by preparative HPLC (Method P1) to afford the title compound as an off-white solid (36 mg, 96% purity, 18% Yield).1H NMR (400 MHz, DMSO) δ 7.84 (s, 1H), 7.47 – 7.32 (m, 2H), 7.30 – 7.19 (m, 2H), 7.15 (s, 1H), 6.77 (dd, J = 8.1, 8.1 Hz, 1H), 5.33 (d, J = 12.8 Hz, 1H), 5.03 (d, J = 12.8 Hz, 1H). LCMS: m / z = 468.0 / 470.0 [M-H]-, (ESI-), RT = 4.10, Method AExample 26 – Synthesis of 13-Chloro-4,19,21-trifluoro-14-hydroxy-6-methyl-16,16- dioxo-9-oxa-16λ6-thia-17-azatetracyclo[16.3.1.111,15.02,7]tricosa- 1(21),2(7),3,5,11(23),12,14,18(22),19-nonaen-10-one (Compound 26) C

[0264] 13-chloro-4,19,21-trifluoro-14-methoxy-6-methyl-16,16-dioxo-9-oxa-16λ6-thia-17- azatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2(7),3,5,11(23),12,14,18(22),19-nonaen-10- one (synthesised using a similar method to intermediate 7, 94% purity, 269 mg, 0.508 mmol), anhydrous DMF (20 mL) and iodocyclohexane (0.65 mL, 5.03 mmol) were added to a pressure vial. The vial was sealed and heated at 120 °C for 1 h then allowed to cool to r.t.. The reaction mixture was added to sat aq. Na2S2O3(50 mL) and extracted with DCM (3 x 50 mL). The combined organic extracts were washed with 1 M aq. HCl (50 mL), then brine (50 mL) and were dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified by preparative HPLC (Method P1) to afford the title compound as an off-white solid (72 mg, 97% purity, 28% Yield).1H NMR (500 MHz, DMSO) δ 10.02 (s, 1H), 8.00 – 7.92 (m, 1H), 7.62 – 7.53 (m, 1H), 7.20 (dd, J = 9.7, 2.8 Hz, 1H), 7.15 (d, J = 2.2 Hz, 1H), 6.93 (dd, J = 8.9, 2.8 Hz, 1H), 6.63 – 6.54 (m, 1H), 5.68 (d, J = 13.1 Hz, 1H), 4.84 (d, J = 13.1 Hz, 1H), 2.58 (s, 3H). LCMS: m / z = 482.0 / 484.0 [M-H]-, (ESI-), RT = 4.33, Method AExample 27 – Synthesis of 13-Chloro-19,21-difluoro-14-hydroxy-16,16-dioxo-5- (trifluoromethyl)-9-oxa-16λ6-thia-17-azatetracyclo[16.3.1.111,15.02,7]tricosa- 1(21),2,4,6,11,13,15(23),18(22),19-nonaen-10-one (Compound 27)

[0265] 13-chloro-19,21-difluoro-14-methoxy-16,16-dioxo-5-(trifluoromethyl)-9-oxa-16λ6- thia-17-azatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2,4,6,11,13,15(23),18(22),19-nonaen- 10-one (synthesised using a similar method to intermediate 7, 85% purity, 156 mg, 0.29 mmol) and iodocyclohexane (0.19 mL, 1.43 mmol) were weighed in a pressure vial and anhydrous DMF (4.9 mL) was added. The reaction mixture was stirred at 120 ºC for 1.5 h. The mixture was diluted with EtOAc (40 mL), washed with 1 M HCl (50 mL), Na2S2O3(40 mL of a sat. aq. solution), then brine (40 mL). The EtOAc layer was passed through a phase separator and concentrated in vacuo. The residue was purified by preparative HPLC (Method P1) to afford the title compound as a brown solid (33 mg, 97% purity, 21% Yield).1H NMR (400 MHz, DMSO) δ 10.15 (br. s, 1H), 8.01 (d, J = 2.0 Hz, 1H), 7.95 (d, J = 2.2 Hz, 1H), 7.84 (dd, J = 8.2, 2.0 Hz, 1H), 7.58 – 7.48 (m, 2H), 7.23 (d, J = 2.2 Hz, 1H), 6.93 – 6.84 (m, 1H), 5.59 (d, J = 13.0 Hz, 1H), 5.16 (d, J = 13.0 Hz, 1H). LCMS: m / z = 518.0 / 519.9 [M-H]-, (ESI-), RT = 4.23, Method AExample 28 – Synthesis of 13-Chloro-19,21-difluoro-14-hydroxy-16,16-dioxo-4- (trifluoromethyl)-9-oxa-16λ6-thia-17-azatetracyclo[16.3.1.111,15.02,7]tricosa- 1(21),2,4,6,11,13,15(23),18(22),19-nonaen-10-one (Compound 28)

[0266] 13-chloro-19,21-difluoro-14-methoxy-16,16-dioxo-4-(trifluoromethyl)-9-oxa-16λ6- thia-17-azatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2,4,6,11,13,15(23),18(22),19-nonaen- 10-one (synthesised using a similar method to intermediate 7, 100% purity, 28 mg, 0.0524 mmol) and iodocyclohexane (0.033 mL, 0.257 mmol) were weighed in a pressure vial and anhydrous DMF (0.9 mL) was added. The reaction mixture was stirred at 120 ºC for 1.5 h. The mixture was diluted with EtOAc (40 mL), washed with 1 M HCl (50 mL), Na2S2O3(40 mL of a sat. aq. solution), then brine (40 mL). The organic layer was passed through a phase separator and concentrated in vacuo. The residue was purified by preparative HPLC (Method P1) to afford the title compound as a white powder (12 mg, 97% purity, 43% Yield).1H NMR (500 MHz, DMSO) δ 7.89 – 7.84 (m, 2H), 7.82 (d, J = 8.1 Hz, 1H), 7.66 (s, 1H), 7.51 – 7.46 (m, 1H), 7.23 (d, J = 2.2 Hz, 1H), 6.96 – 6.92 (m, 1H), 5.51 (d, J = 13.3 Hz, 1H), 5.17 (d, J = 13.1 Hz, 1H). LCMS: m / z = 518.0 / 520.0 [M-H]-, (ESI-), RT = 4.22, Method AExample 29 – Synthesis of 4-Bromo-13-chloro-19,21-difluoro-14-hydroxy-16,16-dioxo-9- oxa-16λ6-thia-17-azatetracyclo[16.3.1.111,15.02,7]tricosa- 1(21),2,4,6,11,13,15(23),18(22),19-nonaen-10-one (Compound 29) C

[0267] 4-bromo-13-chloro-19,21-difluoro-14-methoxy-16,16-dioxo-9-oxa-16λ6-thia-17- azatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2,4,6,11,13,15(23),18(22),19-nonaen-10-one (synthesised using a similar method to intermediate 7, 93% purity, 113 mg, 0.19 mmol) and iodocyclohexane (0.12 mL, 0.946 mmol) were weighed in a pressure vial and anhydrous DMF (3.2 mL) was added. The reaction mixture was stirred at 120 ºC for 1.5 h. The mixture was diluted with EtOAc (40 mL), washed with 1 M HCl (50 mL), Na2S2O3 (40 mL of a sat. aq. solution), then brine (40 mL). The EtOAc layer was passed through a phase separator and concentrated in vacuo. The residue was purified by preparative HPLC (Method P1) to afford the title compound as a brown solid (57 mg, 95% purity, 53% Yield).1H NMR (500 MHz, DMSO) δ 10.10 (s, 1H), 7.94 (d, J = 2.2 Hz, 1H), 7.72 – 7.66 (m, 1H), 7.56 – 7.47 (m, 3H), 7.21 (d, J = 2.2 Hz, 1H), 6.87 – 6.80 (m, 1H), 5.44 (d, J = 12.9 Hz, 1H), 5.05 (d, J = 12.8 Hz, 1H). LCMS: m / z = 529.9 / 531.9 [M-H]-, (ESI-), RT = 4.22, Method AExample 30 – Synthesis of 13-Chloro-20-cyclopropyl-5-fluoro-14-hydroxy-16,16-dioxo- 9-oxa-16λ6-thia-17-azatetracyclo[16.3.1.111,15.02,7]tricosa- 1(21),2(7),3,5,11,13,15(23),18(22),19-nonaen-10-one (Compound 30)

[0268] To a solution of 13-chloro-20-cyclopropyl-5-fluoro-14-methoxy-16,16-dioxo-9-oxa- 16λ6-thia-17-azatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2(7),3,5,11,13,15(23),18(22),19- nonaen-10-one (synthesised using a similar method to intermediate 7, 91% purity, 295 mg, 0.6 mmol) in anhydrous DMF (8.9 mL) was added iodocyclohexane (150 uL, 1.16 mmol). The reaction mixture was stirred at 120 °C for 1.75 h. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC (Method P1) to afford the title compound as an off-white solid (171 mg, 99% purity, 59% Yield).1H NMR (500 MHz, DMSO) δ 10.81 (br s, 1H), 10.00 (s, 1H), 7.90 (d, J = 2.1 Hz, 1H), 7.45 (dd, J = 9.5, 2.3 Hz, 1H), 7.30 – 7.21 (m, 2H), 7.13 (d, J = 2.1 Hz, 1H), 7.06 – 7.02 (m, 1H), 6.71 (d, J = 1.9 Hz, 1H), 6.62 – 6.57 (m, 1H), 5.39 (d, J = 12.6 Hz, 1H), 5.30 (d, J = 12.6 Hz, 1H), 1.85 (tt, J = 8.4, 5.0 Hz, 1H), 0.97 – 0.87 (m, 2H), 0.64 – 0.58 (m, 1H), 0.58 – 0.49 (m, 1H). LCMS: m / z = 472.1 / 474.1 [M-H]-, (ESI-), RT = 4.41, Method AExample 31 – Synthesis of 13-Chloro-4-fluoro-14-hydroxy-16,16-dioxo-19- (trifluoromethoxy)-9-oxa-16λ6-thia-17-azatetracyclo[16.3.1.111,15.02,7]tricosa- 1(21),2,4,6,11(23),12,14,18(22),19-nonaen-10-one (Compound 31) C

[0269] 13-chloro-4-fluoro-14-methoxy-16,16-dioxo-19-(trifluoromethoxy)-9-oxa-16λ6- thia-17-azatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2,4,6,11(23),12,14,18(22),19-nonaen- 10-one (synthesised using a similar method to intermediate 7, 98% purity, 170 mg, 0.313 mmol) and iodocyclohexane (330 mg, 1.57 mmol) were combined and the mixture dissolved into anhydrous DMF (5 mL). The mixture was heated to 80 ºC and stirred for 24 h. Sat. aq. Na2S2O3 (50 mL) was added, and the mixture extracted with DCM (3 x 50 mL). The combined organic extracts were washed with 1 M aq. HCl (50 mL), then brine (50 mL) and were dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified by preparative HPLC (Method P1) to afford the title compound as a white solid (74 mg, 97% purity, 44% Yield).1H NMR (500 MHz, DMSO) δ 10.22 (s, 1H), 7.89 (d, J = 2.2 Hz, 1H), 7.62 (dd, J = 8.5, 5.8 Hz, 1H), 7.49 (dd, J = 8.5, 2.2 Hz, 1H), 7.33 (dd, J = 8.5, 1.8 Hz, 1H), 7.30 – 7.25 (m, 2H), 7.20 (dd, J = 9.3, 2.8 Hz, 1H), 7.06 (d, J = 2.2 Hz, 1H), 5.37 – 5.28 (m, 2H). LCMS: m / z = 516.2 / 518.3 [M-H]-, (ESI-), RT = 4.30, Method AExample 32 – Synthesis of 13-Bromo-20-fluoro-14-hydroxy-19-methoxy-16,16-dioxo-5- (trifluoromethyl)-9-oxa-16λ6-thia-4,17-diazatetracyclo[16.3.1.111,15.02,7]tricosa- 1(21),2(7),3,5,11,13,15(23),18(22),19-nonaen-10-one (Compound 32)

[0270] Intermediate 24 (95 mg, 99% purity, 0.153 mmol) and lithium iodide (25 mg, 0.187 mmol) were dissolved into anhydrous pyridine (3 mL). The mixture was heated to 80 °C and stirred for 18 h. The mixture was cooled to r.t. Sat. aq. Na2S2O3 (50 mL) was added, and the mixture was extracted with DCM (3 x 50 mL). The combined organic extracts were washed with 1 M aq. HCl (50 mL), then brine (50 mL) and were dried over Na2SO4, filtered and concentrated. The residue was purified by preparative HPLC (Method P1) to afford the title compound as an off-white solid (56 mg, 98% purity, 62% Yield).1H NMR (500 MHz, DMSO) δ 9.78 (s, 1H), 8.70 (s, 1H), 8.21 (s, 1H), 8.05 (d, J = 2.2 Hz, 1H), 7.50 – 7.43 (m, 2H), 7.12 (d, J = 2.0 Hz, 1H), 5.64 (d, J = 13.2 Hz, 1H), 5.38 (d, J = 13.2 Hz, 1H), 3.60 (d, J = 2.1 Hz, 3H). LCMS: m / z = 577.0 / 579.0 [M+H]+, (ESI+), RT = 4.16, Method AExample 33 – Synthesis of 13-Bromo-4-fluoro-14-hydroxy-19-methoxy-16,16-dioxo-9- oxa-16λ6-thia-17,20-diazatetracyclo[16.3.1.111,15.02,7]tricosa- 1(21),2(7),3,5,11(23),12,14,18(22),19-nonaen-10-one (Compound 33) B

[0271] Lithium iodide (83 mg, 0.620 mmol) was added to a stirred solution of 13-bromo-4- fluoro-14,19-dimethoxy-16,16-dioxo-9-oxa-16λ6-thia-17,20- diazatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2(7),3,5,11(23),12,14,18(22),19-nonaen-10- one (synthesised using a similar method to intermediate 24, 88% purity, 145 mg, 0.244 mmol) in anhydrous pyridine (4 mL) in a pressure tube (10 mL) and the mixture stirred at 90 °C for 3 h 30 m. The reaction vessel was allowed to cool to r.t., and the reaction mixture was diluted with EtOAc (25 mL) and washed with sat. aq. sodium thiosulphate (25 mL), 1 M aq. HCl (25 mL), and brine (25 mL). The organic phase was passed through a phase separator and concentrated. The residue was purified by preparative HPLC (Method P1) to afford the title compound as a light pink solid (57 mg, 99% purity, 46 % Yield).1H NMR (500 MHz, DMSO) δ 9.78 (s, 1H), 8.15 (d, J = 2.2 Hz, 1H), 8.04 (d, J = 2.2 Hz, 1H), 7.66 – 7.57 (m, 1H), 7.46 (d, J = 2.2 Hz, 1H), 7.32 (d, J = 2.2 Hz, 1H), 7.31 – 7.25 (m, 2H), 5.61 (d, J = 13.0 Hz, 1H), 5.22 (d, J = 13.0 Hz, 1H), 3.58 (s, 3H). LCMS: m / z = 508.9, 510.9 [M+H]+, (ESI+), RT = 3.97, Method AExample 34 – Synthesis of 13-Bromo-14-hydroxy-19-methoxy-10,16,16-trioxo-9-oxa- 16λ6-thia-17,20-diazatetracyclo[16.3.1.111,15.02,7]tricosa- 1(22),2(7),3,5,11,13,15(23),18,20-nonaene-4-carbonitrile (Compound 34)

[0272] A mixture of intermediate 26 (86% purity, 150 mg, 0.283 mmol), lithium iodide (191 mg, 1.41 mmol) and anhydrous pyridine (3 mL) was stirred at 90 °C for 2 h 30. The reaction mixture was diluted with EtOAc (40 mL), washed with sat. aq. Na2S2O3 (30 ml), 1 M aq. HCl (30 mL) and brine (30 mL), then passed through a phase separator and concentrated. The residue was purified by preparative HPLC (Method P1) to afford the title compound as an off-white solid (26.5 mg, 99% purity, 18% yield).1H NMR (500 MHz, DMSO) δ 9.73 (s, 1H), 8.15 (d, J = 2.2 Hz, 1H), 8.02 (d, J = 2.2 Hz, 1H), 7.93 (dd, J = 7.9, 1.8 Hz, 1H), 7.90 – 7.83 (m, 1H), 7.78 (d, J = 8.0 Hz, 1H), 7.53 (d, J = 2.2 Hz, 1H), 7.31 (d, J = 2.2 Hz, 1H), 5.73 (d, J = 13.3 Hz, 1H), 5.28 (d, J = 13.3 Hz, 1H), 3.58 (s, 3H). LCMS: m / z = 516.0 / 518.0 [M+H]+, (ESI+), RT = 3.76, Method AExample 35 – Synthesis of 13-Bromo-14-hydroxy-19-methoxy-16,16-dioxo-5- (trifluoromethyl)-9-oxa-16λ6-thia-4,17,20-triazatetracyclo[16.3.1.111,15.02,7]tricosa- 1(21),2(7),3,5,11,13,15(23),18(22),19-nonaen-10-one (Compound 35)

[0273] In a pressure vial, 13-bromo-14,19-dimethoxy-16,16-dioxo-5-(trifluoromethyl)-9- oxa-16λ6-thia-4,17,20-triazatetracyclo[16.3.1.111,15.02,7]tricosa- 1(21),2(7),3,5,11,13,15(23),18(22),19-nonaen-10-one (synthesised using a similar method to intermediate 26, 90% purity, 151 mg, 0.250 mmol) was dissolved in anhydrous pyridine (6.4 mL) and lithium iodide (293 mg, 2.19 mmol) was added. The reaction mixture was heated at 70 °C for 16 h. The reaction mixture was concentrated. The residue was purified by preparative HPLC (Method P1) to afford the title compound as an off-white solid (88.0 mg, 98% purity, 62% yield).1H NMR (500 MHz, DMSO) δ 9.82 (s, 1H), 8.75 (s, 1H), 8.20 (s, 1H), 8.18 (d, J = 2.2 Hz, 1H), 8.05 (d, J = 2.2 Hz, 1H), 7.64 (d, J = 2.2 Hz, 1H), 7.32 (d, J = 2.2 Hz, 1H), 5.90 – 5.68 (m, 1H), 5.44 – 5.32 (m, 1H), 3.59 (s, 3H). LCMS: m / z = 558.0 / 560.0 [M-H]-, (ESI-), RT = 3.98, Method AExample 36 – Synthesis of 13-Bromo-19,21-difluoro-14-hydroxy-16,16-dioxo-5- (trifluoromethyl)-9-oxa-16λ6-thia-17-azatetracyclo[16.3.1.111,15.02,7]tricosa- 1(21),2(7),3,5,11,13,15(23),18(22),19-nonaen-10-one (Compound 36)

[0274] 13-bromo-19,21-difluoro-14-methoxy-16,16-dioxo-5-(trifluoromethyl)-9-oxa-16λ6- thia-17-azatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2(7),3,5,11,13,15(23),18(22),19- nonaen-10-one (synthesised using a similar method to intermediate 24, 95% purity, 140 mg, 0.230 mmol) and lithium iodide (155 mg, 1.16 mmol) were combined and the mixture dissolved into anhydrous pyridine (7 mL). The mixture was heated to 80 °C and stirred for 18 h. The mixture was cooled to r.t. Sat. aq. Na2S2O3 (50 mL) was added, and the mixture was extracted with DCM (3 x 50 mL). The combined organic extracts were washed with 1 M aq. HCl (50 mL), then brine (50 mL) and were dried over Na2SO4, filtered and concentrated. The residue was purified by preparative HPLC (Method P1) to afford the title compound as an off-white solid (70 mg, 95% purity, 51% Yield).1H NMR (500 MHz, DMSO) δ 10.15 (s, 1H), 8.09 (d, J = 2.2 Hz, 1H), 8.00 (d, J = 2.0 Hz, 1H), 7.82 (dd, J = 8.0, 2.0 Hz, 1H), 7.62 – 7.55 (m, 1H), 7.50 (d, J = 7.9 Hz, 1H), 7.21 (d, J = 2.2 Hz, 1H), 6.85 – 6.74 (m, 1H), 5.63 (d, J = 13.0 Hz, 1H), 5.13 (d, J = 13.0 Hz, 1H). LCMS: m / z = 561.9 / 563.9 [M-H]-, (ESI-), RT = 4.42, Method AExample 37 – Synthesis of 13-Bromo-14-hydroxy-19-methoxy-10,16,16-trioxo-9-oxa- 16λ6-thia-17-azatetracyclo[16.3.1.111,15.02,7]tricosa- 1(21),2(7),3,5,11,13,15(23),18(22),19-nonaene-4-carbonitrile (Compound 37) B

[0275] To a solution of 13-bromo-14,19-dimethoxy-10,16,16-trioxo-9-oxa-16λ6-thia-17- azatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2(7),3,5,11,13,15(23),18(22),19-nonaene-4- carbonitrile (synthesised using a similar method to intermediate 24, 79% purity, 100 mg, 0.179 mmol) in anhydrous pyridine (3 mL) was added lithium iodide (84 mg, 0.628 mmol). The reaction mixture was heated at 100 °C for 3 h. The reaction mixture was cooled to r.t. The organics were diluted with EtOAc (5 mL), washed with 2 M Na2S2O3(5 mL), 1 M HCl (5 mL), then brine (5 mL). The organic layer was dried over MgSO4, filtered, and concentrated. The residue was purified by preparative HPLC (Method P1) to afford the title compound as a white solid (20 mg, 98% purity, 21% Yield).1H NMR (500 MHz, DMSO) δ 9.32 (s, 1H), 7.99 (d, J=2.2 Hz, 1H), 7.89 (dd, J=7.8, 1.8 Hz, 1H), 7.82 (d, J=1.8 Hz, 1H), 7.75 (d, J=7.9 Hz, 1H), 7.36 (d, J=2.3 Hz, 1H), 7.31 (dd, J=8.4, 2.2 Hz, 1H), 7.22 (d, J=2.2 Hz, 1H), 6.76 (d, J=8.5 Hz, 1H), 5.70 (d, J=13.0 Hz, 1H), 5.18 (d, J=13.2 Hz, 1H), 3.46 (s, 3H). LCMS: m / z = 513.0 / 515.0 [M-H]-, (ESI-), RT = 3.89, Method AExample 38 – Synthesis of 13-Bromo-19,21-difluoro-14-hydroxy-16,16-dioxo-5- (trifluoromethyl)-9-oxa-16λ6-thia-4,17-diazatetracyclo[16.3.1.111,15.02,7]tricosa- 1(21),2(7),3,5,11,13,15(23),18(22),19-nonaen-10-one (Compound 38)

[0276] To a solution of 13-bromo-19,21-difluoro-14-methoxy-16,16-dioxo-5- (trifluoromethyl)-9-oxa-16λ6-thia-4,17-diazatetracyclo[16.3.1.111,15.02,7]tricosa- 1(21),2(7),3,5,11,13,15(23),18(22),19-nonaen-10-one (synthesised using a similar method to intermediate 24, 97% purity, 174 mg, 0.3 mmol) in anhydrous pyridine (4 mL) was added lithium iodide (201 mg, 1.5 mmol). The reaction mixture was heated at 80 °C for 5 h. The reaction mixture was dissolved in EtOAc (30 mL) and washed with 1 M aq. HCl (30 mL). The aqueous phase was extracted further with EtOAc (2 x 30 mL) and the organics were combined, washed with sat. aq. Na2S2O3 (30 mL) and brine (30 mL) and dried over Na2SO4, filtered and concentrated. The residue was purified by preparative HPLC (Method P1) to afford the title compound as a white solid (100 mg, 95% purity, 56% Yield).1H NMR (500 MHz, DMSO) δ 10.24 (br.s, 1H), 8.67 (s, 1H), 8.21 (s, 1H), 8.09 (d, J = 2.2 Hz, 1H), 7.63 – 7.55 (m, 1H), 7.21 (d, J = 2.2 Hz, 1H), 7.06 – 6.96 (m, 1H), 5.66 (d, J = 13.6 Hz, 1H), 5.20 (d, J = 13.5 Hz, 1H). LCMS: m / z = 565.1 / 567.1 [M+H]+, (ESI+), RT = 4.09, Method AExample 39 – Synthesis of 13-Bromo-20-fluoro-14-hydroxy-19-methoxy-10,16,16-trioxo- 9-oxa-16λ6-thia-17-azatetracyclo[16.3.1.111,15.02,7]tricosa- 1(21),2(7),3,5,11,13,15(23),18(22),19-nonaene-4-carbonitrile (Compound 39) B

[0277] 13-bromo-20-fluoro-14,19-dimethoxy-10,16,16-trioxo-9-oxa-16λ6-thia-17- azatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2(7),3,5,11,13,15(23),18(22),19-nonaene-4- carbonitrile (synthesised using a similar method to intermediate 26, 140 mg, 0.238 mmol) and lithium iodide (445 mg, 3.30 mmol) were combined and dissolved into anhydrous pyridine (12 mL). The mixture was then heated to 100 °C and stirred for 3 h. The mixture was cooled to r.t. Sat. aq. Na2S2O3(30 mL) was added, and the mixture was extracted with DCM (3 x 30 mL). The combined organic extracts were washed with 1 M aq. HCl (30 mL), then brine (30 mL) and were dried over Na2SO4, filtered and concentrated. The residue was purified by preparative HPLC (Method P1) to afford the title compound as a pale brown solid (115 mg, 96% purity, 62% Yield).1H NMR (500 MHz, DMSO) δ 9.78 (s, 1H), 8.05 (d, J = 2.2 Hz, 1H), 7.92 (dd, J = 7.9, 1.8 Hz, 1H), 7.81 (d, J = 1.8 Hz, 1H), 7.78 (d, J = 8.0 Hz, 1H), 7.46 (d, J = 2.2 Hz, 1H), 7.42 (dd, J = 12.1, 2.1 Hz, 1H), 7.06 – 7.01 (m, 1H), 5.60 (d, J = 12.9 Hz, 1H), 5.27 (d, J = 13.0 Hz, 1H), 3.57 (d, J = 2.0 Hz, 3H). LCMS: m / z = 531.0 / 532.9 [M-H]-, (ESI-), RT = 4.04, Method AExample 40 – Synthesis of 13-Bromo-14-hydroxy-19-methoxy-16,16-dioxo-5- (trifluoromethyl)-9-oxa-16λ6-thia-4,17-diazatetracyclo[16.3.1.111,15.02,7]tricosa- 1(21),2(7),3,5,11,13,15(23),18(22),19-nonaen-10-one (Compound 40)

[0278] 13-Bromo-14,19-dimethoxy-16,16-dioxo-5-(trifluoromethyl)-9-oxa-16λ6-thia-4,17- diazatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2(7),3,5,11,13,15(23),18(22),19-nonaen-10- one (synthesised using a similar method to intermediate 26, 375 mg, 0.634 mmol) and lithium iodide (100 mg, 0.747 mmol) were combined and the mixture dissolved into anhydrous pyridine (12 mL). The mixture was heated to 80 °C and stirred for 18 h. The mixture was cooled to r.t.. Sat. aq. Na2S2O3 (50 mL) was added, and the mixture was extracted with DCM (3 x 50 mL). The combined organic extracts were washed with 1 M aq. HCl (2 x 50 mL), then brine (50 mL) and were dried over Na2SO4, filtered and concentrated. The crude material was taken into EtOH (200 mL) with heat (80 °C) and stirring until observed dissolution and evaporated to dryness. This process was repeated and the resultant solid was transferred to a vial and dried in a vacuum oven to give the title compound (235 mg, 98% purity, 65% Yield) as an off-white solid.1H NMR (500 MHz, DMSO) δ 9.42 (s, 1H), 8.73 (s, 1H), 8.16 (s, 1H), 8.01 (d, J = 2.2 Hz, 1H), 7.39 – 7.32 (m, 2H), 7.30 (d, J = 2.2 Hz, 1H), 6.81 (d, J = 8.5 Hz, 1H), 5.77 (d, J = 13.5 Hz, 1H), 5.29 (d, J = 13.6 Hz, 1H), 3.48 (s, 3H). LCMS: m / z = 559.0 / 560.9 [M+H]+, (ESI+), RT = 4.09, Method AExample 41 – Synthesis of 13-Bromo-21-fluoro-14-hydroxy-19-methoxy-16,16-dioxo-5- (trifluoromethyl)-9-oxa-16λ6-thia-4,17-diazatetracyclo[16.3.1.111,15.02,7]tricosa- 1(21),2(7),3,5,11,13,15(23),18(22),19-nonaen-10-one (Compound 41)

[0279] 13-Bromo-21-fluoro-14,19-dimethoxy-16,16-dioxo-5-(trifluoromethyl)-9-oxa-16λ6- thia-4,17-diazatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2(7),3,5,11,13,15(23),18(22),19- nonaen-10-one (synthesised using a similar method to intermediate 26, 210 mg, 0.355 mmol) and lithium iodide (55 mg, 0.411 mmol) were combined and the mixture dissolved into anhydrous pyridine (7 mL). The mixture was heated to 80 °C and stirred for 18 h. The mixture was cooled to r.t. Sat. aq. Na2S2O3 (50 mL) was added, and the mixture was extracted with DCM (3 x 50 mL). The combined organic extracts were washed with 1 M aq. HCl (50 mL), then brine (50 mL) and were dried over Na2SO4, filtered and concentrated. The residue was purified by preparative HPLC (Method P1) to afford the title compound as an off-white solid (142 mg, 97% purity, 67% Yield).1H NMR (500 MHz, DMSO) δ 9.50 (s, 1H), 8.77 (s, 1H), 8.18 (s, 1H), 8.04 (d, J = 2.1 Hz, 1H), 7.38 (d, J = 2.2 Hz, 1H), 7.29 (d, J = 8.0 Hz, 1H), 6.91 (d, J = 11.8 Hz, 1H), 5.47 (d, J = 13.9 Hz, 1H), 5.40 (d, J = 14.0 Hz, 1H), 3.52 (s, 3H). LCMS: m / z = 577.0 / 578.9 [M+H]+, (ESI+), RT = 4.15, Method AExample 42 – Synthesis of 13-Bromo-19,21-difluoro-14-hydroxy-16,16-dioxo-5- (trifluoromethyl)-9-oxa-16λ6-thia-6,17-diazatetracyclo[16.3.1.111,15.02,7]tricosa- 1(22),2(7),3,5,11,13,15(23),18,20-nonaen-10-one (Compound 42)

[0280] To a solution of 13-bromo-19,21-difluoro-14-methoxy-16,16-dioxo-5- (trifluoromethyl)-9-oxa-16λ6-thia-6,17-diazatetracyclo[16.3.1.111,15.02,7]tricosa- 1(22),2(7),3,5,11,13,15(23),18,20-nonaen-10-one (synthesised using a similar method to intermediate 26, 98% purity, 250 mg, 0.423 mmol) in anhydrous pyridine (3 mL) was added lithium iodide (566 mg, 4.23 mmol). The reaction mixture was heated at 90 °C for 3 h. Organics were diluted with EtOAc (10 mL), washed with sat. aq. Na2S2O3 (10 mL), 1 M HCl (3 x 10 mL), then brine (10 mL). The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative HPLC (Method P1) to afford the title compound as an off-white solid (107 mg, 96% purity, 43% Yield).1H NMR (500 MHz, DMSO) δ 10.21 (s, 1H), 8.11 – 8.06 (m, 2H), 8.03 (d, J = 8.0 Hz, 1H), 7.61 – 7.54 (m, 1H), 7.25 (d, J = 2.2 Hz, 1H), 7.09 – 7.02 (m, 1H), 5.55 (d, J = 13.6 Hz, 1H), 5.39 (d, J = 13.5 Hz, 1H). LCMS: m / z = 562.9 / 565.0 [M-H]-, (ESI-), RT = 4.28, Method AExample 43 – Synthesis of 13-Bromo-21-fluoro-14-hydroxy-19-methoxy-10,16,16-trioxo- 9-oxa-16λ6-thia-17-azatetracyclo[16.3.1.111,15.02,7]tricosa- 1(21),2(7),3,5,11,13,15(23),18(22),19-nonaene-4-carbonitrile (Compound 43) B

[0281] 13-Bromo-21-fluoro-14,19-dimethoxy-10,16,16-trioxo-9-oxa-16λ6-thia-17- azatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2(7),3,5,11,13,15(23),18(22),19-nonaene-4- carbonitrile (synthesised using a similar method to intermediate 26, 100% purity, 215 mg, 0.393 mmol) and lithium iodide (524 mg, 3.89 mmol) were dissolved into anhydrous pyridine (14 mL). The mixture was then heated to 80 °C and stirred for 5.5 h. The reaction mixture was concentrated. The residue was purified by preparative HPLC (Method P1) to afford the title compound as an off-white solid (130 mg, 100% purity, 62% Yield).1H NMR (500 MHz, DMSO) δ 9.49 – 9.36 (m, 1H), 8.05 – 8.01 (m, 1H), 7.96 (dd, J = 7.9, 1.8 Hz, 1H), 7.88 (d, J = 1.7 Hz, 1H), 7.77 (d, J = 8.0 Hz, 1H), 7.38 (d, J = 2.2 Hz, 1H), 7.16 (d, J = 8.0 Hz, 1H), 6.87 (d, J = 11.8 Hz, 1H), 5.39 (d, J = 13.3 Hz, 1H), 5.31 (d, J = 13.4 Hz, 1H), 3.52 (s, 3H). LCMS: m / z = 531.4 / 533.5 [M-H]-, (ESI-), RT = 3.84, Method AExample 44 – Synthesis of 13-Bromo-14-hydroxy-19-methoxy-20-methyl-16,16-dioxo-5- (trifluoromethyl)-9-oxa-16λ6-thia-4,17-diazatetracyclo[16.3.1.111,15.02,7]tricosa- 1(21),2(7),3,5,11,13,15(23),18(22),19-nonaen-10-one (Compound 44)

[0282] 13-Bromo-14,19-dimethoxy-20-methyl-16,16-dioxo-5-(trifluoromethyl)-9-oxa- 16λ6-thia-4,17-diazatetracyclo[16.3.1.111,15.02,7]tricosa- 1(21),2(7),3,5,11,13,15(23),18(22),19-nonaen-10-one (synthesised using a similar method to intermediate 26, 193 mg, 0.325 mmol) and lithium iodide (50 mg, 0.374 mmol) were dissolved in anhydrous pyridine (6 mL) and the reaction mixture was stirred at 80 °C for 20 h. The reaction mixture was cooled to r.t. then diluted with EtOAc (30 mL) and washed with sat. aq. Na2S2O3 solution (30 mL), 1 M aq. HCl (30 mL), and brine (30 mL). The organic component was dried over MgSO4, filtered, and concentrated. The residue was purified by preparative HPLC (Method P1) to afford the title compound as an off-white solid (126 mg, 99% purity, 67% yield).1H NMR (400 MHz, DMSO) δ 9.65 (br. s, 1H), 8.64 (s, 1H), 8.18 (s, 1H), 8.04 (d, J = 2.2 Hz, 1H), 7.44 (d, J = 2.2 Hz, 1H), 7.29 – 7.24 (m, 1H), 7.02 (d, J = 2.2 Hz, 1H), 5.59 (d, J = 13.2 Hz, 1H), 5.42 (d, J = 13.3 Hz, 1H), 3.50 (s, 3H), 2.11 (s, 3H) LCMS: m / z = 573.0 / 575.0 [M+H]+, (ESI+), RT = 3.98, Method CExample 45 – Synthesis of 13-Bromo-20-chloro-14-hydroxy-19-methoxy-16,16-dioxo-5- (trifluoromethyl)-9-oxa-16λ6-thia-4,17-diazatetracyclo[16.3.1.111,15.02,7]tricosa- 1(21),2,4,6,11(23),12,14,18(22),19-nonaen-10-one (Compound 45) B

[0283] To a solution of 13-bromo-20-chloro-14,19-dimethoxy-16,16-dioxo-5- (trifluoromethyl)-9-oxa-16λ6-thia-4,17-diazatetracyclo[16.3.1.111,15.02,7]tricosa- 1(21),2,4,6,11(23),12,14,18(22),19-nonaen-10-one (synthesised using a similar method to intermediate 26, 250 mg, 0.41 mmol) in anhydrous pyridine (4 mL) was added lithium iodide (137.637 mg, 1.03 mmol). The mixture was heated at 80 °C for 5 h. The mixture was dissolved in EtOAc (30 mL) and washed with 1 M aq. HCl (30 mL). The aqueous phase was extracted further with EtOAc (2 x 30 mL) and the organics were combined, washed with sat. aq. Na2S2O3 (30 mL) and brine (30 mL) and dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (Method P1) to afford the title compound as an off-white solid (136 mg, 98% purity, 55% Yield).1H NMR (500 MHz, DMSO) δ 9.98 (br s, 1H), 8.68 (s, 1H), 8.21 (s, 1H), 8.07 (d, J = 2.1 Hz, 1H), 7.64 (d, J = 2.1 Hz, 1H), 7.47 (d, J = 2.1 Hz, 1H), 7.21 (d, J = 2.1 Hz, 1H), 5.61 (d, J = 13.2 Hz, 1H), 5.43 (d, J = 13.3 Hz, 1H), 3.58 (s, 3H). LCMS: m / z = 593.0 / 595.0 [M+H]+, (ESI+), RT = 4.34, Method AExample 46 – Synthesis of 13-Bromo-14-hydroxy-19-methoxy-20-methyl-10,16,16- trioxo-9-oxa-16λ6-thia-17-azatetracyclo[16.3.1.111,15.02,7]tricosa- 1(22),2(7),3,5,11,13,15(23),18,20-nonaene-4-carbonitrile (Compound 46) B

[0284] A mixture of 13-bromo-14,19-dimethoxy-20-methyl-10,16,16-trioxo-9-oxa-16λ6- thia-17-azatetracyclo[16.3.1.111,15.02,7]tricosa-1(22),2(7),3,5,11,13,15(23),18,20-nonaene- 4-carbonitrile (synthesised using a similar method to intermediate 26, 518 mg, 0.925 mmol) and lithium iodide (300 mg, 2.22 mmol) in anhydrous pyridine (10 mL) was stirred at 90 °C under N2 for 3 h. The mixture was diluted with EtOAc (50 mL) and washed successively with sat aq. Na2S2O3solution (50 mL), water (50 mL), 1 M aq. HCl solution (50 mL), and brine (50 mL). The organic component was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (Method P1) followed by lyophilisation to afford the title compound as a beige solid (178 mg, 99% purity, 36% yield).1H NMR (500 MHz, DMSO) δ 9.60 (br. s, 1H), 8.02 (d, J = 2.1 Hz, 1H), 7.89 (dd, J = 7.9, 1.7 Hz, 1H), 7.76 (d, J = 8.0 Hz, 1H), 7.73 (d, J = 1.7 Hz, 1H), 7.46 (d, J = 2.1 Hz, 1H), 7.22 (d, J = 2.1 Hz, 1H), 6.95 (d, J = 2.1 Hz, 1H), 5.53 (d, J = 12.8 Hz, 1H), 5.30 (d, J = 12.8 Hz, 1H), 3.45 (s, 3H), 2.10 (s, 3H). LCMS: m / z = 527.0 / 529.0 [M-H]-, (ESI-), RT = 3.80, Method CExample 47 – Synthesis of 13-Bromo-5-fluoro-14-hydroxy-19-methoxy-16,16-dioxo-9- oxa-16λ6-thia-4,17-diazatetracyclo[16.3.1.111,15.02,7]tricosa- 1(21),2(7),3,5,11,13,15(23),18(22),19-nonaen-10-one (Compound 47)

[0285] To a solution of 13-bromo-5-fluoro-14,19-dimethoxy-16,16-dioxo-9-oxa-16λ6-thia- 4,17-diazatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2(7),3,5,11,13,15(23),18(22),19- nonaen-10-one (synthesised from intermediate 11, using a similar method to intermediate 24, 95% purity, 84 mg, 0.152 mmol) in anhydrous pyridine (4 mL) was added lithium iodide (166 mg, 1.24 mmol) and the mixture was heated at 80 °C for 15 h. Further lithium iodide (35 mg, 0.261 mmol) was added and the mixture was heated to 100 °C for 3 h. The mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC (Method P1) to afford the title compound as an off-white solid (51 mg, 95% purity, 62% Yield).1H NMR (500 MHz, DMSO) δ 9.39 (s, 1H), 8.20 (s, 1H), 8.01 (d, J = 2.1 Hz, 1H), 7.45 (d, J = 1.9 Hz, 1H), 7.37 (d, J = 2.2 Hz, 1H), 7.30 (dd, J = 8.5, 2.2 Hz, 1H), 7.22 (d, J = 2.2 Hz, 1H), 6.78 (d, J = 8.5 Hz, 1H), 5.67 (d, J = 13.3 Hz, 1H), 5.18 (d, J = 13.4 Hz, 1H), 3.47 (s, 3H). LCMS: m / z = 506.9 / 508.9 [M-H]-, (ESI-), RT = 3.65, Method AExample 48 – Synthesis of 13-Bromo-19,21-difluoro-14-hydroxy-5-methoxy-16,16- dioxo-9-oxa-16λ6-thia-4,17-diazatetracyclo[16.3.1.111,15.02,7]tricosa- 1(21),2,4,6,11(23),12,14,18(22),19-nonaen-10-one (Compound 48)

[0286] To a solution of 13-bromo-19,21-difluoro-5,14-dimethoxy-16,16-dioxo-9-oxa-16λ6- thia-4,17-diazatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2,4,6,11(23),12,14,18(22),19- nonaen-10-one (synthesised from intermediate 12, using a similar method to intermediate 24, 95% purity, 44 mg, 0.0772 mmol) in anhydrous pyridine (2 mL) was added lithium iodide (36 mg, 0.273 mmol) and the mixture was heated at 100 °C for 3 h. The mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC (Method P1) to afford the title compound as an off-white solid (20 mg, 98% purity, 48% Yield). ¹H NMR (500 MHz, DMSO) δ 10.09 (br s, 1H), 8.05 (d, J=18.3 Hz, 2H), 7.56 - 7.44 (m, 1H), 7.20 (d, J=2.2 Hz, 1H), 7.07 (s, 1H), 6.86 - 6.79 (m, 1H), 5.42 (d, J=13.1 Hz, 1H), 5.05 (d, J=13.0 Hz, 1H), 3.90 (s, 3H). LCMS: m / z = 524.9 / 526.9 [M-H]-, (ESI-), RT = 3.99, Method AExample 49 – Synthesis of 13-Bromo-19,21-difluoro-14-hydroxy-4-methoxy-16,16- dioxo-9-oxa-16λ6-thia-5,17-diazatetracyclo[16.3.1.111,15.02,7]tricosa- 1(21),2,4,6,11(23),12,14,18(22),19-nonaen-10-one (Compound 49) B

[0287] To a solution of 13-bromo-19,21-difluoro-4,14-dimethoxy-16,16-dioxo-9-oxa-16λ6- thia-5,17-diazatetracyclo[16.3.1.111,15.02,7]tricosa-1(22),2(7),3,5,11,13,15(23),18,20- nonaen-10-one (synthesised from intermediate 28, using a similar method to intermediate 26, 97% purity, 60 mg, 0.108 mmol) in anhydrous pyridine (2 mL) was added lithium iodide (72 mg, 0.538 mmol) and the mixture was heated at 90 °C for 3 h. The mixture was diluted with EtOAc (10 mL), washed with 2 M Na2S2O3 (10 mL), 1 M HCl (3 x 10 mL), then brine (10 mL). The organic layer was dried over Na2SO4, filtered, then concentrated and lyophilised to afford the title compound as a white solid (40 mg, 98% purity, 68% Yield).1H NMR (500 MHz, DMSO) δ 10.15 (s, 1H), 8.32 (s, 1H), 8.08 (d, J = 2.1 Hz, 1H), 7.63 – 7.56 (m, 1H), 7.18 (d, J = 2.1 Hz, 1H), 6.79 – 6.72 (m, 2H), 5.49 (d, J = 12.8 Hz, 1H), 4.96 (d, J = 12.7 Hz, 1H), 3.88 (s, 3H). LCMS: m / z = 524.9 / 526.9 [M-H]-, (ESI-), RT = 3.99, Method AExample 50 – Synthesis of 13-Bromo-14-hydroxy-5,19-dimethoxy-16,16-dioxo-9-oxa- 16λ6-thia-4,17-diazatetracyclo[16.3.1.111,15.02,7]tricosa- 1(22),2(7),3,5,11,13,15(23),18,20-nonaen-10-one (Compound 50)

[0288] A mixture of 13-bromo-5,14,19-trimethoxy-16,16-dioxo-9-oxa-16λ6-thia-4,17- diazatetracyclo[16.3.1.111,15.02,7]tricosa-1(22),2(7),3,5,11,13,15(23),18,20-nonaen-10-one (synthesised from intermediate 12, using a similar method to intermediate 26, 81% purity, 215 mg, 0.325 mmol), lithium iodide (109 mg, 0.813 mmol) and anhydrous pyridine (2 mL) was heated at 90 °C for 3 h. The mixture was cooled to r.t., diluted with EtOAc (50 mL), washed with sat. aq. Na2S2O3(50 ml), 1 M aq. HCl (50 mL) and brine (30 mL), then dried over Na2SO4, filtered and concentrated. The residue was purified by preparative HPLC (Method P1) to afford the title compound as a white solid (76 mg, 98% purity, 44% Yield) as a white solid.1H NMR (500 MHz, DMSO) δ 9.29 (s, 1H), 8.09 (s, 1H), 7.99 (s, 1H), 7.36 (d, J = 2.2 Hz, 1H), 7.23 (dd, J = 8.4, 2.3 Hz, 1H), 7.16 (d, J = 2.2 Hz, 1H), 7.04 (s, 1H), 6.75 (d, J = 8.5 Hz, 1H), 5.58 (d, J = 13.0 Hz, 1H), 5.07 (d, J = 13.1 Hz, 1H), 3.90 (s, 3H), 3.46 (s, 3H). LCMS: m / z = 518.9 / 520.9 [M-H]-, (ESI-), RT = 3.85, Method AExample 51 – Synthesis of 13-Bromo-20-fluoro-14-hydroxy-5,19-dimethoxy-16,16- dioxo-9-oxa-16λ6-thia-4,17-diazatetracyclo[16.3.1.111,15.02,7]tricosa- 1(22),2(7),3,5,11,13,15(23),18,20-nonaen-10-one (Compound 51)

[0289] A mixture of 13-bromo-20-fluoro-5,14,19-trimethoxy-16,16-dioxo-9-oxa-16λ6-thia- 4,17-diazatetracyclo[16.3.1.111,15.02,7]tricosa-1(22),2(7),3,5,11,13,15(23),18,20-nonaen- 10-one (synthesised from intermediate 12, using a similar method to intermediate 26, 260 mg, 0.446 mmol), lithium iodide (150 mg, 1.12 mmol) and anhydrous pyridine (2 mL) was heated at 90 °C for 3 h. The mixture was cooled to r.t., diluted with EtOAc (5 mL), washed with sat. aq. Na2S2O3 (5 ml), 1 M aq. HCl (3 x 5 mL) and brine (5 mL), then dried over Na2SO4, filtered and concentrated. The residue was purified by preparative HPLC (Method P1) to afford the title compound as a yellow solid (73 mg, 99% purity, 30% Yield).1H NMR (500 MHz, DMSO) δ 9.74 (s, 1H), 8.07 (s, 1H), 8.05 (d, J = 2.1 Hz, 1H), 7.45 (d, J = 2.2 Hz, 1H), 7.35 (dd, J = 12.1, 2.1 Hz, 1H), 7.07 (s, 1H), 6.99 (s, 1H), 5.48 (s, 1H), 5.17 (s, 1H), 3.90 (s, 3H), 3.57 (d, J = 2.0 Hz, 3H). LCMS: m / z = 537.0 / 539.0 [M-H]-, (ESI-), RT = 4.04, Method AExample 52 – Synthesis of 13-Bromo-21-fluoro-14-hydroxy-4,19-dimethoxy-16,16- dioxo-9-oxa-16λ6-thia-5,17-diazatetracyclo[16.3.1.111,15.02,7]tricosa- 1(21),2(7),3,5,11,13,15(23),18(22),19-nonaen-10-one (Compound 52)

[0290] To a solution of 13-bromo-21-fluoro-4,14,19-trimethoxy-16,16-dioxo-9-oxa-16λ6- thia-5,17-diazatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2(7),3,5,11,13,15(23),18(22),19- nonaen-10-one (synthesised from intermediate 28, using a similar method to intermediate 26, 95% purity, 162 mg, 0.293 mmol) in anhydrous pyridine (8.0 mL) was added lithium iodide (345 mg, 2.58 mmol) and the mixture was heated at 80 °C for 6 h. The mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC (Method P1) to afford the title compound as a white solid (89 mg, 99% purity, 56% Yield).1H NMR (500 MHz, DMSO) δ 9.53 (s, 1H), 8.31 (s, 1H), 8.05 (d, J = 2.2 Hz, 1H), 7.35 (d, J = 2.2 Hz, 1H), 7.05 (d, J = 7.9 Hz, 1H), 6.92 (d, J = 11.8 Hz, 1H), 6.86 (s, 1H), 5.28 (dd, J = 12.7, 2.0 Hz, 1H), 5.20 (d, J = 12.7 Hz, 1H), 3.91 (s, 3H), 3.54 (s, 3H). LCMS: m / z = 539.0 / 540.9 [M+H]+, (ESI+), RT = 3.96, Method AExample 53 – Synthesis of 13-Bromo-20-fluoro-14-hydroxy-4,19-dimethoxy-16,16- dioxo-9-oxa-16λ6-thia-5,17-diazatetracyclo[16.3.1.111,15.02,7]tricosa- 1(21),2(7),3,5,11,13,15(23),18(22),19-nonaen-10-one (Compound 53)

[0291] To a solution of 13-bromo-20-fluoro-4,14,19-trimethoxy-16,16-dioxo-9-oxa-16λ6- thia-5,17-diazatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2(7),3,5,11,13,15(23),18(22),19- nonaen-10-one (synthesised from intermediate 28, using a similar method to intermediate 26, 90% purity, 191 mg, 0.345 mmol) in anhydrous pyridine (9.5 mL) was added lithium iodide (407 mg, 3.04 mmol) and the mixture was heated at 80 °C for 16 h. The mixture was concentrated and the residue was purified by preparative HPLC (Method P1) to afford the title compound as a white solid (51 mg, 96% purity, 26% Yield).1H NMR (500 MHz, DMSO) δ 9.85 (s, 1H), 8.31 (s, 1H), 8.07 (d, J = 2.2 Hz, 1H), 7.50 – 7.36 (m, 2H), 6.97 – 6.91 (m, 1H), 6.79 (s, 1H), 5.38 (br. s, 1H), 5.25 (br. s, 1H), 3.90 (s, 3H), 3.59 (d, J = 2.0 Hz, 3H). LCMS: m / z = 539.0 / 541.0 [M+H]+, (ESI+), RT = 4.04, Method AExample 54- Synthesis of 13-Bromo-19,21-difluoro-14-hydroxy-5-methoxy-16,16-dioxo- 9-oxa-16λ6-thia-6,17-diazatetracyclo[16.3.1.111,15.02,7]tricosa- 1(22),2(7),3,5,11,13,15(23),18,20-nonaen-10-one (Compound 54)

[0292] To a solution of 13-bromo-19,21-difluoro-5,14-dimethoxy-16,16-dioxo-9-oxa-16λ6- thia-6,17-diazatetracyclo[16.3.1.111,15.02,7]tricosa-1(22),2(7),3,5,11,13,15(23),18,20- nonaen-10-one (synthesised from intermediate 29, using a similar method to intermediate 26, 98% purity, 250 mg, 0.453 mmol) in anhydrous pyridine (3 mL) was added lithium iodide (303 mg, 2.26 mmol) and the mixture was heated at 90 °C for 3 h. The mixture was diluted with EtOAc (10 mL), washed with sat. aq. Na2S2O3 (10 mL), 1 M HCl (3 x 10 mL), then brine (10 mL). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to afford the title compound as an off-white solid (115 mg, 97% purity, 47% yield).1H NMR (500 MHz, DMSO) δ 10.15 (s, 1H), 8.10 (d, J = 2.2 Hz, 1H), 7.64 (d, J = 8.4 Hz, 1H), 7.51 – 7.43 (m, 1H), 7.27 (d, J = 2.1 Hz, 1H), 6.95 – 6.88 (m, 2H), 5.35 (d, J = 13.2 Hz, 1H), 5.27 (d, J = 13.1 Hz, 1H), 3.92 (s, 3H). LCMS: m / z = 525.0 / 527.0 [M-H]-, (ESI-), RT = 4.22, Method AExample 55 – Synthesis of 13-Bromo-14-hydroxy-5,19-dimethoxy-20-methyl-16,16- dioxo-9-oxa-16λ6-thia-4,17-diazatetracyclo[16.3.1.111,15.02,7]tricosa- 1(21),2(7),3,5,11,13,15(23),18(22),19-nonaen-10-one (Compound 55)

[0293] 13-Bromo-5,14,19-trimethoxy-20-methyl-16,16-dioxo-9-oxa-16λ6-thia-4,17- diazatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2(7),3,5,11,13,15(23),18(22),19-nonaen-10- one (synthesised from intermediate 12, using a similar method to intermediate 26, 95% purity, 110 mg, 0.201 mmol) and lithium iodide (268 mg, 1.99 mmol) were dissolved into anhydrous pyridine (7.2 mL). The mixture was then heated to 80 ºC and stirred for 20 h. The mixture was concentrated and the residue was purified by preparative HPLC (Method P1) followed by lyophilisation to afford the title compound as an off-white solid (75.6 mg, 99% purity, 70% yield) as an off-white solid.1H NMR (500 MHz, DMSO) δ 9.63 – 9.53 (m, 1H), 8.04 – 8.02 (m, 1H), 8.00 (s, 1H), 7.45 (d, J = 2.2 Hz, 1H), 7.18 – 7.14 (m, 1H), 7.05 (s, 1H), 6.89 (s, 1H), 5.42 (d, J = 12.8 Hz, 1H), 5.20 (d, J = 12.7 Hz, 1H), 3.89 (s, 3H), 3.47 (s, 3H), 2.09 (s, 3H). LCMS: m / z = 535.0 / 537.0 [M+H]+, (ESI+), RT = 4.11, Method AExample 56 – Synthesis of 13-Bromo-14-hydroxy-5-methoxy-16,16-dioxo-19- (trifluoromethoxy)-9-oxa-16λ6-thia-4,17-diazatetracyclo[16.3.1.111,15.02,7]tricosa- 1(21),2(7),3,5,11,13,15(23),18(22),19-nonaen-10-one (Compound 56)

[0294] 13-Bromo-5,14-dimethoxy-16,16-dioxo-19-(trifluoromethoxy)-9-oxa-16λ6-thia- 4,17-diazatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2(7),3,5,11,13,15(23),18(22),19- nonaen-10-one (synthesised from intermediate 12, using a similar method to intermediate 26, 98% purity , 40 mg, 0.0679 mmol) and lithium iodide (91 mg, 0.671 mmol) were dissolved into anhydrous pyridine (2.4 mL). The mixture was then heated to 80 ºC and stirred for 4 h. The mixture was concentrated and the residue was purified by preparative HPLC (Method P1) followed by lyophilisation to afford the title compound as an off-white solid (17.4 mg, 97% purity, 43% yield).1H NMR (500 MHz, DMSO) δ 10.36 – 10.08 (m, 1H), 8.05 (s, 1H), 8.03 (s, 1H), 7.49 (dd, J = 8.6, 2.1 Hz, 1H), 7.37 (dd, J = 8.3, 1.8 Hz, 1H), 7.24 (d, J = 2.1 Hz, 1H), 7.07 (s, 1H), 6.97 (d, J = 2.2 Hz, 1H), 5.32 (s, 2H), 3.89 (s, 3H). LCMS: m / z = 575.2 / 577.2 [M+H]+, (ESI+), RT = 4.17, Method AExample 57- Synthesis of 13-Bromo-19-chloro-14-hydroxy-4-methoxy-16,16-dioxo-9- oxa-16λ6-thia-5,17-diazatetracyclo[16.3.1.111,15.02,7]tricosa- 1(22),2(7),3,5,11,13,15(23),18,20-nonaen-10-one (Compound 57)

[0295] To a solution of 13-bromo-19-chloro-4,14-dimethoxy-16,16-dioxo-9-oxa-16λ6-thia- 5,17-diazatetracyclo[16.3.1.111,15.02,7]tricosa-1(22),2(7),3,5,11,13,15(23),18,20-nonaen- 10-one (synthesised from intermediate 28, using a similar method to intermediate 26, 88 mg, 0.163 mmol) in anhydrous pyridine (3 mL) was added lithium iodide (111 mg, 0.829 mmol). The reaction mixture was heated at 80 °C overnight. The mixture was cooled to r.t., diluted with EtOAc (20 mL), washed with sat. aq. Na2S2O3 (20 ml), 2 M aq. HCl (20 mL) and brine (20 mL), then dried over Na2SO4, filtered, and concentrated. The resulting solid was dried in the vacuum oven overnight to afford the title compound as a light pink solid (68.8 mg, 98% purity, 79% yield).1H NMR (500 MHz, DMSO) δ 10.07 (br. s, 1H), 8.30 (s, 1H), 8.00 (s, 1H), 7.45 (d, J = 8.2 Hz, 1H), 7.41 (dd, J = 8.2, 2.0 Hz, 1H), 7.25 (d, J = 2.2 Hz, 1H), 7.03 (s, 1H), 6.76 (s, 1H), 5.29 (s, 2H), 3.89 (s, 3H) LCMS: m / z = 522.9 / 524.9 [M-H]-, (ESI-), RT = 4.01, Method AExample 58 – Synthesis of 13-Bromo-20-chloro-14-hydroxy-4,19-dimethoxy-16,16- dioxo-9-oxa-16λ6-thia-5,17-diazatetracyclo[16.3.1.111,15.02,7]tricosa- 1(22),2(7),3,5,11,13,15(23),18,20-nonaen-10-one (Compound 58)

[0296] To a solution of 13-bromo-20-chloro-4,14,19-trimethoxy-16,16-dioxo-9-oxa-16λ6- thia-5,17-diazatetracyclo[16.3.1.111,15.02,7]tricosa-1(22),2(7),3,5,11,13,15(23),18,20- nonaen-10-one (synthesised from intermediate 28, using a similar method to intermediate 26, 70 mg, 0.113 mmol) in anhydrous pyridine (2 mL) was added lithium iodide (77 mg, 0.575 mmol). The reaction mixture was heated at 80 °C overnight. The mixture was cooled to r.t., diluted with EtOAc (20 mL), washed with sat. aq. Na2S2O3 (20 ml), 2 M aq. HCl (20 mL) and brine (20 mL), then dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative HPLC (Method P1) to afford the title compound as a white solid (16.6 mg, 99% purity, 26% yield).1H NMR (500 MHz, DMSO) δ 9.92 (br s, 1H), 8.31 (s, 1H), 8.05 (d, J = 2.1 Hz, 1H), 7.58 (d, J = 2.1 Hz, 1H), 7.44 (d, J = 2.2 Hz, 1H), 7.07 (s, 1H), 6.78 (s, 1H), 5.33 (s, 1H), 5.26 (s, 1H), 3.89 (s, 3H), 3.55 (s, 3H). LCMS: m / z = 553.0 / 555.0 [M-H]-, (ESI-), RT = 4.22, Method AExample 59 – Synthesis of 13-Bromo-14-hydroxy-4,19-dimethoxy-16,16-dioxo-9-oxa- 16λ6-thia-5,17,20-triazatetracyclo[16.3.1.111,15.02,7]tricosa- 1(21),2(7),3,5,11,13,15(23),18(22),19-nonaen-10-one (Compound 59)

[0297] In a pressure vial, 13-bromo-4,14,19-trimethoxy-16,16-dioxo-9-oxa-16λ6-thia- 5,17,20-triazatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2(7),3,5,11,13,15(23),18(22),19- nonaen-10-one (synthesised from intermediate 28, using a similar method to intermediate 26, 210 mg, 0.380 mmol) was dissolved in anhydrous pyridine (7.0 mL) and lithium iodide (450 mg, 3.36 mmol) was added. The reaction mixture was heated at 80 °C for 1 h 45 min. The mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC (Method P1) to afford the title compound as an off-white solid (104 mg, 99% purity, 52% yield).1H NMR (500 MHz, DMSO) δ 9.79 (s, 1H), 8.32 (s, 1H), 8.18 (d, J = 2.3 Hz, 1H), 8.04 (d, J = 2.2 Hz, 1H), 7.44 (d, J = 2.2 Hz, 1H), 7.28 (d, J = 2.2 Hz, 1H), 6.87 (s, 1H), 5.48 (s, 1H), 5.26 (s, 1H), 3.90 (s, 3H), 3.60 (s, 3H). LCMS: m / z = 520.0 / 522.0 [M-H]-, (ESI-), RT = 3.74, Method AExample 60 -Synthesis of 13-Bromo-21-fluoro-14-hydroxy-5,19-dimethoxy-16,16-dioxo- 9-oxa-16λ6-thia-4,17-diazatetracyclo[16.3.1.111,15.02,7]tricosa- 1(22),2,4,6,11(23),12,14,18,20-nonaen-10-one (Compound 60)

[0298] Lithium iodide (128 mg, 0.956 mmol) was added to a stirring solution of 13-bromo- 21-fluoro-5,14,19-trimethoxy-16,16-dioxo-9-oxa-16λ6-thia-4,17- diazatetracyclo[16.3.1.111,15.02,7]tricosa-1(22),2,4,6,11(23),12,14,18,20-nonaen-10-one (synthesised from intermediate 12, using a similar method to intermediate 26, 180 mg, 0.322 mmol) in anhydrous pyridine (4.0 mL) and the mixture was stirred at 90 °C for 1 hour 45 minutes. The reaction mixture was allowed to cool to r.t., diluted with EtOAc (~15 mL), and washed sequentially with sat. aq. sodium thiosulphate (~15 mL), 1 M HCl (aq.) (~15 mL), and brine (~15 mL). The organic phase was passed through a phase separator and concentrated to dryness in vacuo. The residue was purified by preparative HPLC (Method P1) to afford the title compound as a beige solid (59.0 mg, 100% purity, 34% yield).1H NMR (500 MHz, DMSO) δ 9.48 (s, 1H), 8.12 (s, 1H), 8.05 (d, J = 2.1 Hz, 1H), 7.38 (d, J = 2.1 Hz, 1H), 7.10 (d, J = 8.1 Hz, 1H), 7.06 (s, 1H), 6.85 (d, J = 11.5 Hz, 1H), 5.29 (d, J = 13.2 Hz, 1H), 5.20 (d, J = 13.4 Hz, 1H), 3.91 (s, 3H), 3.52 (s, 3H). LCMS: m / z = 539.0, 541.0 [M+H]+, (ESI+), RT = 4.00, Method AExample 61 – Synthesis of 13-Bromo-5-(difluoromethoxy)-14-hydroxy-19-methoxy- 16,16-dioxo-9-oxa-16λ6-thia-4,17,20-triazatetracyclo[16.3.1.111,15.02,7]tricosa- 1(21),2(7),3,5,11,13,15(23),18(22),19-nonaen-10-one (Compound 61)

[0299] 13-Bromo-5-(difluoromethoxy)-14,19-dimethoxy-16,16-dioxo-9-oxa-16λ6-thia- 4,17,20-triazatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2(7),3,5,11,13,15(23),18(22),19- nonaen-10-one (synthesised from intermediate 31, using a similar method to intermediate 26, 100 mg, 0.168 mmol) and lithium iodide (25 mg, 0.187 mmol) were combined and the mixture dissolved into anhydrous pyridine (3 mL). The mixture was heated to 80 ºC and stirred for 18 h. The mixture was cooled to r.t., diluted with EtOAc (50 mL), washed with sat. aq. Na2S2O3(50 mL), 2 M aq. HCl (2 x 50 mL) and brine (50 mL), then dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (Method P1) to afford the title compound as an off-white solid (59 mg, 99% purity, 62% Yield).1H NMR (500 MHz, DMSO) δ 9.73 (s, 1H), 8.25 (s, 1H), 8.12 (d, J = 2.2 Hz, 1H), 8.03 (d, J = 2.2 Hz, 1H), 7.76 (t, J = 72.6 Hz, 1H), 7.52 (d, J = 2.2 Hz, 1H), 7.37 (s, 1H), 7.31 (d, J = 2.2 Hz, 1H), 5.68 (d, J = 13.5 Hz, 1H), 5.24 (d, J = 13.5 Hz, 1H), 3.59 (s, 3H). LCMS: m / z = 558.0 / 560.0 [M+H]+, (ESI+), RT = 4.02, Method AExample 62 – Synthesis of 13-Bromo-5-(difluoromethoxy)-21-fluoro-14-hydroxy-19- methoxy-16,16-dioxo-9-oxa-16λ6-thia-4,17-diazatetracyclo[16.3.1.111,15.02,7]tricosa- 1(22),2(7),3,5,11,13,15(23),18,20-nonaen-10-one (Compound 62)

[0300] To a solution of 13-bromo-5-(difluoromethoxy)-21-fluoro-14,19-dimethoxy-16,16- dioxo-9-oxa-16λ6-thia-4,17-diazatetracyclo[16.3.1.111,15.02,7]tricosa- 1(22),2(7),3,5,11,13,15(23),18,20-nonaen-10-one (synthesised from intermediate 31, using a similar method to intermediate 26, 250 mg, 0.390 mmol) in anhydrous pyridine (3 mL) was added lithium iodide (157 mg, 1.17 mmol). The reaction mixture was heated at 70 °C for 3 h. The mixture was cooled to r.t., diluted with EtOAc (20 mL), washed with sat. aq. Na2S2O3(20 ml), 2 M aq. HCl (20 mL) and brine (20 mL), then dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative HPLC (Method P1) to afford a crude product. This dissolved in anhydrous pyridine (3.0 mL), lithium iodide (80.0 mg, 0.598 mmol) was added, and the reaction stirred again for 3 h at 70 °C. The mixture was cooled to r.t., diluted with EtOAc (20 mL), washed with sat. aq. Na2S2O3 (20 ml), 2 M aq. HCl (20 mL) and brine (20 mL), then dried over Na2SO4, filtered, and concentrated to afford the title compound as an off-white solid (74.4 mg, 97% purity, 32% yield).1H NMR (400 MHz, DMSO) δ 9.48 (s, 1H), 8.26 (s, 1H), 8.05 (d, J = 2.2 Hz, 1H), 7.76 (t, J = 72.5 Hz, 1H), 7.38 (d, J = 2.2 Hz, 1H), 7.36 (s, 1H), 7.17 (d, J = 8.1 Hz, 1H), 6.88 (d, J = 11.7 Hz, 1H), 5.35 (d, J = 13.5 Hz, 1H), 5.30 – 5.26 (m, 1H), 3.52 (s, 3H). LCMS: m / z = 573.0 / 575.0 [M-H]-, (ESI-), RT = 4.21, Method AExample 63 – Synthesis of 12-Bromo-4-(difluoromethyl)-13-hydroxy-18-methoxy-15,15- dioxo-8-oxa-15λ6-thia-4,5,16,19-tetrazatetracyclo[15.3.1.110,14.02,6]docosa- 1(20),2,5,10(22),11,13,17(21),18-octaen-9-one (Compound 63)

[0301] A mixture of 12-bromo-4-(difluoromethyl)-13,18-dimethoxy-15,15-dioxo-8-oxa- 15λ6-thia-4,5,16,19-tetrazatetracyclo[15.3.1.110,14.02,6]docosa- 1(20),2,5,10(22),11,13,17(21),18-octaen-9-one (synthesised from intermediate 33, using a similar method to intermediate 26, 195 mg, 0.350 mmol), lithium iodide (50.0 mg, 0.37 mmol) and anhydrous pyridine (5 mL) was heated at 80 °C for 16 h. The mixture was cooled to r.t., sat. aq. Na2S2O3 (50 mL) was added, and the mixture was extracted with EtOAc (3 x 50 mL). The combined organic extracts were washed with 2 M aq. HCl (2 x 50 mL), then brine (50 mL) and were dried over Na2SO4, filtered and concentrated under reduced pressure to afford the title compound as a white solid (175 mg, 98% purity, 92% yield).1H NMR (500 MHz, DMSO) δ 9.75 (s, 1H), 8.42 (s, 1H), 8.08 (d, J = 2.2 Hz, 1H), 8.01 (d, J = 2.2 Hz, 1H), 7.86 (t, J = 59.0 Hz, 1H), 7.47 (d, J = 2.2 Hz, 1H), 7.40 (d, J = 2.2 Hz, 1H), 5.42 (s, 2H), 3.62 (s, 3H). LCMS: m / z = 531.0 / 533.0 [M-H]-, (ESI-), RT = 3.60, Method AExample 64 – Synthesis of 12-Bromo-4-(2,2-difluoroethyl)-18,20-difluoro-13-hydroxy- 15,15-dioxo-8-oxa-15λ6-thia-4,5,16-triazatetracyclo[15.3.1.110,14.02,6]docosa- 1(20),2,5,10(22),11,13,17(21),18-octaen-9-one (Compound 64)

[0302] A mixture of 12-bromo-4-(2,2-difluoroethyl)-18,20-difluoro-13-methoxy-15,15- dioxo-8-oxa-15λ6-thia-4,5,16-triazatetracyclo[15.3.1.110,14.02,6]docosa- 1(20),2,5,10(22),11,13,17(21),18-octaen-9-one (synthesised from intermediate 36, using a similar method to intermediate 26, 250 mg, 0.430 mmol), lithium iodide (290 mg, 2.17 mmol) and anhydrous pyridine (4 mL) was heated at 80 °C for 16 h. The mixture was cooled to r.t., diluted with EtOAc (50 mL), washed with sat. aq. Na2S2O3(50 mL), 2 M aq. HCl (2 x 50 mL) and brine (50 mL), then dried over Na2SO4, filtered and concentrated under reduced pressure to afford the title compound as a white solid (217 mg, 99% purity, 91% yield).1H NMR (500 MHz, DMSO) δ 10.18 (br. s, 1H), 8.15 (d, J = 2.1 Hz, 1H), 7.94 (s, 1H), 7.49 – 7.42 (m, 2H), 6.97 – 6.90 (m, 1H), 6.41 (tt, J = 54.7, 3.7 Hz, 1H), 5.30 (s, 2H), 4.65 (td, J = 15.2, 3.7 Hz, 2H). LCMS: m / z = 550.0 / 552.0 [M+H]+, (ESI+), RT = 3.69, Method AExample 65 – Synthesis of 12-Bromo-5-(2,2-difluoroethyl)-18,20-difluoro-13-hydroxy- 15,15-dioxo-8-oxa-15λ6-thia-4,5,16-triazatetracyclo[15.3.1.110,14.02,6]docosa- 1(20),2(6),3,10(22),11,13,17(21),18-octaen-9-one (Compound 65)

[0303] A mixture of 12-bromo-5-(2,2-difluoroethyl)-18,20-difluoro-13-methoxy-15,15- dioxo-8-oxa-15λ6-thia-4,5,16-triazatetracyclo[15.3.1.110,14.02,6]docosa- 1(20),2(6),3,10(22),11,13,17(21),18-octaen-9-one (synthesised from intermediate 37, using a similar method to intermediate 26, 400 mg, 0.709 mmol), lithium iodide (480 mg, 3.59 mmol) and anhydrous pyridine (7 mL) was heated at 80 °C for 16 h. The mixture was cooled to r.t., diluted with EtOAc (50 mL), washed with sat. aq. Na2S2O3 (50 mL), 2 M aq. HCl (2 x 50 mL) and brine (50 mL), then dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (Method P1) to afford the title compound as a white solid (220 mg, 98% purity, 55% yield).1H NMR (500 MHz, DMSO) δ 10.13 (br. s, 1H), 8.15 (d, J = 2.2 Hz, 1H), 7.61 (s, 1H), 7.51 – 7.43 (m, 1H), 7.39 (d, J = 2.1 Hz, 1H), 6.86 – 6.77 (m, 1H), 6.45 (tt, J = 54.7, 3.4 Hz, 1H), 5.41 (s, 2H), 4.84 (td, J = 15.4, 3.4 Hz, 2H). LCMS: m / z = 548.0 / 549.9 [M-H]-, (ESI-), RT = 3.69, Method AExample 66 – Synthesis of 13-Bromo-20-fluoro-14-hydroxy-19-methoxy-10,16,16-trioxo- 9-oxa-16λ6-thia-5,17-diazatetracyclo[16.3.1.111,15.02,7]tricosa- 1(22),2(7),3,5,11,13,15(23),18,20-nonaene-4-carbonitrile (Compound 66)

[0304] Intermediate 41 (60 mg), lithium iodide (70.0 mg, 0.52 mmol) and anhydrous pyridine (3 mL) was stirred at 80 °C for 1.5 h. The mixture was diluted with EtOAc (40 mL), washed with sat. aq. Na2S2O3 (30 ml), 1 M aq. HCl (30 mL) and brine (30 mL), then passed through a phase separator and concentrated. The residue was purified by preparative HPLC (Method P1) to afford the title compound as an off-white solid (1.8 mg, 90% purity, 5.3 % Yield).1H NMR (500 MHz, DMSO) δ 9.53 (br. s, 1H), 8.92 (s, 1H), 8.08 (s, 1H), 7.97 (s, 1H), 7.45 (dd, J = 11.9, 2.2 Hz, 1H), 7.40 (d, J = 2.3 Hz, 1H), 7.14 (s, 1H), 5.94 – 5.06 (m, 2H), 3.57 (d, J = 2.2 Hz, 3H). LCMS: m / z = 534.0 / 536.0 [M-H]-, (ESI-), RT = 3.78, Method AExample 67 – Synthesis of 13-Bromo-20-fluoro-14-hydroxy-19-methoxy-10,16,16-trioxo- 9-oxa-16λ6-thia-5,17-diazatetracyclo[16.3.1.111,15.02,7]tricosa- 1(22),2(7),3,5,11,13,15(23),18,20-nonaene-4-carboxamide (Compound 67)

[0305] The title compound was isolated during the purification of Example 66 to afford an off-white solid (5.0 mg, 99% purity, 15.8 % Yield).1H NMR (500 MHz, DMSO) δ 9.96 – 9.47 (m, 1H), 8.79 (s, 1H), 8.28 – 8.21 (m, 1H), 8.06 – 7.94 (m, 1H), 7.86 (s, 1H), 7.77 – 7.72 (m, 1H), 7.51 – 7.43 (m, 1H), 7.42 – 7.38 (m, 1H), 7.03 – 6.94 (m, 1H), 5.62 – 5.26 (m, 2H), 3.74 – 3.55 (m, 3H). LCMS: m / z = 552.0 / 554.0 [M+H]+, (ESI+), RT = 3.23, Method A Example 68 – Synthesis of 13-Bromo-4,19,21-trifluoro-14-hydroxy-16,16-dioxo-9-oxa- 16λ6-thia-17-azatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2,4,6,11,13,15(23),18(22),19- nonaen-10-one (Compound 68)

[0306] 13-Bromo-4,19,21-trifluoro-14-methoxy-16,16-dioxo-9-oxa-16λ6-thia-17- azatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2(7),3,5,11,13,15(23),18(22),19-nonaen-10- one (synthesised using a similar method to intermediate 24, 98% purity, 146 mg, 0.27 mmol)and iodocyclohexane (0.18 mL, 1.35 mmol) were dissolved in anhydrous DMF (5 mL) and the mixture was stirred at 120 °C for 1 h. After cooling to r.t., organics were diluted with EtOAc (25 mL), washed with 1 M HCl (25 mL), 2 M Na2S2O3 (25 mL), then brine (25 mL). The organic layer was dried over MgSO4, filtered, and concentrated. The residue was purified by preparative HPLC (Method P1) to afford the title compound as a brown solid (78 mg, 98% purity, 55% Yield).1H NMR (500 MHz, DMSO) δ 10.13 (br. s, 1H), 8.07 (d, J = 2.2 Hz, 1H), 7.63 (dd, J = 8.6, 5.8 Hz, 1H), 7.59 – 7.52 (m, 1H), 7.35 – 7.27 (m, 1H), 7.24 – 7.16 (m, 2H), 6.80 – 6.73 (m, 1H), 5.48 (d, J = 12.7 Hz, 1H), 5.04 (d, J = 12.7 Hz, 1H). LCMS: m / z = 511.9 / 514.0 [M-H]-, (ESI-), RT = 4.19, Method A Example 69 – Synthesis of 13-Bromo-14-hydroxy-19-methoxy-16,16-dioxo-5- (trifluoromethyl)-9-oxa-16λ6-thia-17-azatetracyclo[16.3.1.111,15.02,7]tricosa- 1(21),2(7),3,5,11,13,15(23),18(22),19-nonaen-10-one (Compound 69)

[0307] 13-Bromo-14,19-dimethoxy-16,16-dioxo-5-(trifluoromethyl)-9-oxa-16λ6-thia-17- azatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2(7),3,5,11,13,15(23),18(22),19-nonaen-10- one (synthesised using a similar method to intermediate 24, 95% purity, 100 mg, 0.166 mmol) and iodocyclohexane (42 mg, 0.200 mmol) were combined and the mixture dissolved into DMF (3 mL). The mixture was heated to 100 °C and stirred for 18 h. The mixture was cooled to r.t. Sat. aq. Na2S2O3(50 mL) was added, and the mixture was extracted with DCM (3 x 50 mL). The combined organic extracts were washed with 1 M aq. HCl (50 mL), then brine (50 mL) and were dried over Na2SO4, filtered and concentrated. The residue was purified by preparative HPLC (Method P1) to afford the title compound as an off-white solid (61 mg, 96% purity, 63% Yield).1H NMR (500 MHz, DMSO) δ 9.35 (s, 1H), 8.00 (d, J = 2.2 Hz, 1H), 7.97 (d, J = 2.0 Hz, 1H), 7.82 (dd, J = 8.0, 2.0 Hz, 1H), 7.56 (d, J = 7.9 Hz, 1H), 7.37 (d, J = 2.2 Hz, 1H), 7.34 (dd, J = 8.4, 2.3 Hz, 1H), 7.19 (d, J = 2.3 Hz, 1H), 6.77 (d, J = 8.5 Hz, 1H), 5.69 (d, J = 12.9 Hz, 1H), 5.26 (d, J = 12.8 Hz, 1H), 3.47 (s, 3H). LCMS: m / z = 556.0 / 558.0 [M-H]-, (ESI-), RT = 4.50, Method A Example 70 – Synthesis of 13-Bromo-14-hydroxy-19-methoxy-16,16-dioxo-4- (trifluoromethyl)-9-oxa-16λ6-thia-17-azatetracyclo[16.3.1.111,15.02,7]tricosa- 1(21),2(7),3,5,11,13,15(23),18(22),19-nonaen-10-one (Compound 70)

[0308] 13-Bromo-14,19-dimethoxy-16,16-dioxo-4-(trifluoromethyl)-9-oxa-16λ6-thia-17- azatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2(7),3,5,11,13,15(23),18(22),19-nonaen-10- one (synthesised using a similar method to intermediate 24, 95% purity, 100 mg, 0.166 mmol) and iodocyclohexane (42 mg, 0.200 mmol) were combined and the mixture dissolved into DMF (3 mL). The mixture was heated to 100 °C and stirred for 18 h. The mixture was cooled to r.t. Sat. aq. Na2S2O3(50 mL) was added, and the mixture was extracted with DCM (3 x 50 mL). The combined organic extracts were washed with 1 M aq. HCl (50 mL), then brine (50 mL) and were dried over Na2SO4, filtered and concentrated. The residue was purified by preparative HPLC (Method P1) to afford the title compound as a pale brown solid (77 mg, 95% purity, 79% Yield).1H NMR (500 MHz, DMSO) δ 9.37 (s, 1H), 8.01 (d, J = 2.1 Hz, 1H), 7.81 – 7.75 (m, 2H), 7.65 (s, 1H), 7.38 (d, J = 2.2 Hz, 1H), 7.33 (dd, J = 8.4, 2.2 Hz, 1H), 7.20 (d, J = 2.2 Hz, 1H), 6.78 (d, J = 8.5 Hz, 1H), 5.70 (d, J = 13.0 Hz, 1H), 5.22 (d, J = 13.0 Hz, 1H), 3.48 (s, 3H). LCMS: m / z = 556.0 / 558.0 [M-H]-, (ESI-), RT = 4.45, Method AExample 71 – Synthesis of 13-Chloro-19,21-difluoro-14-hydroxy-16,16-dioxo-4- (trifluoromethyl)-9-oxa-16λ6-thia-3,5,17-triazatetracyclo[16.3.1.111,15.02,7]tricosa- 1(21),2(7),3,5,11,13,15(23),18(22),19-nonaen-10-one (Compound 71)

[0309] A pressure vial was charged with 13-chloro-19,21-difluoro-14-methoxy-16,16- dioxo-4-(trifluoromethyl)-9-oxa-16λ6-thia-3,5,17-triazatetracyclo[16.3.1.111,15.02,7]tricosa- 1(21),2(7),3,5,11,13,15(23),18(22),19-nonaen-10-one (synthesised from intermediate 47, using a similar method to intermediate 7, 90% purity, 25 mg, 0.04 mmol), lithium iodide (56.0 mg, 0.42 mmol), and anhydrous pyridine (2.5 mL) and the reaction mixture was heated at 80 °C overnight. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC (Method P1) to afford the title compound as a white solid (12 mg, 99% purity, 54% Yield).1H NMR (500 MHz, DMSO) δ 10.16 (br s, 1H), 9.26 (s, 1H), 7.92 (d, J = 2.2 Hz, 1H), 7.67 – 7.60 (m, 1H), 7.17 (d, J = 2.2 Hz, 1H), 7.14 – 7.07 (m, 1H), 5.66 (d, J = 13.7 Hz, 1H), 5.21 (d, J = 13.6 Hz, 1H). LCMS: m / z = 520.0 / 521.9 [M-H]-, (ESI-), RT = 3.98, Method AExample 72- Synthesis of 13-Chloro-14-hydroxy-5-methoxy-16,16-dioxo-19- (trifluoromethyl)-9-oxa-16λ6-thia-4,17,20-triazatetracyclo[16.3.1.111,15.02,7]tricosa- 1(22),2(7),3,5,11,13,15(23),18,20-nonaen-10-one (Compound 72)

[0310] A mixture of 13-chloro-5,14-dimethoxy-16,16-dioxo-19-(trifluoromethyl)-9-oxa- 16λ6-thia-4,17,20-triazatetracyclo[16.3.1.111,15.02,7]tricosa- 1(22),2(7),3,5,11,13,15(23),18,20-nonaen-10-one (synthesised from intermediates 49 and 50, using a similar method to intermediate 13, 235 mg, 0.435 mmol) and lithium iodide (140.0 mg, 1.04 mmol) in anhydrous pyridine (5 mL) was stirred at 90 °C for 1 h and then at 80 ºC for 17 h. The reaction mixture was concentrated in vacuo then suspended in EtOAc (60 mL) and washed successively with sat. aq. Na2S2O3 solution (40 mL), 1 M aq. HCl solution (40 mL) and brine (40 mL). The organic component was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (Method P1) to afford the title compound as an off-white solid (111 mg, 96% purity, 48% yield).1H NMR (500 MHz, DMSO) δ 10.61 (br. s, 1H), 8.82 (s, 1H), 8.04 (s, 1H), 7.95 (d, J = 2.1 Hz, 1H), 7.27 (s, 1H), 7.13 (s, 1H), 6.94 (d, J = 2.2 Hz, 1H), 5.43 (s, 2H), 3.90 (s, 3H). LCMS: m / z = 516.0 [M+H]+, (ESI+), RT = 3.48, Method CExample 73 – Synthesis of 12-Chloro-18,20-difluoro-13-hydroxy-15,15-dioxo-8-oxa- 5,15λ6-dithia-3,16-diazatetracyclo[15.3.1.110,14.02,6]docosa- 1(20),2(6),3,10,12,14(22),17(21),18-octaen-9-one (Compound 73)

[0311] To a solution of 12-chloro-18,20-difluoro-13-methoxy-15,15-dioxo-8-oxa-5,15λ6- dithia-3,16-diazatetracyclo[15.3.1.110,14.02,6]docosa-1(20),2(6),3,10,12,14(22),17(21),18- octaen-9-one (synthesised from intermediate 52, using a similar method to intermediate 7, 84% purity, 43 mg, 0.0764 mmol) in anhydrous pyridine (4.5 mL) was added lithium iodide (108 mg, 0.807 mmol). The reaction mixture was heated at 100 °C for 4 h and then 80 °C overnight. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC (Method P1) to afford the title compound as a white solid (29 mg, 95% purity, 78% Yield).1H NMR (500 MHz, DMSO) δ 10.13 (s, 1H), 9.13 (s, 1H), 8.01 (d, J = 2.2 Hz, 1H), 7.59 – 7.52 (m, 1H), 7.30 (d, J = 2.2 Hz, 1H), 6.88 – 6.82 (m, 1H), 5.49 (s, 2H). LCMS: m / z = 457.0 / 459.0 [M-H]-, (ESI-), RT = 3.38, Method A Example 74 – Synthesis of 12-Chloro-18,20-difluoro-13-hydroxy-4-methyl-15,15-dioxo- 8-oxa-3,15λ6-dithia-5,16-diazatetracyclo[15.3.1.110,14.02,6]docosa- 1(20),2(6),4,10,12,14(22),17(21),18-octaen-9-one (Compound 74)

[0312] To a solution of 12-chloro-18,20-difluoro-13-methoxy-4-methyl-15,15-dioxo-8- oxa-3,15λ6-dithia-5,16-diazatetracyclo[15.3.1.110,14.02,6]docosa- 1(20),2(6),4,10,12,14(22),17(21),18-octaen-9-one (synthesised from methyl 5-bromo-2- methyl-thiazole-4-carboxylate, using a similar method to intermediate 7, 78% purity, 165 mg, 0.26 mmol) in anhydrous pyridine (8 mL) was added lithium iodide (354 mg, 2.64 mmol). The reaction mixture was heated at 90 °C for 1 h 45 min. The cooled RM was diluted with EtOAc (50 mL) and washed with 1 M aq. HCl (30 mL), sat. aq. Na2S2O3 (30 mL) and brine (30 mL), then passed through a phase separator and then concentrated. The residue was purified by preparative HPLC (Method P1) to afford the title compound as an off-white solid (52 mg, 99% purity, 41% Yield).1H NMR (500 MHz, DMSO) δ 8.02 – 7.92 (m, 1H), 7.54 – 7.40 (m, 2H), 7.20 – 7.05 (m, 1H), 5.39 (s, 2H), 2.68 (s, 3H). LCMS: m / z = 473.1 / 475.1 [M+H]+, (ESI+), RT = 3.55, Method A Example 75 – Synthesis of 12-Chloro-18,20-difluoro-13-hydroxy-15,15-dioxo-8-oxa- 3,15λ6-dithia-5,16-diazatetracyclo[15.3.1.110,14.02,6]docosa- 1(20),2(6),4,10,12,14(22),17(21),18-octaen-9-one (Compound 75)

[0313] To a solution of 12-chloro-18,20-difluoro-13-methoxy-15,15-dioxo-8-oxa-3,15λ6- dithia-5,16-diazatetracyclo[15.3.1.110,14.02,6]docosa-1(20),2(6),4,10,12,14(22),17(21),18- octaen-9-one (synthesised from methyl 5-bromo-1,3-thiazole-4-carboxylate, using a similar method to intermediate 6, 95% purity, 80 mg, 0.16 mmol) in anhydrous pyridine (4 mL) was added lithium iodide (215 mg, 1.61 mmol). The reaction mixture was heated at 90 °C for 1 h 45 min. The cooled RM was diluted with EtOAc (50 mL) and washed with 1 M aq. HCl (30 mL), sat. aq. Na2S2O3 (30 mL) and brine (30 mL), then passed through a phase separator and then concentrated. The residue was purified by preparative HPLC (Method P1) to afford thetitle compound as an off-white solid (40 mg, 99% purity, 54% Yield).1H NMR (400 MHz, DMSO) δ 9.20 (s, 1H), 8.01 (d, J = 2.1 Hz, 1H), 7.64 – 7.48 (m, 1H), 7.45 (d, J = 2.2 Hz, 1H), 7.20 – 7.01 (m, 1H), 5.49 (s, 2H). LCMS: m / z = 457.0 / 459.0 [M-H]-, (ESI-), RT = 3.48, Method A Example 76 – Synthesis of 12-Chloro-18,20-difluoro-13-hydroxy-15,15-dioxo-4,8-dioxa- 15λ6-thia-5,16-diazatetracyclo[15.3.1.110,14.02,6]docosa-1(21),2,5,10,12,14(22),17,19- octaen-9-one (Compound 76)

[0314] A mixture of 12-chloro-18,20-difluoro-13-methoxy-15,15-dioxo-4,8-dioxa-15λ6- thia-5,16-diazatetracyclo[15.3.1.110,14.02,6]docosa-1(21),2,5,10,12,14(22),17,19-octaen-9- one (synthesised from intermediate 53, using a similar method to intermediate 13, 280 mg, 0.613 mmol), lithium iodide (410.208 mg, 3.06 mmol) and anhydrous pyridine (5 mL) was heated at 90 °C for 3 h. The mixture was cooled to r.t., diluted with EtOAc (50 mL), washed with sat. aq. Na2S2O3(50 ml), 1 M aq. HCl (50 mL) and brine (30 mL), then dried over Na2SO4, filtered, concentrated and dried in the vacuum oven for 3 h at 50 °C to afford the title compound as a white solid (241 mg, 98% purity, 87% Yield).1H NMR (500 MHz, DMSO) δ 10.23 (s, 1H), 9.15 (s, 1H), 8.03 (d, J = 2.2 Hz, 1H), 7.68 – 7.48 (m, 1H), 7.42 (d, J = 2.2 Hz, 1H), 7.16 – 7.01 (m, 1H), 5.45 (s, 2H). LCMS: m / z = 441.0 / 443.0 [M-H]-, (ESI-), RT = 3.52, Method AExample 77 – Synthesis of 12-Chloro-19-fluoro-13-hydroxy-18-methoxy-15,15-dioxo-4- (trifluoromethyl)-8-oxa-3,15λ6-dithia-5,16-diazatetracyclo[15.3.1.110,14.02,6]docosa- 1(21),2(6),4,10(22),11,13,17,19-octaen-9-one (Compound 77)

[0315] Lithium iodide (63.0 mg, 0.471 mmol) was added to a stirring solution of 12-chloro- 19-fluoro-13,18-dimethoxy-15,15-dioxo-4-(trifluoromethyl)-8-oxa-3,15λ6-dithia-5,16- diazatetracyclo[15.3.1.110,14.02,6]docosa-1(21),2(6),4,10(22),11,13,17,19-octaen-9-one (synthesised from intermediate 54, using a similar method to intermediate 13, 93% purity, 121 mg, 0.204 mmol) in anhydrous pyridine (4.0 mL) at r.t. The reaction vessel was sealed and the mixture stirred at 90 °C for 1 h 30 m. The reaction mixture was allowed to cool to r.t., diluted with EtOAc (~15 mL), and washed sequentially with sat. aq. sodium thiosulphate (~15 mL), 1 M HCl (aq.) (~15 mL), and brine (~15 mL). The organic phase was passed through a phase separator and concentrated to dryness in vacuo. The residue was purified by preparative HPLC (Method P1) to afford the title compound as an off-white solid (19.8 mg, 98% purity, 18% yield).1H NMR (500 MHz, DMSO) δ 9.89 (s, 1H), 7.96 (d, J = 2.2 Hz, 1H), 7.56 (d, J = 2.2 Hz, 1H), 7.48 (dd, J = 11.9, 2.1 Hz, 1H), 7.30 – 7.25 (m, 1H), 5.56 (s, 2H), 3.63 (d, J = 2.4 Hz, 3H). LCMS: m / z = 539.0 [M+H]+, (ESI+), RT = 4.42, Method AExample 78 – Synthesis of 13-Chloro-5-(difluoromethoxy)-19,21-difluoro-14-hydroxy- 16,16-dioxo-9-oxa-16λ6-thia-4,17-diazatetracyclo[16.3.1.111,15.02,7]tricosa- 1(21),2(7),3,5,11,13,15(23),18(22),19-nonaen-10-one (Compound 78)

[0316] To a solution of 13-chloro-5-(difluoromethoxy)-19,21-difluoro-14-methoxy-16,16- dioxo-9-oxa-16λ6-thia-4,17-diazatetracyclo[16.3.1.111,15.02,7]tricosa- 1(21),2(7),3,5,11,13,15(23),18(22),19-nonaen-10-one (synthesised from intermediate 31, using a similar method to intermediate 13, 394 mg, 0.643 mmol) in anhydrous pyridine (4 mL) was added lithium iodide (753 mg, 5.63 mmol) and the reaction mixture was heated at 80 °C for 16 h. The mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC (Method P1) to afford the title compound (203 mg, 95% purity, 58% Yield) as a pale-yellow solid.1H NMR (500 MHz, DMSO) δ 10.20 (s, 1H), 8.19 (s, 1H), 7.97 (d, J = 2.2 Hz, 1H), 7.75 (t, J = 72.4 Hz, 1H), 7.55 – 7.46 (m, 1H), 7.39 (s, 1H), 7.22 (d, J = 2.3 Hz, 1H), 7.03 – 6.88 (m, 1H), 5.49 (d, J = 13.9 Hz, 1H), 5.13 (d, J = 13.3 Hz, 1H). LCMS: m / z = 517.0 / 519.0 [M-H]-, (ESI-), RT = 4.05, Method AExample 79 – Synthesis of 13-Chloro-5,20-difluoro-14-hydroxy-19-methoxy-16,16- dioxo-9-oxa-16λ6-thia-4,17-diazatetracyclo[16.3.1.111,15.02,7]tricosa- 1(21),2(7),3,5,11,13,15(23),18(22),19-nonaen-10-one (Compound 79)

[0317] To a solution of 13-chloro-5,20-difluoro-14,19-dimethoxy-16,16-dioxo-9-oxa-16λ6- thia-4,17-diazatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2(7),3,5,11,13,15(23),18(22),19- nonaen-10-one (synthesised from intermediate 11, using a similar method to intermediate 13, 101 mg, 0.161 mmol) in anhydrous pyridine (4 mL) was added lithium iodide (188 mg, 1.40 mmol) and the mixture was heated at 80 °C for 16 h. The mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC (Method P1) to afford the title compound as an off-white solid (29 mg, 100% purity, 38% Yield).1H NMR (500 MHz, DMSO) δ 9.46 (s, 1H), 8.26 (s, 1H), 7.92 (d, J = 2.2 Hz, 1H), 7.47 (d, J = 1.8 Hz, 1H), 7.37 (d, J = 2.2 Hz, 1H), 7.24 (d, J = 8.1 Hz, 1H), 6.84 (d, J = 11.8 Hz, 1H), 5.40 (d, J = 13.6 Hz, 1H), 5.28 (dd, J = 13.7, 2.0 Hz, 1H), 3.49 (s, 3H). LCMS: m / z = 481.0 / 483.0 [M-H]-, (ESI-), RT = 3.69, Method AExample 80 – Synthesis of 13-Chloro-5,21-difluoro-14-hydroxy-19-methoxy-16,16- dioxo-9-oxa-16λ6-thia-4,17-diazatetracyclo[16.3.1.111,15.02,7]tricosa- 1(21),2(7),3,5,11,13,15(23),18(22),19-nonaen-10-one (Compound 80)

[0318] To a solution of 13-chloro-5,21-difluoro-14,19-dimethoxy-16,16-dioxo-9-oxa-16λ6- thia-4,17-diazatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2(7),3,5,11,13,15(23),18(22),19- nonaen-10-one (synthesised from intermediate 11, using a similar method to intermediate 13, 83 mg, 0.149 mmol) in anhydrous pyridine (4 mL) was added lithium iodide (175 mg, 1.31 mmol) and the reaction mixture was heated at 80 °C for 16 h. The mixture was concentrated under reduced pressure and purified by preparative HPLC (Method P1) to afford the title compound as an off-white solid (38 mg, 95% purity, 50% Yield).1H NMR (500 MHz, DMSO) δ 9.46 (s, 1H), 8.26 (s, 1H), 7.92 (d, J = 2.2 Hz, 1H), 7.47 (d, J = 1.8 Hz, 1H), 7.37 (d, J = 2.2 Hz, 1H), 7.24 (d, J = 8.1 Hz, 1H), 6.84 (d, J = 11.8 Hz, 1H), 5.40 (d, J = 13.6 Hz, 1H), 5.28 (dd, J = 13.7, 2.0 Hz, 1H), 3.49 (s, 3H). LCMS: m / z = 481.0 / 483.0 [M-H]-, (ESI-), RT = 3.61, Method AExample 81- Synthesis of 13-Chloro-19-ethoxy-5-fluoro-14-hydroxy-16,16-dioxo-9-oxa- 16λ6-thia-4,17-diazatetracyclo[16.3.1.111,15.02,7]tricosa- 1(22),2(7),3,5,11(23),12,14,18,20-nonaen-10-one (Compound 81)

[0319] Lithium iodide (53 mg, 0.396 mmol) was added to a stirring solution of 13-chloro- 19-ethoxy-5-fluoro-14-methoxy-16,16-dioxo-9-oxa-16λ6-thia-4,17- diazatetracyclo[16.3.1.111,15.02,7]tricosa-1(22),2(7),3,5,11(23),12,14,18,20-nonaen-10-one (synthesised from intermediate 11, using a similar method to intermediate 13, 146 mg, 0.195 mmol) in anhydrous pyridine (4 mL) in a pressure vial (10 mL) and the mixture was stirred at 90 °C for 3 hours. The mixture was allowed to cool to r.t., diluted with EtOAc (~15 mL), and washed sequentially with sat. aq. sodium thiosulphate (~15 mL), 1 M HCl (aq.) (~15 mL), and brine (~15 mL). The organic phase was passed through a phase separator and concentrated to dryness. The residue was purified by preparative HPLC (Method P1) to afford the title compound as a white solid (40.3 mg, 94% purity, 40.5 % Yield).1H NMR (500 MHz, DMSO) δ 9.18 (s, 1H), 8.22 (s, 1H), 7.85 (d, J = 2.2 Hz, 1H), 7.45 (d, J = 1.9 Hz, 1H), 7.37 (d, J = 2.2 Hz, 1H), 7.32 (d, J = 2.2 Hz, 1H), 7.25 (dd, J = 8.4, 2.3 Hz, 1H), 6.69 (d, J = 8.5 Hz, 1H), 5.70 (d, J = 13.4 Hz, 1H), 5.13 (d, J = 13.4 Hz, 1H), 3.92 – 3.83 (m, 1H), 1.21 (t, J = 6.9 Hz, 3H). LCMS: m / z = 477.3, 479.3 [M-H]-, (ESI-), RT = 3.74, Method AExample 82 – Synthesis of 13-Chloro-5-fluoro-14-hydroxy-19-methoxy-20-methyl-16,16- dioxo-9-oxa-16λ6-thia-4,17-diazatetracyclo[16.3.1.111,15.02,7]tricosa- 1(22),2(7),3,5,11,13,15(23),18,20-nonaen-10-one (Compound 82) C

[0320] A mixture of 13-chloro-5-fluoro-14,19-dimethoxy-20-methyl-16,16-dioxo-9-oxa- 16λ6-thia-4,17-diazatetracyclo[16.3.1.111,15.02,7]tricosa-1(22),2(7),3,5,11,13,15(23),18,20- nonaen-10-one (synthesised from intermediate 11, using a similar method to intermediate 13, 92% purity, 119 mg, 0.241 mmol), lithium iodide (163 mg, 1.21 mmol) and anhydrous pyridine (2.4 mL) was stirred at 90 °C for 3 h and then at r.t. overnight. The mixture was diluted with EtOAc (40 mL), washed with sat. aq. Na2S2O3 (30 ml), 1 M aq. HCl (30 mL) and brine (30 mL), then passed through a phase separator and concentrated. The residue was purified by preparative HPLC (Method P1) to afford the title compound as a white solid (48 mg, 41 % yield).1H NMR (400 MHz, DMSO) δ 8.12 (s, 1H), 7.51 (d, J = 2.6 Hz, 1H), 7.44 (d, J = 2.0 Hz, 1H), 7.39 (d, J = 2.5 Hz, 1H), 7.34 (d, J = 2.2 Hz, 1H), 7.14 (Br. s, 2H), 6.97 (d, J = 2.1 Hz, 1H), 5.29 (d, J = 12.6 Hz, 1H), 4.96 (d, J = 12.7 Hz, 1H), 3.33 (s, 3H), 2.04 (s, 3H). LCMS: m / z = 479.3 / 481.2 [M+H]+, (ESI+), RT = 3.80, Method AExample 83 - Synthesis of 5,19-Dichloro-11-fluoro-20-hydroxy-2,2-dioxo-15-oxa-2λ6,6- dithia-3,10-diazatetracyclo[15.3.1.14,7.08,13]docosa-1(21),4,7(22),8,10,12,17,19-octaen- 16-one (Compound 83)

[0321] A crude mixture containing 5,19-dichloro-11,20-dimethoxy-2,2-dioxo-15-oxa- 2λ6,6-dithia-3,10-diazatetracyclo[15.3.1.14,7.08,13]docosa-1(21),4,7(22),8,10,12,17,19- octaen-16-one and 5,19-dichloro-11-fluoro-20-methoxy-2,2-dioxo-15-oxa-2λ6,6-dithia-3,10- diazatetracyclo[15.3.1.14,7.08,13]docosa-1(21),4,7(22),8,10,12,17,19-octaen-16-one (synthesised from intermediate 60, using a similar method to intermediate 13, total of 200 mg, 0.12 mmol) was dissolved in anhydrous pyridine (2.0 mL) was added lithium iodide (130 mg, 0.971 mmol) and the reaction mixture was heated at 90 °C for 4.5 h. The mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC (Method P1) to afford the title compound (24.4 mg, 98% purity, 43% yield) as a light brown solid.1H NMR (500 MHz, DMSO) δ 10.28 (br. s, 1H), 8.27 (s, 1H), 8.03 (d, J = 2.3 Hz, 1H), 7.48 (d, J = 1.8 Hz, 1H), 7.35 (d, J = 2.2 Hz, 1H), 6.77 (s, 1H), 5.50 (s, 2H). LCMS: m / z = 474.9 / 476.9 / 479.1 [M+H]+, (ESI+), RT = 3.83, Method AExample 84 – Synthesis of 5,19-Dichloro-20-hydroxy-11-methoxy-2,2-dioxo-15-oxa- 2λ6,6-dithia-3,10-diazatetracyclo[15.3.1.14,7.08,13]docosa-1(21),4,7(22),8,10,12,17,19- octaen-16-one (Compound 84)

[0322] The title compound was isolated as a second component from the purification of Example 83, as an off-white solid (18.7 mg, 95% purity, 31% yield).1H NMR (500 MHz, DMSO) δ 10.89 (br. s, 1H), 10.23 (br. s, 1H), 8.18 (s, 1H), 8.03 (d, J = 2.2 Hz, 1H), 7.35 (d, J = 2.2 Hz, 1H), 7.06 (s, 1H), 6.66 (s, 1H), 5.41 (s, 2H), 3.90 (s, 3H). LCMS: m / z = 486.9 / 488.9 / 491.0 [M+H]+, (ESI+), RT = 4.08, Method A Example 85 – Synthesis of 13-Chloro-4-fluoro-14-hydroxy-16,16-dioxo-9-oxa-16λ6-thia- 17,19-diazatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2(7),3,5,11,13,15(23),18(22),19- nonaen-10-one (Compound 85)

[0323] To a solution of 13-chloro-4-fluoro-14-methoxy-16,16-dioxo-9-oxa-16λ6-thia- 17,19-diazatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2(7),3,5,11,13,15(23),18(22),19- nonaen-10-one (synthesised from intermediate 62, using a similar method to intermediate 7, 152 mg, 0.34 mmol) in anhydrous pyridine (4.5 mL) was added lithium iodide (227 mg, 1.69mmol). The reaction mixture was heated at 80 °C for 5 h. The reaction mixture was dissolved in EtOAc (30 mL) and washed with 1 M aq. HCl (30 mL). The aqueous phase was extracted further with EtOAc (2 x 30 mL) and the organics were combined, washed with sat. aq. Na2S2O3(30 mL) and brine (30 mL) and dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (Method P1) to afford the title compound as a white solid (34 mg, 99% purity, 23% Yield).1H NMR (500 MHz, DMSO) δ 8.07 (d, J = 5.3 Hz, 1H), 7.88 (d, J = 2.2 Hz, 1H), 7.71 – 7.65 (m, 1H), 7.62 – 7.53 (m, 1H), 7.45 – 7.42 (m, 1H), 7.38 – 7.33 (m, 2H), 7.31 (dd, J = 5.2, 1.5 Hz, 1H), 5.43 – 5.32 (m, 1H), 5.27 – 5.18 (m, 1H). LCMS: m / z = 435.0 / 437.0 [M+H]+, (ESI+), RT = 3.50, Method A Example 86 – Synthesis of 13-Chloro-5-fluoro-14-hydroxy-10,16,16-trioxo-9-oxa-16λ6- thia-4,17-diazatetracyclo[16.3.1.111,15.02,7]tricosa-1(22),2(7),3,5,11,13,15(23),18,20- nonaene-19-carbonitrile (Compound 86)

[0324] To a solution of 13-chloro-5-fluoro-14-methoxy-10,16,16-trioxo-9-oxa-16λ6-thia- 4,17-diazatetracyclo[16.3.1.111,15.02,7]tricosa-1(22),2(7),3,5,11,13,15(23),18,20-nonaene- 19-carbonitrile (synthesised from intermediate 11, using similar methods to intermediates 62 and 7, 240 mg, 0.31 mmol) in anhydrous pyridine (4 mL) was added lithium iodide (210 mg, 1.57 mmol). The reaction mixture was heated at 80 °C for 5 h. The reaction mixture was dissolved in EtOAc (30 mL) and washed with 1 M aq. HCl (20 mL). The aqueous phase was extracted further with EtOAc (2 x 30 mL) and the organics were combined, washed with sat. aq. Na2S2O3 (30 mL) and brine (30 mL) and dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (Method P1) to afford the title compound as a white solid (49 mg, 99% purity, 34% Yield).1H NMR (500 MHz, DMSO) δ 8.08 (s, 1H), 8.01 (d, J = 7.9 Hz, 1H), 7.95 (d, J = 2.2 Hz, 1H), 7.70 (dd, J = 7.9, 1.6 Hz, 1H), 7.52 (d, J = 1.9 Hz, 1H), 6.85 (d, J = 2.1 Hz, 1H), 6.77 (d, J = 1.6 Hz, 1H), 5.58 – 5.46 (m, 1H), 5.41 – 5.25 (m, 1H), OH, NH peaks not observed LCMS: m / z = 460.0 / 461.9 [M+H]+, (ESI+), RT = 3.38, Method A Example 87 – Synthesis of 13-Chloro-4-fluoro-14-hydroxy-16,16-dioxo-19- (trifluoromethyl)-9-oxa-16λ6-thia-17-azatetracyclo[16.3.1.111,15.02,7]tricosa- 1(21),2,4,6,11(23),12,14,18(22),19-nonaen-10-one (Compound 87)

[0325] 13-Chloro-4-fluoro-14-methoxy-16,16-dioxo-19-(trifluoromethyl)-9-oxa-16λ6-thia- 17-azatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2,4,6,11(23),12,14,18(22),19-nonaen-10- one (synthesised from (2-bromo-4-fluoro-phenyl)methanol, using similar methods to intermediates 62 and 7, 95% purity, 300 mg, 0.552 mmol) and iodocyclohexane (600 mg, 2.86 mmol) were combined and the mixture dissolved into anhydrous DMF (7.5 mL). The mixture was heated to 120 ºC and stirred for 2 h. The reaction mixture was allowed to cool to r.t., sat aq. Na2S2O3(50 mL) was added, and the mixture extracted with DCM (3 x 50 mL). The combined organic extracts were washed with 1 M aq. HCl (50 mL), then brine (50 mL) and were dried over Na2SO4, filtered and concentrated. The residue was purified by FCC (25 g SiO2 cartridge, 0-40% MeOH in DCM) followed by preparative HPLC (Method P1) to afford the title compound as an off-white solid (102 mg, 99% purity, 36% Yield).1H NMR (500 MHz, DMSO) δ 10.33 (br. s, 1H), 7.90 (d, J = 2.1 Hz, 1H), 7.70 (d, J = 8.1 Hz, 1H), 7.67 – 7.61 (m, 2H), 7.33 – 7.26 (m, 1H), 7.22 (d, J = 2.2 Hz, 1H), 7.18 (dd, J = 9.3, 2.7 Hz, 1H), 7.04 (s, 1H), 5.35 (s, 2H). LCMS: m / z = 500.2 / 502.2 [M-H]-, (ESI-), RT = 4.18, Method AExample 88 – Synthesis of 12-Chloro-18,20-difluoro-13-hydroxy-4-methyl-15,15-dioxo- 8-oxa-15λ6-thia-4,5,16-triazatetracyclo[15.3.1.110,14.02,6]docosa- 1(20),2,5,10,12,14(22),17(21),18-octaen-9-one (Compound 88) C

[0326] 12-Chloro-18,20-difluoro-13-methoxy-4-methyl-15,15-dioxo-8-oxa-15λ6-thia- 4,5,16-triazatetracyclo[15.3.1.110,14.02,6]docosa-1(20),2,5,10,12,14(22),17(21),18-octaen- 9-one (synthesised from methyl 4-bromo-1-methyl-pyrazole-3-carboxylate, using similar methods to intermediates 52 and 6, 38.0 mg, 0.08 mmol) and iodocyclohexane (0.05 mL, 0.4 mmol) were dissolved in anhydrous DMF (2 mL) and the mixture was stirred at 120 °C for 30 mins. The mixture was diluted with EtOAc (25 mL), washed with 1 M HCl (25 mL), 2 M Na2S2O3(25 mL), then brine (25 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (Method P1) to afford the title compound as a white solid (8.0 mg, 97% yield, 21% Yield).1H NMR (500 MHz, DMSO) δ 10.10 (br s, 1H), 7.97 (s, 1H), 7.84 (s, 1H), 7.43 (d, J = 2.2 Hz, 1H), 7.41 – 7.34 (m, 1H), 7.00 – 6.93 (m, 1H), 5.24 (s, 2H), 3.85 (s, 3H). LCMS: m / z = 454.0 / 456.0 [M-H]-, (ESI-), RT = 3.32, Method AExample 89 – Synthesis of 12-Chloro-18,20-difluoro-13-hydroxy-15,15-dioxo-4- (trifluoromethyl)-8-oxa-3,15λ6-dithia-5,16-diazatetracyclo[15.3.1.110,14.02,6]docosa- 1(21),2(6),4,10,12,14(22),17,19-octaen-9-one (Compound 89) C

[0327] To a stirred solution of 12-chloro-18,20-difluoro-13-methoxy-15,15-dioxo-4- (trifluoromethyl)-8-oxa-3,15λ6-dithia-5,16-diazatetracyclo[15.3.1.110,14.02,6]docosa- 1(21),2(6),4,10,12,14(22),17,19-octaen-9-one (synthesised from methyl 5-bromo-2- (trifluoromethyl)thiazole-4-carboxylate, using similar methods to intermediates 52 and 7, 92% purity, 125 mg, 0.213 mmol) in anhydrous DMF (2 mL) was added iodocyclohexane (0.14 mL, 1.06 mmol) and the reaction mixture was heated to 100 °C for 3 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC (Method P1) to afford the title compound as an off-white solid (74 mg, 99%, 65% Yield).1H NMR (400 MHz, DMSO) δ 10.32 (s, 1H), 8.01 (d, J = 2.2 Hz, 1H), 7.67 – 7.54 (m, 1H), 7.43 (d, J = 2.2 Hz, 1H), 7.34 – 7.25 (m, 1H), 5.54 (s, 2H). LCMS: m / z = 524.9 / 526.8 [M-H]-, (ESI-), RT = 4.15, Method AExample 90 – Synthesis of 13-Bromo-5,19,21-trifluoro-14-hydroxy-16,16-dioxo-9-oxa- 16λ6-thia-6,17-diazatetracyclo[16.3.1.111,15.02,7]tricosa- 1(21),2(7),3,5,11,13,15(23),18(22),19-nonaen-10-one (Compound 90)

[0328] 13-Bromo-5,19,21-trifluoro-14-methoxy-16,16-dioxo-9-oxa-16λ6-thia-6,17- diazatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2(7),3,5,11,13,15(23),18(22),19-nonaen-10- one (synthesised from intermediate 9, using similar methods to intermediates 47 and 24, 120 mg, 0.215 mmol) and lithium iodide (145 mg, 1.08 mmol) were combined and the mixture dissolved into anhydrous pyridine (4 mL). The mixture was heated to 80 ºC and stirred for 18 h. The mixture was cooled to r.t., sat aq. Na2S2O3(50 mL) was added, and the mixture was extracted with DCM (3 x 50 mL). The combined organic extracts were washed with 1 M aq. HCl (50 mL), then brine (50 mL) and were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (Method P1) to afford the title compound as an off-white solid (94 mg, 95% purity, 80% Yield).1H NMR (500 MHz, DMSO) δ 10.15 (br s, 1H), 8.08 (s, 1H), 7.99 – 7.93 (m, 1H), 7.56 – 7.48 (m, 1H), 7.32 (dd, J = 8.3, 2.9 Hz, 1H), 7.25 (d, J = 2.2 Hz, 1H), 7.01 – 6.94 (m, 1H), 5.37 – 5.25 (m, 2H). LCMS: m / z = 513.0 / 515.0 [M-H]-, (ESI-), RT = 3.88, Method AExample 91 – Synthesis of 13-Bromo-5-fluoro-14-hydroxy-19-methoxy-16,16-dioxo-9- oxa-16λ6-thia-6,17-diazatetracyclo[16.3.1.111,15.02,7]tricosa- 1(21),2(7),3,5,11,13,15(23),18(22),19-nonaen-10-one (Compound 91)

[0329] 13-Bromo-5-fluoro-14,19-dimethoxy-16,16-dioxo-9-oxa-16λ6-thia-6,17- diazatetracyclo[16.3.1.111,15.02,7]tricosa-1(21),2(7),3,5,11,13,15(23),18(22),19-nonaen-10- one (synthesised from intermediate 9, using similar methods to intermediates 47 and 24, 120 mg, 0.115 mmol) and lithium iodide (30 mg, 0.224 mmol) were combined and the mixture dissolved into anhydrous pyridine (2 mL). The mixture was heated to 80 ºC and stirred for 18 h. The mixture was cooled to r.t., sat. aq. Na2S2O3(50 mL) was added, and the mixture was extracted with DCM (3 x 50 mL). The combined organic extracts were washed with 1 M aq. HCl (50 mL), then brine (50 mL) and were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (Method P1) to afford the title compound as an off-white solid (20 mg, 96% purity, 33% Yield).1H NMR (500 MHz, DMSO) δ 9.26 (s, 1H), 8.03 – 7.96 (m, 2H), 7.38 (d, J = 2.2 Hz, 1H), 7.31 – 7.28 (m, 2H), 7.25 (d, J = 2.2 Hz, 1H), 6.73 (d, J = 8.5 Hz, 1H), 5.88 (d, J = 13.5 Hz, 1H), 4.89 (d, J = 13.5 Hz, 1H), 3.45 (s, 3H). LCMS: m / z = 507.0 / 509.0 [M-H]-, (ESI-), RT = 3.84, Method AExample 92 – Synthesis of 13-Bromo-5-(difluoromethoxy)-20-fluoro-14-hydroxy-19- methoxy-16,16-dioxo-9-oxa-16λ6-thia-4,17-diazatetracyclo[16.3.1.111,15.02,7]tricosa- 1(21),2(7),3,5,11,13,15(23),18(22),19-nonaen-10-one (Compound 92)

[0330] In a pressure vial, 13-bromo-5-(difluoromethoxy)-20-fluoro-14,19-dimethoxy- 16,16-dioxo-9-oxa-16λ6-thia-4,17-diazatetracyclo[16.3.1.111,15.02,7]tricosa- 1(21),2(7),3,5,11,13,15(23),18(22),19-nonaen-10-one (synthesised from intermediate 30, using similar methods to intermediates 52 and 26, 207 mg, 0.351 mmol) was dissolved in anhydrous pyridine (9.5 mL) and lithium iodide (415 mg, 3.10 mmol) was added. The reaction mixture was heated at 70 °C for 3 h. The mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC (Method P1) to afford the title compound as a white solid (143 mg, 99% purity, 70% yield).1H NMR (500 MHz, DMSO) δ 9.82 (s, 1H), 8.19 (s, 1H), 8.07 (d, J = 2.2 Hz, 1H), 7.75 (t, J = 72.6 Hz, 1H), 7.46 (d, J = 2.2 Hz, 1H), 7.41 (dd, J = 12.0, 2.1 Hz, 1H), 7.37 (s, 1H), 7.05 – 7.01 (m, 1H), 5.55 (d, J = 13.0 Hz, 1H), 5.25 (d, J = 13.2 Hz, 1H), 3.58 (d, J = 2.0 Hz, 3H). LCMS: m / z = 573.0 / 575.0 [M-H]-, (ESI-), RT = 4.25, Method AExample 93- Synthesis of 12-Bromo-18,20-difluoro-13-hydroxy-4-methyl-15,15-dioxo-8- oxa-15λ6-thia-4,5,16-triazatetracyclo[15.3.1.110,14.02,6]docosa- 1(20),2,5,10(22),11,13,17(21),18-octaen-9-one (Compound 93)

[0331] A mixture of 12-bromo-18,20-difluoro-13-methoxy-4-methyl-15,15-dioxo-8-oxa- 15λ6-thia-4,5,16-triazatetracyclo[15.3.1.110,14.02,6]docosa- 1(20),2,5,10(22),11,13,17(21),18-octaen-9-one (synthesised from methyl 4-bromo-1-methyl- pyrazole-3-carboxylate, using similar methods to intermediates 52 and 24, 321 mg, 0.437 mmol), lithium iodide (292 mg, 2.18 mmol) and anhydrous pyridine (4 mL) was heated at 90 °C for 4 h. The mixture was diluted with EtOAc (50 mL), washed with sat. aq. Na2S2O3 (540 ml), 2 M aq. HCl (40 mL) then brine (40 mL). The organic was passed through a phase separator and then concentrated. The residue was purified by preparative HPLC (Method P1) to afford the title compound as a white solid (90 mg, 99% purity, 41 % yield).1H NMR (500 MHz, DMSO) δ 10.13 (br. s, 1H), 8.13 (s, 1H), 7.82 (s, 1H), 7.55 – 7.19 (m, 2H), 7.01 – 6.81 (m, 1H), 5.25 (s, 2H), 3.84 (s, 3H). LCMS: m / z = 498.0 / 499.9 [M-H]-, (ESI-), RT = 3.44, Method AExample 94 – Synthesis of 12-Bromo-13-hydroxy-18-methoxy-4-methyl-15,15-dioxo-8- oxa-15λ6-thia-4,5,16-triazatetracyclo[15.3.1.110,14.02,6]docosa- 1(20),2,5,10(22),11,13,17(21),18-octaen-9-one (Compound 94)

[0332] Lithium iodide (111 mg, 0.829 mmol) was added to a stirring solution of 12-bromo- 13,18-dimethoxy-4-methyl-15,15-dioxo-8-oxa-15λ6-thia-4,5,16- triazatetracyclo[15.3.1.110,14.02,6]docosa-1(21),2,5,10(22),11,13,17,19-octaen-9-one (synthesised from methyl 4-bromo-1-methyl-pyrazole-3-carboxylate, using similar methods to intermediates 52 and 24, 68% purity, 274 mg, 0.350 mmol) in anhydrous pyridine (5 mL) in a 10 mL pressure vial. The vessel was sealed and the mixture stirred at 90 °C for 3 h 30 m. The mixture was allowed to cool to r.t and diluted with sat. aq. sodium thiosulphate (~25 mL), 1 M aq. HCl (~25 mL), forming a white precipitate. The mixture was filtered, then extracted with CHCl3 / IPA (3:1) (3 x ~15 mL then 3 x ~20 mL). The organic phase was combined with the collected precipitate and concentrated to dryness in vacuo. The residue was purified by preparative HPLC (Method P1) to afford the title compound as a white solid (49 mg, 100% purity, 28% Yield).1H NMR (400 MHz, DMSO) δ 9.32 (s, 1H), 8.03 (d, J = 2.2 Hz, 1H), 7.78 (s, 1H), 7.41 (d, J = 2.2 Hz, 1H), 7.10 (d, J = 2.1 Hz, 1H), 7.06 (dd, J = 8.3, 2.2 Hz, 1H), 6.72 (d, J = 8.4 Hz, 1H), 5.27 (s, 2H), 3.85 (s, 3H), 3.48 (s, 3H). LCMS: m / z = 492.3,494.3 [M-H]-, (ESI-), RT = 3.20, Method AExample 95 – Synthesis of 12-Bromo-4-(difluoromethyl)-18,20-difluoro-13-hydroxy- 15,15-dioxo-8-oxa-15λ6-thia-4,5,16-triazatetracyclo[15.3.1.110,14.02,6]docosa- 1(20),2,5,10(22),11,13,17(21),18-octaen-9-one (Compound 95)

[0333] A mixture of 12-bromo-4-(difluoromethyl)-18,20-difluoro-13-methoxy-15,15- dioxo-8-oxa-15λ6-thia-4,5,16-triazatetracyclo[15.3.1.110,14.02,6]docosa- 1(20),2,5,10(22),11,13,17(21),18-octaen-9-one (synthesised from intermediate 32, using similar methods to intermediates 52 and 24, 91% purity, 340 mg, 0.433 mmol), lithium iodide (289.445 mg, 2.16 mmol) and anhydrous pyridine (4 mL) was heated at 90 °C for 3 h. The mixture was cooled to r.t., diluted with EtOAc (40 mL), washed with sat. aq. Na2S2O3(30 ml), 1 M aq. HCl (30 mL) and brine (30 mL), then passed through a phase separator and then concentrated. The residue was purified by preparative HPLC (Method P1) to afford the title compound as an off-white solid (139 mg, 0.257 mmol, 59% Yield).1H NMR (500 MHz, DMSO) δ 10.20 (s, 1H), 8.44 (s, 1H), 8.24 – 8.12 (m, 1H), 7.85 (t, J = 58.9 Hz, 1H), 7.56 – 7.48 (m, 1H), 7.44 (d, J = 2.2 Hz, 1H), 7.05 – 6.85 (m, 1H), 5.35 (s, 2H). LCMS: m / z = 534.0 / 536.0 [M-H]-, (ESI-), RT = 3.81, Method AExample 96 – Synthesis of 12-Bromo-18,20-difluoro-13-hydroxy-4-(2-methoxyethyl)- 15,15-dioxo-8-oxa-15λ6-thia-4,5,16-triazatetracyclo[15.3.1.110,14.02,6]docosa- 1(21),2,5,10,12,14(22),17,19-octaen-9-one (Compound 96)

[0334] A mixture of 12-bromo-18,20-difluoro-13-methoxy-4-(2-methoxyethyl)-15,15- dioxo-8-oxa-15λ6-thia-4,5,16-triazatetracyclo[15.3.1.110,14.02,6]docosa- 1(21),2,5,10,12,14(22),17,19-octaen-9-one (synthesised from intermediate 63, using similar methods to intermediates 52 and 24, 250 mg, 0.448 mmol), lithium iodide (300 mg, 2.24 mmol) and anhydrous pyridine (10 mL) was heated at 90 °C for 3 h. The mixture was cooled to r.t., diluted with EtOAc (50 mL), washed with sat. aq. Na2S2O3(50 ml), 1 M aq. HCl (50 mL) and brine (30 mL), then dried over Na2SO4, filtered and concentrated. The residue was purified by preparative HPLC (Method P1) to afford the title compound as a white solid (92 mg, 100% purity, 38% Yield).1H NMR (500 MHz, DMSO) δ 10.04 (br. s, 1H), 8.04 (s, 1H), 7.86 (s, 1H), 7.45 (d, J = 2.3 Hz, 1H), 7.41 – 7.33 (m, 1H), 7.02 – 6.94 (m, 1H), 5.23 (s, 2H), 4.26 (t, J = 5.3 Hz, 2H), 3.72 (t, J = 5.3 Hz, 2H), 3.25 (s, 3H). LCMS: m / z = 543.9 / 545.0 [M-H]-, (ESI-), RT = 3.50, Method AExample 97 – Synthesis of 19-Bromo-5-chloro-20-hydroxy-10-methoxy-2,2-dioxo-15- oxa-2λ6,6-dithia-3,11-diazatetracyclo[15.3.1.14,7.08,13]docosa- 1(21),4,7(22),8,10,12,17,19-octaen-16-one (Compound 97)

[0335] In a pressure vial, 19-bromo-5-chloro-10,20-dimethoxy-2,2-dioxo-15-oxa-2λ6,6- dithia-3,11-diazatetracyclo[15.3.1.14,7.08,13]docosa-1(21),4,7(22),8,10,12,17,19-octaen-16- one (synthesised from intermediate 66, using a similar method to intermediate 26, 150 mg, 0.253 mmol) was dissolved in anhydrous pyridine (6.5 mL) and lithium iodide (298 mg, 2.23 mmol) was added. The reaction mixture was heated at 80 °C for 3 h. The mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC (Method P1) to afford the title compound as an off-white solid (73.6 mg, 98% purity, 54% yield).1H NMR (500 MHz, DMSO) δ 10.32 (s, 1H), 8.30 (s, 1H), 8.15 (d, J = 2.2 Hz, 1H), 7.29 (d, J = 2.2 Hz, 1H), 6.90 (s, 1H), 6.69 (s, 1H), 5.39 (s, 2H), 3.89 (s, 3H). LCMS: m / z = 528.9 / 530.9 / 532.9 [M-H]-, (ESI-), RT = 4.18, Method AExample 98 – Synthesis of 19-Bromo-5-chloro-20-hydroxy-2,2-dioxo-11- (trifluoromethyl)-15-oxa-2λ6,6-dithia-3,10-diazatetracyclo[15.3.1.14,7.08,13]docosa- 1(21),4,7(22),8,10,12,17,19-octaen-16-one (Compound 98)

[0336] In a pressure vial, intermediate 69 (62 mg, 0.104 mmol) was dissolved in anhydrous pyridine (3.0 mL) and lithium iodide (123 mg, 0.919 mmol) was added. The reaction mixture was heated at 80 °C for 4 h. The mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC (Method P1) to afford the title compound as an off-white solid (20.8 mg, 100% purity, 35% yield).1H NMR (500 MHz, DMSO) δ 10.31 (s, 1H), 8.74 (s, 1H), 8.19 (s, 1H), 8.16 (d, J = 2.2 Hz, 1H), 7.33 (d, J = 2.1 Hz, 1H), 6.81 (s, 1H), 5.60 (s, 2H). LCMS: m / z = 566.9 / 568.9 / 570.9 [M-H]-, (ESI-), RT = 4.27, Method AExample 99 – Synthesis of 19-Bromo-20-hydroxy-2,2-dioxo-11-(trifluoromethyl)-15-oxa- 2λ6,6-dithia-3,10-diazatetracyclo[15.3.1.14,7.08,13]docosa-1(21),4,7(22),8,10,12,17,19- octaen-16-one (Compound 99)

[0337] In a pressure vial, intermediate 70 (56 mg, 0.0652 mmol) was dissolved in anhydrous pyridine (1.8 mL) and lithium iodide (80 mg, 0.598 mmol) was added. The reaction mixture was heated at 70 °C for 6 h. The mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC (Method P1) to afford the title compound as an off-white solid (31.7 mg, 98% purity, 89% yield).1H NMR (500 MHz, DMSO) δ 10.18 (s, 1H), 8.72 (s, 1H), 8.18 (s, 1H), 8.10 (d, J = 2.1 Hz, 1H), 7.36 (s, 1H), 7.07 (d, J = 2.1 Hz, 1H), 6.68 (s, 1H), 5.61 (s, 2H). LCMS: m / z = 532.9 / 534.9 [M-H]-, (ESI-), RT = 4.15, Method A Example 100 – Synthesis of 19-Bromo-11-fluoro-20-hydroxy-2,2-dioxo-15-oxa-2λ6,5- dithia-3,10-diazatetracyclo[15.3.1.14,7.08,13]docosa-1(21),4(22),6,8,10,12,17,19-octaen- 16-one (Compound 100)

[0338] To a solution of 19-bromo-11-fluoro-20-methoxy-2,2-dioxo-15-oxa-2λ6,5-dithia- 3,10-diazatetracyclo[15.3.1.14,7.08,13]docosa-1(21),4(22),6,8,10,12,17,19-octaen-16-one (synthesised from intermediate 11 and tert-butyl (4-bromothiophen-2-yl)carbamate, using a similar method to intermediate 26, 33% purity, 44 mg, 0.0291 mmol) in anhydrous pyridine (4 mL) was added lithium iodide (166 mg, 1.24 mmol). The reaction mixture was heated at 80 °C for 4 h. The mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC (Method P1) to afford the title compound as a yellow solid (7.2 mg, 97% purity, 49% Yield) as a yellow solid .1H NMR (500 MHz, DMSO) δ 10.57 (br. s, 1H), 8.16 (s, 1H), 8.12 (d, J = 2.1 Hz, 1H), 7.47 – 7.42 (m, 2H), 7.26 – 7.22 (m, 1H), 6.67 (s, 1H), 5.72 – 5.29 (m, 2H). LCMS: m / z = 482.9 / 484.9 [M-H]-, (ESI-), RT = 3.66, Method A Example 101 – Synthesis of 12-Bromo-18,20-difluoro-13-hydroxy-5-methyl-15,15-dioxo- 8-oxa-15λ6-thia-4,5,16-triazatetracyclo[15.3.1.110,14.02,6]docosa- 1(20),2(6),3,10,12,14(22),17(21),18-octaen-9-one (Compound 101)

[0339] 12-Bromo-18,20-difluoro-13-methoxy-5-methyl-15,15-dioxo-8-oxa-15λ6-thia- 4,5,16-triazatetracyclo[15.3.1.110,14.02,6]docosa-1(20),2(6),3,10,12,14(22),17(21),18- octaen-9-one (synthesised from methyl 4-bromo-1-methyl-1H-pyrazole-5-carboxylate, using similar methods to intermediates 52 and 26, 73 mg, 0.13 mmol) and iodocyclohexane (0.08 mL, 0.65 mmol) were dissolved in anhydrous DMF (3 mL) and the mixture was stirred at 120 °C for 30 mins. The mixture was diluted with EtOAc (25 mL), washed with 2 M Na2S2O3(25 mL), 1 M HCl (25 mL), then brine (25 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (Method P1) to afford the title compound as a white solid (5.0 mg, 7.5% Yield).1H NMR (500 MHz, DMSO) δ 8.12 (s, 1H), 7.51 - 7.44 (m, 1H), 7.43 (s, 1H), 7.38 (d, J=2.2 Hz, 1H), 6.74 - 6.67 (m, 1H), 5.37 (s, 2H), 3.96 (s, 3H).LCMS: m / z = 498.0 / 500.0 [M-H]-, (ESI-), RT = 3.48, Method A Example 102 – Synthesis of 13-Cyclopropyl-4,19,21-trifluoro-14-hydroxy-16,16-dioxo-9- oxa-16λ6-thia-17-azatetracyclo[16.3.1.111,15.02,7]tricosa- 1(21),2,4,6,11(23),12,14,18(22),19-nonaen-10-one (Compound 102)

[0340] To a solution of intermediate 73 (88 mg, 0.180 mmol) in anhydrous pyridine (4 mL) was added lithium iodide (192 mg, 1.43 mmol) and the reaction mixture was heated at 100 °C for 16 h. The mixture was allowed to cool to r.t. and concentrated under reduced pressure. The residue was purified by preparative HPLC (Method P1) to afford the title compound as a white solid (47.9 mg, 97% purity, 54.4 % Yield).1H NMR (500 MHz, DMSO) δ 10.08 (br. s, 1H), 9.91 (br. s, 1H), 7.61 (dd, J = 8.5, 5.8 Hz, 1H), 7.58 – 7.51 (m, 1H), 7.41 (d, J = 2.1 Hz, 1H), 7.31 – 7.26 (m, 1H), 7.17 (dd, J = 9.2, 2.8 Hz, 1H), 7.06 (d, J = 2.1 Hz, 1H), 6.68 – 6.60 (m, 1H), 5.48 (d, J = 12.8 Hz, 1H), 5.00 (d, J = 12.7 Hz, 1H), 2.12 - 2.03 (m, 1H), 1.00 – 0.91 (m, 2H), 0.71 – 0.60 (m, 2H). LCMS: m / z = 474.1 [M-H]-, (ESI-), RT = 4.22, Method AExample 103 – Synthesis of 13-(3,6-Dihydro-2H-pyran-4-yl)-4,19,21-trifluoro-14- hydroxy-16,16-dioxo-9-oxa-16λ6-thia-17-azatetracyclo[16.3.1.111,15.02,7]tricosa- 1(21),2,4,6,11(23),12,14,18(22),19-nonaen-10-one (Compound 103)

[0341] To a solution of intermediate 75 (80% purity, 174 mg, 0.262 mmol) in anhydrous pyridine (4 mL) was added lithium iodide (307 mg, 2.29 mmol). The reaction mixture was heated at 90 °C for 5 h. The mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC (Method P1) to afford the title compound as a white solid (77 mg, 99% purity, 56% Yield).1H NMR (500 MHz, DMSO) δ 10.03 (s, 2H), 7.69 (d, J = 2.3 Hz, 1H), 7.63 (dd, J = 8.6, 5.8 Hz, 1H), 7.60 – 7.53 (m, 1H), 7.35 – 7.27 (m, 1H), 7.18 (dd, J = 9.3, 2.8 Hz, 1H), 7.16 (d, J = 2.2 Hz, 1H), 6.71 – 6.65 (m, 1H), 5.98 (t, J = 2.1 Hz, 1H), 5.51 (d, J = 12.7 Hz, 1H), 5.02 (d, J = 12.7 Hz, 1H), 4.21 – 4.16 (m, 2H), 3.78 (t, J = 5.4 Hz, 2H), 2.40 – 2.34 (m, 2H). LCMS: m / z = 516.1 [M-H]-, (ESI-), RT = 4.04, Method AExample 104 – Synthesis of 4,19,21-Trifluoro-14-hydroxy-16,16-dioxo-13- tetrahydropyran-4-yl-9-oxa-16λ6-thia-17-azatetracyclo[16.3.1.111,15.02,7]tricosa- 1(21),2,4,6,11(23),12,14,18(22),19-nonaen-10-one (Compound 104)

[0342] A solution of Example 103 (60.0 mg, ...

Claims

CLAIMS WE CLAIM:

1. A compound of formula (I)or a stereoisomer and / or a pharmaceutically acceptable salt thereof, wherein: Ring A is phenyl or 9-membered bicyclic heteroaryl; Ring B is phenyl or 5-6 membered heteroaryl; Ring C is selected from the group consisting of phenyl, 9-membered bicyclic heterocyclyl, 9-membered bicyclic carbocyclyl, and 5-6 membered heteroaryl; R1is independently, for each occurrence, selected from the group consisting of halogen, hydroxyl, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, and 6-membered heterocyclyl; R2is independently, for each occurrence, selected from the group consisting of halogen, hydroxyl, cyano, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C1-6haloalkoxy, -O-C3-6cycloalkyl, and 4-6 membered heterocyclyl, wherein the 4-6 membered heterocyclyl is optionally substituted with one or more substituents independently selected from R2A; or optionally two R2may be taken together, along with the ring to which they are attached, to form a 9-membered bicyclic carbocyclyl, a 9-membered bicyclic heterocyclyl, or a 9-membered bicyclic heteroaryl; R3is independently, for each occurrence, selected from the group consisting of cyano, halogen, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, and -C(O)N(RA)(RB), wherein the C1-6alkyl is optionally substituted with one or more substituents independently selected from C1-6alkoxy; L1is *-S(O)2N(RC)-**, wherein * denotes the point of attachment to Ring A and ** denotes the point of attachment to Ring B;L2is selected from the group consisting of #-C(O)O-##, #-C(O)-(C1-6alkyl)-##, #- C(O)O-(C1-6alkyl)-##, #-C(O)O-(C1-6alkyl)-O-##, #-C(O)O-(C1-6haloalkyl)-##, and C1-6alkyl, wherein # denotes the point of attachment to Ring A and ## denotes the point of attachment to Ring C; R2Ais halogen or C1-6alkoxy; RAis hydrogen or C1-6alkyl; RBis hydrogen or C1-6alkyl; RCis hydrogen or C1-3alkyl; n is 2 or 3; o is 0, 1, or 2; and p is 0, 1, or 2.

2. The compound of claim 1, wherein Ring A is phenyl, indazolyl, or benzo[d]isoxazolyl.

3. The compound of claim 1 or 2, wherein Ring,, , wherein Δ denotes the point ofattachment to L1and ΔΔ denotes the point of attachment to L2.

4. The compound of any one of claims 1-3, wherein L1is *-S(O)2N(H)-**, wherein * denotes the point of attachment to Ring A and ** denotes the point of attachment to Ring B.

5. A compound of formula (Ia)or a stereoisomer and / or a pharmaceutically acceptable salt thereof, wherein: Ring B is phenyl or 5-6 membered heteroaryl; Ring C is selected from the group consisting of phenyl, 9-membered bicyclic heterocyclyl, 9-membered bicyclic carbocyclyl, and 5-6 membered heteroaryl; R1is independently, for each occurrence, selected from the group consisting of halogen, hydroxyl, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, and 6-membered heterocyclyl; R2is independently, for each occurrence, selected from the group consisting of halogen, hydroxyl, cyano, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C1-6haloalkoxy, -O-C3-6cycloalkyl, and 4-6 membered heterocyclyl, wherein the 4-6 membered heterocyclyl is optionally substituted with one or more substituents independently selected from R2A; or optionally two R2may be taken together, along with the ring to which they are attached, to form a 9-membered bicyclic carbocyclyl, a 9-membered bicyclic heterocyclyl, or a 9-membered bicyclic heteroaryl; R3is independently, for each occurrence, selected from the group consisting of cyano, halogen, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, and -C(O)N(RA)(RB), wherein the C1-6alkyl is optionally substituted with one or more substituents independently selected from C1-6alkoxy; L2is selected from the group consisting of #-C(O)O-##, #-C(O)-(C1-6alkyl)-##, #- C(O)O-(C1-6alkyl)-##, #-C(O)O-(C1-6alkyl)-O-##, #-C(O)O-(C1-6haloalkyl)-##, and C1-6alkyl, wherein # denotes the point of attachment to Ring A and ## denotes the point of attachment to Ring C;R2Ais halogen or C1-6alkoxy; RAis hydrogen or C1-6alkyl; RBis hydrogen or C1-6alkyl; n is 2 or 3; o is 1 or 2; and p is 0, 1, or 2.

6. The compound of any one of claims 1-5, wherein n is 2.

7. The compound of any one of claims 1-5, wherein n is 3.

8. The compound of any one of claims 1-7, wherein R1is, independently, for each occurrence, selected from the group consisting of bromo, chloro, fluoro, hydroxyl, -CH3, -or a stereoisomer and / or a pharmaceutically acceptable salt thereof, wherein: Ring B is phenyl or 5-6 membered heteroaryl;Ring C is phenyl, 9-membered bicyclic heterocyclyl, 9-membered bicyclic carbocyclyl, C3-6cycloalkyl, or 5-6 membered heteroaryl; R2is independently, for each occurrence, selected from the group consisting of halogen, hydroxyl, cyano, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C1-6haloalkoxy, -O-C3-6cycloalkyl, and 4-6 membered heterocyclyl, wherein the 4-6 membered heterocyclyl is optionally substituted with one or more substituents independently selected from R2A; or optionally two R2may be taken together, along with the ring to which they are attached, to form a 9-membered bicyclic carbocyclyl, a 9-membered bicyclic heterocyclyl, or a 9-membered bicyclic heteroaryl; R3is independently, for each occurrence, selected from the group consisting of cyano, halogen, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, and -C(O)N(RA)(RB), wherein the C1-6alkyl is optionally substituted with one or more substituents independently selected from C1-6alkoxy; R4is selected from the group consisting of halogen, C1-6haloalkyl, C3-6cycloalkyl, and 6-membered heterocyclyl; R5is hydrogen or halogen; L2is selected from the group consisting of #-C(O)O-##, #-C(O)-(C1-6alkyl)-##, #- C(O)O-(C1-6alkyl)-##, #-C(O)O-(C1-6alkyl)-O-##, #-C(O)O-(C1-6haloalkyl)-##, and C1-6alkyl, wherein # denotes the point of attachment to Ring A and ## denotes the point of attachment to Ring C; R2Ais halogen or C1-6alkoxy; RAis hydrogen or C1-6alkyl; RBis hydrogen or C1-6alkyl; o is 1 or 2; and p is 0, 1, or 2.

10. The compound of any one of claims 1-9, wherein Ring B is phenyl, thiophenyl, or pyridinyl.1 The compound of any one of claims 1-10, wherein Ring B is selected from the group consistingwherein ● denotes the point of attachment to L1and ●● denotes the point of attachment to Ring C.

12. The compound of any one of claims 1-11, wherein o is 1.

13. The compound of any one of claims 1-11, wherein o is 2.

14. The compound of any one of claims 1-13, wherein R2is, independently, for each occurrence, selected from the group consisting of chloro, fluoro, cyano, hydroxyl, -CH3, - CF3, -O-CH3, -O-CH2CH3, -O-CHF2, -O-CF3, cyclopropyl, -O-cyclopropyl, morpholinyl, and, optionally substituted with one or more substituents independently selected from fluoro and -O-CH3.

15. The compound of any one of claims 1-14, wherein R2is, independently, for each occurrence, selected from the group consisting of chloro, fluoro, cyano, hydroxyl, -CH3, -CF3, -O-CH3, -O-CH2CH3, -O-CHF2, -O-CF3, cyclopropyl, -O-cyclopropyl, morpholinyl,16. The compound of any one of claims 1-11 and 13, wherein two R2groups on different carbon atoms are taken together, along with the atoms to which they are attached, to form a 5 membered carbocyclyl, a 5-membered heterocyclyl, or a 5-membered heteroaryl.

17. The compound of any one of claims 1-11, wherein o is 0.

18. A compound of formula (Ic)or a stereoisomer and / or a pharmaceutically acceptable salt thereof, wherein: Ring C is selected from the group consisting of phenyl, 9-membered bicyclic heterocyclyl, 9-membered bicyclic carbocyclyl, and 5-6 membered heteroaryl; R3is independently, for each occurrence, selected from the group consisting of cyano, halogen, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, and -C(O)N(RA)(RB), wherein the C1-6alkyl is optionally substituted with one or more substituents independently selected from C1-6alkoxy;R4is selected from the group consisting of halogen, C1-6haloalkyl, C3-6cycloalkyl, and 6-membered heterocyclyl; R5is hydrogen or halogen; X1is CR6or N; X2 is CR7or N; X3is CR8or N; R6is selected from the group consisting of hydrogen, cyano, halogen, hydroxyl, C1-6alkoxy, C1-6haloalkyl, C1-6haloalkoxy, C3-6cycloalkyl, and 4-6 membered heterocyclyl, wherein the 4-6 membered heterocyclyl is optionally substituted with one or more substituents independently selected from halogen; R7is selected from the group consisting of hydrogen, cyano, halogen, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -O-C3-6cycloalkyl, and 4-6 membered heterocyclyl, wherein the 4- 6 membered heterocyclyl is optionally substituted with C1-6alkoxy; or R6and R7may be taken together, along with the ring to which they are attached, to form a 9-membered bicyclic heteroaryl or a 9-membered bicyclic heterocyclyl; R8is hydrogen or halogen; or R7and R8may be taken together, along with the ring to which they are attached, to form a 9-membered bicyclic carbocyclyl; L2is selected from the group consisting of #-C(O)O-##, #-C(O)-(C1-6alkyl)-##, #- C(O)O-(C1-6alkyl)-##, #-C(O)O-(C1-6alkyl)-O-##, #-C(O)O-(C1-6haloalkyl)-##, and C1-6alkyl, wherein # denotes the point of attachment to Ring A and ## denotes the point of attachment to Ring C; RAis hydrogen or C1-6alkyl; RBis hydrogen or C1-6alkyl; and p is 0, 1, or 2.

19. The compound of any one of claims 1-18, wherein Ring C is selected from the group consisting of cyclopropyl, phenyl, pyridinyl, thiazolyl, pyrimidinyl, pyrazolyl, isoxazolyl,20. The compound of any one of claims 1-19, wherein Ring C is selected from the group, denotes the point of attachment to L2.

21. The compound of any one of claims 1-20, wherein p is 1.

22. The compound of any one of claims 1-20, wherein p is 2.

23. The compound of any one of claims 1-22, wherein R3is, independently, for each occurrence, selected from the group consisting of cyano, bromo, fluoro, -CH3, -CHF2, -CF3, - O-CH3, -O-CHF2, -CH2CH2-O-CH3, -C(O)NH2, and -CH2CHF2.

24. The compound of any one of claims 1-20, wherein p is 0.

25. A compound of formula (Id)or a stereoisomer and / or a pharmaceutically acceptable salt thereof, wherein: R4is selected from the group consisting of halogen, C1-6haloalkyl, C3-6cycloalkyl, and 6-membered heterocyclyl; R5is hydrogen or halogen; X1 is CR6or N; X2is CR7or N; X3 is CR8or N; X4is CH or N; X5 is CR9or N; X6is CR10or N; X7 is CR11or N; R6is selected from the group consisting of hydrogen, cyano, halogen, hydroxyl, C1-6alkoxy, C1-6haloalkyl, C1-6haloalkoxy, C3-6cycloalkyl, and 4-6 membered heterocyclyl, wherein the 4-6 membered heterocyclyl is optionally substituted with one or more substituents independently selected from halogen; R7is selected from the group consisting of hydrogen, cyano, halogen, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -O-C3-6cycloalkyl, and 4-6 membered heterocyclyl, wherein the 4- 6 membered heterocyclyl is optionally substituted with C1-6alkoxy; or R6and R7may be taken together, along with the ring to which they are attached, to form a 9-membered bicyclic heteroaryl or a 9-membered bicyclic heterocyclyl; R8is hydrogen or halogen; or R7and R8may be taken together, along with the ring to which they are attached, to form a 9-membered bicyclic carbocyclyl;R9is selected from the group consisting of hydrogen, cyano, halogen, C1-6haloalkyl, - C(O)N(RA)(RB), and C1-6alkoxy; R10is selected from the group consisting of hydrogen, halogen, C1-6haloalkyl, C1-6haloalkoxy, and C1-6alkoxy; R11is hydrogen, halogen, or C1-6alkyl; and L2is selected from the group consisting of #-C(O)O-##, #-C(O)-(C1-6alkyl)-##, #- C(O)O-(C1-6alkyl)-##, #-C(O)O-(C1-6alkyl)-O-##, #-C(O)O-(C1-6haloalkyl)-##, and C1-6alkyl, wherein # denotes the point of attachment to Ring A and ## denotes the point of attachment to Ring C; RAis hydrogen or C1-6alkyl; and RBis hydrogen or C1-6alkyl.

26. The compound of any one of claims 1-25, wherein L2is selected from the group consisting of #-C(O)O-##, #-C(O)O-CH2-##, #-C(O)O-C(CH3)(H)-##, #-C(O)O- C(CH2F)(H)-##, #-C(O)O-(CH2)2-##, #-C(O)O-(CH2)2-O-##, -(CH2)2-, -(CH2)3-, and #-C(O)- (CH2)3-##, wherein # denotes the point of attachment to Ring A and ## denotes the point of attachment to Ring C.

27. A compound of formula (Ie)or a stereoisomer and / or a pharmaceutically acceptable salt thereof, wherein: R4is selected from the group consisting of halogen, C1-6haloalkyl, C3-6cycloalkyl, and 6-membered heterocyclyl;R5is hydrogen or halogen; X1is CR6or N; X2 is CR7or N; X3is CR8or N; X4 is CH or N; X5is CR9or N; X6 is CR10or N; X7is CR11or N; R6is selected from the group consisting of hydrogen, cyano, halogen, hydroxyl, C1-6alkoxy, C1-6haloalkyl, C1-6haloalkoxy, C3-6cycloalkyl, and 4-6 membered heterocyclyl, wherein the 4-6 membered heterocyclyl is optionally substituted with one or more substituents independently selected from halogen; R7is selected from the group consisting of hydrogen, cyano, halogen, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -O-C3-6cycloalkyl, and 4-6 membered heterocyclyl, wherein the 4- 6 membered heterocyclyl is optionally substituted with C1-6alkoxy; or R6and R7may be taken together, along with the ring to which they are attached, to form a 9-membered bicyclic heteroaryl or a 9-membered bicyclic heterocyclyl; R8is hydrogen or halogen; or R7and R8may be taken together, along with the ring to which they are attached, to form a 9-membered bicyclic carbocyclyl; R9is selected from the group consisting of hydrogen, cyano, halogen, C1-6haloalkyl, - C(O)N(RA)(RB), and C1-6alkoxy; R10is selected from the group consisting of hydrogen, halogen, C1-6haloalkyl, C1-6haloalkoxy, and C1-6alkoxy; R11is hydrogen, halogen, or C1-6alkyl; RAis hydrogen or C1-6alkyl; and RBis hydrogen or C1-6alkyl.

28. The compound of any one of claims 9-27, wherein R4is selected from the group29. The compound of any one of claims 9-28, wherein R5is hydrogen or fluoro.

30. The compound of any one of claims 18-29, wherein X1is CR6, X2is CR7, and X3is CR8.

31. The compound of any one of claims 18-29, wherein X1 is CR6, X2 is N, and X3 is CR8.

32. The compound of any one of claims 18-29, wherein X1is N, X2is CR7, and X3is CR8.

33. The compound of any one of claims 18-31, wherein R6is selected from the group consisting of hydrogen, cyano, chloro, fluoro, -CF3, -O-CH3, -O-CH2-CH3, -O-CHF2, -O-CF3, cyclopropyl, an .

34. The compound of any one of claims 18-30 and 32, wherein R7is selected from the group consisting of hydrogen, cyano, chloro, fluoro, -CH3, -CF3, cyclopropyl, -O- cyclopropyl, morpholinyl,35. The compound of any one of claims 18-34, wherein R8is hydrogen or fluoro.

36. The compound of any one of claims 18-30, wherein R6and R7are taken together, along with the atoms to which they are attached, to form a 5 membered heteroaryl or a 5 membered heterocyclyl.

37. The compound of any one of claims 18-30, wherein R7and R8may be taken together, along with the atoms to which they are attached, to form a 5-6 membered carbocyclyl.

38. The compound of any one of claims 25-37, wherein X4 is CH, X5 is CR9, X6 is CR10, and X7 is CR11.

39. The compound of any one of claims 25-37, wherein X4 is CH, X5 is N, X6 is CR10, and X7is CR11.

40. The compound of any one of claims 25-37, wherein X4is CH, X5is CR9, X6is N, and X7 is CR11.

41. The compound of any one of claims 25-37, wherein X4 is CH, X5 is CR9, X6 is CR10, and X7is N.

42. The compound of any one of claims 25-37, wherein X4is N, X5is CR9, X6is N, and X7 is CR11.

43. The compound of any one of claims 25-38 and 40-42, wherein R9is selected from the group consisting of hydrogen, cyano, bromo, fluoro, -CF3, -O-CH3, and -C(O)NH2.

44. The compound of any one of claims 25-39 and 41, wherein R10is selected from the group consisting of hydrogen, fluoro, -CHF2, -CF3, -O-CH3, and -O-CHF2.

45. The compound of any one of claims 25-40 and 42, wherein R11is hydrogen, fluoro, or CH3.

46. The compound of any one of claims 1-42, wherein the compound of formula (I) is not a compound selected from the group consisting of: ,,,, , ,, thereof.

47. A compound selected from any compound set forth in Table 1, or a pharmaceutically acceptable salt thereof.

48. A pharmaceutical composition comprising a compound of any one of claims 1-47; and a pharmaceutically acceptable carrier.

49. A method of inhibiting ACLY in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-47 or a pharmaceutical composition of claim 48.

50. The method of claim 49, wherein the subject has a liver condition, disease, or disorder.

51. The method of claim 49, wherein the liver condition, disease, or disorder is NAFLD / MAFLD or NASH / MASH.

52. The method of claim 49, wherein the subject has type-2 diabetes.

53. The method of claim 49, wherein the subject has inflammation.

54. The method of claim 49, wherein the subject has chronic kidney disease.

55. The method of claim 49, wherein the subject has autoimmunity.

56. The method of claim 49, wherein the subject has cancer.

57. A method of treating NAFLD / MAFLD in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-47 or a pharmaceutical composition of claim 48.

58. A method of treating NASH / MASH in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-47 or a pharmaceutical composition of claim 48.

59. A method of treating type-2 diabetes in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-47 or a pharmaceutical composition of claim 48.

60. A method of treating inflammation in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-47 or a pharmaceutical composition of claim 48.

61. A method of treating chronic kidney disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-47 or a pharmaceutical composition of claim 48.

62. A method of treating autoimmunity in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-47 or a pharmaceutical composition of claim 48.

63. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-47 or a pharmaceutical composition of claim 48.

64. A method of treating a condition, disease, or disorder as described herein in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-47 or of the pharmaceutical composition of claim 48.

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