Macrocyclic inhibitors of ATP citrate lyase

Abstract

The present disclosure provides a compound of formula (I) or a stereoisomer and / or a pharma- ceutically acceptable salt thereof, a pharmaceutical composition comprising the compound, and a method of using the compound to treat conditions, diseases, and disorders associated with abnormalities in lipid levels, wherein each symbol is defined as described in the specification. TIFF2025515002000290.tif6295 [Drawing] None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to and the benefit of U.S. Provisional Patent Application No. 63 / 337,344, filed May 2, 2022, and U.S. Provisional Patent Application No. 63 / 481,045, filed January 23, 2023, the contents of each of which are incorporated herein by reference in their entirety. [Background technology]

[0002] Human genetic factors, overnutrition, and a sedentary lifestyle combine to promote abnormalities in cholesterol and triglyceride metabolism, which may manifest as one or more risk factors associated with an increased susceptibility to a number of life-threatening metabolic and cardiovascular diseases. The importance of maintaining cholesterol homeostasis in humans is strongly supported by both epidemiological cohort studies and meta-analyses of multiple Mendelian and randomized statin trials, which clearly demonstrate an association between elevated plasma low-density lipoprotein cholesterol (LDL-C) levels (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] Although the relationship 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), abnormalities in triglyceride metabolism also appear as other metabolic risk factors for ASCVD, 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). Furthermore, NAFLD is one of the most common causes of chronic liver disease and hepatocellular carcinoma, and is the leading cause of liver-related morbidity and mortality in Western countries, making it an independent health challenge (Loomba and Sanyal, (2013), The global NAFLD epidemic., Nat. Rev. Gastroenterol. Hepatol., 10, 686-690). Summary of the Invention [Problem to be solved by the invention]

[0004] Neither ASCVD nor NAFLD is adequately addressed by currently available therapies. Many subjects do not receive effective treatment for dyslipidemia with current standard therapies, and ASCVD remains a leading cause of death and disability in Western countries (Mendis, (2010), The contribution of the Framingham Heart Study to the prevention of cardiovascular disease: a global perspective., Prog. Cardiovasc. Dis., 53, 10-14). Therefore, new therapeutic strategies targeting cholesterol and triglyceride metabolism are needed. ATP-citrate lyase (ACLY) is a unique enzyme located at the crossroads of nutrient catabolism and cholesterol and fatty acid biosynthesis, and this metabolic link has been shown to be dysregulated in multiple disease states. Significant evidence supports that ACLY-derived acetyl-coenzyme A (CoA) functions not only as a carbon precursor for cholesterol and fatty acid biosynthesis but also as a critical metabolic checkpoint used by multiple cell types to sense nutrient availability and coordinate metabolic adaptations 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. [Means for solving the problem]

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

[0006] In one aspect, provided herein are compounds of formula (I) or stereoisomers and / or pharmaceutically acceptable salts thereof, wherein the variables are as defined herein. TIFF2025515002000291.tif5285

[0007] In another aspect, provided herein are compounds of Formula (Ia) or stereoisomers and / or pharmaceutically acceptable salts thereof, wherein the variables are as defined herein. TIFF2025515002000292.tif4873

[0008] In certain embodiments, the compound of Formula (I) or Formula (Ia) is selected from the compounds of Table 1 or a stereoisomer and / or pharmaceutically acceptable salt thereof.

[0009] In another aspect, provided herein are pharmaceutical compositions comprising a compound disclosed herein or a stereoisomer and / or pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers.

[0010] The compound of Formula (I) or its stereoisomer and / or pharmaceutically acceptable salt, or pharmaceutical composition of the present invention can be used to treat various conditions, diseases, and disorders described herein. For example, the treatment method 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 or NASH, and the method includes treating the liver condition, disease, or disorder, such as NAFLD or NASH. In some embodiments, the condition, disease, or disorder can be type 2 diabetes, and the method includes treating type 2 diabetes. In some embodiments, the condition, disease, or disorder can be inflammation, and the method includes treating inflammation. In some embodiments, the condition, disease, or disorder can be chronic kidney disease, and the method includes treating chronic kidney disease. In some embodiments, the condition, disease, or disorder is autoimmune, and the method includes treating autoimmunity. In some embodiments, the condition, disease, or disorder is cancer, and the method includes treating cancer. DETAILED DESCRIPTION OF THE INVENTION

[0011] As generally described herein, the present disclosure provides compounds of Formula (I), such as compounds of Formula (Ia), Formula (Ib), or Formula (II), or stereoisomers and / or pharmaceutically acceptable salts thereof, as well as pharmaceutical compositions comprising the same. The compounds and compositions described herein function as modulators (e.g., inhibitors) of ACLY. The present disclosure also provides methods of using the compounds and compositions disclosed herein to treat various conditions, diseases, and disorders associated with metabolic disorders. Such conditions, diseases, and disorders include, but are not limited to, NAFLD, NASH, type 2 diabetes, chronic kidney disease, inflammation, autoimmunity, and cancer.

[0012] definition To facilitate the understanding of this invention, a number of terms and phrases are defined below.

[0013] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this invention belongs. Abbreviations used herein have their conventional meanings in the chemical and biological arts. The chemical structures and formulas described herein are constructed according to the standard rules of chemical valency known in the chemical arts.

[0014] Throughout this specification, when compositions and kits are described as having, comprising or consisting of particular components, or when processes and methods are described as having, comprising or consisting of particular steps, it is further contemplated that there are compositions and kits of the invention that consist essentially of, or consist of, the recited components, and that there are processes and methods of the invention that consist essentially of, or consist of, the recited processing steps.

[0015] In this application, when an element or component is said to be included in and / or selected from a list of recited elements or components, it is to be understood that the element or component can be any one of the recited elements or components, or that the element or component can be selected from a group consisting of two or more of the recited elements or components.

[0016] Furthermore, it should be understood that the elements and / or features of the compositions or methods described herein, whether expressly or implicitly stated herein, can be combined in various ways without departing from the spirit and scope of the invention. For example, when a particular compound is referred to, that compound can be used in various embodiments of the compositions of the invention and / or in the methods of the invention, unless otherwise understood from the context. In other words, within this application, although embodiments have been described and depicted in a manner that allows for a clear and concise application to be written and drawn, it is intended and understood that the embodiments can be combined or separated in various ways without departing from the present teachings and invention(s). For example, it will be understood that all features described and depicted herein are applicable to all aspects of the invention described and depicted herein.

[0017] The articles "a" and "an" are used in this disclosure to refer to one or to more than one (i.e., 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 analog" means one analog or more than one analog.

[0018] In this disclosure, the term "and / or" means either "and" or "or," unless otherwise indicated.

[0019] The phrase "at least one," unless otherwise understood from context and usage, should be understood to include each subsequent recited subject matter individually and various combinations of two or more recited subjects. Also, the phrase "and / or" in the context of more than two recited subjects should be understood to have the same meaning unless otherwise understood from context.

[0020] Use of the terms "include," "includes," "including," "have," "has," "having," "contain," "contains," or "containing" should generally be understood as open-ended and open-ended, including grammatical equivalents thereof, and not excluding, for example, additional, unrecited elements or steps, unless otherwise stated or understood from context.

[0021] When the term "about" is used before a quantitative value, the present invention also includes the specific quantitative value itself unless otherwise specified. As used herein, the term "about" refers to a variation of ±10%, ±5%, ±3%, ±2%, or ±1% from the nominal value, unless otherwise indicated or inferred from the context.

[0022] For example, when the molecular weight of a polymer is given, it is to be understood that the molecular weight is an average molecular weight, not an absolute value, unless otherwise stated or understood from the context.

[0023] It should be understood that the order of steps or order for performing certain actions is immaterial so long as the invention remains operable. Moreover, two or more steps or actions may be conducted simultaneously.

[0024] At various places in the specification, variables or parameters are disclosed in groups or ranges. It is specifically intended herein to include each individual subcombination of the members of such groups or ranges. For example, "C 1-6 "Alkyl" refers to C1, C2, C3, C4, C5, C6, C 1-6 , C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-5 , C 2-4 , C 2-3 , C 3-6 , C 3-5 , C 3-4 , C 4-6 , C 4-5 and C5-6 As another example, integers in the range of 0 to 40 are 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 integers in the range of 1 to 20 are 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 to 5 substituents" is specifically intended to individually disclose chemical groups 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.

[0025] Any examples or use of exemplary language herein, such as "such as" or "including," are intended merely to better describe the invention and do not limit 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 invention.

[0026] Chemical term definitions Definitions of certain functional groups and chemical terms are detailed below. Chemical elements are identified according to the Periodic Table of the Elements, CAS edition, Handbook of Chemistry and Physics, 75th Ed., inside cover, and certain functional groups are generally defined as set forth therein. Additionally, general principles of organic chemistry, as well as specific functional groups and reactivities, can be found in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5th ed., John Wiley & Sons, New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3rd ed., Cambridge University Press, 1999. Press, Cambridge, 1987.

[0027] The compounds of the present disclosure may contain one or more chiral centers and / or double bonds and therefore may exist as stereoisomers, such as geometric isomers, enantiomers, or diastereomers. As used herein, the term "stereoisomer" consists of all geometric isomers, enantiomers, and / or diastereomers of a compound. For example, if a compound is depicted with a particular chiral center(s), compounds depicted without such chirality at that and other chiral centers of the compound are within the scope of the present disclosure, i.e., compounds depicted in two dimensions with "flat" or "straight" bonds, rather than in three dimensions with, for example, solid or dashed wedge bonds.

[0028] More specifically, the compounds described herein (e.g., compounds of Formula (I), Formula (Ia), Formula (Ib), or Formula (II)) may contain one or more asymmetric centers and, therefore, may exist in various isomeric forms, e.g., enantiomers and / or diastereomers. For example, the compounds described herein may be in the form of individual enantiomers, diastereomers, or geometric isomers, or may be in the form of mixtures of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. 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 synthesis. 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 (EL Eliel, Ed., University of Notre Dame Press, Notre Dame, IN 1972). The present disclosure further encompasses the compounds described herein as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

[0029] As used herein, a pure enantiomer compound is substantially free from other enantiomers or stereoisomers of the compound (i.e., in enantiomeric excess). In other words, the "S" form of a 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" means that the compound is 75% by weight or more, 80% by weight or more, 85% by weight or more, 90% by weight or more, 91% by weight or more, 92% by weight or more, 93% by weight or more, 94% by weight or more, 95% by weight or more, 96% by weight or more, 97% by weight or more, 98% by weight or more, 98.5% by weight or more, 99% by weight or more, 99.2% by weight or more, 99.5% by weight or more, 99.6% by weight or more, 99.7% by weight or more, 99.8% by weight or more, or 99.9% by weight or more of an enantiomer. In certain embodiments, the weight is based on the total weight of all enantiomers or stereoisomers of the compound.

[0030] Geometric isomers resulting from the arrangement of substituents around a carbon-carbon double bond or the arrangement of substituents around a cycloalkyl or heterocycloalkyl may also exist in the compounds of the present disclosure. Symbols represent bonds that can be single, double, or triple bonds as described herein. Substituents around a carbon-carbon double bond are designated as being in the "Z" or "E" configuration, where the terms "Z" and "E" are used according to IUPAC standards. Unless otherwise specified, structures depicting double bonds encompass both "E" and "Z" isomers.

[0031] Substituents around a carbon-carbon double bond can be designated "cis" or "trans," with "cis" referring to substituents on the same side of the double bond and "trans" referring to substituents on opposite sides of the double bond. The arrangement of substituents around a carbocyclic ring can also be designated "cis" or "trans." The term "cis" refers to substituents on the same side of the plane of the ring and the term "trans" refers to substituents on opposite sides of the plane of the ring. A mixture of compounds in which substituents are located on both the same and opposite sides of the plane of the ring is called "cis / trans."

[0032] The compounds described herein may contain one or more isotopic substitutions. For example, H is: 1 H, 2 H (D or deuterium) and 3 It may be in any isotopic form, including H (T or tritium), and C is 12 C. 13 C and 14 C may be in any isotopic form, including O 16 O and 18 F may be in any isotopic form, including O, 18 F and 19 Any isotopic form may be used, including F. Other examples of isotopes that may be incorporated into the compounds described herein include isotopes of nitrogen, phosphorus, and chlorine, such as isotopes of nitrogen, phosphorus, and chlorine, respectively. 15 N, 31 P, 32 P, 35 S and 36 Cl. As examples of isotopic compounds, the compounds described herein may have one or more H atoms replaced with deuterium.

[0033] The terms described herein are intended to have the meanings provided and may be useful in understanding the description and intended scope of the present disclosure. When describing the present disclosure, which may include the compounds disclosed herein or their stereoisomers and / or pharmaceutically acceptable salts, pharmaceutical compositions containing such compounds, and methods of using such compounds and compositions, defined terms, if present, have their ascribed meanings unless otherwise indicated.

[0034] Unless otherwise indicated, the term "substituted" is defined as provided herein. It is further understood that as used herein, the terms "group" and "radical" are considered interchangeable.

[0035] As used herein, "alkyl" refers to a linear or branched saturated hydrocarbon group having, for example, 1 to 20 carbon atoms ("C 1-20"C-C alkyl" refers to a radical of a straight-chain or branched hydrocarbon containing 1-6 carbon atoms, for example, 1-4 carbon atoms, or 1-3 carbon atoms, referred to herein as C-C alkyl, C-C alkyl, and C-C alkyl, respectively. For example, "C-C alkyl" refers to a straight-chain or branched saturated hydrocarbon containing 1-6 carbon atoms. Examples of C-C alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, and the like. In another example, "C-C alkyl" refers to a straight-chain or branched saturated hydrocarbon containing 1-4 carbon atoms. Examples of C-C alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, isopropyl, isobutyl, sec-butyl, and tert-butyl. Exemplary alkyl groups include 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.

[0036] As used herein, carbocyclyl or carbocyclic refers to a ring having 3 to 10 ring carbon atoms ("C 3-10 In some embodiments, a carbocyclyl group refers to a radical of a non-aromatic cyclic hydrocarbon group having 3 to 8 ring carbon atoms ("C 3-8 carbocyclyl"), 3 to 7 ring carbon atoms ("C 3-7 carbocyclyl"), 3 to 6 ring carbon atoms ("C 3-6 carbocyclyl") or 5 to 10 ring carbon atoms ("C 5-10carbocyclyl). 3-6 Carbocyclyl groups include, but are not limited to, cyclopropyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. 3-8 The carbocyclyl group includes, but is not limited to, the above-mentioned C 3-6 Included are carbocyclyl 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 C 3-10 The carbocyclyl group includes, but is not limited to, the above-mentioned C 3-8 In addition to carbocyclyl groups, cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C 10 ), spiro[4.5]decanyl (C 10 As the foregoing examples illustrate, in certain embodiments, carbocyclyl groups are monocyclic ("monocyclic carbocyclyl") or contain fused, bridged, or spiro ring systems such as bicyclic ("bicyclic carbocyclyl"), and can be saturated or partially unsaturated.

[0037] As used herein, "cycloalkyl" refers to a monovalent saturated cyclic, bicyclic, or bridged (e.g., adamantyl) hydrocarbon group having 3 to 12, 3 to 8, 3 to 6, 4 to 8, or 4 to 6 carbon atoms, and is used herein, for example, to refer to "C 3-6"cycloalkyl" is derived from cycloalkane. Exemplary cycloalkyl groups include, but are not limited to, cyclohexanes such as cyclohexyl and cyclohexenyl, cyclopentanes such as cyclopentyl and cyclopentenyl, cyclobutanes such as cyclobutyl, and cyclopropanes such as cyclopropyl.

[0038] As used herein, "heteroatom" refers to an atom of an element other than carbon or hydrogen, and includes, for example, nitrogen (N), oxygen (O), silicon (Si), sulfur (S), phosphorus (P), and selenium (Se).

[0039] As used herein, "heterocyclyl" or "heterocyclic" refers to a radical of a 3- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("3- to 10-membered heterocyclyl"). In some embodiments, the heterocyclyl is 5 to 10-membered ("5- to 10-membered heterocyclyl"). In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment can be at a carbon atom or a nitrogen atom, where valence permits. Heterocyclyl groups can be monocyclic ("monocyclic heterocyclyl") or fused, bridged, or spiro ring systems, such as bicyclic ("bicyclic heterocyclyl"), and can be saturated or partially unsaturated. Heterocyclyl bicyclic ring systems can contain one or more heteroatoms in one or both rings. "Heterocyclyl" also includes ring systems in which a heterocyclyl ring, as defined above, is fused to one or more carbocyclyl groups, where the point of attachment is on either the carbocyclyl ring or the heterocyclyl ring, or in which a heterocyclyl ring, as defined above, is fused to one or more aryl or heteroaryl groups, where the heterocyclyl ring is fused to one or more aryl or heteroaryl groups, as defined above, where the point of attachment is on the heterocyclyl ring, in such cases the number of ring members indicates 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.

[0040] As used herein, "heteroaryl" refers to the radical of a 5- to 14-membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 electrons shared in the cyclic arrangement) having ring carbon atoms and 1 to 4 ring heteroatoms as indicated in the aromatic ring system ("5- to 10-membered heteroaryl"). In certain embodiments, each heteroatom is independently selected from nitrogen, oxygen, and sulfur. In heteroaryl groups containing one or more nitrogen atoms, the point of attachment can be a carbon atom or a nitrogen atom, valence permitting. Heteroaryl bicyclic ring systems can contain one or more heteroatoms in one or both rings. "Heteroaryl" also includes ring systems in which a heteroaryl ring, as defined above, is fused with one or more aryl groups, in which case the point of attachment is on either the aryl ring or the heteroaryl ring, and in such cases the number of ring members refers to the number of ring members in the fused (aryl / heteroaryl) ring system. In bicyclic heteroaryl groups in which one ring does not contain heteroatoms (e.g., indolyl, quinolinyl, carbazolyl, etc.), the point of attachment can be at either ring, i.e., the ring containing the heteroatom (e.g., 2-indolyl) or the ring without the heteroatom (e.g., 5-indolyl). Other non-limiting examples of heteroaryl groups include pyridyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, and isoquinolinyl.

[0041] As used herein, "=hetero" can be used to refer to a compound or group present on a compound in which one or more carbon atoms have been replaced with a heteroatom. Hetero can apply to any of the above hydrocarbyl groups, such as alkyl (e.g., heteroalkyl), carbocyclyl (e.g., heterocyclyl), and aryl (e.g., heteroaryl), having 1 to 5, especially 1 to 3, heteroatoms.

[0042] As used herein, "carbonyl" refers to the radical -C(O)- or C=O.

[0043] As used herein, "cyano" refers to --CN.

[0044] As used herein, "hydroxy" and "hydroxyl" refer to the radical --OH.

[0045] As used herein, "oxo" refers to the radical =O (double-bonded oxygen).

[0046] 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, a halo group is either fluoro or chloro.

[0047] As used herein, "alkoxy" refers to an alkyl group that is attached to another moiety via an oxygen atom (-O(alkyl)). Alkoxy groups can have 1 to 6 or 2 to 6 carbon atoms and are referred to herein as C1-C6 alkoxy and C2C6 alkoxy, respectively. Exemplary alkoxy groups include, but are not limited to, methoxy, ethoxy, propyloxy, isopropoxy, and tert-butoxy.

[0048] As used herein, "haloalkyl" refers to mono-, poly-, and perhaloalkyl groups substituted with one or more halogen atoms, where the halogens are independently selected from fluorine, chlorine, bromine, and iodine. In some embodiments, haloalkyl has 1 to 6 carbon atoms ("C 1-6 haloalkyl").

[0049] As used herein, "haloalkoxy" refers to a haloalkyl group that is attached to another moiety through an oxygen atom, such as, but not limited to, -OCHCF2 or -OCF3. In some embodiments, the haloalkoxy has 1 to 6 carbon atoms ("C 1-6 haloalkoxy").

[0050] As generally used herein, "substituted," whether preceded by the term "optionally" or not, means that at least one hydrogen atom present on a group (e.g., a carbon atom or nitrogen atom) is replaced with an acceptable substituent, e.g., a substituent that, upon substitution, results in a stable compound, e.g., a compound that does not spontaneously undergo transformation, such as by rearrangement, cyclization, elimination, or other reaction. Unless otherwise specified, a "substituted" group has a substituent at one or more substitutable positions of the group, and when more than one position in any structure is substituted, the substituents are either the same or different at each position.

[0051] Nitrogen atoms can be substituted or unsubstituted, where valence allows, and include primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents include hydrogen, -OH, -OR aa , -N(R cc )2, -CN, -C(=O)R aa , -C(=O)N(R cc )2, -CO2R aa , -SO2R aa , -C(=NR bb )R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , -P(=O)2R aa , -P(=O)(R aa )2, -P(=O)2N(R cc )2, -P(=O)(NR cc )2, C 1-10 Alkyl, C 1-10 Perhaloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10Carbocyclyl, 3- to 14-membered heterocyclyl, C 6-14 Aryl and 5- to 14-membered heteroaryl, or two R attached to a nitrogen atom cc groups join to form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd is substituted with an R aa , R bb , R cc and R dd is as defined above.

[0052] These and other exemplary substituents are described in more detail in the Detailed Description, Examples, and Claims. The present invention is not intended to be limited in any way by the above list of exemplary substituents.

[0053] As used herein, "compound," unless understood from the context of this specification or expressly limited to one particular form of the compound, i.e., the compound itself, a particular stereoisomer and / or isotopically labeled compound, or a pharmaceutically acceptable salt, hydrate, ester, or N-oxide thereof, refers to the compound itself and its pharmaceutically acceptable salts, hydrates, esters, and N-oxides, including various stereoisomers and isotopically labeled forms thereof. It should be understood that a compound can refer to a pharmaceutically acceptable salt, or hydrate, ester, or N-oxide of a stereoisomer of the compound and / or isotopically labeled compound.

[0054] Further, if a variable is not provided with a definition, the variable will be defined as found elsewhere in this disclosure unless understood differently from the context. Additionally, each variable and / or substituent, e.g., C1-C6 alkyl, R 2 , R b , w, etc., when it occurs more than once in any structure or compound, may be independent of its definition elsewhere in the same structure or compound.

[0055] The definitions of variables and / or substituents in formulas and / or compounds herein encompass multiple chemical groups. The present disclosure includes embodiments in which, for example, i) the definition of a variable and / or substituent is a single chemical group selected from the chemical groups defined herein, ii) the definition is a collection of two or more chemical groups selected from the chemical groups defined herein, or iii) the compound is defined by a combination of the variables and / or substituents defined by (i) or (ii).

[0056] Other definitions As used herein, "pharmaceutically acceptable" and "pharmacologically acceptable" refer to compounds, molecular entities, compositions, materials, and / or dosage forms that do not produce adverse, allergic, or other untoward reactions when administered to animals or humans. For human administration, preparations should meet sterility, pyrogenicity, general safety, and purity standards required by the FDA Office of Biologics.

[0057] As used herein, "pharmaceutically acceptable carrier" and "pharmaceutically acceptable excipient" refer to any and all solvents, dispersion media, coatings, isotonic and absorption delaying agents, etc., that are compatible with pharmaceutical administration. Pharmaceutically acceptable carriers can include phosphate buffered saline, water, emulsions (e.g., oil / water emulsions or water / oil emulsions), and various types of wetting agents. The composition can also include stabilizers and preservatives.

[0058] As used herein, "pharmaceutically acceptable salts" refers to any salt of an acidic or basic group that may be present in a compound of the present disclosure, which salt is compatible with pharmaceutical administration. As known to those skilled in the art, "salts" of the compounds of the present disclosure can be derived from inorganic or organic acids and bases. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. provide a detailed description of pharmaceutically acceptable salts in J. Pharmaceutical Sciences (1977) 66:1-19. Pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts include salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, and malonic acid, or by 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, and cyclopentanepropionate. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and the like. + (C 1-4Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cation salts formed, where appropriate, with counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, aryl sulfonates, and the like.

[0059] As used herein, a "subject" to which administration is contemplated includes, but is not limited to, a human (i.e., male or female of any age, e.g., a pediatric subject (e.g., infant, child, adolescent) or an adult subject (e.g., young adult, middle-aged adult, or elderly adult)), and / or a non-human animal, e.g., a mammal such as a primate (e.g., cynomolgus monkey, rhesus monkey), cow, pig, horse, sheep, goat, rodent, cat, and / or dog. 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.

[0060] As used herein, unless otherwise specified, the terms "treat," "treating," and "treatment" contemplate actions that occur while a subject is afflicted with a particular disease, disorder, or condition and that reduce the severity of the disease, disorder, or condition or slow or delay the progression of the disease, disorder, or condition ("therapeutic treatment"), as well as actions that occur before a subject begins to suffer from a particular disease, disorder, or condition ("prophylactic treatment").

[0061] As used herein, the term "effective amount" of a compound refers to an amount sufficient to induce a desired biological response. As will be understood by those skilled in the art, the effective amount of the compound of the present invention may vary depending on factors such as the desired biological endpoint, the pharmacokinetics of the compound, the disease to be treated, the mode of administration, and the age, health, and symptoms of the subject. The effective amount encompasses both therapeutic and prophylactic treatments.

[0062] As used herein, and unless otherwise specified, a "therapeutically effective amount" of a compound (e.g., a compound of the present invention) refers to an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder, or condition, or to delay or minimize one or more symptoms associated with a disease, disorder, or condition. A therapeutically effective amount of a compound (e.g., a compound of the present invention) means an amount of a therapeutic agent that, alone or in combination with other therapies, provides a therapeutic benefit in the treatment of a disease, disorder, or condition. The term "therapeutically effective amount" can encompass an amount that improves overall treatment, reduces or avoids the symptoms or causes of a disease or condition, or enhances the therapeutic efficacy of another therapeutic agent.

[0063] As used herein, the terms "disease," "disorder," "condition," or "illness" may be used interchangeably unless otherwise indicated or understood from context, and refer to a subject or a state or condition of a subject that can be treated with the compounds, pharmaceutical compositions, or methods provided herein. In some embodiments, the compounds and methods described herein involve the reduction or elimination of one or more symptoms of a disease, disorder, or condition, or illness, by administration of a compound of Formula (I) or a stereoisomer and / or pharmaceutically acceptable salt thereof.

[0064] As used herein, "administering" refers to oral administration, administration as a suppository, topical contact, intravenous administration, parenteral administration, intraperitoneal administration, intramuscular administration, intraarticular administration, intrathecal administration, intracranial administration, intranasal administration, or subcutaneous administration, or implantation of a sustained-release device, such as a mini-osmotic pump, into a subject. Administration may be by any route, including parenteral and transmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or transdermal). Parenteral administration includes, for example, intravenous, intramuscular, intraarterial, 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, and the like. "Co-administration" refers to administration of a composition described herein simultaneously with, immediately before, or immediately after administration of one or more additional therapies (e.g., anti-cancer agents, chemotherapeutic agents, or agents for treating neurodegenerative diseases). The compounds of the present invention can be administered alone or co-administered to a subject. Co-administration refers to simultaneous or sequential administration of compounds, either alone or in combination (multiple compounds or agents). Thus, formulations can also be combined with other active agents, if desired (e.g., to reduce metabolic degradation).

[0065] As used herein, "liver damage" generally refers to diseases, disorders, and / or conditions that affect the liver and can have a wide range of severity, including, for example, simple accumulation of fat within hepatocytes (steatosis), macrovesicular steatosis, perihepatic and lobular inflammation (steatohepatitis), cirrhosis, fibrosis, liver cancer, and liver failure.

[0066] As used herein, "fatty liver disease" ("FLD"), also known as "fatty liver," refers to a disease leading to liver damage caused by abnormal fat accumulation in hepatocytes. FLD can result from many causes, including excessive alcohol consumption and metabolic disorders associated with insulin resistance, obesity, and hypertension.

[0067] As used herein, "nonalcoholic fatty liver disease" ("NAFLD") refers to a spectrum of disorders resulting from the accumulation of fat in liver cells in individuals without a history of excessive alcohol consumption. In its mildest form, NAFLD refers to hepatic steatosis.

[0068] As used herein, "drug-induced liver disease" or "toxic liver injury" refers to a disease or condition in which an active drug causes damage to the liver.

[0069] As used herein, "alcoholic liver disease" is also called "alcoholic liver damage", and refers to a disease caused by fat accumulation in hepatocytes, which is at least partially caused by alcohol consumption.For example, it includes, but is not limited to, diseases such as alcoholic simple fatty liver, alcoholic steatohepatitis ("ASH"), alcoholic liver fibrosis, alcoholic cirrhosis, and alcoholic fatty liver disease.In addition, alcoholic steatohepatitis is also called alcoholic steatohepatitis, and also includes alcoholic liver fibrosis.

[0070] As used herein, "fatty liver of pregnancy" refers to an acute, potentially life-threatening condition of fatty liver that occurs during pregnancy.

[0071] 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, blood total lipids, blood HDL cholesterol, blood LDL cholesterol, blood VLDL cholesterol, blood triglycerides, blood Lp(a), blood apoA-I, blood apoE, and blood non-esterified fatty acids.

[0072] As used herein, "altering glucose metabolism" means an observable (measurable) change in at least one aspect of glucose metabolism, including, but not limited to, total blood glucose content, blood insulin, blood insulin / blood glucose ratio, insulin sensitivity, and oxygen consumption.

[0073] Although various aspects of the present disclosure are described herein under headings and / or sections for clarity, it is understood that any aspect, embodiment, or feature of the present disclosure described in one particular section is not limited to that particular section, but rather may be applicable to any aspect, embodiment, or feature of the present disclosure.

[0074] compound Disclosed herein, in one aspect, is a compound of formula (I) or a stereoisomer and / or pharmaceutically acceptable salt thereof: TIFF2025515002000293.tif6295[in the formula, Ring A is phenyl or pyridonyl, and the nitrogen atom of the pyridonyl is optionally C 1-6 may be substituted with alkyl, Ring B is phenyl or 5- to 10-membered heterocyclyl; Ring C is phenyl, 5- to 10-membered heterocyclyl, or 5- to 10-membered heteroaryl, or Ring C is absent; R 1 is independently for each occurrence a halogen, a hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OC(O)C 1-6 Alkyl and -OC(O)C 3-6 cycloalkyl; R 2 is independently for each occurrence a halogen, a hydroxyl, C 1-6 Haloalkyl, C 1-6 selected from the group consisting of alkoxy and COOH; R 3 is cyano, halogen or C 3-6 is cycloalkyl, X 1 is *-S(O)2N(R A )-**, -C(O)-, *-C(O)N(R A )-**, *-CH2N(R A)-** and *-S(O)2CH2-**, where * indicates the point of attachment to ring A and ** indicates the point of attachment to ring B; X 2 is a bond or -O-, X 3 is #-L 1 -L 2 -L 3 -##, where # indicates the point of attachment to ring A and ## indicates the point of attachment to ring C, or to ring B if ring C is absent; L 1 are -CH2-, -O-, -C(O)-, -C(O)N(R B )-, -C(O)O-, C 1-6 selected from the group consisting of alkyl-O-, and 5- to 6-membered heteroaryl; L 2 is C 1-6 alkyl or 4- to 6-membered heterocyclyl, wherein the 4- to 6-membered heterocyclyl is optionally substituted with oxo; L 3 is a bond, -O-, -OC 1-6 Alkyl, C 1-6 selected from the group consisting of alkyl-O- and 4- to 6-membered heterocyclyl; R A is hydrogen or C 1-6 is alkyl, R B is hydrogen or C 1-6 is alkyl, n is 0, 1 or 2; о is 1 or 2, p is 0 or 1.

[0075] In another aspect, provided herein are compounds of formula (I) or stereoisomers and / or pharmaceutically acceptable salts thereof. TIFF2025515002000294.tif6292[In the formula, Ring A is phenyl, pyridinyl or pyridonyl, wherein the nitrogen atom of the pyridonyl is optionally C 1-6 may be substituted with alkyl, Ring B is phenyl or 5- to 10-membered heterocyclyl; Ring C is phenyl, 5- to 10-membered heterocyclyl, or 5- to 10-membered heteroaryl, or Ring C is absent; R 1 is independently for each occurrence a halogen, a hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OC(O)C 1-6 Alkyl, -OC(O)C 3-6 Cycloalkyl and N(R E )2, R 2 is independently for each occurrence a halogen, a hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-6 selected from the group consisting of cycloalkyl and COOH; R 3 is cyano, halogen, C 1-6 Alkyl, and C 3-6 cycloalkyl; X 1 is *-S(O)2N(R A )-**, -C(O)-, *-C(O)N(R A )-**, *-CH2N(R A )-** and *-S(O)2CH2-**, where * indicates the point of attachment to ring A and ** indicates the point of attachment to ring B; X 2 is a bond or -O-, X 3 is #-L 1 -L 2 -L 3 -##, where # indicates the point of attachment to ring A and ## indicates the point of attachment to ring C, or to ring B if ring C is absent; L 1 are -CH2-, -O-, -C(O)-, -C(O)N(R B)-, -C(O)O-, -CH2-C(O)O-, -CH2-N(R B )C(O)-, C 1-6 selected from the group consisting of alkyl-O- and 5- to 6-membered heteroaryl; L 2 is C 1-6 alkyl or 4- to 6-membered heterocyclyl, wherein the 4- to 6-membered heterocyclyl is optionally substituted with oxo; or L 2 does not exist, L 3 is a bond, -O-, -OC 1-6 Alkyl, C 1-6 selected from the group consisting of alkyl-O- and 4- to 6-membered heterocyclyl; R A is hydrogen or C 1-6 is alkyl, R B is hydrogen or C 1-6 is alkyl, R E is, independently for each occurrence, hydrogen or C 1-6 is alkyl, n is 0, 1 or 2; о is 1 or 2, p is 0 or 1.

[0076] In another aspect, provided herein are compounds of formula (I) or stereoisomers and / or pharmaceutically acceptable salts thereof. TIFF2025515002000295.tif6296[in the formula, Ring A is phenyl, pyridinyl or pyridonyl, wherein the nitrogen atom of the pyridonyl is optionally C 1-6 may be substituted with alkyl, Ring B is phenyl or 5- to 10-membered heterocyclyl; Ring C is phenyl, 5- to 10-membered heterocyclyl, or 5- to 10-membered heteroaryl, or Ring C is absent; R 1 is independently for each occurrence a halogen, a hydroxyl, C 1-6Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OC(O)C 1-6 Alkyl, -OC(O)C 3-6 Cycloalkyl and N(R E )2, R 2 is independently for each occurrence a halogen, a hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-6 selected from the group consisting of cycloalkyl and COOH; R 3 is cyano, halogen, C 1-6 Alkyl and C 3-6 cycloalkyl; X 1 is *-S(O)2N(R A )-**, -C(O)-, *-C(O)N(R A )-**, *-CH2N(R A )-** and *-S(O)2CH2-**, where * indicates the point of attachment to ring A and ** indicates the point of attachment to ring B; X 2 is a bond or -O-, X 3 is #-L 1 -L 2 -L 3 -##, where # indicates the point of attachment to ring A and ## indicates the point of attachment to ring C, or to ring B if ring C is absent; L 1 -CH2-, -C(O)-, -C(O)O-, -CH2-C(O)O-, -CH2-N(R B )C(O)-, C 1-6 selected from the group consisting of alkyl-O- and 5- to 6-membered heteroaryl; L 2 is C 1-6alkyl or 4- to 6-membered heterocyclyl, wherein the 4- to 6-membered heterocyclyl is optionally substituted with oxo; or L 2 does not exist, L 3 is a bond, -O-, -OC 1-6 Alkyl, C 1-6 selected from the group consisting of alkyl-O- and 4- to 6-membered heterocyclyl; R A is hydrogen or C 1-6 is alkyl, R B is hydrogen or C 1-6 is alkyl, R E is, independently for each occurrence, hydrogen or C 1-6 is alkyl, n is 0, 1 or 2; о is 1 or 2, p is 0 or 1.

[0077] In some embodiments, ring A is phenyl or 2-pyridonyl, wherein the nitrogen atom of the 2-pyridonyl is optionally C 1-6 In some embodiments, Ring A is phenyl, pyridinyl, or 2-pyridonyl, wherein the nitrogen atom of the 2-pyridonyl is optionally substituted with C 1-6 It may be substituted with alkyl.

[0078] In some embodiments, Ring A is phenyl or 2-pyridonyl, where the nitrogen atom of the 2-pyridonyl is optionally substituted with CH. In some embodiments, Ring A is phenyl, pyridinyl, or 2-pyridonyl, where the nitrogen atom of the 2-pyridonyl is optionally substituted with CH.

[0079] In some embodiments, ring A is: TIFF2025515002000296.tif50117 where Δ is X 1indicates the point of attachment to X, and ΔΔ indicates the point of attachment to X. 3 In some embodiments, ring A is selected from the group consisting of: TIFF2025515002000297.tif92131 where Δ is X 1 indicates the point of attachment to X, and ΔΔ indicates the point of attachment to X. 3 indicates the attachment point to

[0080] In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2.

[0081] In some embodiments, R 1 is chloro or hydroxyl. In some embodiments, R 1 is selected from the group consisting of chloro, hydroxyl, CH3, CHF2 and NH2.

[0082] In some embodiments, R 1 is independently for each occurrence selected from the group consisting of chloro, hydroxyl, CH3, -O-CH3, -O-CHF2, -OC(O)CH3, and TIFF2025515002000298.tif2943 In some embodiments, R 1 is independently for each occurrence selected from the group consisting of chloro, fluoro, hydroxyl, CH3, CHF2, -O-CH3, -O-CHF2, -OC(O)CH3, and TIFF2025515002000299.tif2943

[0083] In some embodiments, Ring B is phenyl or 9-membered heterocyclyl.

[0084] In some embodiments, Ring B is phenyl or: TIFF2025515002000300.tif2336

[0085] In some embodiments, ring B is: TIFF2025515002000301.tif4134 TIFF2025515002000302.tif3656 where ● is X 1 indicates the point of attachment to X 2 indicates the attachment point to

[0086] In some embodiments, o is 1. In some embodiments, o is 2.

[0087] In some embodiments, R 2 is selected from the group consisting of fluoro, hydroxyl, —O—CH and C(O)OH. 2 is selected from the group consisting of fluoro, hydroxy, cyclopropyl, CF3, -O-CH3, -O-CHF2, -O-CF3 and C(O)OH.

[0088] In some embodiments, R 2 is independently for each occurrence selected from the group consisting of chloro, fluoro, CF, and —O—CH. In some embodiments, R 2 is independently for each occurrence selected from the group consisting of chloro, fluoro, CH3, CF3, and -O-CH3.

[0089] In some embodiments, ring C is absent.

[0090] In some embodiments, Ring C is selected from the group consisting of phenyl, pyrrolidinyl, piperidinyl, pyridinyl, and: TIFF2025515002000303.tif2577 In some embodiments, Ring C is selected from the group consisting of phenyl, pyrrolidinyl, piperidinyl, pyridinyl, and the following: TIFF2025515002000304.tif56128

[0091] In some embodiments, ring C is selected from the group consisting of: TIFF2025515002000305.tif153152Here, □ is X 2 indicates the point of attachment to X 3 indicates the attachment point to

[0092] In some embodiments, ring C is selected from the group consisting of: TIFF2025515002000306.tif209153Here, □ is X 2 indicates the point of attachment to X 3 indicates the attachment point to

[0093] In some embodiments, p is 1. In some embodiments, p is 0.

[0094] In some embodiments, R 3 is selected from the group consisting of bromo, chloro, fluoro, cyano, and cyclopropyl. 3 is selected from the group consisting of bromo, chloro, fluoro, cyano, CH3 and cyclopropyl.

[0095] In some embodiments, X 1 is selected from the group consisting of *-S(O)N(H)-**, *-S(O)N(CH)-**, -C(O)-, *-C(O)N(H)-**, *-CHN(H)-** and *-S(O)CH-**, where * indicates the point of attachment to ring A and ** indicates the point of attachment to ring B.

[0096] In some embodiments, X 2 is a bond. In some embodiments, X 2 is -O-.

[0097] In some embodiments, L 1 is selected from the group consisting of -C(O)N(H)-, -C(O)N(CH3)-, -C(O)O-, -CH2-, -CH2-O-, -C(O)-, -O- and the following: TIFF2025515002000307.tif3334 In some embodiments, L 1 is selected from the group consisting of -C(O)N(H)-, -C(O)N(CH3)-, -C(O)O-, -CH2-, -CH2-O-, -C(O)-, -CH2-C(O)O-, -CH2-N(CH3)C(O)-, -O- and the following: TIFF2025515002000308.tif3334 In some embodiments, L 1 is selected from the group consisting of -C(O)O-, -CH2-, -CH2-O-, -C(O)-, -CH2-C(O)O-, -CH2-N(CH3)C(O)- and the following: TIFF2025515002000309.tif3334

[0098] In some embodiments, L 2 is selected from the group consisting of -CH2CH2-, -(CH2)3-, -CH2-, -(CH2)4-, -CH(CH3)CH2- and the following: TIFF2025515002000310.tif35140 In some embodiments, L 2 is selected from the group consisting of -CH2CH2-, -(CH2)3-, -CH2-, -(CH2)4-, -CH(CH3)CH2-, -CH2CH2C(H)(CH3)- and the following: TIFF2025515002000311.tif33138

[0099] In some embodiments, L 2 does not exist.

[0100] In some embodiments, L 3 is a bond.

[0101] In some embodiments, L 3 is -O- or the following: TIFF2025515002000312.tif2343 In some embodiments, L 3 is -O-, -CH2-O- or the following: TIFF2025515002000313.tif2343

[0102] In some embodiments, X 3 is selected from the group consisting of: TIFF2025515002000314.tif61139 TIFF2025515002000315.tif201128 TIFF2025515002000316.tif64126Here, # indicates the point of attachment to ring A and ## indicates the point of attachment to ring C.

[0103] In some embodiments, X 3 is selected from the group consisting of: TIFF2025515002000317.tif160159 TIFF2025515002000318.tif239156 TIFF2025515002000319.tif46130Here, # indicates the point of attachment to ring A and ## indicates the point of attachment to ring C.

[0104] In some embodiments, X 3 is selected from the group consisting of: TIFF2025515002000320.tif144149 TIFF2025515002000321.tif165132Here, # indicates the point of attachment to ring A and ## indicates the point of attachment to ring C.

[0105] Also disclosed herein, in various embodiments, are compounds of Formula (Ia) or a stereoisomer and / or pharmaceutically acceptable salt thereof: TIFF2025515002000322.tif4873[in the formula, R 4 is hydrogen, halogen or C 1-6 is alkyl, R 5 is hydrogen, hydroxy, C 1-6 Alkoxy, C1-6 Haloalkoxy, -C(O)OC 1-6 Alkyl and -C(O)OC 1-6 cycloalkyl; R 6 is hydrogen, halogen, hydroxy, C 1-6 Alkoxy, C 1-6 selected from the group consisting of alkyl and C(O)OH; R 7 is hydrogen, halogen, C 1-6 Haloalkyl and C 1-6 alkoxy; R 8 is hydrogen or halogen, R 9 is hydrogen, cyano, halogen and C 3-6 cycloalkyl; R 10 is hydrogen or halogen, X 4 is *-S(O)2N(R C )-**, *-C(O)N(R C )-**, *-CH2N(R C )-** and *-S(O)2CH2-**, where * is ** indicates the connection point to TIFF2025515002000323.tif4944. Indicates the connection point to TIFF2025515002000324.tif4947, X 5 is #-L 4 -L 5 -L 6 -##, where # is ## indicates the connection point to TIFF2025515002000325.tif4944. Indicates the connection point to TIFF2025515002000326.tif4742, L 4 is CH2, C 1-6 Alkyl-O-, -O-, -C(O)-, -C(O)N(R D )-, -C(O)O-, and 5-6 membered heteroaryl; L 5 is a 4- to 6-membered heterocyclyl, wherein the 4- to 6-membered heterocyclyl is optionally substituted by oxo; L 6 is a bond, -O-, C 1-6 selected from the group consisting of alkyl-O- and 4- to 6-membered heterocyclyl; R C is hydrogen or C 1-6 is alkyl, R D is hydrogen or C 1-6 It is alkyl.

[0106] In various embodiments, provided herein are compounds of Formula (Ia) or a stereoisomer and / or pharmaceutically acceptable salt thereof: TIFF2025515002000327.tif7193[in the formula, R 4 is hydrogen, hydroxy, halogen and C 1-6 alkyl, R 5 is hydrogen, halogen, hydroxyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, -C(O)OC 1-6 Alkyl and -C(O)OC 1-6 cycloalkyl; R 6 is hydrogen, halogen, hydroxyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 selected from the group consisting of cycloalkyl and C(O)OH; R 7 is hydrogen, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl and C 1-6 alkoxy; R 8 is hydrogen, halogen or C 1-6is alkyl, R 9 is hydrogen, cyano, halogen and C 3-6 cycloalkyl; R 10 is hydrogen, cyano or halogen, X 4 is *-S(O)2N(R C )-**, *-C(O)N(R C )-**, *-CH2N(R C )-** and *-S(O)2CH2-**, where * is ** indicates the connection point to TIFF2025515002000328.tif4944. Indicates the connection point to TIFF2025515002000329.tif4947, X 5 is #-L 4 -L 5 -L 6 -##, where # is ## indicates the connection point to TIFF2025515002000330.tif4944. Indicates the connection point to TIFF2025515002000331.tif4742, L 4 is CH2, C 1-6 Alkyl-O-, -O-, -C(O)-, -C(O)N(R D )-, -C(O)O-, -CH2-C(O)O-, -CH2-N(R D )C(O)— and 5- to 6-membered heteroaryl; L 5 is C 1-6 alkyl or 4- to 6-membered heterocyclyl, wherein the 4- to 6-membered heterocyclyl is optionally substituted by oxo; L 6 is a bond, -O-, C 1-6 selected from the group consisting of alkyl-O- and 4- to 6-membered heterocyclyl; R C is hydrogen or C 1-6 is alkyl, R D is hydrogen or C1-6 It is alkyl.

[0107] In various embodiments, provided herein are compounds of Formula (Ia) or a stereoisomer and / or pharmaceutically acceptable salt thereof: TIFF2025515002000332.tif6484[in the formula, R 4 is hydrogen, hydroxyl, halogen and C 1-6 alkyl, R 5 is hydrogen, hydroxyl, C 1-6 Alkoxy, C 1-6 Haloalkyl and C 1-6 haloalkoxy; R 6 is halogen, hydroxyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Haloalkyl and C 3-6 cycloalkyl; R 7 is hydrogen, halogen, C 1-6 Alkyl and C 1-6 alkoxy; R 8 is hydrogen or C 1-6 is alkyl, R 9 is hydrogen, cyano, halogen and C 3-6 cycloalkyl; R 10 is hydrogen, cyano or halogen, X 4 is *-S(O)2N(R C )-**, *-C(O)N(R C )-**, *-CH2N(R C )-** and *-S(O)2CH2-**, where * is ** indicates the connection point to TIFF2025515002000333.tif4944. Indicates the connection point to TIFF2025515002000334.tif4947, X 5 is #-L 4 -L 5 -L 6 -##, where # is ## indicates the connection point to TIFF2025515002000335.tif4944. Indicates the connection point to TIFF2025515002000336.tif4742, L 4 is C 1-6 Alkyl-O-, -C(O)-, -C(O)N(R D )-, -C(O)O-, -CH2-C(O)O-, -CH2-N(R D )C(O)— and 5- to 6-membered heteroaryl; L 5 is C 1-6 alkyl or 4- to 6-membered heterocyclyl; L 6 is a bond, -O-, C 1-6 selected from the group consisting of alkyl-O- and 4- to 6-membered heterocyclyl; R C is hydrogen or C 1-6 is alkyl, R D is hydrogen or C 1-6 It is alkyl.

[0108] In various embodiments, provided herein are compounds of Formula (Ia) or a stereoisomer and / or pharmaceutically acceptable salt thereof: TIFF2025515002000337.tif6484[in the formula, R 4 is hydrogen, hydroxyl, halogen and C 1-6 alkyl, R 5 is hydrogen, halogen, hydroxyl, C 1-6 Alkoxy, C 1-6 Haloalkyl and C 1-6 haloalkoxy; R6 is halogen, hydroxyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Haloalkyl and C 3-6 cycloalkyl; R 7 is hydrogen, halogen, C 1-6 Alkyl and C 1-6 alkoxy; R 8 is hydrogen or C 1-6 is alkyl, R 9 is hydrogen, cyano, halogen and C 3-6 cycloalkyl; R 10 is hydrogen, cyano or halogen, X 4 is *-S(O)2N(R C )-**, *-C(O)N(R C )-**, *-CH2N(R C )-** and *-S(O)2CH2-**, where * is ** indicates the connection point to TIFF2025515002000338.tif4944. Indicates the connection point to TIFF2025515002000339.tif4947, X 5 is #-L 4 -L 5 -L 6 -##, where # is ## indicates the connection point to TIFF2025515002000340.tif4944. Indicates the connection point to TIFF2025515002000341.tif4742, L 4 is C 1-6 Alkyl-O-, -C(O)-, -C(O)O-, -CH2-C(O)O-, -CH2-N(R D )C(O)— and 5- to 6-membered heteroaryl; L 5 is C 1-6alkyl or 4- to 6-membered heterocyclyl; L 6 is a bond, -O-, C 1-6 selected from the group consisting of alkyl-O- and 4- to 6-membered heterocyclyl; R C is hydrogen or C 1-6 is alkyl, R D is hydrogen or C 1-6 It is alkyl.

[0109] In some embodiments, R 4 is hydrogen, chloro, or CH. In some embodiments, R 4 is hydrogen, hydroxyl, chloro or CH3.

[0110] In some embodiments, R 5 is selected from the group consisting of hydrogen, hydroxyl, —O—CH 3 , —O—CHF 2 , —OC(O)CH 3 and the following: TIFF2025515002000342.tif2943 In some embodiments, R 5 is selected from the group consisting of hydrogen, fluoro, hydroxyl, CHF2, -O-CH3, -O-CHF2, -OC(O)CH3 and TIFF2025515002000343.tif2943 In some embodiments, R 5 is selected from the group consisting of hydrogen, fluoro, hydroxyl, CHF2, -O-CH3, and -O-CHF2.

[0111] In some embodiments, R 6 is selected from the group consisting of hydrogen, hydroxyl, fluoro, chloro, —O—CH3, and C(O)OH. In some embodiments, R 6 is selected from the group consisting of hydrogen, hydroxyl, fluoro, chloro, cyclopropyl, CF, —O—CH, —O—CHF, —O—CF, and C(O)OH. 6is selected from the group consisting of hydroxyl, fluoro, cyclopropyl, CF3, -O-CH3, -O-CHF2, and -O-CF3.

[0112] In some embodiments, R 7 is selected from the group consisting of hydrogen, chloro, fluoro, —O—CH and CF. In some embodiments, R 7 is selected from the group consisting of hydrogen, fluoro, —O—CH 3 and CH 3 .

[0113] In some embodiments, R 8 is hydrogen or chloro. In some embodiments, R 8 is hydrogen, CH, or chloro. In some embodiments, R 8 is hydrogen or CH3.

[0114] In some embodiments, R 9 is selected from the group consisting of hydrogen, cyano, chloro, bromo, fluoro, and cyclopropyl. 9 is selected from the group consisting of hydrogen, cyano, chloro, bromo, fluoro and cyclopropyl.

[0115] In some embodiments, R 10 is hydrogen, chloro, or fluoro. In some embodiments, R 10 is selected from the group consisting of hydrogen, cyano, chloro and fluoro.

[0116] In some embodiments, X 4 is selected from the group consisting of *-S(O)2N(H)-**, *-S(O)2N(CH3)-**, *-C(O)N(H)-**, *-CH2N(H)-** and *-S(O)2CH2-**, wherein * is ** indicates the connection point to TIFF2025515002000344.tif4944. Indicates the connection point to TIFF2025515002000345.tif4947.

[0117] In some embodiments, L 4 is selected from the group consisting of —CH—, —O—, —C(O)—, —C(O)N(H)—, —C(O)N(CH)—, —C(O)O—, —CH—O—, and the following: TIFF2025515002000346.tif3334 In some embodiments, L 4 is selected from the group consisting of -CH2-, -O-, -C(O)-, -C(O)N(H)-, -C(O)N(CH3)-, -C(O)O-, -CH2-C(O)O-, -CH2-N(CH3)C(O)-, -CH2-O- and the following: TIFF2025515002000347.tif3334 In some embodiments, L 4 is selected from the group consisting of -CH2-, -C(O)-, -C(O)N(H)-, -C(O)N(CH3)-, -C(O)O-, -CH2-C(O)O-, -CH2-N(CH3)C(O)-, -CH2-O- and the following: TIFF2025515002000348.tif3334 In some embodiments, L 4 is selected from the group consisting of -CH2-, -C(O)-, -C(O)O-, -CH2-C(O)O-, -CH2-N(CH3)C(O)-, -CH2-O- and the following: TIFF2025515002000349.tif3334

[0118] In some embodiments, L 5 is selected from the group consisting of -CH2-, -CH2CH2-, -(CH2)3-, -CH(CH3)CH2-, -(CH2)4- and the following: TIFF2025515002000350.tif36140 In some embodiments, L 5 is selected from the group consisting of -CH2-, -CH2CH2-, -(CH2)3-, -C(H)(CH3)CH2-, -CH2CH2C(H)(CH3)-, -(CH2)4- and the following: TIFF2025515002000351.tif35141 In some embodiments, L5 is selected from the group consisting of -CH2-, -CH2CH2-, -(CH2)3-, -C(H)(CH3)CH2-, -CH2CH2C(H)(CH3)- and the following: TIFF2025515002000352.tif2343

[0119] In some embodiments, L 6 is a bond.

[0120] In some embodiments, L 6 is -O- or the following: TIFF2025515002000353.tif2343 In some embodiments, L 6 is -O-, -CH2-O- or the following: TIFF2025515002000354.tif2343

[0121] In some embodiments, X 5 is selected from the group consisting of: TIFF2025515002000355.tif219149 TIFF2025515002000356.tif84110 Where # is ## indicates the connection point to TIFF2025515002000357.tif4440. Indicates the connection point to TIFF2025515002000358.tif4136.

[0122] In some embodiments, X 5 is selected from the group consisting of: TIFF2025515002000359.tif49125 TIFF2025515002000360.tif192133 TIFF2025515002000361.tif148134 where # is ## indicates the connection point to TIFF2025515002000362.tif4944. Indicates the connection point to TIFF2025515002000363.tif4036.

[0123] In some embodiments, X 5 is selected from the group consisting of: TIFF2025515002000364.tif22105 TIFF2025515002000365.tif153107 TIFF2025515002000366.tif95121where # is ## indicates the connection point to TIFF2025515002000367.tif4944. Indicates the connection point to TIFF2025515002000368.tif4742.

[0124] In some embodiments, X 5 is selected from the group consisting of: TIFF2025515002000369.tif63120 TIFF2025515002000370.tif119118 where # is ## indicates the connection point to TIFF2025515002000371.tif4944. Indicates the connection point to TIFF2025515002000372.tif4742.

[0125] In various embodiments, provided herein are compounds of formula (Ib) or a stereoisomer and / or pharmaceutically acceptable salt thereof: TIFF2025515002000373.tif81107[In the formula, R 11 is hydrogen, hydroxyl, halogen and C 1-6 alkyl, R 12 is hydrogen, halogen, hydroxyl, C 1-6 Alkoxy, C 1-6 Haloalkyl and C 1-6 haloalkoxy; R13 is hydrogen, hydroxyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Haloalkyl and C 3-6 cycloalkyl; R 14 is hydrogen or halogen, R 15 is hydrogen, halogen, C 1-6 Alkyl and C 1-6 alkoxy; R 16 is hydrogen or halogen, R 17 is hydrogen or C 1-6 is alkyl, R 18 is hydrogen, cyano, halogen and C 3-6 cycloalkyl; R 19 is hydrogen, cyano, halogen, X 6 is *-S(O)2N(R E )-**, *-C(O)N(R E )-**, *-CH2N(R E )-** and *-S(O)2CH2-**, where * is ** indicates the connection point to TIFF2025515002000374.tif4944. Indicates the connection point to TIFF2025515002000375.tif4949, X 7 is #-L 7 -L 8 -L 9 -##, where # is ## indicates the connection point to TIFF2025515002000376.tif4944. Indicates the connection point to TIFF2025515002000377.tif4748. L 7 is C 1-6 Alkyl-O-, -C(O)-, -C(O)N(R F)-, -C(O)O-, -CH2-C(O)O-, -CH2-N(R F )C(O)— and 5- to 6-membered heteroaryl; L 8 is C 1-6 alkyl or 4- to 6-membered heterocyclyl; L 9 is a bond, -O-, C 1-6 selected from the group consisting of alkyl-O- and 4- to 6-membered heterocyclyl; R E is hydrogen or C 1-6 is alkyl, R F is hydrogen or C 1-6 It is alkyl.

[0126] In various embodiments, provided herein are compounds of formula (Ib) or a stereoisomer and / or pharmaceutically acceptable salt thereof: TIFF2025515002000378.tif81105[In the formula, R 11 is hydrogen, hydroxyl, halogen and C 1-6 alkyl, R 12 is hydrogen, halogen, hydroxyl, C 1-6 Alkoxy, C 1-6 Haloalkyl and C 1-6 haloalkoxy; R 13 is hydroxyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Haloalkyl and C 3-6 cycloalkyl; R 14 is hydrogen or halogen, R 15 is hydrogen, halogen, C 1-6 Alkyl and C 1-6 alkoxy; R 16 is hydrogen or halogen, R17 is hydrogen or C 1-6 is alkyl, R 18 is hydrogen, cyano, halogen and C 3-6 cycloalkyl; R 19 is hydrogen, cyano, halogen, X 6 is *-S(O)2N(R E )-**, *-C(O)N(R E )-**, *-CH2N(R E )-** and *-S(O)2CH2-**, where * is ** indicates the connection point to TIFF2025515002000379.tif4944. Indicates the connection point to TIFF2025515002000380.tif4949, X 7 is #-L 7 -L 8 -L 9 -##, where # is ## indicates the connection point to TIFF2025515002000381.tif4944. Indicates the connection point to TIFF2025515002000382.tif4748. L 7 is C 1-6 Alkyl-O-, -C(O)-, -C(O)O-, -CH2-C(O)O-, -CH2-N(R F )C(O)— and 5- to 6-membered heteroaryl; L 8 is C 1-6 alkyl or 4- to 6-membered heterocyclyl; L 9 is a bond, -O-, C 1-6 selected from the group consisting of alkyl-O- and 4- to 6-membered heterocyclyl; R E is hydrogen or C 1-6 is alkyl, R F is hydrogen or C 1-6 It is alkyl.

[0127] In one embodiment, R 11 is selected from the group consisting of hydrogen, hydroxyl, chloro, and CH3.

[0128] In some embodiments, R 12 is selected from the group consisting of hydrogen, fluoro, hydroxyl, CHF2, -O-CH3, and -O-CHF2.

[0129] In some embodiments, R 13 is selected from the group consisting of hydroxyl, fluoro, cyclopropyl, CF3, -O-CH3, -O-CHF2, and -O-CF3.

[0130] In some embodiments, R 14 is hydrogen or fluoro.

[0131] In some embodiments, R 15 is selected from the group consisting of hydrogen, chloro, fluoro, —O—CH 3 , CH 3 and CF 3 .

[0132] In some embodiments, R 16 is hydrogen or fluoro.

[0133] In some embodiments, R 17 is hydrogen or CH3.

[0134] In some embodiments, R 18 is selected from the group consisting of hydrogen, cyano, chloro, bromo, fluoro and cyclopropyl.

[0135] In some embodiments, R 19 is selected from the group consisting of hydrogen, cyano, chloro and fluoro.

[0136] In some embodiments, X 6is selected from the group consisting of *-S(O)2N(H)-**, *-S(O)2N(CH3)-**, *-C(O)N(H)-**, *-CH2N(H)-** and *-S(O)2CH2-**, and * is ** indicates the connection point to TIFF2025515002000383.tif4944. Indicates the connection point to TIFF2025515002000384.tif4949.

[0137] In some embodiments, L 7 is selected from the group consisting of -CH2-, -C(O)-, -C(O)N(H)-, -C(O)N(CH3)-, -C(O)O-, -CH2-C(O)O-, -CH2-N(CH3)C(O)-, -CH2-O- and the following: TIFF2025515002000385.tif3334 In some embodiments, L 7 -CH2-, -C(O)-, -C(O)O-, -CH2-C(O)O-, -N(CH3)C(O)-, -CH2-O- and TIFF2025515002000386.tif3334.

[0138] In some embodiments, L 8 is selected from the group consisting of -CH2-, -CH2CH2-, -(CH2)3-, -C(H)(CH3)CH2-, -CH2CH2C(H)(CH3)- and the following: TIFF2025515002000387.tif2343

[0139] In some embodiments, L 9 is a bond.

[0140] In some embodiments, L 9 is -O-, -CH2-O- or the following: TIFF2025515002000388.tif2343

[0141] In some embodiments, X 7is selected from the group consisting of: TIFF2025515002000389.tif171132 TIFF2025515002000390.tif144124 where # is ## indicates the connection point to TIFF2025515002000391.tif4944. Indicates the connection point to TIFF2025515002000392.tif4748.

[0142] In some embodiments, X 7 is selected from the group consisting of: TIFF2025515002000393.tif124139 TIFF2025515002000394.tif84134 where # is ## indicates the connection point to TIFF2025515002000395.tif4944. Indicates the connection point to TIFF2025515002000396.tif4748.

[0143] In various embodiments, provided herein are compounds of formula (II) or stereoisomers and / or pharmaceutically acceptable salts thereof: TIFF2025515002000397.tif7194[In the formula, X1 and X2 are C(R G ), or X1 is C=O and X2 is N(R H ) or X1 is N(R H ) and X2 is C=O. TIFF2025515002000398.tif312 is a compound in which X1 is C=O and X2 is N(R H ), it is a single bond, TIFF2025515002000399.tif312 is X1 is C(R G ), it is a double bond. R 20 is H or C 1-3 is alkyl, R 21 is independently for each occurrence a halogen, a hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-6 selected from the group consisting of cycloalkyl and COOH; R 22 is cyano, halogen, C 1-6 Alkyl and C 3-6 cycloalkyl; X 8 is -C(O)C 1-6 Alkyl-, -C(O)-(C 1-6 (5-6 membered heteroaryl)-(C alkyl)-O- or (5-6 membered heteroaryl)-(C alkyl)-O-; R G is independently for each occurrence a halogen, a hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OC(O)C 1-6 Alkyl and -OC(O)C 3-6 cycloalkyl; R H is H or C 1-3 is alkyl, r is 0, 1 or 2; s is 0 or 1.

[0144] In some embodiments, X1 and X2 are C(R G In some embodiments, R G is, independently for each occurrence, halogen or hydroxyl. In some embodiments, R G is independently for each occurrence chloro or hydroxyl.

[0145] In some embodiments, X1 is C=O and X2 is N(R H In some embodiments, R His hydrogen. In some embodiments, R H is C 1-3 It is alkyl.

[0146] In some embodiments, X is N(R H ) and X2 is C=O. In some embodiments, R H is hydrogen. In some embodiments, R H is C 1-3 It is alkyl.

[0147] In some embodiments, R 20 is hydrogen. In some embodiments, R 20 is C 1-3 It is alkyl.

[0148] In some embodiments, r is 0.

[0149] In some embodiments, r is 1. In some embodiments, R 21 is C 1-6 In some embodiments, R 21 is CF3.

[0150] In some embodiments, r is 2. In some embodiments, R 21 is independently for each occurrence halogen. In some embodiments, R 21 is, independently for each occurrence, fluoro.

[0151] In some embodiments, s is 0.

[0152] In some embodiments, s is 1. In some embodiments, R 22 is halogen. In some embodiments, R 22 is fluoro.

[0153] In some embodiments, X 8is —C(O)CH—, —C(O)(CH)O— or TIFF2025515002000400.tif3661

[0154] In some embodiments, X 8 is #-C(O)CH2-##, #-C(O)(CH2)2O-## or the following: TIFF2025515002000401.tif3563 where # is the attachment point to TIFF2025515002000402.tif4035## is the binding point to: TIFF2025515002000403.tif4233

[0155] In some embodiments, the compound is selected from Table 1. [Table 1] TIFF2025515002000405.tif244103 TIFF2025515002000406.tif241102 TIFF2025515002000407.tif195103 TIFF2025515002000408.tif194103 TIFF2025515002000409.tif185102 TIFF2025515002000410.tif192103 TIFF2025515002000411.tif196103 TIFF2025515002000412.tif199103 TIFF2025515002000413.tif232102 TIFF2025515002000414.tif218103 TIFF2025515002000415.tif229104 TIFF2025515002000416.tif235104 TIFF2025515002000417.tif233107 TIFF2025515002000418.tif198105 TIFF2025515002000419.tif243106 TIFF2025515002000420.tif223106 TIFF2025515002000421.tif211106 TIFF2025515002000422.tif219105 TIFF2025515002000423.tif222110 TIFF2025515002000424.tif219108 TIFF2025515002000425.tif208109 TIFF2025515002000426.tif208105 TIFF2025515002000427.tif208106 TIFF2025515002000428.tif206104

[0156] Pharmaceutical Compositions and Routes of Administration The compounds provided according to the present disclosure are typically administered in the form of pharmaceutical compositions. Accordingly, the present invention provides pharmaceutical compositions comprising, as an active ingredient, one or more of the compounds described herein, or stereoisomers and / or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable excipients, carriers including inert solid diluents and fillers, diluents including sterile aqueous solutions and various organic solvents, penetration enhancers, solubilizers, and adjuvants. The pharmaceutical compositions described herein can be administered alone or in combination with other therapeutic agents. Such compositions are prepared by methods well known in the pharmaceutical arts (see, for example, Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa. 17th Ed. (1985) and Modern Pharmaceutics, Marcel Dekker, Inc. 3rd Ed. (GS Banker & CT Rhodes, Eds.)).

[0157] The pharmaceutical compositions described herein may be administered in either single or multiple doses by any of the accepted modes of administration for agents having similar utilities, for example, as described in the patents and patent applications incorporated by reference, including rectal, buccal, transdermal, intra-arterial injection, intravenous, intraperitoneal, parenteral, intramuscular, subcutaneous, oral, nasal and transdermal routes, intra-arterial injection, intravenous, intraperitoneal, parenteral, intramuscular, subcutaneous, oral, topical, as an inhalant, or via an impregnated or coated device such as a stent, an arterially inserted cylindrical polymer, or the like.

[0158] One mode of administration is parenteral administration, particularly by injection. Forms in which the novel compositions of the present disclosure can be incorporated for injection include aqueous or oily suspensions or emulsions with sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or sterile aqueous solutions, and similar pharmaceutical vehicles. Aqueous saline solutions are also conventionally used for injection, but are 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 can also be used. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, the maintenance of the required particle size in the case of dispersions, and the use of surfactants. Prevention of microbial action can be achieved by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.

[0159] Sterile injectable solution can be prepared by incorporating the compound of the present disclosure in the required amount in a suitable solvent with various other ingredients as listed above, if necessary, and then filter sterilization.Generally, dispersion is prepared by incorporating various sterilized active ingredients into a sterile vehicle that contains a basic dispersion medium and other ingredients as listed above.For the preparation of sterile powder for sterile injectable solution, the preferred preparation method is vacuum drying and freeze-drying technology, which can be used to obtain the powder of active ingredient plus desired additional ingredients from a previously sterile-filtered solution.

[0160] Oral administration is another route for administering the compounds according to the present disclosure. Administration can be via capsules or enteric-coated tablets, etc. When preparing pharmaceutical compositions containing at least one compound described herein, the active ingredient is usually diluted with an excipient and / or enclosed in such a carrier, which 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 described above) that acts as a vehicle, carrier, or medium for the active ingredient. Thus, the composition can be in the form of a tablet, pill, powder, lozenge, sachet, cachet, elixir, suspension, emulsion, solution, syrup, aerosol (in a solid or liquid medium), for example, an ointment containing up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injection solutions, and sterile packaged powders.

[0161] Examples of suitable excipients include, but are not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterilized water, syrup, and methylcellulose.The preparation can further include lubricants such as talc, magnesium stearate, and mineral oil, wetting agents, emulsifying and suspending agents, preservatives such as methylhydroxybenzoates and propylhydroxybenzoates, sweeteners, and flavoring agents.

[0162] The compositions of the present disclosure can be formulated to provide rapid, sustained, or delayed release of the active ingredient after administration to a subject by employing procedures known in the art. Controlled-release drug delivery systems for oral administration include osmotic pump systems and dissolution systems containing polymer-coated reservoirs or drug-polymer matrix formulations. Examples of controlled-release systems are described in U.S. Patent 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 uses transdermal delivery devices ("patches"). Such transdermal patches can be used to provide continuous or discontinuous infusion of a controlled amount of the compounds of the present disclosure. The structure and use of transdermal patches for the delivery of pharmaceutical agents are well known in the art. See, for example, U.S. Patent 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.

[0163] The composition is preferably formulated into a unit dosage form. The term "unit dosage form" refers to a physically discrete unit suitable as a unit dose for human subjects and other mammals, each unit containing a predetermined amount of active substance calculated to produce a desired therapeutic effect in association with a suitable pharmaceutical excipient (e.g., tablet, capsule, ampoule). The compound is generally administered in a pharmaceutically effective amount. However, it will be understood that the amount of the compound actually administered will usually be determined by a physician in light of relevant circumstances, including the condition to be treated, the selected administration route, the compound actually administered and its relative activity, the age, weight and response of the individual subject, the severity of the subject's symptoms, etc.

[0164] To prepare solid compositions such as tablets, the primary active ingredient is mixed with pharmaceutical excipients to form a solid preformulation composition containing a homogeneous mixture of the compounds of the present disclosure. When such a preformulation composition is referred to as homogeneous, it means that the active ingredient is dispersed evenly throughout the composition, allowing the composition to be readily subdivided into uniformly effective unit dosage forms such as tablets, pills, and capsules.

[0165] The tablets or pills of the present disclosure can be coated or otherwise compounded to provide a dosage form offering the advantage of prolonged action or to protect against the acidic conditions of the stomach. For example, the tablets or pills can consist of an inner dosage and an outer dosage, the latter in the form of an envelope surrounding the former. The two components can be separated by an enteric layer that serves to resist disintegration in the stomach and allow the inner component to pass intact into the duodenum or be delayed in release. A variety of materials can be used for such enteric layers or coatings, including numerous polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

[0166] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients, as described above. Preferably, the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions, preferably in pharmaceutically acceptable solvents, may be nebulized using an inert gas. Nebulized solutions may be inhaled directly from the nebulizer, or the nebulizer may be attached to a face mask tent or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from a device that delivers the formulation in an appropriate manner.

[0167] In some embodiments, the pharmaceutical composition comprises a disclosed compound (e.g., a compound of Formula (I), Formula (Ia), Formula (Ib), or Formula (II)), or a stereoisomer and / or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0168] Treatment method In various embodiments, the compounds disclosed herein (e.g., compounds of Formula (I), Formula (Ia), Formula (Ib), or Formula (II)), or stereoisomers and / or pharmaceutically acceptable salts thereof (including pharmaceutical compositions) can be used for the treatment or prevention of various conditions, diseases, and disorders. Methods of treating the conditions, diseases, or disorders described herein generally involve administering to a subject in need thereof a therapeutically effective amount of a compound described herein (e.g., a compound of Formula (I), Formula (Ia), Formula (Ib), or Formula (II)), or stereoisomers and / or pharmaceutically acceptable salts thereof, to treat the condition, disease, or disorder.

[0169] In typical embodiments, the present disclosure is intended to encompass the compounds disclosed herein or stereoisomers thereof, and / or pharmaceutically acceptable salts thereof. In some embodiments, the present disclosure includes an enantiomer, a mixture of enantiomers, a stereoisomer, or a 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), or Formula (II)).

[0170] Conditions, diseases, and disorders include, but are not limited to, cardiovascular disease, atrial fibrillation, blood clotting, coronary heart disease, hypercoagulability conditions, ischemia, myocardial infarction, myopathy, myositis, pulmonary embolism, stroke, peripheral vascular disease, pulmonary hypertension, pulmonary arterial hypertension, dyslipidemia, dyslipoproteinemia, glucose metabolism disorders, Alzheimer's disease, Parkinson's disease, diabetic nephropathy, diabetic retinopathy, insulin resistance, metabolic syndrome disorders (e.g., syndrome X), galactosemia, HIV infection, peroxisome proliferator-activated receptor-associated disorders, sepsis, thrombotic disorders, obesity, pancreatitis, hypertension, kidney disease, cancer, inflammation (e.g., hepatic inflammation), inflammatory muscle diseases (e.g., polymyalgia rheumatica, polymyositis, fibromyositis), impotence, gastrointestinal disorders, irritable bowel syndrome, inflammatory bowel disease, inflammatory diseases (e.g., asthma, vasculitis, ulcerative colitis, Crohn's disease, Kawasaki disease, Wegener's granulomatosis (RA), systemic lupus erythematosus Examples of the conditions that may be affected include systemic lupus erythematosus (SLE), multiple sclerosis (MS), autoimmune chronic hepatitis), arthritis (e.g., rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis), osteoporosis, soft tissue rheumatism (e.g., tendonitis), bursitis, autoimmune diseases (e.g., systemic lupus erythematosus), scleroderma, ankylosing spondylitis, gout, pseudogout, non-insulin-dependent diabetes mellitus, diabetes (e.g., type 2), polycystic ovarian disease, hyperlipidemia (e.g., primary hyperlipidemia, familial hypercholesterolemia (FH), Frederickson hypercholesterolemia type IIa, Frederickson hypercholesterolemia type IIb, familial mixed hyperlipidemia (FCH)), lipoprotein lipase deficiency (e.g., hypertriglyceridemia, hypoalphalipoproteinemia, hypercholesterolemia), lipoprotein abnormalities associated with diabetes, lipoprotein abnormalities associated with obesity, and lipoprotein abnormalities associated with Alzheimer's disease. In certain embodiments, the methods include treating and / or preventing hyperlipidemia, such as primary hyperlipidemia. In some embodiments, the methods include treating and / or preventing cardiovascular disease.

[0171] In certain embodiments, the compounds disclosed herein (e.g., compounds of Formula (I), Formula (Ia), Formula (Ib), or Formula (II)), or stereoisomers and / or pharmaceutically acceptable salts thereof (including pharmaceutical compositions) can be used to treat or prevent 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 lipoprotein 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, the methods of the present disclosure may include lowering LDL-C, lowering apoB, lowering Lp(a), lowering VLDL, lowering non-HDL-C, lowering TC, and / or lowering hsCRP. The methods of the present disclosure may 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), or Formula (II)), or a stereoisomer and / or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure, can be used as an adjunct to dietary therapy 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), or Formula (II)) or a stereoisomer and / or pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure, can be used to treat non-insulin dependent diabetes mellitus without increasing weight gain.

[0172] In certain embodiments, the compounds disclosed herein (e.g., compounds of Formula (I), Formula (Ia), Formula (Ib), or Formula (II)), or stereoisomers and / or pharmaceutically acceptable salts thereof, and pharmaceutical compositions can be used to treat or prevent a variety of diseases and conditions, including aging, Alzheimer's disease, cancer, cardiovascular disease, diabetic nephropathy, diabetic retinopathy, impaired glucose metabolism, dyslipidemia, increased bile production, hypertension, impotence, inflammation, insulin resistance, biliary lipid excretion, modulation of C-reactive protein, obesity, biliary oxysterol excretion, pancreatitis, pancreatitis, Parkinson's disease, peroxisome proliferator-activated receptor-related diseases, biliary phospholipid excretion, kidney disease, rhabdomyolysis, sepsis, sleep apnea, syndrome X, and thrombotic diseases.

[0173] In certain embodiments, provided herein are methods for treating a liver disorder selected from the group consisting of steatohepatitis, alcoholic liver disease, fatty liver, hepatic steatosis, cirrhosis, liver fibrosis, and acute fatty liver of pregnancy. In some embodiments, the disorder is steatohepatitis. In some embodiments, the steatohepatitis is NASH. In some embodiments, the steatohepatitis is NASH. In some embodiments, the disorder is alcoholic liver disease. In some embodiments, the disorder is fatty liver. In some embodiments, the disorder is hepatic steatosis, cirrhosis, or liver fibrosis. In some embodiments, the disorder is acute fatty liver of pregnancy. In some embodiments, the subject is an adult human.

[0174] In certain embodiments, the present disclosure relates to aging, Alzheimer's disease, cancer, cardiovascular disease, diabetic nephropathy, diabetic retinopathy, glucose metabolism disorders, dyslipidemia, dyslipidemia, enhanced bile production, enhanced reverse lipid transport, hypertension, impotence, inflammation, insulin resistance, biliary lipid clearance, C-reactive protein regulation, obesity, biliary oxysterol clearance, pancreatitis, pancreatitis, Parkinson's disease, peroxisome proliferator-activated receptor-associated disorders, biliary phospholipid clearance, renal disease, sepsis, metabolic syndrome disorders (e.g., Syndrome X), or thrombotic disorders.

[0175] In certain embodiments, the disorder is selected from the group consisting of lipodystrophy, lysosomal acid lipase deficiency, and glycogen storage disease. In some embodiments, the subject is an adult human.

[0176] In certain embodiments, the disorder is selected from the group consisting of hepatitis C, infection with human immunodeficiency virus, alpha-1 antitrypsin deficiency, Bassen-Korzweig 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 infection with human immunodeficiency virus. In some embodiments, the disorder is alpha-1 antitrypsin deficiency. In some embodiments, the disorder is Bassen-Korzweig 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 subject is an adult human.

[0177] 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 subject is an adult human.

[0178] In various embodiments, provided herein are methods of treating NAFLD in a subject in need thereof, which generally include administering to the subject a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula (I), Formula (Ia), Formula (Ib), or Formula (II)), or a stereoisomer and / or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein.

[0179] In various embodiments, provided herein are methods of treating NASH in a subject in need thereof, which generally involve administering to the subject a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula (I), Formula (Ia), Formula (Ib), or Formula (II)), or a stereoisomer and / or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein.

[0180] In various embodiments, provided herein are methods of treating type 2 diabetes in a subject in need thereof, the methods generally comprising administering to the subject a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula (I), Formula (Ia), Formula (Ib), or Formula (II)), or a stereoisomer and / or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein.

[0181] In various embodiments, provided herein are methods of treating inflammation in a subject in need thereof, the methods generally comprising administering to the subject a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula (I), Formula (Ia), Formula (Ib), or Formula (II)), or a stereoisomer and / or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein.

[0182] In various embodiments, provided herein are methods of treating chronic kidney disease in a subject in need thereof, which generally involve administering to the subject a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula (I), Formula (Ia), Formula (Ib), or Formula (II)), or a stereoisomer and / or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein.

[0183] In various embodiments, provided herein are methods of treating autoimmunity in a subject in need thereof, the methods generally comprising administering to the subject a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula (I), Formula (Ia), Formula (Ib), or Formula (II)), or a stereoisomer and / or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein.

[0184] In various embodiments, provided herein are methods of treating cancer (e.g., liver cancer) in a subject in need thereof, the methods generally comprising administering to the subject a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula (I), Formula (Ia), Formula (Ib), or Formula (II)), or a stereoisomer and / or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein.

[0185] In certain embodiments, to prolong the effect of a drug, a compound described herein (e.g., a compound of Formula (I), Formula (Ia), Formula (Ib), or Formula (II)), or a stereoisomer and / or pharmaceutically acceptable salt thereof, is administered by subcutaneous or intramuscular injection, or by dissolving or suspending the drug in an oil vehicle.

[0186] In certain embodiments, the actual dosage level of a compound described herein (e.g., a compound of Formula (I), Formula (Ia), Formula (Ib), or Formula (II)), or a stereoisomer and / or pharmaceutically acceptable salt thereof, in the pharmaceutical compositions of the present disclosure is such that the compound (e.g., a compound of Formula (I), Formula (Ia), Formula (Ib), or Formula (II)), or a stereoisomer and / or pharmaceutically acceptable salt thereof, is effective to achieve the desired therapeutic response for the particular subject, composition, and mode of administration, and is not toxic to the subject.

[0187] In certain embodiments, the selected dosage will depend on a variety of factors, including the route of administration, the time of administration, the rate of excretion or metabolism of the particular compound employed, the rate and extent of absorption, the duration of treatment, other drugs, compounds and / or materials used in combination with the particular compound employed, the age, sex, weight, symptoms, general health and prior medical history of the subject being treated, and such factors as are well known in the medical arts.

[0188] 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.

[0189] In certain embodiments, a suitable daily dose of a compound described herein (e.g., a compound of Formula (I), Formula (Ia), Formula (Ib), or Formula (II)), or a stereoisomer and / or pharmaceutically acceptable salt thereof, will be the amount corresponding 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), or Formula (II)), or a stereoisomer and / or 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), or Formula (II)), or a stereoisomer and / or pharmaceutically acceptable salt thereof, is used alone.

[0190] In certain embodiments, an effective daily amount of a compound described herein (e.g., a compound of Formula (I), Formula (Ia), Formula (Ib), or Formula (II)), or a stereoisomer and / or pharmaceutically acceptable salt thereof, may be administered as two, three, four, five, six, or more subdoses. In certain embodiments, the two, three, four, five, six, or more subdoses are administered separately at appropriate intervals throughout the day, optionally in unit dosage form. In some embodiments, administration is once daily. In some embodiments, a compound described herein (e.g., a compound of Formula (I), Formula (Ia), Formula (Ib), or Formula (II)), or a stereoisomer and / or pharmaceutically acceptable salt thereof, is administered to a subject for 1 day, 5 days, 10 days, 20 days, 30 days, 1 week, 2 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), or Formula (II)), or a stereoisomer and / or pharmaceutically acceptable salt thereof, is administered to a subject for the duration of the subject's life.

[0191] Combination therapy In various embodiments, a compound disclosed herein (e.g., a compound of Formula (I), Formula (Ia), Formula (Ib), or Formula (II)), or a stereoisomer and / or pharmaceutically acceptable salt thereof, including a pharmaceutical composition of the present disclosure, can be part of a combination therapy. In certain embodiments, the combination therapy includes a compound described herein (e.g., a compound of Formula (I), Formula (Ia), Formula (Ib), or Formula (II)), or a stereoisomer and / or pharmaceutically acceptable salt thereof, and a second therapeutic agent. In certain embodiments, the combination therapy includes a pharmaceutical composition comprising an effective amount of a compound described herein (e.g., a compound of Formula (I), Formula (Ia), Formula (Ib), or Formula (II)), or a stereoisomer and / or pharmaceutically acceptable salt thereof, and a second therapeutic agent.

[0192] In some embodiments, the second therapeutic agent is selected from the group comprising lovastatin, a thiazolidinedione or fibrate, a bile acid-binding resin, niacin, an anti-obesity drug, a hormone, an antiviral drug (e.g., to treat an underlying hepatitis C infection causing liver disease in the subject), an anti-cancer drug (e.g., to treat hepatocellular carcinoma or other cancers that cause liver disease or fatty liver), an antioxidant, a drug that reduces insulin resistance or a drug that improves lipid metabolism (e.g., a drug for treating hyperlipidemia), tyrphostin, a sulfonylurea-based drug, a biguanide, an α-glucosidase inhibitor, an apolipoprotein AI agonist, apolipoprotein E, a cardiovascular drug, an HDL-raising drug, an HDL-enhancing agent, or a modulator of apolipoprotein AI, apolipoprotein A-IV and / or an apolipoprotein gene.

[0193] In various embodiments, the second therapeutic agent can be bempedoic acid, a statin, and / or ezetimibe.

[0194] 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.

[0195] 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), or Formula (II)), or a stereoisomer and / or 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), or Formula (II)), or a stereoisomer and / or pharmaceutically acceptable salt thereof, and the second therapeutic agent. In some embodiments, the beneficial effect of the combination therapy may include pharmacokinetic or pharmaceutical co-action resulting from the combination of the compound (e.g., a compound of Formula (I), Formula (Ia), Formula (Ib), or Formula (II)), or a stereoisomer and / or pharmaceutically acceptable salt thereof, and the second therapeutic agent.

[0196] kit In various embodiments, the present disclosure provides kits for treating a condition, disease, or disorder described herein. In some embodiments, the kit includes: i) instructions for treating, e.g., a condition, disease, or disorder described herein; and ii) a compound described herein (e.g., a compound of Formula (I), Formula (Ia), Formula (Ib), or Formula (II)), or a stereoisomer and / or 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), or Formula (II)), or a stereoisomer and / or pharmaceutically acceptable salt thereof). In some embodiments, the kit may include 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), or Formula (II)), or a stereoisomer and / or pharmaceutically acceptable salt thereof) effective to treat the condition, disease, or disorder.

[0197] The description herein includes multiple aspects and embodiments of the disclosure, including methods for making a compound described herein (e.g., a compound of Formula (I), Formula (Ia), Formula (Ib), or Formula (II)), or a stereoisomer and / or pharmaceutically acceptable salt thereof; methods for using a compound described herein (e.g., a compound of Formula (I), Formula (Ia), Formula (Ib), or Formula (II)), or a stereoisomer and / or 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), or Formula (II)), or a stereoisomer and / or pharmaceutically acceptable salt thereof; and kits. The present disclosure specifically includes all combinations and permutations of the aspects and embodiments described herein. [Example]

[0198] The following representative examples are intended to illustrate the disclosure and are not intended, nor should they be construed, to limit the scope of the disclosure.

[0199] The compounds provided herein can be prepared from readily available starting materials using the following general methods and procedures. Where typical or preferred process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.) are given, it will be understood that other process conditions can also be used unless otherwise specified. Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by one skilled in the art by routine optimization.

[0200] Furthermore, 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 selection of an appropriate 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 the following references: TW Greene and PGM Wuts, Protecting Groups in Organic Synthesis, Second Edition, Wiley, New York, 1991, and references cited therein.

[0201] The compounds provided herein can 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). It should be noted that flash chromatography can be performed manually or via an automated system. The compounds provided herein can 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 parts per million (ppm) and are generated using methods well known to those skilled in the art.

[0202] Analysis method Method A: Ultra-high performance liquid chromatography-mass spectrometry (UHPLC-MS) was performed using a Phenomenex Kinetex-XB C18 column (2.1 mm x 100 mm, 1.7 μm, 40 °C temperature) with a 1 μL injection volume, a flow rate of 0.6 mL / min, and a gradient of 5-100% B in 5.30 min, followed by 100% B in 0.50 min in reverse phase (where A = 0.1% formic acid in water, B = 0.1% formic acid in acetonitrile). A second gradient of 100-5% B was performed over 0.02 min and held for 1.18 min. UV spectra were recorded at 215 nm. Spectral range: 200-400 nm. ELS data, where reported, were collected on a Waters ELS detector. Mass spectra were acquired using a Waters SQD, SQD2, or QDA detector. Ionization mode: electrospray positive or negative. Data were integrated and reported using Waters MassLynx and OpenLynx software.

[0203] Method B: UHPLC-MS was performed using a Waters UPLC® BEH® C18 column (2.1 mm × 50 mm, 1.7 μm, temperature: 40°C) in a reversed-phase system with an injection volume of 1 μL, a flow rate of 0.9 mL / min, and a gradient of 5–100% B over 1.10 min, followed by a 0.25 min hold at 100% B (where A = 0.1% formic acid in water, B = 0.1% formic acid in acetonitrile). A second gradient of 100–5% B was performed over 0.05 min and held for 0.10 min. UV spectra were recorded at 215 nm. Spectral range: 200–400 nm. Mass spectra were acquired using a Waters SQD, SQD2, or QDA detector. Ionization mode: electrospray positive or negative. Data were integrated and reported using Waters MassLynx and OpenLynx software.

[0204] Method C: UHPLC-MS was performed using a Waters UPLC® CORTECS® C8 column (2.1 mm × 100 mm, 1.6 μm, 40°C temperature) in reverse phase with a 1 μL injection volume, a flow rate of 0.6 mL / min, and a gradient of 5–100% B over 5.30 min followed by 100% B over 0.50 min (where A = 0.1% formic acid in water, B = 0.1% formic acid in acetonitrile). A second gradient of 100–5% B was performed over 0.02 min and held for 1.18 min. UV spectra were recorded at 215 nm. Spectral range: 200–400 nm. ELS data, where reported, were collected using a Waters ELS detector. Mass spectra were acquired using a Waters SQD, QD2, or QDA. Ionization mode: electrospray positive or negative. Data were integrated and reported using Waters MassLynx and OpenLynx software.

[0205] Preparative HPLC method Method P1: Liquid chromatography (LC) was performed using a Waters Sunfire® C18 column (30 mm x 100 mm, 5 μm, room temperature) with an injection volume of 1500 μL and a flow rate of 40 mL / min. The LC gradient was 30% B in 1.90 min, followed by a gradient from 30 to 95% B over 9.60 min and a hold time of 1.97 min (where A = 0.1% formic acid in water, B = 0.1% formic acid in acetonitrile). This was followed by a second gradient from 95 to 30% B over 0.33 min and a hold time of 1.65 min. UV spectra were recorded at 215 nm.

[0206] Method P2: LC was performed in reverse phase on a Waters Sunfire® C18 column (30 mm × 100 mm, 5 μm, room temperature) with an injection volume of 1500 μL and a flow rate of 40 mL / min. 10% B was run for 1.90 min, followed by a gradient from 10 to 95% B over 14.10 min and held for 2.0 min (where A = 0.1% formic acid in water, B = 0.1% formic acid in acetonitrile). A second gradient from 95 to 10% B was run over 0.20 min and held for an additional 1.25 min. UV spectra were recorded at 215 nm.

[0207] Method P3: Reversed-phase LC was performed using a Waters XBridge® C18 column (30 mm x 100 mm, 5 μm, room temperature) with an injection volume of 1500 μL and a flow rate of 40 mL / min. The run consisted of 10% B in 2.00 min, followed by a gradient from 10 to 95% B over 14.00 min and a hold of 2.00 min (where A = 0.2% ammonium hydroxide in water, B = 0.2% ammonium hydroxide in acetonitrile). This was followed by a second gradient from 95 to 10% B over 0.20 min and a hold of 1.25 min. UV spectra were recorded at 215 nm. Abbreviation Aq.:Aqueous solution Boc: tert-butylcarbamoyl Boc2O: di-tert-butyl carbonate CDCl3: deuterated chloroform CHCl3: Chloroform CO2: Carbon dioxide CV: column volume DAST: Diethylaminosulfur trifluoride DCC: N,N'-dicyclohexylcarbodiimide DCE: dichloroethane DCM: dichloromethane DIAD: Diisopropyl azodicarboxylate DIBAL: Diisobutylaluminum hydride DIPEA: N,N-diisopropylethylamine DMAP: 4-(dimethylamino)pyridine DMF: N,N-dimethylformamide DMSO: dimethyl sulfoxide dppf: 1,1'-bis(diphenylphosphino)ferrocene ESI: electrospray ionization Et2O: Diethyl ether EtOH: ethanol EtOAc: ethyl acetate FCC: flash column chromatography HCl: Hydrogen chloride H2O: Water HPLC: High-performance liquid chromatography IPA: Isopropanol K2CO3: Potassium carbonate LCMS: Liquid Chromatography Mass Spectrometry LiAlH4: Lithium aluminum hydride LiHMDS: lithium bis(trimethylsilyl)amide M: mole mCPBA: metachloroperbenzoic acid MeCN: acetonitrile MeOH: Methanol MgSO4: Magnesium sulfate MnO2: Manganese(IV) oxide NaHCO3: Sodium bicarbonate Na2SO4: Sodium sulfate Na2S2O3: Sodium thiosulfate NH3: Ammonia NH4Cl: Ammonium hydrochloride NMR: nuclear magnetic resonance Pd2(dba)3: Tris(dibenzylideneacetone)dipalladium(0) Pd(dppf)Cl2:1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) RT: retention time rt: room temperature sat.: saturation SCX: Strong cation exchange cartridge (benzenesulfonic acid functionalized silica) SFC: Supercritical Fluid Chromatography SiO2: Silicon dioxide (FCC silica gel) T3P: Propylphosphonic anhydride TBAF: Tetrabutylammonium fluoride TBME: tert-butyl methyl ether TBS: tert-butyldimethylsilyl THF: tetrahydrofuran UV: Ultraviolet light wt%: weight percent

[0208] In some embodiments, compounds of the present disclosure can be synthesized using the procedures outlined in General Scheme 1. General Scheme 1 TIFF2025515002000429.tif175159

[0209] In General Scheme 1, starting material A is reacted with alcohol starting material B bearing R1'- and R2'-, for example, using Mitsunobu reaction conditions (e.g., PPh3, DIAD, THF, 30-40°C, 1-3 hours) to provide intermediate D, where X is oxygen. In some embodiments, R1' and R2' are selected from hydrogen and lower alkyl, e.g., methyl. In some embodiments, m is 1 to 3.

[0210] Alternatively, amine starting material C undergoes amine protection using Boc protection conditions (e.g., BocO, sodium bicarbonate (aq), THF, room temperature, 1 hour) to provide intermediate D, where R1' and R2' are both hydrogen, X is CH2, and m is 0 to 1. Alternatively, starting material C undergoes amine protection using Boc protection conditions (e.g., BocO, sodium bicarbonate (aq), THF, room temperature, 1 hour) followed by methylation of the carbamate nitrogen using alkylation conditions (e.g., NaH, MeI, DMF, 1 hour) to provide intermediate D, where R1' is methyl, R2' is hydrogen, X is CH2, and m is 0 to 1.

[0211] Intermediate D is reacted with an R3'-containing pinacol boronate ester intermediate E using palladium-catalyzed cross-coupling conditions (e.g., Pd(dppf)Cl2, potassium carbonate, dioxane / water, 100°C, about 18 hours) to produce intermediate F. In some embodiments, R3' is selected from H or lower alkyl (e.g., methyl). Intermediate F is reacted with an R4'-containing sulfonyl chloride intermediate G under basic conditions (e.g., pyridine, 50°C, 1 to 2.5 hours) to produce intermediate H. In some embodiments, R4' is selected from lower alkyl (e.g., methyl) or haloalkyl (e.g., -CHF2). Intermediate H undergoes ester hydrolysis under basic conditions (e.g., sodium hydroxide (aqueous), THF or THF / methanol, room temperature, 2 to 18 hours) to provide intermediate I. Intermediate I is Boc-deprotected under acidic conditions (4 M hydrochloric acid in dioxane, room temperature, 1 to 2.5 hours) to give intermediate J. Intermediate J is then cyclized using amide coupling conditions (e.g., T3P, DIPEA, DMF, room temperature, about 0.5 to 1 hour) to give product K. Optionally, when R4' is methyl, intermediate K is etherolyzed using, for example, DCM, 1 M BBr3 in DMF, 80°C, typically for 18 to 24 hours, or 1 M BBr3 in DCM, room temperature, typically for 18 hours, to give final product L.

[0212] In some embodiments, compounds of the present disclosure are synthesized using the procedures outlined in General Scheme 2. General Scheme 2 TIFF2025515002000430.tif163158

[0213] In General Scheme 2, starting material A is reacted with starting material B to produce intermediate D, where X is oxygen. In some embodiments, A is selected from CH or N, Y is selected from Br or I, and R is selected from halogen (e.g., F, Cl, Br), alkyl (e.g., methyl), cycloalkyl (e.g., cyclopropyl), or —CN. In some embodiments, Q is selected from hydroxyl or Br, and m is 1 to 2. When Q is hydroxyl, starting material A is reacted with starting material B using Mitsunobu reaction conditions (e.g., PPh, DIAD, THF, 40° C., 1 to 3 hours) to produce intermediate D. When Q is Br, starting material A is reacted with starting material B using alkylation conditions (e.g., base (KCO), acetonitrile, ∼70° C., ∼18 hours) to produce intermediate D. Alternatively, alcohol starting material C, where m is 0 to 1, undergoes alcohol protection using silyl ether protection conditions (e.g., TBS-Cl, imidazole, DMF, hold time, 4 hours) to generate intermediate D, where X is CH2.

[0214] Intermediate D reacts with pinacol boronic ester intermediate E having R2' and R3' using palladium-catalyzed cross-coupling conditions (e.g., Pd(dppf)Cl2, base (K2CO3), dioxane, 100°C, 18 hours) to produce intermediate F. In some embodiments, R2' is selected from F or methoxy, and R3' is selected from H, F, methyl, or methoxy. Intermediate F reacts with sulfonyl chloride intermediate G under basic conditions (e.g., pyridine, 50°C, 1 to 2.5 hours) to produce intermediate H. Intermediate H undergoes ester hydrolysis under basic conditions (e.g., aqueous sodium hydroxide, THF, hold time, 4 hours) to produce intermediate I. Intermediate I undergoes silyl ether deprotection using a fluoride source (e.g., TBAF, THF, hold time, 18 to 72 hours) to produce intermediate J. Intermediate J then undergoes cyclization using ester coupling conditions, such as Yamaguchi esterification conditions (e.g., 2,4,6-trichlorobenzoyl chloride, DIPEA, DMAP, room temperature for 1 hour, then 65°C for 3 to 18 hours, purified by acidic reverse-phase preparative HPLC) to produce intermediate K. Finally, intermediate K is etherolyzed using, for example, 1MBBr3 in DCM, DMF at 80°C for 20 hours to give final product L.

[0215] In some embodiments, compounds of the present disclosure can be synthesized using the procedures outlined in General Scheme 3. General Scheme 3 JPEG2025515002000431.jpg144158

[0216] 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)Cl, base (KCO), dioxane, 100°C, 18 hours) to give intermediate C. Intermediate C is reacted with sulfonyl chloride intermediate D under basic conditions (e.g., pyridine, 50°C, 1 hour) to give intermediate E. Intermediate E undergoes ester hydrolysis under basic conditions (e.g., aqueous sodium hydroxide, THF, room temperature, 3 hours) to give intermediate F. Intermediate F undergoes cyclization using ester coupling conditions (e.g., DCC, DMAP, DCM, room temperature, 24 hours) to give intermediate G. Finally, intermediate G undergoes ether cleavage (e.g., using iodocyclohexane, anhydrous DMF, 120°C, 1-3 hours, or lithium iodide, anhydrous pyridine, 80°C, 6-18 hours) to give final product H.

[0217] Intermediate A may have additional substituents or may incorporate heteroatoms in the aryl ring.

[0218] Intermediate B may have different substituents, may have additional substituents, or may incorporate heteroatoms into the aryl ring.

[0219] Example 1: 15-chloro-21,23-difluoro-16-methoxy-8-oxa-18lambda 6-thia-11,19-diazatetracyclo[18.3.1.1 13,17 .0 2,7 ]Synthesis of pentacosa-1(24),2,4,6,13,15,17(25),20,22-nonaene-12,18,18-trione (compound 1) TIFF2025515002000432.tif5758 To a solution of DIPEA (0.13 mL, 0.740 mmol) and T3P (50 wt%, 0.44 mL, 0.740 mmol) in ethyl acetate (50 mL) was added a solution of Intermediate 6 (253 mg, 0.493 mmol) in anhydrous DMF (50 mL) over 1.5 h. The colorless solution was stirred at room temperature for 23 h. To the reaction mixture was added T3P (50 wt%, 0.44 mL, 0.740 mmol) and DIPEA (0.13 mL, 0.740 mmol) in ethyl acetate, and the reaction mixture was stirred at room temperature for 2.5 h. The reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (4 × 200 mL). The combined organic extracts were washed with brine (4 x 200 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to give a yellow residue (530 mg). The residue was triturated with DCM / methanol, sonicated, and the resulting white suspension was collected by suction filtration. The filter cake was washed with DCM and dried in vacuo to give the title compound as a white solid (180 mg, 72% yield, 98% purity). 1 H NMR (400 MHz, DMSO) δ 10.39 (s, 1H), 8.16 - 8.07 (m, 1H), 8.01 (d, J = 1.7 Hz, 1H), 7.52 (d, J = 2.1 Hz, 1H), 7.48 - 7.41 (m, 1H), 7.37 - 7.31 (m, 1H), 7.28 - 7.24 (m, 1H), 7.17 - 7.13 (m, 1H), 7.11 - 7.03 (m, 2H), 4.21 (t, J = 5.0 Hz, 2H), 3.99 (s, 3H), 3.53 - 3.44 (m, 2H). 19 F NMR (376 MHz, DMSO-d6) δ -109.21, -120.11. LCMS: m / z = 494.9 / 496.9 [M+H]+, (ESI+), RT = 3.44, Method A

[0220] Example 2: 15-chloro-21,23-difluoro-16-hydroxy-8-oxa-18lambda 6-thia-11,19-diazatetracyclo[18.3.1.1 13,17 .0 2,7 ]Synthesis of pentacosa-1(24),2,4,6,13,15,17(25),20,22-nonaene-12,18,18-trione (compound 2) TIFF2025515002000433.tif5558 To a suspension of compound 1 (140 mg, 0.283 mmol) in anhydrous DCM (2.0 mL) and anhydrous toluene (2.0 mL) was added 1 M BBr3 in DCM (0.85 mL, 0.849 mmol) dropwise at 0 °C. The resulting white suspension was heated at 60 °C for 22 h. The reaction mixture was cooled to room temperature, transferred to a large vial, and diluted with anhydrous DCM (6 mL) and anhydrous toluene (6 mL). To the reaction mixture was added 1 M BBr3 in DCM (0.85 mL, 0.849 mmol) dropwise, and the reaction mixture was heated at 70 °C for 0.5 h and then at 80 °C for 6 h. The reaction mixture was cooled to room temperature and slowly added to a saturated aqueous solution of sodium bicarbonate at 0 °C. The layers were separated, and the organics were washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. Purification by FCC (10 g SiO 2 column, 0-20% methanol in DCM) afforded the title compound as an off-white solid (76 mg, 54% yield, 96% purity). 1 H NMR (400 MHz, DMSO) δ 10.39 (broad s, 1H), 8.00–7.92 (m, 1H), 7.90 (d, J = 1.9 Hz, 1H), 7.46–7.40 (m, 2H), 7.30–7.24 (m, 1H), 7.24–7.20 (m, 1H), 7.18–7.11 (m, 2H), 7.07–7.01 (m, 1H), 4.20 (t, J = 4.7 Hz, 2H), 3.49–3.41 (m, 2H). 1H was not observed. 19 F NMR (376 MHz, DMSO-d6) δ -109.64, -120.02. LCMS: m / z = 480.9 / 482.9 [M+H]+, (ESI+), RT = 3.22, Method A

[0221] Example 3: 11-chloro-3,5-difluoro-10-hydroxy-18-oxa-8 lambda 6-thia-7,15-diazatetracyclo[17.3.1.1 2,6 .1 9,13 ]Synthesis of pentacosa-1(22),2(25),3,5,9(24),10,12,19(23),20-nonaene-8,8,14-trione (compound 3) To a solution of 11-chloro-3,5-difluoro-10-methoxy-8,8-dioxo-18-oxa-8λ6-thia-7,15-diazatetracyclo[17.3.1.12,6.19,13]pentacosa-1(22),2(25),3,5,9(24),10,12,19(23),20-nonaen-14-one (synthesized according to General Scheme 1, 94%, 100 mg, 0.190 mmol) in anhydrous DCE (2.5 mL) and anhydrous DMF (1.5 mL) at room temperature, 1 M BBr in DCM (0.19 mL, 0.190 mmol) was added dropwise. The resulting solution was heated at 80 °C for 18 h and then cooled to room temperature. To the reaction mixture was added 1M BBr3 in DCM (0.76 mL, 0.760 mmol), and the reaction mixture was heated at 80 °C for 5 h, then cooled to room temperature. The reaction mixture was slowly added to saturated aqueous sodium bicarbonate. The mixture was diluted with water and 1:3 IPA / CHCl3. The layers were separated, and the aqueous solution was extracted with 1:3 IPA / CHCl3. The organics were combined and passed through a hydrophobic frit. Purification by FCC (10 g silicon dioxide, 0-30% methanol in DCM), followed by trituration with acetonitrile, afforded the title compound as an off-white solid (47 mg, 98% pure). 1H NMR (500 MHz, DMSO) δ 8.72 (broad s, 1H), 8.36 (apparent s, 1H), 7.80 (apparent s, 1H), 7.34 - 7.27 (m, 1H), 7.25 - 7.12 (m, 2H), 7.11 - 7.05 (m, 1H), 7.03 - 6.97 (m, 1H), 6.73 (apparent s, 1H), 4.19 - 4.01 (m, 2H), 3.62 - 3.46 (m, 2H). No 2H was observed. LCMS: m / z = 481.2 / 483.2 [M+H]+, (ESI+), RT = 2.98, Method A

[0222] Example 4: 15-chloro-21,23-difluoro-16-hydroxy-11-methyl-8-oxa-18lambda 6-thia-11,19-diazatetracyclo[18.3.1.1 13,17 .0 2,7 ]Synthesis of pentacosa-1(24),2,4,6,13,15,17(25),20,22-nonaene-12,18,18-trione (compound 4) To a suspension of 15-chloro-21,23-difluoro-16-methoxy-11-methyl-18,18-dioxo-8-oxa-18λ6-thia-11,19-diazatetracyclo[18.3.1.113,17.02,7]pentacosa-1(24),2,4,6,13,15,17(25),20,22-nonaen-12-one (synthesized according to General Scheme 1, 92%, 250 mg, 0.452 mmol) in anhydrous DCE (6.0 mL) and anhydrous DMF (3.0 mL) was added 1 M BBr in DCM (2.0 mL, 2.0 mmol) dropwise at 0 °C. The resulting pale yellow suspension was heated at 80 °C for 5 h. The reaction mixture was cooled to 0 °C, and additional 1 M BBr3 in DCM (2.0 mL, 2.0 mmol) was added. The reaction mixture was heated at 80 °C for 17 h and then cooled to room temperature. The reaction mixture was slowly added to a saturated aqueous solution of sodium bicarbonate (30 mL) at 0 °C. The aqueous solution was extracted with DCM (2 × 20 mL), and the combined organics were washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Purification by FCC (10 g silicon dioxide, 0 to 40% methanol in DCM) gave the product, which was further purified by FCC (10 g silicon dioxide, 100% DCM, then 0 to 30% methanol in DCM) to give a tan solid (110 mg). This solid was purified by preparative HPLC (Method P1) to give the title compound as a white solid (34 mg, 15% yield, 99% purity). 1 H NMR (400 MHz, DMSO) δ 11.21 (broad s, 1H), 10.29 (broad s, 1H), 7.67 (d, J = 2.0 Hz, 1H), 7.48 - 7.35 (m, 1H), 7.35 - 7.16 (m, 5H), 7.12 - 7.05 (m, 1H), 4.12 - 3.93 (m, 2H), 2.90 (broad s, 3H). 2H was not observed. LCMS: m / z = 495.2 / 497.2 [M+H]+, (ESI+), RT = 3.11, Method A

[0223] Example 5: 11-chloro-3,5-difluoro-10-hydroxy-19-oxa-8 lambda 6-thia-7,15-diazatetracyclo[18.3.1.1 2,6 .1 9,13 ]Synthesis of hexacosa-1(23),2(26),3,5,9(25),10,12,20(24),21-nonaene-8,8,14-trione (compound 5) To a solution of 11-chloro-3,5-difluoro-10-methoxy-8,8-dioxo-19-oxa-8λ6-thia-7,15-diazatetracyclo[18.3.1.12,6.19,13]hexacosa-1(23),2(26),3,5,9(25),10,12,20(24),21-nonaen-14-one (synthesized according to General Scheme 1, 90%, 200 mg, 0.354 mmol) in anhydrous DMF (4.0 mL) was added 1 M BBr in DCM (0.71 mL, 0.710 mmol) at room temperature. The reaction mixture was heated at 80 °C for 6 h and then cooled to room temperature. To the reaction mixture was added 1M BBr3 in DCM (1.42 mL, 1.42 mmol), and the reaction mixture was heated at 80 °C for 16 h. After the reaction mixture was cooled to room temperature, it was slowly added to saturated aqueous NaHCO3. The mixture was extracted with DCM (3 times), and the combined organics were passed through a hydrophobic frit. The residue was purified by preparative HPLC (Method P2) to give the title compound as an off-white solid (93 mg, 53% yield, 100% purity). 1 H NMR (500 MHz, DMSO) δ 8.78 (t, J = 6.2 Hz, 1H), 8.50 (d, J = 2.2 Hz, 1H), 8.22 (d, J = 2.2 Hz, 1H), 7.41–7.36 (m, 1H), 7.34–7.30 (m, 1H), 7.10–7.02 (m, 2H), 6.95 (dd, J = 8.1, 2.5 Hz, 1H), 6.19–6.18 (m, 1H), 4.13 (t, J = 5.8 Hz, 2H), 3.51–3.46 (m, 2H), 1.99–1.92 (m, 2H). 2H was not observed. LCMS: m / z = 495.0 / 496.9 [M+H]+, (ESI+), RT = 3.24, Method A

[0224] Example 6: 16-chloro-22,24-difluoro-17-hydroxy-8-oxa-19lambda 6-thia-12,20-diazatetracyclo[19.3.1.1 14,18 .0 2,7 ]Synthesis of hexacosa-1(25),2,4,6,14,16,18(26),21,23-nonaene-13,19,19-trione (compound 6) To a solution of 16-chloro-22,24-difluoro-17-methoxy-19,19-dioxo-8-oxa-19λ6-thia-12,20-diazatetracyclo[19.3.1.114,18.02,7]hexacosa-1(25),2,4,6,14,16,18(26),21,23-nonaen-13-one (synthesized according to General Scheme 1, 93%, 140 mg, 0.256 mmol) in anhydrous DMF (3.8 mL) was added 1 M BBr in DCM (1.00 mL, 1.00 mmol) at room temperature. The resulting solution was heated at 80 °C for 18 h and then cooled to room temperature. The reaction mixture was slowly added to saturated aqueous NaHCO solution, and the mixture was extracted with DCM (three times). The combined organics were passed through a phase separator and concentrated in vacuo. The residue was purified by preparative HPLC (Method P2) to give the title compound as an off-white solid (14 mg, 11% yield, 99% purity). 1 H NMR (500 MHz, DMSO) δ 7.98–7.85 (m, 1H), 7.43–7.38 (m, 1H), 7.36–7.32 (m, 1H), 7.19–7.05 (m, 4H), 7.03–6.98 (m, 1H), 4.10 (t, J = 4.8 Hz, 2H), 1.87–1.80 (m, 2H). No 5H was observed. LCMS: m / z = 495.2 / 497.2 [M+H]+, (ESI+), RT = 3.36, Method A

[0225] Example 7: 15-chloro-21,23-difluoro-16-hydroxy-8,11-dioxa-18 lambda 6-thia-19-azatetracyclo[18.3.1.1 13,17 .0 2,7 ]Synthesis of pentacosa-1(24),2,4,6,13,15,17(25),20,22-nonaene-12,18,18-trione (compound 7) TIFF2025515002000438.tif5558 To a suspension of intermediate 12 (98%, 60 mg, 0.119 mmol) in anhydrous DMF (3.0 mL) at 0 °C was added 1MBBr3 in DCM (2.0 mL, 2.0 mmol) dropwise. The resulting pale yellow solution was heated at 80 °C for 20 h and then cooled to room temperature. The reaction mixture was added to saturated aqueous NaHCO3 (30 mL), and the aqueous solution was extracted with DCM (2 × 20 mL). The organics were combined, washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Purification using preparative HPLC (Method P1) afforded the title compound as a white solid (42 mg, 74% yield, 100% purity). 1 H NMR (500 MHz, DMSO) δ 11.53–9.83 (m, 1H), 8.04 (d, J = 2.1 Hz, 1H), 7.47 (d, J = 2.2 Hz, 1H), 7.47–7.43 (m, 1H), 7.33–7.25 (m, 2H), 7.25–7.16 (m, 2H), 7.12–7.04 (m, 1H), 4.36–4.32 (m, 2H), 4.31–4.27 (m, 2H). 1H was not observed. LCMS: m / z = 480.2 / 482.2 [MH]-, (ESI-), RT = 3.79, Method A

[0226] Example 8: 15-chloro-21,23-difluoro-16-hydroxy-18 lambda 6-thia-11,19-diazatetracyclo[18.3.1.1 13,17 .0 2,7]Synthesis of pentacosa-1(24),2,4,6,13,15,17(25),20,22-nonaene-12,18,18-trione (compound 8) To a solution of 15-chloro-21,23-difluoro-16-methoxy-18,18-dioxo-18λ6-thia-11,19-diazatetracyclo[18.3.1.113,17.02,7]pentacosa-1(24),2,4,6,13,15,17(25),20,22-nonaen-12-one (synthesized according to General Scheme 1, 80%, 170 mg, 0.276 mmol) in anhydrous DMF (4 mL) was added 1 M BBr in DCM (1.1 mL, 1.10 mmol) at room temperature. The reaction mixture was heated at 80 °C for 4 h and then cooled to room temperature. To the reaction mixture was added 1M BBr3 in DCM (1.1 mL, 1.10 mmol), and the reaction mixture was heated at 80 °C for 16 h, then cooled to room temperature. Water (40 mL) was added to the reaction mixture. The aqueous solution was extracted with DCM (3 × 30 mL), and the combined organics were passed through a hydrophobic frit and concentrated in vacuo. Purification was carried out by FCC (10 g silicon dioxide, 0-30% methanol in DCM). Fractions containing the product were combined and concentrated in vacuo, and the resulting solid was purified by preparative HPLC (Method P1) to give the title compound as a white solid (55 mg, 41% yield, 98% purity). 1 H NMR (400 MHz, DMSO) δ 11.07 - 9.88 (m, 2H), 8.30 - 8.18 (m, 1H), 7.88 (d, J = 2.1 Hz, 1H), 7.60 (d, J = 2.3 Hz, 1H), 7.45 - 7.35 (m, 2H), 7.33 - 7.20 (m, 3H), 7.20 - 7.14 (m, 1H), 3.50 - 3.38 (m, 1H), 3.08 - 2.94 (m, 1H), 2.47 - 2.41 (m, 1H), 2.26 - 2.06 (m, 2H), 1.73 - 1.54 (m, 1H). LCMS: m / z = 479.0 / 480.8 [M+H]+, (ESI+), RT = 3.34, Method A

[0227] Example 9: 15-chloro-21,23-difluoro-16-hydroxy-19-methyl-8-oxa-18lambda 6-thia-11,19-diazatetracyclo[18.3.1.1 13,17 .0 2,7 Synthesis of pentacosa-1(24),2,4,6,13,15,17(25),20,22-nonaene-12,18,18-trione (compound 9) To a solution of 15-chloro-21,23-difluoro-16-methoxy-19-methyl-18,18-dioxo-8-oxa-18λ6-thia-11,19-diazatetracyclo[18.3.1.113,17.02,7]pentacosa-1(24),2,4,6,13,15,17(25),20,22-nonaen-12-one (synthesized according to General Scheme 1, 80%, 200 mg, 0.314 mmol) in anhydrous DMF (5.0 mL) was added dropwise 1 M BBr in DCM (3.0 mL, 3.00 mmol) at 0 °C. The resulting solution was heated at 80 °C for 20 h and then cooled to room temperature. The reaction mixture was added to saturated aqueous NaHCO3 (30 mL) at 0 °C. The organics were extracted with DCM (2 × 20 mL). The organics were combined, washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Purification by preparative HPLC (Method P1) afforded the title compound as a white solid (66 mg, 40% yield, 95% purity). 1 H NMR (400 MHz, DMSO) δ 10.59 (broad s, 1H), 8.24 (t, J = 4.7 Hz, 1H), 7.95 (d, J = 2.2 Hz, 1H), 7.46 (d, J = 2.2 Hz, 1H), 7.41 - 7.34 (m, 2H), 7.14 - 7.03 (m, 3H), 7.00 - 6.93 (m, 1H), 4.21 (t, J = 5.1 Hz, 2H), 3.47 - 3.43 (m, 2H), 3.19 (s, 3H). LCMS: m / z = 495.2 / 497.2 [M+H]+, (ESI+), RT = 3.60, Method A

[0228] Example 10: 15-chloro-21,23-difluoro-16-hydroxy-11-methyl-18 lambda 6-thia-11,19-diazatetracyclo[18.3.1.1 13,17 .0 2,7 ]Synthesis of pentacosa-1(24),2,4,6,13,15,17(25),20,22-nonaene-12,18,18-trione (compound 10) To a solution of 15-chloro-21,23-difluoro-16-methoxy-11-methyl-18,18-dioxo-18λ6-thia-11,19-diazatetracyclo[18.3.1.113,17.02,7]pentacosa-1(24),2,4,6,13,15,17(25),20,22-nonaen-12-one (synthesized according to General Scheme 1, 91%, 153 mg, 0.275 mmol) in anhydrous DMF (4.0 mL) was added 1 M BBr in DCM (1.1 mL, 1.10 mmol). The reaction mixture was heated at 80 °C for 18 h and then cooled to room temperature. The reaction mixture was added to water (40 mL) and the organics were extracted with DCM (3 x 30 mL), combined and passed through a hydrophobic frit. Purification by preparative HPLC (Method P1) gave the title compound as a white solid (78 mg, 56% yield, 97% purity). 1 H NMR (400 MHz, DMSO) δ 11.46 (broad s, 1H), 10.28 (broad s, 1H), 7.61 (d, J = 2.1 Hz, 1H), 7.41 - 7.23 (m, 6H), 7.18 - 7.15 (m, 1H), 2.89 (s, 3H), 2.85 - 2.61 (m, 2H), 2.42 - 2.24 (m, 1H), 1.97 - 1.79 (m, 1H), 1.72 - 1.54 (m, 1H), 1.38 - 1.16 (m, 1H). LCMS: m / z = 493.2 / 495.3 [M+H]+, (ESI+), RT = 3.17, Method A

[0229] Example 11: 24-Fluoro-16-hydroxy-8-oxa-11,19-diazapentacyclo[17.5.2.1 13,17 .0 2,7 .0 22,26 ]Synthesis of heptacosa-1(24),2,4,6,13,15,17(27),22,25-nonaene-12,18-dione (compound 11) TIFF2025515002000442.tif5552 Step 1 A mixture of Intermediate 2 (92%, 500 mg, 1.45 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1,3,2-dioxaborolane (406 mg, 1.60 mmol), and potassium acetate (428 mg, 4.36 mmol) in anhydrous 1,4-dioxane (4.6 mL) was sparged with nitrogen for 20 minutes, after which Pd(dppf)Cl2 (107 mg, 0.145 mmol) was added and the solution was sparged for an additional 5 minutes. The reaction mixture was heated at 100 °C for a total of approximately 20 minutes. The mixture was then filtered through Celite and washed with ethyl acetate. Water was added to the filtrate and the layers were separated. The aqueous phase was extracted with ethyl acetate. The combined organics were washed with water, then brine, dried (sodium sulfate), filtered, and concentrated. The residue was purified by FCC (50 g SiO column, 0-100% ethyl acetate in heptane) to give tert-butyl N-[2-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]ethyl]carbamate (75.0%) (458 mg, 65% yield, 75% purity) as a pale yellow oil. 1 H NMR (500 MHz, DMSO) δ 7.52 (dd, J = 7.3, 1.8 Hz, 1H), 7.43 (ddd, J = 8.2, 7.3, 1.8 Hz, 1H), 6.99 - 6.91 (m, 2H), 6.49 (t, J = 5.6 Hz, 1H), 3.98 (t, J = 5.6 Hz, 2H), 3.39 - 3.34 (m, 2H), 1.40 (s, 9H), 1.31 (s, 12H).

[0230] Step 2 To a solution of tert-butyl N-[2-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]ethyl]carbamate (75%, 444 mg, 0.916 mmol) and 6-bromo-5-fluoroindoline (90%, 200 mg, 0.833 mmol) in 1,4-dioxane (4.5 mL) was added potassium carbonate (230 mg, 1.67 mmol), and the mixture was sparged with nitrogen for 5 minutes. Next, Pd(dppf)Cl2 (61 mg, 0.0833 mmol) was added, and the reaction mixture was sparged for an additional 5 minutes. The vessel was sealed, and the reaction mixture was heated at 100 °C overnight. The mixture was filtered through Celite, washing with ethyl acetate, and the filtrate was concentrated under reduced pressure. The residue was purified by FCC (25 g SiO2 column, 0-100% ethyl acetate in heptane) to give tert-butyl N-[2-[2-(5-fluoroindolin-6-yl)phenoxy]ethyl]carbamate (283 mg, 67% yield, 74% purity) as a light brown oil. 1 H NMR (400 MHz, DMSO) δ 7.32 (ddd, J = 8.3, 7.3, 1.8 Hz, 1H), 7.20 - 7.15 (m, 1H), 7.08 (dd, J = 8.4, 1.1 Hz, 1H), 6.99 (td, J = 7.4, 1.0 Hz, 1H), 6.89 (d, J = 9.7 Hz, 1H), 6.71 (t, J = 5.5 Hz, 1H), 6.38 (d, J = 6.1 Hz, 1H), 5.31 (d, J = 2.3 Hz, 1H), 3.97 - 3.89 (m, 2H), 3.43 (td, J = 8.5, 2.2 Hz, 2H), 3.17 (q, J = 6.3 Hz, 2H), 2.93 (t, J = 8.4 Hz, 2H), 1.37 (s, 9H). LCMS: m / z = 373.1 [M+H]+, (ESI+), RT = 0.74, Method B

[0231] Step 3 To a solution of 2-methoxy-5-methoxycarbonylbenzoic acid (96%, 94 mg, 0.429 mmol), tert-butyl N-[2-[2-(5-fluoroindolin-6-yl)phenoxy]ethyl]carbamate (74%, 180 mg, 0.358 mmol), and DIPEA (249 μL, 1.43 mmol) in anhydrous DMF (6.3 mL) was added T3P (50% in ethyl acetate) (0.64 mL, 1.07 mmol) dropwise. The mixture was stirred at room temperature for 1 hour. The mixture was diluted with water (40 mL) and extracted with ethyl acetate (2 × 40 mL). The combined organics were washed with water (30 mL) and brine (30 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by FCC (10 g SiO column, 0-100% ethyl acetate in heptane) to give methyl 3-[6-[2-[2-(tert-butoxycarbonylamino)ethoxy]phenyl]-5-fluoroindoline-1-carbonyl]-4-methoxybenzoate (95.0%) as a white solid (155 mg, 73% yield, 95% purity). 1 H NMR (400 MHz, DMSO) δ 8.09 (d, J = 6.7 Hz, 1H), 8.06 (dd, J = 8.8, 2.2 Hz, 1H), 7.89 (d, J = 2.3 Hz, 1H), 7.43 - 7.34 (m, 1H), 7.29 (d, J = 8.9 Hz, 1H), 7.25 (dd, J = 7.5, 1.8 Hz, 1H), 7.15 (dd, J = 11.7, 8.8 Hz, 2H), 7.05 (td, J = 7.5, 1.0 Hz, 1H), 6.73 (t, J = 5.7 Hz, 1H), 3.99 (t, J = 6.3 Hz, 2H), 3.92 (s, 3H), 3.87 - 3.76 (m, 5H), 3.20 (q, J = 6.3 Hz, 2H), 3.12 (t, J = 8.4 Hz, 2H), 1.36 (s, 9H). LCMS: m / z = 587.3 [M+Na]+, (ESI+), RT = 1.05, Method B

[0232] Step 4 Methyl 3-[6-[2-[2-(tert-butoxycarbonylamino)ethoxy]phenyl]-5-fluoro-indoline-1-carbonyl]-4-methoxybenzoate (95%, 155 mg, 0.261 mmol) was dissolved in THF (4 mL) and 2 M aqueous sodium hydroxide (1.0 mL, 2.00 mmol) was added. The reaction mixture was stirred at room temperature for 45 minutes. 6 M aqueous sodium hydroxide (1.0 mL, 6.00 mmol) was then added, and the mixture was stirred at room temperature for 2.5 hours. Methanol (1.5 mL) was then added, and the mixture was stirred at room temperature for 45 minutes. The mixture was then warmed to 40° C. for 3 hours. The mixture was concentrated in vacuo, and the remaining aqueous solution was diluted with water (20 mL) and acidified with 1 M aqueous HCl. The mixture was extracted with DCM (3 × 20 mL) and the combined organics were passed through a phase separator and concentrated to give 3-[6-[2-[2-(tert-butoxycarbonylamino)ethoxy]phenyl]-5-fluoroindoline-1-carbonyl]-4-methoxybenzoic acid (144 mg, 92% yield, 92% purity) as a pale yellow solid. LCMS: m / z = 549.2 [MH]-, (ESI-), RT = 1.05, Method B

[0233] Step 5 To 3-[6-[2-[2-(tert-butoxycarbonylamino)ethoxy]phenyl]-5-fluoro-indoline-1-carbonyl]-4-methoxybenzoic acid (92%, 140 mg, 0.234 mmol) was added 4 M hydrochloric acid in dioxane (1.8 mL, 7.23 mmol). The mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was taken up in DCM and concentrated (three times) to give 3-[6-[2-(2-aminoethoxy)phenyl]-5-fluoro-indoline-1-carbonyl]-4-methoxybenzoic acid hydrochloride (120 mg, 95% yield, 90% purity) as a pale yellow solid. LCMS: m / z = 451.1 [M+H]+, (ESI+), RT = 0.66, Method B

[0234] Step 6 To a solution of T3P (50% in ethyl acetate) (330 μL, 0.555 mmol) and DIPEA (128 μL, 0.739 mmol) in anhydrous DMF (8 mL) was added a solution of 3-[6-[2-(2-aminoethoxy)phenyl]-5-fluoro-indoline-1-carbonyl]-4-methoxybenzoic acid hydrochloride (90%, 100 mg, 0.185 mmol) in anhydrous DMF (8 mL) dropwise over 5 min. The mixture was stirred at room temperature for 30 min. The mixture was concentrated in vacuo. The residue was taken up in ethyl acetate and water, and the layers were separated. The aqueous phase was further extracted with ethyl acetate. The combined organics were washed with water and brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by reverse-phase FCC (12 g C18 column, 10-100% acetonitrile in water (0.1% formic acid)) to afford 24-fluoro-16-methoxy-8-oxa-11,19-diazapentacyclo[17.5.2.113,17.02,7.022,26]heptacosa-1 (24), 2,4,6,13,15,17 (27), 22,25-nonane-12,18-dione (17 mg, 24% yield, 100% purity) as a white solid. 1 H NMR (400 MHz, DMSO) δ 8.06 (s, 1H), 7.91 (d, J = 8.7 Hz, 1H), 7.65 - 7.56 (m, 1H), 7.32 - 7.24 (m, 1H), 7.23 - 7.15 (m, 2H), 6.98 (d, J = 8.3 Hz, 1H), 6.90 - 6.83 (m, 2H), 5.66 (d, J = 6.2 Hz, 1H), 4.57 - 4.39 (m, 1H), 4.14 - 3.96 (m, 3H), 3.87 - 3.70 (m, 4H), 3.27 - 3.02 (m, 3H). LCMS: m / z = 433.0 [M+H]+, (ESI+), RT = 0.78, Method B

[0235] Step 7 24-Fluoro-16-methoxy-8-oxa-11,19-diazapentacyclo[17.5.2.113,17.02,7.022,26]heptacosa-1(24),2,4,6,13,15,17(27),22,25-nonane-12,18-dione (18 mg, 95% purity) was dissolved in 2,4,6-trimethylpyridine (1.3 mL, 9.71 mol). Lithium iodide (26 mg, 0.198 mmol) was added to the reaction mixture, and the reaction mixture was heated at 80 °C for 18 h before being cooled to room temperature. The reaction was acidified with 1 M aqueous HCl. The organics were extracted with DCM (3 times), combined, passed through a hydrophobic frit, and concentrated in vacuo. Purification by acidic reverse phase FCC (6 g C18 silicon dioxide, 10-100% acetonitrile (0.1% formic acid) in water (0.1% formic acid)) afforded the title compound as an off-white solid (8 mg, 48% yield, 99% purity). 1 H NMR (500 MHz, DMSO) δ 11.07 (broad s, 1H), 8.23 ​​(s, 1H), 7.83 - 7.76 (m, 2H), 7.29 (ddd, J = 8.4, 7.1, 2.1 Hz, 1H), 7.25 (d, J = 8.7 Hz, 1H), 6.99 (d, J = 8.3 Hz, 1H), 6.96 - 6.78 (m, 3H), 6.20 (d, J = 6.0 Hz, 1H), 4.47 - 4.39 (m, 1H), 4.13 - 3.95 (m, 3H), 3.80 - 3.69 (m, 1H), 3.26 - 3.02 (m, 3H). LCMS: m / z = 419.1 [M+H]+, (ESI+), RT = 3.20, Method A

[0236] Example 12: 21,23-Difluoro-16-hydroxy-8-oxa-11,19-diazatetracyclo[18.3.1.1 13,17 .0 2,7 ]Synthesis of pentacosa-1(23),2,4,6,13,15,17(25),20(24),21-nonaene-12,18-dione (compound 12) TIFF2025515002000443.tif5552 Step 1 To a solution of 4-methoxy-3-methoxycarbonylbenzoic acid (387 mg, 1.84 mmol), 2-(2-bromophenoxy)ethanamine hydrochloride (96%, 440 mg, 1.67 mmol), and DIPEA (1165 μL, 6.69 mmol) in anhydrous DMF (10 mL) was added T3P (50% in ethyl acetate) (2.5 mL, 4.18 mmol). The mixture was stirred at room temperature for 1.5 hours. An additional 1.5 mL of T3P (50% in ethyl acetate) (1.5 mL, 2.51 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The mixture was diluted with water (40 mL) and extracted with ethyl acetate (2 × 40 mL). The combined organic layers were washed with water (30 mL) and brine (30 mL), then dried over magnesium sulfate, filtered, and concentrated in vacuo to give 5-[2-(2-bromophenoxy)ethylcarbamoyl]-2-methoxybenzoate (565 mg, 71% yield, 86% purity) as a yellow oil. 1 H NMR (500 MHz, DMSO) δ 8.68 (t, J = 5.4 Hz, 1H), 8.19 (d, J = 2.4 Hz, 1H), 8.05 (dd, J = 8.8, 2.4 Hz, 1H), 7.57 (dd, J = 7.9, 1.6 Hz, 1H), 7.34 (ddd, J = 8.2, 7.4, 1.6 Hz, 1H), 7.24 (d, J = 8.9 Hz, 1H), 7.18 (dd, J = 8.3, 1.4 Hz, 1H), 6.90 (td, J = 7.6, 1.4 Hz, 1H), 4.20 (t, J = 6.1 Hz, 2H), 3.88 (s, 3H), 3.81 (s, 3H), 3.64 (q, J = 5.9 Hz, 2H). LCMS: m / z = 407.9 / 409.9 [M+H]+, (ESI+), RT = 0.84, Method B

[0237] Step 2 To a solution of methyl 5-[2-(2-bromophenoxy)ethylcarbamoyl]-2-methoxybenzoate (86%, 550 mg, 1.16 mmol) and 2,4-difluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (95%, 373 mg, 1.39 mmol) in 1,4-dioxane (5 mL) was added potassium carbonate (320 mg, 2.32 mmol), and the mixture was sparged with nitrogen for 5 minutes. Pd(dppf)Cl2 (85 mg, 0.116 mmol) was added, and the reaction mixture was sparged for an additional 5 minutes. The vessel was sealed, and the reaction mixture was heated at 100 °C overnight. The mixture was cooled to room temperature, filtered through Celite, and washed with ethyl acetate. The filtrate was concentrated in vacuo. The residue was purified by FCC (25 g SiO column, 0-100% ethyl acetate in heptane) to give methyl 5-[2-[2-(5-amino-2,4-difluorophenyl)phenoxy]ethylcarbamoyl]-2-methoxybenzoate (425 mg, 76% yield, 95% purity) as a yellow solid. 1 H NMR (400 MHz, DMSO) δ 8.50 (t, J = 5.5 Hz, 1H), 8.16 (d, J = 2.3 Hz, 1H), 8.00 (dd, J = 8.8, 2.4 Hz, 1H), 7.35 (ddd, J = 9.0, 7.4, 1.8 Hz, 1H), 7.24 (d, J = 8.9 Hz, 1H), 7.16 (td, J = 7.2, 1.4 Hz, 2H), 7.01 (td, J = 7.4, 1.1 Hz, 1H), 6.88 (dd, J = 11.3, 9.7 Hz, 1H), 6.70 (dd, J = 10.1, 7.5 Hz, 1H), 4.94 (s, 2H), 4.10 (t, J = 6.3 Hz, 2H), 3.89 (s, 3H), 3.81 (s, 3H), 3.51 (q, J = 6.1 Hz, 2H). LCMS: m / z = 457.1 [M+H]+, (ESI+), RT = 0.83, Method B

[0238] Step 3 To a mixture of methyl 5-[2-[2-(5-amino-2,4-difluorophenyl)phenoxy]ethylcarbamoyl]-2-methoxybenzoate (95%, 200 mg, 0.421 mmol), THF (4.5 mL), and methanol (1.8 mL) was added 4 M aqueous sodium hydroxide (0.53 mL, 2.10 mmol), and the mixture was stirred at room temperature for 3.5 h. The THF was removed in vacuo, and the remaining aqueous solution was diluted with water (20 mL) and acidified with 1 M aqueous hydrochloric acid. The mixture was extracted with DCM (3 × 20 mL), and the combined organics were passed through a phase separator and concentrated to give 5-[2-[2-(5-amino-2,4-difluorophenyl)phenoxy]ethylcarbamoyl]-2-methoxybenzoate (195 mg, quantitative yield, 100% purity) as a pale yellow solid. LCMS: m / z = 443.1 [M+Na]+, (ESI+), RT = 0.74, Method B

[0239] Step 4 To a solution of T3P (50% in ethyl acetate) (690 μL, 1.16 mmol) and DIPEA (269 μL, 1.55 mmol) in anhydrous DMF (35 mL) was added a solution of 5-[2-[2-(5-amino-2,4-difluoro-phenyl)phenoxy]ethylcarbamoyl]-2-methoxybenzoic acid (95%, 180 mg, 0.387 mmol) in anhydrous DMF (5 mL) dropwise over 10 min. The mixture was stirred overnight at room temperature. The mixture was diluted with ethyl acetate and water, and the layers were separated. The aqueous solution was further extracted with ethyl acetate (3 times). The combined organics were washed with 0.5 M aqueous sodium hydroxide, then brine, dried (sodium sulfate), filtered, and concentrated to give 21,23-difluoro-16-methoxy-8-oxa-11,19-diazatetracyclo[18.3.1.113,17.02,7]pentacosa-1(23),2,4,6,13,15,17(25),20(24),21-nonaene-12,18-dione (15 mg, 6.4% yield, 70% purity) as a light brown solid. LCMS: m / z = 425.0 [M+H]+, (ESI+), RT = 0.73, Method B

[0240] Step 5 A suspension of 21,23-difluoro-16-methoxy-8-oxa-11,19-diazatetracyclo[18.3.1.113,17.02,7]pentacosa-1(23),2,4,6,13,15,17(25),20(24),21-nonaene-12,18-dione (70%, 15 mg, 0.0247 mmol) and lithium iodide (33 mg, 0.247 mmol) in anhydrous pyridine (1.1 mL) was heated at 85 °C for 18 h and then cooled to room temperature. Lithium iodide (33 mg, 0.247 mmol) was added to the reaction mixture, and the reaction mixture was heated at 85 °C for 3 h, then at 100 °C for 18 h, then at 110 °C for 22.5 h, and then cooled to room temperature. The reaction mixture was acidified with 1 M aqueous HCl. The organics were extracted with DCM (3x), combined, passed through a hydrophobic frit and concentrated in vacuo. Purification was by acidic reverse phase FCC (6g C18 silicon dioxide, 10-100% acetonitrile (0.1% formic acid) in water (0.1% formic acid)), followed by lyophilization to give the title compound as a brown solid (2mg, 18% yield, 90% purity). 1 H NMR (500 MHz, DMSO) δ 11.33 (broad s, 1H), 10.03 (broad s, 1H), 7.68 (dd, J = 8.6, 2.3 Hz, 1H), 7.50 - 7.42 (m, 2H), 7.43 - 7.36 (m, 2H), 7.27 - 7.17 (m, 3H), 7.11 - 7.07 (m, 1H), 6.95 (d, J = 8.6 Hz, 1H), 4.32 - 3.92 (m, 2H), 3.56 - 3.40 (m, 2H). LCMS: m / z = 411.0 [M+H]+, (ESI+), RT = 2.86, Method A

[0241] Example 13: 21,23-Difluoro-16-hydroxy-8-oxa-11,19-diazatetracyclo[18.3.1.1 13,17 .0 2,7 ]Synthesis of pentacosa-1(23),2,4,6,13,15,17(25),20(24),21-nonaen-12-one (compound 13) TIFF2025515002000444.tif5552 Step 1 To a solution of 5-bromo-2,4-difluoroaniline (500 mg, 2.40 mmol) and methyl 4-benzyloxy-3-formylbenzoate (780 mg, 2.88 mmol) in DCE (30 mL) was added acetic acid (688 μL, 12.0 mmol), and the mixture was stirred at 85° C. for 5 h. The mixture was cooled to room temperature, STAB (1528 mg, 7.21 mmol) was added, and the mixture was stirred at room temperature for 1 h. The mixture was diluted with DCM (30 mL) and saturated aqueous sodium bicarbonate (50 mL). The mixture was stirred for 20 min, and the layers were separated. The aqueous solution was further extracted with DCM (2 × 30 mL), and the combined organics were passed through a phase separator and concentrated. The residue was purified by FCC (50 g SiO2 column, 0-100% ethyl acetate in heptane) to give methyl 4-benzyloxy-3-[(5-bromo-2,4-difluoroanilino)methyl]benzoate (885 mg, 79% yield, 99% purity) as a white solid. 1 H NMR (500 MHz, DMSO) δ 7.94 - 7.83 (m, 2H), 7.55 - 7.49 (m, 2H), 7.44 - 7.39 (m, 2H), 7.37 - 7.30 (m, 2H), 7.23 (d, J = 8.4 Hz, 1H), 6.72 (dd, J = 9.1, 6.9 Hz, 1H), 6.32 (td, J = 6.2, 2.1 Hz, 1H), 5.30 (s, 2H), 4.35 (d, J = 6.2 Hz, 2H), 3.77 (s, 3H). LCMS: m / z = 461.9 / 463.9 [M+H]+, (ESI+), RT = 1.19, Method B

[0242] Step 2 To a solution of 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (1.50 g, 6.82 mmol), tert-butyl(2-hydroxyethyl)carbamate (1.6 mL, 10.2 mmol), and triphenylphosphine (2.68 g, 10.2 mmol) in anhydrous THF (40 mL) was added DIAD (2.1 mL, 10.9 mmol), and the reaction was stirred at room temperature for 1 hour and then warmed to 35 °C with stirring for 3 hours. Additional triphenylphosphine (1.79 g, 6.82 mmol) was added, and the mixture was stirred at 35 °C for 30 minutes. Additional DIAD (1.3 mL, 6.82 mmol) was added at room temperature, and the mixture was stirred at 35 °C for 25 minutes. Additional tert-butyl(2-hydroxyethyl)carbamate (1.1 mL, 6.82 mmol) was added, and the mixture was stirred at 35 °C for 1 hour. The mixture was then concentrated under reduced pressure, and the residue was purified by FCC (100 g SiO column, 0-100% ethyl acetate in heptane) to give tert-butyl N-[2-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]ethyl]carbamate (680 mg, 25% yield, 92% purity) as a light brown oil. 1 H NMR (500 MHz, DMSO) δ 7.52 (d, J = 1.8 Hz, 1H), 7.44 (ddd, J = 8.3, 7.3, 1.9 Hz, 1H), 6.99 - 6.85 (m, 2H), 6.50 (t, J = 5.6 Hz, 1H), 3.98 (t, J = 5.6 Hz, 2H), 3.38 - 3.34 (m, 2H), 1.40 (s, 9H), 1.31 (s, 12H).

[0243] Step 3 To a solution of tert-butyl N-[2-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]ethyl]carbamate (92%, 282 mg, 0.714 mmol) and methyl 4-benzyloxy-3-[(5-bromo-2,4-difluoroanilino)methyl]benzoate (300 mg, 0.649 mmol) in 1,4-dioxane (4 mL) and water (0.4 mL) was added potassium carbonate (179 mg, 1.30 mmol), and the mixture was sparged with nitrogen for 5 minutes. Pd(dppf)Cl2 (48 mg, 0.0649 mmol) was added, and the reaction mixture was degassed for an additional 5 minutes. The vessel was sealed, and the reaction mixture was heated at 100 °C overnight. The mixture was filtered through Celite, washing with ethyl acetate, and the filtrate was concentrated under reduced pressure. The residue was purified by FCC (25 g SiO column, 0-100% ethyl acetate in heptane) to give methyl 4-benzyloxy-3-[[5-[2-[2-(tert-butoxycarbonylamino)ethoxy]phenyl]-2,4-difluoro-anilino]methyl]benzoate (356 mg, 72% yield, 81% purity) as a pale yellow oil. 1 H NMR (500 MHz, DMSO) δ 7.96 (d, J = 2.3 Hz, 1H), 7.84 (dd, J = 8.6, 2.3 Hz, 1H), 7.40 - 7.24 (m, 6H), 7.19 (d, J = 8.7 Hz, 1H), 7.13 - 7.00 (m, 3H), 6.95 (td, J = 7.3, 1.0 Hz, 1H), 6.65 (t, J = 5.7 Hz, 1H), 6.47 (dd, J = 9.8, 7.2 Hz, 1H), 6.00 (td, J = 6.4, 2.1 Hz, 1H), 5.21 (s, 2H), 4.34 (d, J = 6.2 Hz, 2H), 3.85 (t, J = 6.5 Hz, 2H), 3.78 (s, 3H), 3.06 (q, J = 6.2 Hz, 2H), 1.34 (s, 9H). LCMS: m / z = 619.4 [M+H]+, (ESI+), RT = 1.22, Method B

[0244] Step 4 To a mixture of methyl 4-benzyloxy-3-[[5-[2-[2-(tert-butoxycarbonylamino)ethoxy]phenyl]-2,4-difluoroanilino]methyl]benzoate (81%, 356 mg, 0.466 mmol), THF (4.4367 mL), and methanol (1.4789 mL) was added 4 M aqueous sodium hydroxide (0.58 mL, 2.33 mmol). The mixture was stirred at room temperature for 1 hour, then warmed to 50 °C and stirred for 4.5 hours. The THF was removed in vacuo, and the remaining aqueous phase was diluted with water (20 mL) and acidified with 1 M aqueous hydrochloric acid. The mixture was extracted with DCM (4 × 30 mL) and the combined organic phases were passed through a phase separator and concentrated to give 5-[2-[2-(5-amino-2,4-difluoro-phenyl)phenoxy]ethylcarbamoyl]-2-methoxybenzoic acid (201 mg, 94% yield, 95% purity) as a pale yellow oil. LCMS: m / z = 605.3 [M+H]+, (ESI+), RT = 1.10, Method B

[0245] Step 5 To 4-benzyloxy-3-[[5-[2-[2-(tert-butoxycarbonylamino)ethoxy]phenyl]-2,4-difluoro-anilino]methyl]benzoic acid (91%, 274 mg, 0.412 mmol) was added 4 M hydrochloric acid in dioxane (2.1 mL, 8.25 mmol). The mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. The residue was sonicated in DCM and then concentrated (three times) to give 3-[[5-[2-(2-aminoethoxy)phenyl]-2,4-difluoro-anilino]methyl]-4-benzyloxybenzoic acid dihydrochloride (294 mg, 99% yield, 80% purity) as a light brown solid. LCMS: m / z = 505.1 [M+H]+, (ESI+), RT = 0.78, Method B

[0246] Step 6 To a solution of T3P (50% in ethyl acetate) (807 μL, 1.36 mmol) and DIPEA (394 μL, 2.26 mmol) in anhydrous DMF (26 mL) was added a solution of 3-[[5-[2-(2-aminoethoxy)phenyl]-2,4-difluoro-anilino]methyl]-4-benzyloxybenzoic acid dihydrochloride (80%, 290 mg, 0.452 mmol) in anhydrous DMF (4 mL) dropwise over 5 minutes. The mixture was stirred at room temperature for 30 minutes, then diluted with ethyl acetate (70 mL) and water (70 mL), and the layers were separated. The aqueous layer was further extracted with ethyl acetate (70 mL). The combined organics were washed with water (70 mL), then brine (70 mL), passed through a phase separator, and then concentrated to give 16-benzyloxy-21,23-difluoro-8-oxa-11,19-diazatetracyclo[18.3.1.113,17.02,7]pentacosa-1(23),2,4,6,13,15,17(25),20(24),21-nonaen12-one (208 mg, 79% yield, 84% purity) as a light brown solid. LCMS: m / z = 487.1 [M+H]+, (ESI+), RT = 1.06, Method B

[0247] Step 7 To 16-benzyloxy-21,23-difluoro-8-oxa-11,19-diazatetracyclo[18.3.1.113,17.02,7]pentacosa-1(23),2,4,6,13,15,17(25),20(24),21-nonaen12-one (84%, 60 mg, 0.104 mmol) was added 1 M BBr3 in DCM (1.0 mL, 1.00 mmol) at room temperature. The reaction mixture was stirred at room temperature for 45 min. The reaction mixture was diluted with DCM (30 mL), poured into water (40 mL), and the layers were separated. The aqueous layer was extracted with DCM (2 × 30 mL). The organic phases were combined, passed through a hydrophobic frit, and concentrated in vacuo. The residue was purified by preparative HPLC (Method P1) followed by further purification by preparative HPLC (Method P2) to give the title compound as a white solid (20 mg, 49% yield, 100% purity). 1H NMR (500 MHz, DMSO) δ 10.16 (s, 1H), 7.53 (d, J = 2.4 Hz, 1H), 7.44 (dd, J = 8.3, 2.2 Hz, 1H), 7.37 (ddd, J = 8.3, 7.4, 1.8 Hz, 1H), 7.14 (dd, J = 7.5, 1.8 Hz, 1H), 7.13 - 7.06 (m, 2H), 7.03 - 6.98 (m, 2H), 6.89 (dd, J = 9.8, 7.5 Hz, 1H), 6.82 (d, J = 8.3 Hz, 1H), 5.56 (td, J = 7.0, 2.5 Hz, 1H), 4.43 - 4.19 (m, 2H), 4.16 - 4.01 (m, 2H), 3.57 - 3.40 (m, 2H). LCMS: m / z = 397.1 [M+H]+, (ESI+), RT = 2.97, Method A

[0248] Example 14: 15-chloro-21,23-difluoro-16-hydroxy-8-oxa-18 lambda 6-thia-11-azatetracyclo[18.3.1.1 13,17 .0 2,7 ]Synthesis of pentacosa-1(24),2,4,6,13,15,17(25),20,22-nonaene-12,18,18-trione (compound 14) TIFF2025515002000445.tif5558 Step 1 To a solution of Intermediate 2 (98%, 650 mg, 2.01 mmol) and [2,4-difluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanol (58%, 1.00 g, 2.15 mmol) in 4-dioxane (12 mL), potassium carbonate (550 mg, 3.98 mmol) and water (3 mL) were added, and the mixture was sparged with nitrogen for 10 minutes. Pd(dppf)Cl2 (150 mg, 0.204 mmol) was added, and the reaction mixture was degassed again for an additional 5 minutes. The vessel was then sealed, and the reaction mixture was stirred at reflux for 20 hours. The reaction mixture was cooled to room temperature, filtered through Celite, washed with ethyl acetate, and the filtrate was added to water (50 mL). The layers were separated, and the aqueous phase was extracted with ethyl acetate (2 x 50 mL). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by FCC (50 g SiO column, 0-100% ethyl acetate in heptane) to give tert-butyl N-[2-[2-[2,4-difluoro-5-(hydroxymethyl)phenyl]phenoxy]ethyl]carbamate (792 mg, 98% yield, 95% purity) as a viscous yellow oil. 1 H NMR (500 MHz, DMSO) δ 7.45 - 7.35 (m, 2H), 7.23 (dd, J = 7.5, 1.5 Hz, 1H), 7.18 (t, J = 10.1 Hz, 1H), 7.12 (d, J = 8.2 Hz, 1H), 7.04 (td, J = 7.5, 0.9 Hz, 1H), 6.74 (t, J = 5.5 Hz, 1H), 5.26 (t, J = 5.5 Hz, 1H), 4.54 (d, J = 5.1 Hz, 2H), 3.96 (t, J = 6.3 Hz, 2H), 3.18 (q, J = 6.1 Hz, 2H), 1.35 (s, 9H). LCMS: m / z = 402.0 [M+Na]+, (ESI+), RT = 0.94, Method B

[0249] Step 2 To a solution of tert-butyl N-[2-[2-[2,4-difluoro-5-(hydroxymethyl)phenyl]phenoxy]ethyl]carbamate (95%, 620 mg, 1.55 mmol) and carbon tetrabromide (800 mg, 2.41 mmol) in anhydrous DCM (50 mL) at 0 °C was added triphenylphosphine (620 mg, 2.36 mmol). The resulting mixture was allowed to warm to room temperature while stirring under nitrogen for 4 hours. The reaction mixture was concentrated under reduced pressure and purified by FCC (25 g SiO column, 0-100% ethyl acetate in heptane) to afford tert-butyl N-[2-[2-[5-(bromomethyl)-2,4-difluoro-phenyl]phenoxy]ethyl]carbamate (630 mg, 90% yield, 98% purity) as a pale yellow oil. 1 H NMR (500 MHz, DMSO) δ 7.60 (t, J = 8.4 Hz, 1H), 7.39 (ddd, J = 8.4, 7.5, 1.7 Hz, 1H), 7.31 (t, J = 10.1 Hz, 1H), 7.27 - 7.22 (m, 1H), 7.13 (d, J = 8.2 Hz, 1H), 7.04 (td, J = 7.5, 0.8 Hz, 1H), 6.78 (t, J = 5.4 Hz, 1H), 4.72 (s, 2H), 3.98 (t, J = 6.1 Hz, 2H), 3.20 (q, J = 6.0 Hz, 2H), 1.36 (s, 9H). LCMS: m / z = 342.0 / 343.9 [M-Boc+H]+, (ESI+), RT = 1.13, Method B

[0250] Step 3 To a stirred solution of tert-butyl N-[2-[2-[5-(bromomethyl)-2,4-difluoro-phenyl]phenoxy]ethyl]carbamate (98%, 600 mg, 1.33 mmol) and thioacetic acid (120 mg, 1.58 mmol) in methanol (60 mL) was added potassium carbonate (220 mg, 1.59 mmol). After stirring at room temperature for 30 min, additional potassium carbonate (220 mg, 1.59 mmol) was added, and the reaction was stirred at room temperature for an additional 30 min. The reaction mixture was acidified (pH ∼4 / 5) with 1 M aqueous HCl, after which the solution was diluted with water (20 mL) and extracted with DCM (3 × 30 mL). The organic phases were combined, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by FCC (50 g SiO column, 0-100% ethyl acetate in heptane) to give tert-butyl N-[2-[2,4-difluoro-5-(sulfanylmethyl)phenyl]phenoxy]ethyl]carbamate (316 mg, 60% yield, 99% purity) as a viscous colorless oil. 1 H NMR (500 MHz, DMSO) δ 7.47 (t, J = 8.6 Hz, 1H), 7.38 (ddd, J = 8.3, 7.5, 1.8 Hz, 1H), 7.27 - 7.19 (m, 2H), 7.13 (d, J = 8.2 Hz, 1H), 7.04 (td, J = 7.5, 0.9 Hz, 1H), 6.76 (t, J = 5.4 Hz, 1H), 3.97 (t, J = 6.2 Hz, 2H), 3.75 (s, 2H), 3.20 (q, J = 6.1 Hz, 2H), 2.98 (s, 1H), 1.36 (s, 9H). LCMS: m / z = 296.0 [M-Boc+H]+, (ESI+), RT = 1.11, Method B

[0251] Step 4 To a solution of methyl 3-bromo-5-chloro-4-methoxybenzoate (95%, 200 mg, 0.680 mmol) in anhydrous 1,4-dioxane (5 mL) was added DIPEA (110 mg, 0.851 mmol) and tert-butyl N-[2-[2-[2,4-difluoro-5-(sulfanylmethyl)phenyl]phenoxy]ethyl]carbamate (99%, 310 mg, 0.776 mmol). After bubbling nitrogen through the solution for 5 minutes, Pd(dba) (20 mg, 0.0218 mmol) and Xantphos (30 mg, 0.0518 mmol) were added, and the sealed tube was heated at 100 °C for 3 hours. The reaction mixture was cooled to room temperature, then added to water (50 mL), and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate, filtered, and concentrated. The residue was purified by FCC (100 g SiO cartridge, 0-100% ethyl acetate in heptane) to give methyl 3-[[5-[2-[2-(tert-butoxycarbonylamino)ethoxy]phenyl]-2,4-difluoro-phenyl]methylsulfanyl]-5-chloro-4-methoxybenzoate (357 mg, 88% yield, 99% purity) as a viscous pale yellow oil. 1 H NMR (500 MHz, DMSO) δ 7.86 (d, J = 2.0 Hz, 1H), 7.82 (d, J = 2.0 Hz, 1H), 7.45 (t, J = 8.4 Hz, 1H), 7.38 (ddd, J = 8.4, 7.5, 1.7 Hz, 1H), 7.25 (t, J = 10.0 Hz, 1H), 7.16 - 7.10 (m, 2H), 7.06 - 6.98 (m, 1H), 6.73 (t, J = 5.6 Hz, 1H), 4.33 (s, 2H), 3.94 (t, J = 6.2 Hz, 2H), 3.82 - 3.80 (m, 6H), 3.16 (q, J = 6.1 Hz, 2H), 1.34 (s, 9H). LCMS: m / z = 494.0 [M-Boc+H]+, (ESI+), RT = 1.25, Method B

[0252] Step 5 To a solution of methyl 3-[[5-[2-[2-(tert-butoxycarbonylamino)ethoxy]phenyl]-2,4-difluoro-phenyl]methylsulfanyl]-5-chloro-4-methoxybenzoate (99%, 300 mg, 0.500 mmol) in DCM (10 mL) was added mCPBA (70%, 370 mg, 1.50 mmol) and sodium bicarbonate (50 mg, 0.595 mmol). The resulting solution was stirred at room temperature for 16 h. The reaction mixture was added to a biphasic mixture of DCM (20 mL) and aqueous sodium sulfite (30 mL) and mixed thoroughly in a separatory funnel. The layers were then separated, and the aqueous phase was extracted with additional DCM (20 mL). The combined organic layers were then washed with aqueous sodium bicarbonate (40 mL), and the aqueous phase was extracted a second time with additional DCM (20 mL). The organic phases were combined and finally washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by FCC (10 g SiO column, 0-100% ethyl acetate in heptane) to give methyl 3-[[5-[2-[2-(tert-butoxycarbonylamino)ethoxy]phenyl]-2,4-difluoro-phenyl]methylsulfonyl]-5-chloro-4-methoxybenzoate (272 mg, 78% yield, 90% purity). 1 H NMR (500 MHz, DMSO) δ 8.36 (d, J = 2.1 Hz, 1H), 8.09 (d, J = 2.1 Hz, 1H), 7.46 - 7.35 (m, 2H), 7.27 (t, J = 9.9 Hz, 1H), 7.14 (d, J = 8.3 Hz, 1H), 7.09 (dd, J = 7.4, 1.4 Hz, 1H), 7.04 (t, J = 7.3 Hz, 1H), 6.75 (t, J = 5.5 Hz, 1H), 4.90 (s, 2H), 4.08 (s, 3H), 3.95 (t, J = 6.2 Hz, 2H), 3.87 (s, 3H), 3.19 (q, J = 6.1 Hz, 2H), 1.34 (s, 9H). LCMS: m / z = 526.0 [M-Boc+H]+, (ESI+), RT = 1.15, Method B

[0253] Step 6 Methyl 3-[[5-[2-[2-(tert-butoxycarbonylamino)ethoxy]phenyl]-2,4-difluoro-phenyl]methylsulfonyl]-5-chloro-4-methoxybenzoate (90%, 265 mg, 0.38 mmol) was dissolved in THF (15 mL) and 2 M aqueous sodium hydroxide (3.0 mL, 6.00 mmol) was added. The resulting solution was stirred at room temperature for 3 h. The THF was removed under reduced pressure, and the remaining aqueous solution was added to DCM (30 mL) and acidified with 1 M aqueous HCl (30 mL). The layers were separated and the aqueous phase extracted with additional DCM (2×15 mL), then the combined organic phases were washed with brine (30 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford 3-[[5-[2-[2-(tert-butoxycarbonylamino)ethoxy]phenyl]-2,4-difluoro-phenyl]methylsulfonyl]-5-chloro-4-methoxybenzoic acid (245 mg, 91% yield, 93% purity) as a brown solid. LCMS: m / z = 512.0 [M-Boc+H]+, (ESI+), RT = 1.07, Method B

[0254] Step 7 To 3-[[5-[2-[2-(tert-butoxycarbonylamino)ethoxy]phenyl]-2,4-difluoro-phenyl]methylsulfonyl]-5-chloro-4-methoxybenzoic acid (93%, 240 mg, 0.365 mmol) was added 4 M hydrochloric acid (6.0 mL, 24.0 mmol) in dioxane. The solution was stirred at room temperature for 4 h. The reaction mixture was concentrated under reduced pressure, and the remaining residue was taken up in DCM (sonicated) and concentrated (3 × 20 mL) to give 3-[[5-[2-(2-aminoethoxy)phenyl]-2,4-difluoro-phenyl]methylsulfonyl]-5-chloro-4-methoxybenzoic acid hydrochloride (236 mg, 94% yield, 80% purity) as a golden solid. LCMS: m / z = 512.0 [M+H]+, (ESI+), RT = 0.74, Method B

[0255] Step 8 To a solution of DIPEA (0.30 mL, 1.72 mmol) and T3P (50% in ethyl acetate) (0.70 mL, 1.18 mmol) in DMF (3 mL) was added a solution of 3-[[5-[2-(2-aminoethoxy)phenyl]-2,4-difluoro-phenyl]methylsulfonyl]-5-chloro-4-methoxybenzoic acid and hydrochloride (80%, 230 mg, 0.336 mmol) in DMF (4 mL) over 1 h via pump syringe. After this addition, the mixture was stirred at room temperature for 3 h. A second aliquot of T3P (50% in ethyl acetate) (0.70 mL, 1.18 mmol) was added dropwise, and the mixture was stirred for an additional 16 h. Additional DIPEA (0.30 mL, 1.72 mmol) was then added, and the reaction was finally stirred for 1 h. The reaction was diluted with water (100 mL) and extracted with ethyl acetate (4 × 50 mL). The combined organic phases were washed with brine (100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to give 15-chloro-21,23-difluoro-16-methoxy-18,18-dioxo-8-oxa-18λ6-thia-11-azatetracyclo[18.3.1.113,17.02,7]pentacosa-1(24),2,4,6,13,15,17(25),20,22-nonaen-12-one (150 mg, 81% yield, 90% purity) as a light brown solid. 1 H NMR (500 MHz, DMSO) δ 8.14 (t, J = 4.3 Hz, 1H), 8.09 (d, J = 2.2 Hz, 1H), 7.45 (td, J = 8.2, 1.7 Hz, 1H), 7.40 (d, J = 2.2 Hz, 1H), 7.36 (t, J = 8.2 Hz, 1H), 7.20 (dd, J = 7.4, 1.7 Hz, 1H), 7.18 - 7.14 (m, 1H), 7.07 (td, J = 7.4, 0.8 Hz, 1H), 6.88 (t, J = 9.9 Hz, 1H), 4.65 (s, 2H), 4.01 (s, 3H).

[0256] Step 9 To a solution of 15-chloro-21,23-difluoro-16-methoxy-18,18-dioxo-8-oxa-18λ6-thia-11-azatetracyclo[18.3.1.113,17.02,7]pentacosa-1(24),2,4,6,13,15,17(25),20,22-nonaen-12-one (90%, 120 mg, 0.22 mmol) in anhydrous DMF (4 mL) was added dropwise 1M BBr3 in DCM (2.4 mL, 2.40 mmol) at 0 °C. The resulting solution was heated at 80 °C for 20 h. The reaction mixture was cooled to room temperature and placed on ice, after which an additional 1M BBr3 in DCM (0.60 mL, 0.6 mmol) was added. The reaction mixture was reheated to 80 °C and stirred for an additional 4 h. The reaction mixture was quenched at 0° C. with saturated aqueous NaHCO3 (30 mL) and diluted with DCM (20 mL). The aqueous phase was extracted again with DCM (20 mL), and the combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (Method P1) to give the title compound as a white solid (48 mg, 41% yield, 99% purity). 1 H NMR (500 MHz, DMSO) δ 11.20 (broad s, 1H), 7.94 (d, J = 2.0 Hz, 1H), 7.91 - 7.87 (m, 1H), 7.44 (ddd, J = 8.2, 7.6, 1.7 Hz, 1H), 7.37 - 7.32 (m, 1H), 7.27 (d, J = 2.1 Hz, 1H), 7.19 (dd, J = 7.4, 1.7 Hz, 1H), 7.17 - 7.12 (m, 1H), 7.09 - 7.04 (m, 1H), 6.97 - 6.90 (m, 1H), 4.68 (s, 2H), 4.20 (broad s, 2H). 2H was not observed. LCMS: m / z = 480.0 / 481.9 [M+H]+, (ESI+), RT = 3.28, Method A

[0257] Example 15: 15-chloro-16-(difluoromethoxy)-21,23-difluoro-8-oxa-18lambda 6-thia-11,19-diazatetracyclo[18.3.1.1 13,17 .0 2,7 ]Synthesis of pentacosa-1(24),2,4,6,13,15,17(25),20,22-nonaene-12,18,18-trione (compound 15) To a solution of T3P (50 wt%, 0.52 mL, 0.871 mmol) in ethyl acetate and DIPEA (0.25 mL, 1.45 mmol) in anhydrous DMF (12.0 mL) was added dropwise over 5 min at room temperature a solution of 3-[[5-[2-(2-aminoethoxy)phenyl]-2,4-difluoro-phenyl]sulfamoyl]-5-chloro-4-(difluoromethoxy)benzoic acid hydrochloride (synthesized according to General Scheme 1, 170 mg, 0.290 mmol) in anhydrous DMF (4.0 mL). The reaction mixture was stirred at room temperature for 0.5 h and diluted with water (40 mL). The organics were extracted with ethyl acetate (2 × 30 mL), combined, washed with water (2 × 30 mL), washed with brine (30 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. Purification by preparative HPLC (Method P1) gave the title compound as a white solid (84 mg, 48% yield, 99% purity). 1 H NMR (500 MHz, DMSO) δ 10.58 (s, 1H), 8.35 - 8.27 (m, 1H), 8.11 (d, J = 2.1 Hz, 1H), 7.56 (d, J = 2.2 Hz, 1H), 7.48 - 7.42 (m, 1H), 7.42 - 7.09 (m, 1H), 7.34 - 7.28 (m, 1H), 7.26 (dd, J = 7.4, 1.7 Hz, 1H), 7.19 - 7.09 (m, 2H), 7.10 - 7.03 (m, 1H), 4.29 - 4.16 (m, 2H), 3.57 - 3.45 (m, 2H). LCMS: m / z = 531.0 / 532.9 [M+H]+, (ESI+), RT = 3.61, Method A

[0258] Example 16: 15-chloro-21,23-difluoro-16-hydroxy-11-oxa-18-lambda 6-thia-19-azatetracyclo[18.3.1.1 13,17 .0 2,7 ]Synthesis of pentacosa-1(24),2,4,6,13,15,17(25),20,22-nonaene-12,18,18-trione (compound 16) To a solution of 15-chloro-21,23-difluoro-16-methoxy-18,18-dioxo-11-oxa-18λ6-thia-19-azatetracyclo[18.3.1.113,17.02,7]pentacosa-1(24),2,4,6,13,15,17(25),20,22-nonaen-12-one (synthesized according to General Scheme 2, 100%, 24 mg, 0.0486 mmol) in anhydrous DMF (1.0 mL) at 0 °C, 1 M BBr in DCM (0.60 mL, 0.60 mmol) was added dropwise. The resulting solution was heated at 80 °C for 16 h and then cooled to room temperature. The reaction mixture was added to saturated aqueous NaHCO (30 mL) at 0 °C. The organics were extracted with DCM (2 x 20 mL), combined, washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Purification by preparative HPLC (Method P1) afforded the title compound as a white solid (10 mg, 44% yield, 99% purity). 1 H NMR (500 MHz, DMSO) δ 8.00 - 7.95 (m, 1H), 7.66 (d, J = 2.2 Hz, 1H), 7.45 - 7.41 (m, 2H), 7.40 - 7.35 (m, 1H), 7.33 - 7.29 (m, 1H), 7.28 - 7.24 (m, 1H), 7.24 - 7.20 (m, 1H), 4.43 - 4.32 (m, 1H), 4.04 - 3.95 (m, 1H), 2.68 - 2.58 (m, 1H), 2.35 - 2.28 (m, 1H), 2.16 - 2.03 (m, 1H), 1.81 - 1.69 (m, 1H). LCMS: m / z = 478.2 / 480.2 [MH]-, (ESI-), RT = 4.05, Method A

[0259] Example 17: (10S)-15-chloro-21,23-difluoro-16-hydroxy-10-methyl-8-oxa-18lambda 6-thia-11,19-diazatetracyclo[18.3.1.1 13,17 .0 2,7 ]Synthesis of pentacosa-1(24),2,4,6,13,15,17(25),20,22-nonaene-12,18,18-trione (compound 17) TIFF2025515002000448.tif5558 (10S)-15-chloro-21,23-difluoro-16-methoxy-10-methyl-18,18-dioxo-8-oxa-18λ6-thia-11,19-diazatetracyclo[18.3.1.113,17.02,7]pentacosa-1(24),2,4,6,13,15,17(25),20,22-nonaen-12-one (synthesized according to General Scheme 1, 75%, 120 mg, 0.177 mmol) was added to 1 M BBr in DCM (2.2 mL, 2.2 mmol) at room temperature. The reaction mixture was stirred at room temperature for 18 h. Water (120 mL) was added to the reaction mixture. The organics were extracted with DCM (3 x 120 mL), combined, passed through a hydrophobic frit and concentrated in vacuo. Purification by preparative HPLC (Method P1) gave the title compound as a white solid (45 mg, 49% yield, 97% purity). 1H NMR (400 MHz, DMSO) δ 10.59 - 10.12 (m, 2H), 8.03 - 7.93 (m, 1H), 7.91 (d, J = 2.1 Hz, 1H), 7.48 - 7.39 (m, 1H), 7.33 (d, J = 2.2 Hz, 1H), 7.34 - 7.25 (m, 1H), 7.25 (dd, J = 7.5, 1.7 Hz, 1H), 7.17 - 7.08 (m, 2H), 7.09 - 7.01 (m, 1H), 4.31 (dd, J = 9.4, 4.0 Hz, 1H), 4.15 - 4.03 (m, 1H), 3.82 - 3.72 (m, 1H), 1.10 (d, J = 6.6 Hz, 3H). LCMS: m / z = 495.0 / 497.0 [M+H]+, (ESI+), RT = 3.62, Method A

[0260] Example 18: 5,15-Dichloro-21,23-difluoro-16-hydroxy-8,11-dioxa-18 lambda 6-thia-19-azatetracyclo[18.3.1.1 13,17 .0 2,7 ]Synthesis of pentacosa-1(24),2,4,6,13,15,17(25),20,22-nonaene-12,18,18-trione (compound 18) To 5,15-dichloro-21,23-difluoro-16-methoxy-18,18-dioxo-8,11-dioxa-18λ6-thia-19-azatetracyclo[18.3.1.113,17.02,7]pentacosa-1(24),2,4,6,13,15,17(25),20,22-nonaen-12-one (synthesized according to General Scheme 2, 92%, 60 mg, 0.104 mmol) was added dropwise 1 M BBr in DCM (8.0 mL, 8.0 mmol), and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was added to saturated aqueous NaHCO (30 mL). The organics were extracted with DCM (20 mL, then 2 × 30 mL), combined, washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Purification by preparative HPLC (Method P1) afforded the title compound as an off-white solid (30 mg, 55% yield, 99% purity). 1 H NMR (400 MHz, DMSO) δ 8.03 (d, J = 2.1 Hz, 1H), 7.47 (d, J = 2.2 Hz, 1H), 7.34–7.27 (m, 3H), 7.26–7.19 (m, 1H), 7.15 (dd, J = 8.1, 1.9 Hz, 1H), 4.34–4.33 (m, 4H). 2H was not observed. LCMS: m / z = 514.0 / 516.0 [MH]-, (ESI-), RT = 4.30, Method A

[0261] Example 19: (10R)-15-chloro-21,23-difluoro-16-hydroxy-10-methyl-8-oxa-18lambda 6-thia-11,19-diazatetracyclo[18.3.1.1 13,17 .0 2,7 ]Synthesis of pentacosa-1(24),2,4,6,13,15,17(25),20,22-nonaene-12,18,18-trione (compound 19) To (10R)-15-chloro-21,23-difluoro-16-methoxy-10-methyl-18,18-dioxo-8-oxa-18λ6-thia-11,19-diazatetracyclo[18.3.1.113,17.02,7]pentacosa-1(24),2,4,6,13,15,17(25),20,22-nonaen-12-one (synthesized according to General Scheme 1, 85%, 123 mg, 0.205 mmol) was added 1 M BBr in DCM (2.6 mL, 2.6 mmol) at room temperature. After stirring the reaction mixture at room temperature for 3.5 h, 1 M BBr in DCM (1.00 mL, 1.00 mmol) was added, and the reaction mixture was stirred at room temperature for 14 h. Water (140 mL) was added to the reaction mixture. The organics were extracted with DCM (3 x 140 mL), combined, passed through a hydrophobic frit and concentrated in vacuo. Purification by preparative HPLC (Method P1) gave the title compound as a white solid (50 mg, 48% yield, 97% purity). 1 H NMR (500 MHz, DMSO) δ 10.77 - 9.91 (m, 2H), 8.08 - 7.92 (m, 1H), 7.92 - 7.89 (m, 1H), 7.46 - 7.41 (m, 1H), 7.32 (d, J = 2.2 Hz, 1H), 7.32 - 7.27 (m, 1H), 7.25 (dd, J = 7.4, 1.7 Hz, 1H), 7.16 - 7.09 (m, 2H), 7.07 - 7.03 (m, 1H), 4.31 (dd, J = 9.3, 4.0 Hz, 1H), 4.13 - 4.03 (m, 1H), 3.81 - 3.73 (m, 1H), 1.10 (d, J = 6.6 Hz, 3H). LCMS: m / z = 495.0 / 497.0 [M+H]+, (ESI+), RT = 3.68, Method A

[0262] Example 20: 16-chloro-22,24-difluoro-17-hydroxy-8,12-dioxa-19lambda 6-thia-20-azatetracyclo[19.3.1.1 14,18 .0 2,7]Synthesis of hexacosa-1(25),2,4,6,14,16,18(26),21,23-nonaene-13,19,19-trione (compound 20) TIFF2025515002000451.tif5558 16-Chloro-22,24-difluoro-17-methoxy-19,19-dioxo-8,12-dioxa-19λ6-thia-20-azatetracyclo[19.3.1.114,18.02,7]hexacosa-1(25),2,4,6,14,16,18(26),21,23-nonaen-13-one (synthesized according to General Scheme 2, 70 mg, 0.137 mmol) was added to 1 M BBr in DCM (1.4 mL, 1.40 mmol) at room temperature. The reaction mixture was stirred at room temperature for 1 h, then diluted with DCM (30 mL) and poured into 5 wt% aqueous NaHCO (40 mL). The layers were separated, and the organics were extracted from the aqueous solution using DCM (2 × 30 mL). The organics were combined, passed through a hydrophobic frit and concentrated in vacuo. Purification by acidic reverse phase FCC (30 g C18 silicon dioxide, 10-100% acetonitrile (0.1% formic acid), water (0.1% formic acid)) followed by lyophilization afforded the title compound as an off-white solid (27 mg, 39% yield, 98% purity). 1 H NMR (500 MHz, DMSO) δ 11.95 - 9.45 (m, 1H), 8.00 - 7.94 (m, 1H), 7.43 - 7.35 (m, 2H), 7.25 - 7.18 (m, 1H), 7.15 (dd, J = 7.4, 1.7 Hz, 1H), 7.10 - 7.06 (m, 1H), 7.04 - 6.98 (m, 1H), 6.98 - 6.91 (m, 1H), 4.44 - 4.38 (m, 2H), 4.09 (t, J = 5.0 Hz, 2H), 2.01 - 1.94 (m, 2H). LCMS: m / z = 494.0 / 496.0 [MH]-, (ESI-), RT = 4.18, Method A

[0263] Example 21: 14-chloro-20,22-difluoro-15-hydroxy-10-oxa-17lambda 6-thia-18-azatetracyclo[17.3.1.1 12,16 .0 2,7 ]Synthesis of tetracosa-1(23),2,4,6,12,14,16(24),19,21-nonaene-11,17,17-trione (compound 21) To 15-chloro-21,23-difluoro-16-methoxy-18,18-dioxo-11-oxa-18λ6-thia-19-azatetracyclo[18.3.1.113,17.02,7]pentacosa-1(24),2,4,6,13,15,17(25),20,22-nonaen-12-one (synthesized according to General Scheme 2, 60%, 30 mg, 0.0364 mmol) in anhydrous DCM (0.6 mL) was added 1 M BBr in DCM (0.30 mL, 0.30 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 1 h and then poured into 5 wt% aqueous NaHCO (30 mL). The organics were extracted with DCM (3 x 20 mL), combined, passed through a hydrophobic frit, and concentrated in vacuo. Purification was carried out with basic reverse-phase FCC (30 g C18 silicon dioxide, 10-100% acetonitrile (0.1% NH3) in water (0.1% NH3)), followed by lyophilization to give the title compound as a white solid (64 mg, 40% yield, 97% purity). 1 H NMR (400 MHz, DMSO) δ 11.03 - 9.63 (m, 2H), 7.93 (d, J = 2.1 Hz, 1H), 7.66 - 7.56 (m, 1H), 7.53 - 7.50 (m, 1H), 7.46 - 7.38 (m, 2H), 7.32 - 7.23 (m, 1H), 7.01 (dd, J = 7.7, 1.4 Hz, 1H), 6.66 - 6.56 (m, 1H), 4.62 - 4.43 (m, 1H), 4.30 - 4.20 (m, 1H), 3.06 - 2.98 (m, 1H), 2.91 - 2.75 (m, 1H). LCMS: m / z = 464.0 / 466.0 [MH]-, (ESI-), RT = 4.06, Method A

[0264] Example 22: 18-chloro-24,26-difluoro-19-hydroxy-14-oxa-3,21lambda-6-dithia-22-azapentacyclo[21.3.1.1 16,20 .0 2,10 .0 4,9 ]Synthesis of octacosa-1(27),2(10),4,6,8,16,18,20(28),23,25-decaene-15,21,21-trione (compound 22) TIFF2025515002000453.tif6458 Step 1 To a solution of methyl 3-(benzothiophen-3-yl)propanoate (98%, 1.55 g, 6.90 mmol) in DCM (21 mL) at 0 °C was added a solution of bromine (0.37 mL, 7.22 mmol) in DCM (4.5 mL) dropwise over 5 min. The reaction mixture was stirred at 0 °C for 1.75 h, after which saturated aqueous NaSO (20 mL), sodium bicarbonate (saturated aqueous solution 20 mL), and water (5 mL) were added to the reaction mixture. The organics were separated, and the aqueous was extracted with DCM (3 × 15 mL). The organics were combined, passed through a hydrophobic frit, and concentrated in vacuo to give methyl 3-(2-bromobenzothiophen-3-yl)propanoate (97.0%) as a pale yellow oil (2.09 g, 98% yield, 97% purity). 1 H NMR (400 MHz, CDCl3) δ 7.75 - 7.67 (m, 2H), 7.40 - 7.29 (m, 2H), 3.69 (s, 3H), 3.22 - 3.16 (m, 2H), 2.67 - 2.60 (m, 2H).

[0265] Step 2 To a solution of methyl 3-(2-bromobenzothiophen-3-yl)propanoate (97%, 1.89 g, 6.13 mmol) in anhydrous THF (44 mL) and anhydrous methanol (5.8 mL) at 0 °C, lithium tetrahydroborate (430 mg, 19.7 mmol) was added portionwise over 1 minute. The resulting solution was stirred at room temperature for 30 minutes, after which additional lithium tetrahydroborate (50 mg, 2.30 mmol) was added, and the mixture was stirred at room temperature for 10 minutes. The reaction mixture was cooled to 0 °C and quenched by the slow addition of hydrochloric acid (20 mL of a 1 M aqueous solution). The organics were diluted with ethyl acetate (150 mL) and separated. The organics were washed with sodium bicarbonate (50 mL of saturated aqueous solution) and then with brine. The combined aqueous layers were extracted with ethyl acetate (70 mL). The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated in vacuo to give 3-(2-bromobenzothiophen-3-yl)propan-1-ol (1.97 g, 97% yield, 90% purity) as a pale yellow oil. 1 H NMR (400 MHz, DMSO) δ 7.94 - 7.90 (m, 1H), 7.83 - 7.79 (m, 1H), 7.44 - 7.35 (m, 2H), 4.59 (t, J = 5.1 Hz, 1H), 3.49 - 3.43 (m, 2H), 2.89 - 2.83 (m, 2H), 1.75 - 1.66 (m, 2H).

[0266] Step 3 To a solution of 3-(2-bromobenzothiophen-3-yl)propan-1-ol (90%, 1.97 g, 6.54 mmol) in anhydrous DMF (15 mL) was added imidazole (900 mg, 13.2 mmol) and tert-butyl(chloro)dimethylsilane (1.33 g, 8.82 mmol), and the reaction was stirred at room temperature for 1.5 hours. TBSCl (200 mg) was then added, and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with ethyl acetate (120 mL), washed with water (150 mL), then brine (2 x 150 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by FCC (50 g SiO2 column, 0–10% ethyl acetate in heptane) to give 3-(2-bromobenzothiophen-3-yl)propoxy-tert-butyl-dimethylsilane (2.22 g, 5.47 mmol, 84% yield, 95% purity) as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ 7.74 - 7.69 (m, 2H), 7.37 - 7.28 (m, 2H), 3.69 (t, J = 6.1 Hz, 2H), 2.97 - 2.89 (m, 2H), 1.88 - 1.79 (m, 2H), 0.94 (s, 9H), 0.08 (s, 6H).

[0267] Step 4 A solution of 2,4-difluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (88%, 1.04 g, 3.57 mmol) and 3-(2-bromobenzothiophen-3-yl)propoxy-tert-butyl-dimethylsilane (95%, 1.65 g, 4.07 mmol) in 1,4-dioxane (30 mL) and water (3 mL) was sparged with nitrogen for 10 minutes. Potassium carbonate (1.08 g, 7.81 mmol) and Pd(dppf)Cl (262 mg, 0.357 mmol) were added to the reaction mixture, and the reaction mixture was heated at 100 °C for 16 hours. The reaction mixture was cooled to room temperature. It was then filtered through a pad of Celite® containing silica and washed with ethyl acetate. The filtrate was concentrated in vacuo, and the residue was purified by FCC (50 g SiO column, 0–25% acetone in heptane) to give 5-[3-[3-[tert-butyl(dimethyl)silyl]oxypropyl]benzothiophen-2-yl]-2,4-difluoroaniline (1.50 g, 73% yield, 75% purity) as a yellow oil. 1 H NMR (400 MHz, DMSO) δ 7.98 - 7.92 (m, 1H), 7.87 - 7.82 (m, 1H), 7.47 - 7.35 (m, 2H), 7.17 (dd, J = 11.2, 9.7 Hz, 1H), 6.82 (dd, J = 9.8, 7.6 Hz, 1H), 5.19 (s, 2H), 3.55 (t, J = 6.0 Hz, 2H), 2.79 - 2.73 (m, 2H), 1.71 - 1.63 (m, 2H), 0.81 (s, 9H), -0.03 (s, 6H).

[0268] Step 5 Intermediate 1 (50%, 1.56 g, 2.61 mmol) and 5-[3-[3-[tert-butyl(dimethyl)silyl]oxypropyl]benzothiophen-2-yl]-2,4-difluoroaniline (75%, 1.50 g, 2.59 mmol) were dissolved in anhydrous pyridine (14 mL), and the mixture was heated at 50° C. for 2 hours. The reaction mixture was cooled to room temperature, diluted with 1 M aqueous HCl (230 mL), and extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed with brine (70 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by FCC (50 g SiO column, 0-80% TBME in heptane) to give methyl 3-[[5-[3-[3-[tert-butyl(dimethyl)silyl]oxypropyl]benzothiophen-2-yl]-2,4-difluorophenyl]sulfamoyl]-5-chloro-4-methoxybenzoate (1.12 g, 46% yield, 75% purity) as a yellow oil. 1 H NMR (400 MHz, DMSO) δ 10.54 (s, 1H), 8.25 (d, J = 2.1 Hz, 1H), 8.19 (d, J = 2.1 Hz, 1H), 8.00 - 7.93 (m, 1H), 7.89 - 7.84 (m, 1H), 7.52 - 7.39 (m, 3H), 7.35 - 7.29 (m, 1H), 3.97 (s, 3H), 3.86 (s, 3H), 3.49 (t, J = 6.0 Hz, 2H), 2.73 - 2.66 (m, 2H), 1.64 - 1.57 (m, 2H), 0.78 (s, 9H), -0.06 (s, 6H). LCMS: m / z = 694.3 / 696.3 [MH]-, (ESI-), RT = 1.02, Method B

[0269] Step 6 To a solution of methyl 3-[[5-[3-[3-[tert-butyl(dimethyl)silyl]oxypropyl]benzothiophen-2-yl]-2,4-difluorophenyl]sulfamoyl]-5-chloro-4-methoxybenzoate (75%, 1.12 g, 1.21 mmol) in methanol (7 mL) was added 4-methylbenzenesulfonic acid hydrate (1:1) (26 mg, 0.137 mmol) at room temperature. The reaction mixture was stirred at room temperature for 1 hour and then concentrated in vacuo. The residue was purified by FCC (25 g SiO column, 0-100% ethyl acetate in heptane, followed by 0-30% methanol in ethyl acetate) to give methyl 3-chloro-5-[[2,4-difluoro-5-[3-(3-hydroxypropyl)benzothiophen-2-yl]phenyl]sulfamoyl]-4-methoxybenzoate (758 mg, 100% yield, 93% purity) as a white solid. LCMS: m / z = 580.0 / 582.0 [MH]-, (ESI-), RT = 1.09, Method B

[0270] Step 7 To a solution of methyl 3-chloro-5-[[2,4-difluoro-5-[3-(3-hydroxypropyl)benzothiophen-2-yl]phenyl]sulfamoyl]-4-methoxybenzoate (93%, 421 mg, 0.673 mmol) in THF (6.5 mL) was added 2 M aqueous sodium hydroxide (2.0 mL, 4.00 mmol) at room temperature. The reaction mixture was stirred at room temperature for 15.5 h, and then the organics were concentrated in vacuo. 1 M aqueous HCl (15 mL) was added to the flask, and the organics were extracted with DCM (4 × 15 mL), passed through a hydrophobic frit, and concentrated in vacuo to give 3-chloro-5-[[2,4-difluoro-5-[3-(3-hydroxypropyl)benzothiophen-2-yl]phenyl]sulfamoyl]-4-methoxybenzoic acid (508 mg, 100% yield, 75% purity) as a yellow oil. LCMS: m / z = 566.0 / 568.0 [MH]-, (ESI-), RT = 0.97, Method B

[0271] Step 8 To a solution of 3-chloro-5-[[2,4-difluoro-5-[3-(3-hydroxypropyl)benzothiophen-2-yl]phenyl]sulfamoyl]-4-methoxybenzoic acid (75%, 508 mg, 0.671 mmol) in anhydrous DCM (22 mL) was added 4-dimethylaminopyridine (17 mg, 0.139 mmol) and N,N'-dicyclohexylcarbodiimide (280 mg, 1.36 mmol). The reaction mixture was stirred at room temperature for 2 hours and then concentrated in vacuo. The residue was purified by FCC (25 g SiO column, 0-60% ethyl acetate in heptane) followed by FCC (25 g SiO column, 0-100% ethanol in heptane) to give 18-chloro-24,26-difluoro-19-methoxy-21,21-dioxo-14-oxa-3,21λ-dithia-22-azapentacyclo[21.3.1.116,20.02,10.04,9]octacosa-1(27),2(10),4,6,8,16,18,20(28),23,25-decaen-15-one (253 mg, 60% yield, 88% purity) as a white solid. 1 H NMR (400 MHz, DMSO) δ 10.79 (s, 1H), 8.17 (d, J = 2.1 Hz, 1H), 8.04 - 7.97 (m, 2H), 7.82 (d, J = 2.1 Hz, 1H), 7.66 - 7.60 (m, 1H), 7.52 - 7.43 (m, 2H), 7.41 - 7.35 (m, 1H), 4.32 - 4.27 (m, 2H), 4.07 (s, 3H), 2.90 - 2.83 (m, 2H), 1.97 - 1.88 (m, 2H). LCMS: m / z = 548.0 / 550.0 [MH]-, (ESI-), RT = 1.19, Method B

[0272] Step 9 To a solution of 18-chloro-24,26-difluoro-19-methoxy-21,21-dioxo-14-oxa-3,21λ6-dithia-22-azapentacyclo[21.3.1.116,20.02,10.04,9]octacosa-1(27),2(10),4,6,8,16,18,20(28),23,25-decaen-15-one (87%, 80 mg, 0.127 mmol) in anhydrous DCM (4.0 mL) was added 1M BBr3 in DCM (0.70 mL, 0.70 mmol) at -16 °C. The reaction mixture was allowed to warm gradually to 10 °C over 4 h. Saturated aqueous NaHCO3 (4 mL) was added to the reaction mixture. The aqueous phase was extracted with DCM (3 × 4 mL), and the combined organic phases were passed through a hydrophobic frit and concentrated in vacuo. The residue was purified by preparative HPLC (Method P1) to give the title compound as a white solid (7 mg, 10% yield, 99% purity). 1 H NMR (500 MHz, DMSO) δ 8.03–8.00 (m, 1H), 8.00–7.96 (m, 2H), 7.78 (d, J = 2.2 Hz, 1H), 7.65–7.58 (m, 1H), 7.52–7.46 (m, 1H), 7.46–7.41 (m, 1H), 7.41–7.33 (m, 1H), 4.30–4.21 (m, 2H), 2.89–2.80 (m, 2H), 1.93–1.82 (m, 2H). No 2H was observed. LCMS: m / z = 534.0 / 536.0 [MH]-, (ESI-), RT = 4.63, Method A

[0273] Example 23: 15-chloro-21-fluoro-16-hydroxy-8,11-dioxa-18 lambda 6-thia-19-azatetracyclo[18.3.1.1 13,17 .0 2,7 ]Synthesis of pentacosa-1(24),2,4,6,13,15,17(25),20,22-nonaene-12,18,18-trione (compound 23) To a solution of 15-chloro-21-fluoro-16-methoxy-18,18-dioxo-8,11-dioxa-18λ6-thia-19-azatetracyclo[18.3.1.113,17.02,7]pentacosa-1(24),2,4,6,13,15,17(25),20,22-nonaen-12-one (synthesized according to General Scheme 2, 92%, 180 mg, 0.347 mmol) in anhydrous DCM (3.0 mL) was added 1 M BBr in DCM (1.5 mL, 1.5 mmol) at 0 °C, and the reaction mixture was stirred at 0 °C for 1.5 h. The reaction mixture was poured into 5 wt% aqueous NaHCO (30 mL) at 0 °C. The organics were extracted with DCM (3 x 20 mL), combined, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (Method P1) to give the title compound as a white solid (26 mg, 16% yield, 99% purity). 1 H NMR (500 MHz, DMSO) δ 11.64 - 9.76 (m, 2H), 8.04 (d, J = 2.1 Hz, 1H), 7.67 (d, J = 2.1 Hz, 1H), 7.42 - 7.33 (m, 2H), 7.25 (dd, J = 7.5, 1.7 Hz, 1H), 7.22 - 7.11 (m, 3H), 7.08 - 7.03 (m, 1H), 4.40 - 4.35 (m, 2H), 4.30 - 4.24 (m, 2H). LCMS: m / z = 462.0 / 464.0 [MH]-, (ESI-), RT = 4.04, Method A

[0274] Example 24: 4-Bromo-15-chloro-21,23-difluoro-16-hydroxy-8,11-dioxa-18 lambda 6-thia-19-azatetracyclo[18.3.1.1 13,17 .0 2,7 ]Synthesis of pentacosa-1(24),2,4,6,13,15,17(25),20,22-nonaene-12,18,18-trione (compound 24) To 4-bromo-15-chloro-21,23-difluoro-16-methoxy-18,18-dioxo-8,11-dioxa-18λ6-thia-19-azatetracyclo[18.3.1.113,17.02,7]pentacosa-1(24),2,4,6,13,15,17(25),20,22-nonaen-12-one (synthesized according to General Scheme 2, 95%, 100 mg, 0.165 mmol) in anhydrous DCM (1.5 mL) was added 1 M BBr in DCM (0.80 mL, 0.80 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 1.5 h. The reaction mixture was poured into 5 wt% aqueous NaHCO solution (30 mL) at 0 °C. The organics were extracted with DCM (3 x 20 mL), combined, dried over sodium sulfate, filtered, and concentrated in vacuo. Purification by preparative HPLC (Method P1) afforded the title compound as a white solid (26 mg, 25% yield, 90% purity). 1 H NMR (500 MHz, DMSO) δ 11.67 - 9.84 (m, 2H), 8.04 (d, J = 2.1 Hz, 1H), 7.63 (dd, J = 8.8, 2.6 Hz, 1H), 7.51 (d, J = 2.5 Hz, 1H), 7.47 (d, J = 2.2 Hz, 1H), 7.37 - 7.31 (m, 1H), 7.28 - 7.20 (m, 1H), 7.17 (d, J = 8.8 Hz, 1H), 4.36 - 4.28 (m, 4H). LCMS: m / z = 557.9 / 559.9 / 561.9 [MH]-, (ESI-), RT = 4.29, Method A

[0275] Example 25: 15-chloro-21-hydroxy-16-methoxy-8,11-dioxa-18 lambda 6-thia-19-azatetracyclo[18.3.1.1 13,17 .0 2,7 ]Synthesis of pentacosa-1(24),2,4,6,13,15,17(25),20,22-nonaene-12,18,18-trione (compound 25) Example 26: 15-chloro-16-hydroxy-21-methoxy-8,11-dioxa-18 lambda 6-thia-19-azatetracyclo[18.3.1.1 13,17 .0 2,7 ]Synthesis of pentacosa-1(24),2,4,6,13,15,17(25),20,22-nonaene-12,18,18-trione (compound 26) To a solution of 15-chloro-16,21-dimethoxy-18,18-dioxo-8,11-dioxa-18λ6-thia-19-azatetracyclo[18.3.1.113,17.02,7]pentacosa-1(24),2,4,6,13,15,17(25),20,22-nonaen-12-one (synthesized according to General Scheme 2, 95%, 130 mg, 0.252 mmol) in anhydrous DCM (13.0 mL) was added 1 M BBr in DCM (0.26 mL, 0.26 mmol). The reaction mixture was stirred at 0 °C for 40 min. To the reaction mixture was added 1 M BBr (0.13 mL, 0.13 mmol), and the reaction mixture was stirred at 0 °C for 1 h. Water (65 mL) was added to the reaction mixture and the organics extracted with DCM (3 x 70 mL). The combined organics were passed through a hydrophobic frit and concentrated in vacuo. Purification by preparative HPLC (Method P1) gave the following products: Compound 25: White solid (26 mg, 21% yield, 98% purity) 1 H NMR (500 MHz, DMSO) δ 9.50 (s, 2H), 8.12 (d, J = 2.1 Hz, 1H), 7.58 (s, 1H), 7.36 - 7.31 (m, 1H), 7.27 - 7.23 (m, 1H), 7.23 - 7.21 (m, 1H), 7.17 - 7.14 (m, 1H), 7.07 - 7.02 (m, 1H), 7.03 - 6.98 (m, 1H), 6.60 (d, J = 8.3 Hz, 1H), 4.41 - 4.35 (m, 2H), 4.28 - 4.22 (m, 2H), 4.03 (s, 3H). LCMS: m / z = 474.0 / 476.1 [MH]-, (ESI-), RT = 3.69, Method A Compound 26: White solid (31 mg, 25% yield, 98% purity) 1 H NMR (500 MHz, DMSO) δ 10.89 (br s, 1H), 9.45 (s, 1H), 8.00 (d, J = 2.1 Hz, 1H), 7.43 (d, J = 2.2 Hz, 1H), 7.39 - 7.34 (m, 1H), 7.28 - 7.27 (m, 1H), 7.27 - 7.24 (m, 1H), 7.20 - 7.17 (m, 1H), 7.17 - 7.14 (m, 1H), 7.08 - 7.04 (m, 1H), 6.79 (d, J = 8.5 Hz, 1H), 4.35 - 4.31 (m, 2H), 4.27 - 4.23 (m, 2H), 3.40 (s, 3H). LCMS: m / z = 474.0 / 476.0 [MH]-, (ESI-), RT = 4.08, Method A

[0276] Example 27: 18-chloro-24,26-difluoro-19-hydroxy-14-oxa-21lambda 6-thia-10,22-diazapentacyclo[21.3.1.1 16,20 .0 2,10 .0 4,9 ]Synthesis of octacosa-1(27),2,4,6,8,16,18,20(28),23,25-decaene-15,21,21-trione (compound 27) TIFF2025515002000457.tif6458 Step 1 To a solution of 2-iodo-1H-indole (95%, 775 mg, 3.03 mmol) in anhydrous DMF (30.2 mL) was added NaH in mineral oil (60%, 140 mg, 3.50 mmol), followed by 3-bromopropoxy-tert-butyl-dimethylsilane (96%, 822 μL, 3.19 mmol) at 0° C. The reaction mixture was warmed to room temperature and stirred for 3 h. The reaction mixture was diluted with saturated aqueous NaHCO3 (80 mL) at 0° C. and extracted with ethyl acetate (2×80 mL). The combined organic layers were washed with brine (40 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by FCC (100 g SiO2 column, 0-5% ethyl acetate in heptane) to give tert-butyl-[3-(2-iodoindol-1-yl)propoxy]dimethylsilane (933 mg, 70% yield, 95% purity). 1 H NMR (500 MHz, DMSO) δ 7.49 - 7.45 (m, 2H), 7.10 - 7.06 (m, 1H), 7.02 - 6.98 (m, 1H), 6.77 (d, J = 0.8 Hz, 1H), 4.28 - 4.22 (m, 2H), 3.62 (t, J = 6.0 Hz, 2H), 1.87 - 1.80 (m, 2H), 0.90 (s, 9H), 0.05 (s, 6H).

[0277] Step 2 A solution of tert-butyl-[3-(2-iodoindol-1-yl)propoxy]-dimethylsilane (95%, 413 mg, 0.945 mmol) and 2,4-difluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (85%, 300 mg, 1.00 mmol) in 1,4-dioxane (4 mL) and water (0.5 mL) was sparged with nitrogen for 10 minutes, followed by the addition of potassium carbonate (260 mg, 1.88 mmol) and Pd(dppf)Cl (70 mg, 0.0954 mmol). The reaction mixture was heated at 100 °C under nitrogen for 18 hours. The mixture was cooled to room temperature, filtered through Celite, and washed with ethyl acetate. The filtrate was concentrated in vacuo, and the residue was purified by FCC (25 g SiO column, 0-20% ethyl acetate in heptane) to give 5-[1-[3-[tert-butyl(dimethyl)silyl]oxypropyl]indol-2-yl]-2,4-difluoroaniline (188 mg, 45% yield, 95% purity) as a brown gum. 1 H NMR (400 MHz, DMSO) δ 7.56 (d, J = 7.8 Hz, 1H), 7.51 (d, J = 8.2 Hz, 1H), 7.21 - 7.13 (m, 2H), 7.09 - 7.03 (m, 1H), 6.82 (dd, J = 9.9, 7.5 Hz, 1H), 6.44 (s, 1H), 5.17 (s, 2H), 4.13 (t, J = 7.5 Hz, 2H), 3.45 (t, J = 5.8 Hz, 2H), 1.72 - 1.62 (m, 2H), 0.79 (s, 9H), -0.06 (s, 6H).

[0278] Step 3 Intermediate 1 (50%, 263 mg, 0.440 mmol) and 5-[1-[3-[tert-butyl(dimethyl)silyl]oxypropyl]indol-2-yl]-2,4-difluoroaniline (95%, 188 mg, 0.429 mmol) were dissolved in anhydrous pyridine (2.3 mL), and the mixture was heated at 50 °C for 1 h. The reaction mixture was diluted with 1 M aqueous HCl (5 mL) and extracted with ethyl acetate (3 × 10 mL). The combined organic extracts were washed with brine (10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by FCC (25 g SiO column, 0-20% ethyl acetate in heptane) to give methyl 3-[[5-[1-[3-[tert-butyl(dimethyl)silyl]oxypropyl]indol-2-yl]-2,4-difluoro-phenyl]sulfamoyl]-5-chloro-4-methoxybenzoate (161 mg, 50% yield, 90% purity) as a brown gum. 1 H NMR (400 MHz, DMSO) δ 10.55 (s, 1H), 8.24 (d, J = 2.1 Hz, 1H), 8.19 (d, J = 2.1 Hz, 1H), 7.58 (d, J = 7.8 Hz, 1H), 7.52 (d, J = 8.3 Hz, 1H), 7.50 - 7.43 (m, 1H), 7.35 (t, J = 8.2 Hz, 1H), 7.22 - 7.16 (m, 1H), 7.11 - 7.05 (m, 1H), 6.47 (s, 1H), 4.10 - 4.04 (m, 2H), 3.98 (s, 3H), 3.85 (s, 3H), 3.39 - 3.34 (m, 2H), 1.56 (q, J = 6.6 Hz, 2H), 0.76 (s, 9H), -0.10 (s, 6H). LCMS: m / z = 679.2 / 681.2 [M+H]+, (ESI+), RT = 0.99, Method B

[0279] Step 4 To a solution of methyl 3-[[5-[1-[3-[tert-butyl(dimethyl)silyl]oxypropyl]indol-2-yl]-2,4-difluoro-phenyl]sulfamoyl]-5-chloro-4-methoxybenzoate (90%, 315 mg, 0.413 mmol) in anhydrous THF (3.3 mL) was added 1 M T BAF (1.5 mL, 1.50 mmol) in THF at room temperature, and the reaction mixture was stirred at room temperature for 60 hours. The reaction mixture was diluted with 1 M aqueous HCl (5 mL) and extracted with ethyl acetate (3 × 10 mL). The combined organic extracts were washed with brine (10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by FCC (25 g SiO column, 0-100% ethyl acetate in heptane) to give methyl 3-chloro-5-[[2,4-difluoro-5-[1-(3-hydroxypropyl)indol-2-yl]phenyl]sulfamoyl]-4-methoxybenzoate (85.0%) (167 mg, 61% yield, 88% purity) as a pale yellow gum. LCMS: m / z = 563.1 / 565.0 [MH]-, (ESI-), RT = 1.06, Method B

[0280] Step 5 Methyl 3-chloro-5-[[2,4-difluoro-5-[1-(3-hydroxypropyl)indol-2-yl]phenyl]sulfamoyl]-4-methoxybenzoate (88%, 165 mg, 0.257 mmol) was dissolved in THF (5.4 mL) and methanol (0.52 mL), and 2 M aqueous sodium hydroxide (1.2 mL, 2.40 mmol) was added. The resulting solution was stirred at room temperature for 1 hour. 6.0 M aqueous NaOH (0.5 mL) was added, and the reaction was stirred at room temperature for an additional 1 hour. The THF was evaporated under reduced pressure and the remaining aqueous solution was acidified to pH = 1 with 1 M aqueous HCl (15 mL) and extracted with DCM (3 x 15 mL), after which the combined organic phases were washed with brine (30 mL), passed through a phase separator and concentrated under reduced pressure to give 3-chloro-5-[[2,4-difluoro-5-[1-(3-hydroxypropyl)indol-2-yl]phenyl]sulfamoyl]-4-methoxybenzoic acid (145 mg, 99% yield, 97% purity) as a pale yellow solid. LCMS: m / z = 549.0 / 551.0 [MH]-, (ESI-), RT = 0.93, Method B

[0281] Step 6 To a solution of 3-chloro-5-[[2,4-difluoro-5-[1-(3-hydroxypropyl)indol-2-yl]phenyl]sulfamoyl]-4-methoxybenzoic acid (97%, 150 mg, 0.264 mmol) in anhydrous DCM (8.8 mL) was added 4-dimethylaminopyridine (7.0 mg, 0.0573 mmol) and N,N'-dicyclohexylcarbodiimide (125 mg, 0.606 mmol). The reaction mixture was stirred at room temperature for 20 hours and then concentrated in vacuo. The residue was purified by FCC (25 g SiO column, 0-100% ethyl acetate in heptane) to give 18-chloro-24,26-difluoro-19-methoxy-21,21-dioxo-14-oxa-21λ6-thia-10,22-diazapentacyclo[21.3.1.116,20.02,10.04,9]octacosa-1(27),2,4,6,8,16,18,20(28),23,25-decaen-15-one (107 mg, 68% yield, 90% purity) as a white solid. 1 H NMR (400 MHz, DMSO) δ 10.79 (s, 1H), 8.17 - 8.13 (m, 1H), 7.77 - 7.71 (m, 1H), 7.73 - 7.64 (m, 1H), 7.66 - 7.58 (m, 2H), 7.40 - 7.31 (m, 1H), 7.28 - 7.20 (m, 1H), 7.15 - 7.07 (m, 1H), 6.61 (s, 1H), 4.27 - 4.20 (m, 2H), 4.20 - 4.11 (m, 2H), 4.07 (s, 3H), 2.05 - 1.95 (m, 2H). LCMS: m / z = 531.1 / 533.0 [MH]-, (ESI-), RT = 1.12, Method B

[0282] Step 7 To a solution of 18-chloro-24,26-difluoro-19-methoxy-21,21-dioxo-14-oxa-21λ6-thia-10,22-diazapentacyclo[21.3.1.116,20.02,10.04,9]octacosa-1(27),2,4,6,8,16,18,20(28),23,25-decaen-15-one (90%, 95 mg, 0.160 mmol) in anhydrous DCM (9.5 mL) was added 1 M BBr in DCM (1.0 mL, 1.00 mmol) and the reaction mixture was stirred at 0 °C for 1.5 h. To the reaction mixture was added 1 M BBr in DCM (0.50 mL, 0.50 mmol) and the reaction mixture was stirred at 0 °C for 1 h. Water (50 mL) was added to the reaction mixture. The aqueous phase was extracted with DCM (3 x 50 mL), and the organic phases were combined, passed through a hydrophobic frit, and concentrated in vacuo. 20 wt% of the crude material was purified by preparative HPLC (Method P1). The remaining 80 wt% of the crude material was purified by reverse-phase FCC (12 g of C18 silicon dioxide, eluting with 0.1% NH3 in acetonitrile, 0.1% NH3 in water, 10-100%). The resulting products were combined, and most of the acetonitrile was removed in vacuo. The organics were extracted from the remaining aqueous phase with DCM (3 x 50 mL), combined, passed through a hydrophobic frit, and concentrated in vacuo to give the title compound as an off-white solid (14 mg, 16% yield, 96% purity). 1 H NMR (500 MHz, DMSO) δ 7.99 - 7.94 (m, 1H), 7.69 - 7.67 (m, 1H), 7.67 - 7.64 (m, 1H), 7.64 - 7.59 (m, 2H), 7.39 - 7.33 (m, 1H), 7.26 - 7.21 (m, 1H), 7.14 - 7.08 (m, 1H), 6.59 (s, 1H), 4.24 - 4.19 (m, 2H), 4.17 - 4.12 (m, 2H), 2.01 - 1.93 (m, 2H). LCMS: m / z = 517.0 / 519.0 [MH]-, (ESI-), RT = 4.34, Method A

[0283] Example 28: 15-chloro-21,23-difluoro-16-hydroxy-12,18,18-trioxo-8,11-dioxa-18-lambda 6-thia-19-azatetracyclo[18.3.1.1 13,17 .0 2,7 ]Synthesis of pentacosa-1(24),2,4,6,13,15,17(25),20,22-nonaene 4-carbonitrile (compound 28) To a solution of 15-chloro-21,23-difluoro-16-methoxy-12,18,18-trioxo-8,11-dioxa-18λ6-thia-19-azatetracyclo[18.3.1.113,17.02,7]pentacosa-1(24),2,4,6,13,15,17(25),20,22-nonaene-4-carbonitrile (synthesized according to General Scheme 2, 92%, 100 mg, 0.177 mmol) in anhydrous DCM (1.6 mL) at 0 °C, 1 M BBr in DCM (0.80 mL, 0.800 mmol) was added, and the reaction mixture was stirred at 0 °C for 3 h. The reaction mixture was poured into saturated aqueous NaHCO (30 mL). The organics were extracted with DCM (3 x 30 mL), combined, dried over sodium sulfate, filtered, and concentrated in vacuo. Purification was performed by acidic prep HPLC (standard method). The product-containing fractions were combined, concentrated in vacuo, and dried in a vacuum oven (40 °C) to give the title compound as a white solid (35 mg, 39% yield, 100% purity). 1H NMR (500 MHz, DMSO) δ 8.07 - 7.99 (m, 1H), 7.96 (dd, J = 8.6, 2.2 Hz, 1H), 7.83 (d, J = 2.1 Hz, 1H), 7. 47 (d, J = 2.2 Hz, 1H), 7.41 - 7.33 (m, 2H), 7.32 - 7.22 (m, 1H), 4.42 - 4.38 (m, 2H), 4.37 - 4.34 (m, 2H). LCMS: m / z = 505.0 / 507.0 [MH]-, (ESI-), RT = 3.81, Method A

[0284] Example 29: 16-chloro-5,22,24-trifluoro-17-hydroxy-8,12-dioxa-19lambda 6-thia-20-azatetracyclo[19.3.1.1 14,18 .0 2,7 ]Synthesis of hexacosa-1(25),2,4,6,14,16,18(26),21,23-nonaene-13,19,19-trione (compound 29) To a solution of 16-chloro-5,22,24-trifluoro-17-methoxy-19,19-dioxo-8,12-dioxa-19λ6-thia-20-azatetracyclo[19.3.1.114,18.02,7]hexacosa-1(24),2(7),3,5,14,16,18(26),21(25),22-nonaen-13-one (synthesized according to General Scheme 2, 93%, 230 mg, 0.405 mmol) in anhydrous DCM (4.3 mL) was added 1 M BBr in DCM (2.0 mL, 2.0 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was added dropwise to ice-cold saturated aqueous NaHCO solution. The organics were extracted with DCM (3 x 10 mL), combined, passed through a hydrophobic frit and concentrated in vacuo. The crude material was purified by reverse-phase column chromatography (12 g C18 silica, 10-100% acetonitrile in water (0.1% NH3)) followed by preparative HPLC (Method P3) to give the title compound (11 mg, 5% yield, 98% purity) as a white solid. 1 H NMR (400 MHz, DMSO) δ 7.90 (br s, 1H), 7.36 (d, J = 2.2 Hz, 1H), 7.24 - 7.12 (m, 2H), 7.02 - 6.94 (m, 1H), 6.93 - 6.87 (m, 1H), 6.88 - 6.78 (m, 1H), 4.42 - 4.33 (m, 2H), 4.14 - 4.06 (m, 2H), 2.02 - 1.91 (m, 2H). No 2H was observed. LCMS: m / z = 512.1 / 514.1 [MH]-, (ESI-), RT = 3.93, Method A

[0285] Example 30: 14-chloro-20,22-difluoro-15-hydroxy-17-lambda 6-thia-10,18-diazatetracyclo[17.3.1.1 12,16 .0 2,7 ]Synthesis of tetracosa-1(23),2,4,6,12,14,16(24),19,21-nonaene-11,17,17-trione (compound 30) To a solution of 14-chloro-20,22-difluoro-15-methoxy-17,17-dioxo-17λ6-thia-10,18-diazatetracyclo[17.3.1.112,16.02,7]tetracosa-1(23),2,4,6,12,14,16(24),19,21-nonaen11-one (synthesized according to General Scheme 1, 75%, 270 mg, 0.423 mmol) in anhydrous DCM (4 mL) at 0 °C, 1 M BBr in DCM (2.1 mL, 2.1 mmol) was added. The reaction mixture was stirred at 0 °C for 5 min and then at room temperature for 20 h. To the reaction mixture was added 1M BBr3 in DCM (0.85 mL, 0.85 mmol) at 0 °C, and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was poured into ice-water (60 mL). The aqueous phase was extracted with DCM (3 × 40 mL), and the organic phases were combined, passed through a hydrophobic frit, and concentrated in vacuo. Purification was achieved by preparative HPLC (Method P1), followed by FCC (10 g SiO2 column, 0-20% methanol in DCM) to afford the title compound (32 mg, 16% yield, 99% purity) as an off-white solid. 1 H NMR (400 MHz, DMSO) δ 8.00 - 7.89 (m, 1H), 7.78 (s, 1H), 7.51 - 7.40 (m, 3H), 7.39 - 7.32 (m, 1H), 7.26 - 7.16 (m, 1H), 6.91 (d, J = 7.7 Hz, 1H), 6.48 - 6.32 (m, 1H), 3.76 - 3.57 (m, 1H), 2.89 - 2.77 (m, 1H), 2.73 - 2.59 (m, 1H). LCMS: m / z = 463.0 / 465.0 [MH]-, (ESI-), RT = 3.46, Method A

[0286] Example 31: 15-chloro-4-cyclopropyl-21,23-difluoro-16-hydroxy-8,11-dioxa-18 lambda 6-thia-19-azatetracyclo[18.3.1.1 13,17 .0 2,7 ]Synthesis of pentacosa-1(23),2,4,6,13(25),14,16,20(24),21-nonaene-12,18,18-trione (compound 31) A sealed mixture of 15-chloro-4-cyclopropyl-21,23-difluoro-16-methoxy-18,18-dioxo-8,11-dioxa-18λ6-thia-19-azatetracyclo[18.3.1.113,17.02,7]pentacosa-1(24),2,4,6,13,15,17(25),20,22-nonaen-12-one (synthesized according to General Scheme 2, 100%, 100 mg, 0.187 mmol), iodocyclohexane (400 mg, 1.90 mmol), and anhydrous DMF (3 mL) was heated at 150 °C for 3 h. The reaction mixture was cooled to room temperature and then added to water (50 mL). The organics were extracted with ethyl acetate (3 x 50 mL), combined, washed with brine (100 mL), dried over sodium sulfate, filtered and concentrated in vacuo. Purification by preparative HPLC (Method P1) gave the title compound as a white solid (27 mg, 27% yield, 96% purity). 1 H NMR (400 MHz, DMSO) δ 8.03 (d, J = 2.1 Hz, 1H), 7.45 (d, J = 2.2 Hz, 1H), 7.36 - 7.26 (m, 1H), 7.23 - 7.11 (m, 2H), 7.06 (d, J = 8.5 Hz, 1H), 6.97 (d, J = 2.3 Hz, 1H), 4.35 - 4.29 (m, 2H), 4.27 - 4.20 (m, 2H), 1.92 (tt, J = 8.5, 5.1 Hz, 1H), 0.94 - 0.86 (m, 2H), 0.74 - 0.62 (m, 2H). LCMS: m / z = 520.2 / 522.1 [MH]-, (ESI-), RT = 4.39, Method A

[0287] Example 32: 15-chloro-21,23-difluoro-16-hydroxy-8,11-dioxa-18lambda 6-thia-6,19-diazatetracyclo[18.3.1.1 13,17 .0 2,7 ]Synthesis of pentacosa-1(24),2,4,6,13,15,17(25),20,22-nonaene-12,18,18-trione (compound 32) To a solution of 15-chloro-21,23-difluoro-16-methoxy-18,18-dioxo-8,11-dioxa-18λ6-thia-6,19-diazatetracyclo[18.3.1.113,17.02,7]pentacosa-1(24),2,4,6,13,15,17(25),20,22-nonaen-12-one (synthesized according to General Scheme 2, 95%, 110 mg, 0.210 mmol) in anhydrous DCM (2 mL) was added 1 M BBr in DCM (1.1 mL, 1.1 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 10 min and then at room temperature for 3 h. The reaction mixture was poured into saturated aqueous NaHCO (30 mL). The aqueous phase was extracted with DCM (3 x 30 mL) and the combined organic phases were passed through a hydrophobic frit and concentrated in vacuo. Purification by preparative HPLC (Method P1) gave the title compound (22 mg, 17% yield, 99% purity) as an off-white solid. 1 H NMR (500 MHz, DMSO) δ 8.27 (dd, J = 5.0, 1.9 Hz, 1H), 8.06 - 7.98 (m, 1H), 7.75 (dd, J = 7.3, 1.9 Hz, 1H), 7.68 (d, J = 2.2 Hz, 1H), 7.40 - 7.26 (m, 2H), 7.15 (dd, J = 7.3, 5.0 Hz, 1H), 4.51 - 4.44 (m, 2H), 4.44 - 4.36 (m, 2H). LCMS: m / z = 481.0 / 483.0 [MH]-, (ESI-), RT = 3.85, Method A

[0288] Example 33: Synthesis of 16-chloro-22,24-difluoro-17-hydroxy-19,19-dioxo-8-oxa-19λ6-thia-12,20-diazapentacyclo[19.3.1.110,12.114,18.02,7]heptacosa-1(25),2,4,6,14,16,18(26),21,23-nonaen-13-one (Compound 33) A solution of 16-chloro-22,24-difluoro-17-methoxy-19,19-dioxo-8-oxa-19λ6-thia-12,20-diazapentacyclo[19.3.1.110,12.114,18.02,7]heptacosa-1(25),2,4,6,14,16,18(26),21,23-nonaen-13-one (synthesized using a method similar to that in Example 1, 95% purity, 50 mg, 0.09 mmol) in anhydrous DCM (2 mL) was cooled to 0 °C, 1 M BBr in DCM (0.40 mL, 0.40 mmol) was added, and the mixture was stirred at 40 °C for 20 h. The mixture was poured into ice-cold saturated aqueous NaHCO3 (30 mL) and DCM (30 mL) was added. The layers were separated and the aqueous phase was extracted with DCM (4 x 30 mL). The aqueous phase was acidified with 2 M aqueous HCl to pH 1-2 and then further extracted with DCM (2 x 30 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (Method P1) to give the title compound as a white solid (14 mg, 30% yield, 99% purity). 1H NMR (400 MHz, DMSO) δ 10.77 (br. s, 1H), 7.67 (s, 1H), 7.54 - 7.43 (m, 1H), 7.41 - 7.30 (m, 2H), 7.23 (d, J = 7.9 Hz, 1H), 7.20 - 7.05 (m, 3H), 4.44 - 4.27 (m, 1H), 4.15 - 3.85 (m, 2H), 3.70 - 3.52 (m, 2H), 3.23 - 3.02 (m, 1H), 2.95 - 2.72 (m, 1H). LCMS: m / z = 507.0 / 509.0 [M+H]+, (ESI+), RT = 3.40, Method A

[0289] Example 34: Synthesis of 12-chloro-4,6-difluoro-11-hydroxy-9,9-dioxo-2,16-dioxa-9λ6-thia-8-azatetracyclo[16.3.1.13,7.110,14]tetracosa-1(22),3,5,7(24),10(23),11,13,18,20-nonaen-15-one (Compound 34) TIFF2025515002000464.tif4749 Step 1 Methyl 3-iodobenzoate (500 mg, 1.87 mmol), 5-amino-2,4-difluorophenol (326 mg, 2.24 mmol), pyridine-2-carboxylic acid (23 mg, 0.187 mmol), copper(I) iodide (18 mg, 0.09 mmol), and potassium phosphate tribasic (794 mg, 3.74 mmol) were placed in a pressure vial. The vial was placed under nitrogen and subjected to three vacuum / nitrogen cycles. Anhydrous DMSO (4 mL) was added, and the vial was heated at 80 °C for 24 h. The reaction mixture was cooled to room temperature, filtered through a pad of silica, and washed with ethyl acetate. Water (20 mL) was added to the filtrate, and the layers were separated. The aqueous layer was further extracted with ethyl acetate (2 × 20 mL). The combined organic layers were washed with brine, dried (sodium sulfate), filtered, and concentrated. The residue was purified by FCC (25 g SiO2 column, 0-100% ethyl acetate in heptane) to give methyl 3-(5-amino-2,4-difluorophenoxy)benzoate (265 mg, 48% yield, 94% purity) as a pale yellow oil. 1 H NMR (400 MHz, DMSO) δ 7.72 - 7.67 (m, 1H), 7.57 - 7.49 (m, 1H), 7.38 (dd, J = 2.8, 1.5 Hz, 1H), 7.32 - 7.24 (m, 2H), 6.64 - 6.56 (m, 1H), 5.22 (s, 2H), 3.84 (s, 3H).

[0290] Step 2 To a solution of methyl 3-(5-amino-2,4-difluoro-phenoxy)benzoate (94% purity, 260 mg, 0.875 mmol) in anhydrous THF (6 mL) was added lithium borohydride (95 mg, 4.38 mmol) and the mixture was stirred at 66 °C for 1 h. The mixture was cooled to room temperature, DCM (30 mL) and saturated aqueous NaHCO (30 mL) were added, and the layers were separated. The aqueous solution was further extracted with DCM (2 × 20 mL). The combined organics were passed through a phase separator and concentrated to give [3-(5-amino-2,4-difluoro-phenoxy)phenyl]methanol (214 mg, 90% yield, 92% purity) as a pale yellow oil. 1 H NMR (500 MHz, DMSO) δ 7.32 - 7.26 (m, 1H), 7.26 - 7.17 (m, 1H), 7.05 - 6.98 (m, 1H), 6.89 - 6.85 (m, 1H), 6.84 - 6.75 (m, 1H), 6.58 - 6.50 (m, 1H), 5.22 (t, J = 5.8 Hz, 1H), 5.15 (s, 2H), 4.46 (d, J = 5.4 Hz, 2H).

[0291] Step 3 Intermediate 1 (50% pure, 552 mg, 0.923 mmol) and [3-(5-amino-2,4-difluoro-phenoxy)phenyl]methanol (92% pure, 210 mg, 0.769 mmol) were dissolved in anhydrous pyridine (4 mL), and the mixture was stirred at 50 °C for 1 h. The reaction mixture was cooled to room temperature, diluted with 1 M aqueous HCl (30 mL), and extracted with ethyl acetate (3 × 30 mL). The combined organic extracts were washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by FCC (50 g SiO column, 0-100% ethyl acetate in heptane) to give methyl 3-chloro-5-[[2,4-difluoro-5-[3-(hydroxymethyl)phenoxy]phenyl]sulfamoyl]-4-methoxybenzoate (270 mg, 65% yield, 95% purity) as a pale yellow oil. 1 H NMR (400 MHz, DMSO) δ 10.44 (s, 1H), 8.23 ​​(d, J = 2.1 Hz, 1H), 8.11 (d, J = 2.1 Hz, 1H), 7.57 - 7.47 (m, 1H), 7.32 - 7.23 (m, 1H), 7.10 - 7.04 (m, 1H), 6.95 - 6.85 (m, 2H), 6.73 - 6.65 (m, 1H), 5.23 (t, J = 5.7 Hz, 1H), 4.46 (d, J = 5.5 Hz, 2H), 3.93 (s, 3H), 3.87 (s, 3H).

[0292] Step 4 Methyl 3-chloro-5-[[2,4-difluoro-5-[3-(hydroxymethyl)phenoxy]phenyl]sulfamoyl]-4-methoxybenzoate (95% pure, 270 mg, 0.50 mmol) was dissolved in THF (4 mL) and 2 M aqueous sodium hydroxide (1.2 mL, 2.50 mmol) was added. The reaction mixture was stirred overnight at room temperature. THF was removed in vacuo, and the remaining aqueous phase was diluted with water (30 mL) and acidified with 1 M aqueous HCl. The mixture was extracted with DCM (3 × 30 mL), and the combined organic phase was passed through a phase separator and concentrated to give 3-chloro-5-[[2,4-difluoro-5-[3-(hydroxymethyl)phenoxy]phenyl]sulfamoyl]-4-methoxybenzoic acid (240 mg, 87% yield, 94% purity) as an off-white solid. 1 H NMR (400 MHz, DMSO) δ 13.66 (br. s, 1H), 10.40 (br. s, 1H), 8.19 (d, J = 2.1 Hz, 1H), 8.10 (d, J = 2.1 Hz, 1H), 7.57 - 7.45 (m, 1H), 7.32 - 7.25 (m, 1H), 7.08 (d, J = 7.6 Hz, 1H), 6.95 - 6.87 (m, 2H), 6.69 (dd, J = 8.1, 2.7 Hz, 1H), 5.22 (br. s, 1H), 4.53 - 4.38 (m, 2H), 3.92 (s, 3H). LCMS: m / z = 498.0 / 500.0 [MH]-, (ESI-), RT = 0.87, Method B

[0293] Step 5 To a solution of 3-chloro-5-[[2,4-difluoro-5-[3-(hydroxymethyl)phenoxy]phenyl]sulfamoyl]-4-methoxy-benzoic acid (94% pure, 210 mg, 0.395 mmol) in anhydrous DCM (20 mL) was added DMAP (10 mg, 0.079 mmol) and DCC (163 mg, 0.790 mmol). The mixture was stirred at room temperature for 3 h, diluted with DCM (20 mL) and water (40 mL), and the layers were separated. The aqueous solution was extracted with DCM (2 × 30 mL), and the combined organic phases were passed through a phase separator and concentrated. The residue was purified by FCC (25 g SiO column, 0-100% ethyl acetate in heptane) to give 12-chloro-4,6-difluoro-11-methoxy-9,9-dioxo-2,16-dioxa-9λ6-thia-8-azatetracyclo[16.3.1.13,7.110,14]tetracosa-1(22),3,5,7(24),10(23),11,13,18,20-nonaen-15-one (145 mg, 72% yield, 95% purity) as a white solid. 1 H NMR (400 MHz, DMSO) δ 10.79 (s, 1H), 8.25 (d, J = 2.2 Hz, 1H), 8.08 (d, J = 2.2 Hz, 1H), 7.54 - 7.46 (m, 1H), 7.46 - 7.36 (m, 2H), 7.24 - 7.17 (m, 1H), 7.16 - 7.06 (m, 1H), 6.44 - 6.29 (m, 1H), 5.39 (s, 2H), 4.08 (s, 3H). LCMS: m / z = 480.0 / 482.0 [MH]-, (ESI-), RT = 1.12, Method B

[0294] Step 6 12-Chloro-4,6-difluoro-11-methoxy-9,9-dioxo-2,16-dioxa-9λ6-thia-8-azatetracyclo[16.3.1.13,7.110,14]tetracosa-1(22),3,5,7(24),10(23),11,13,18,20-nonaen-15-one (100 mg, 0.21 mmol), anhydrous DMF (4 mL), and iodocyclohexane (268 μL, 2.08 mmol) were added to a pressure vial. The vial was sealed and heated at 100 °C for 3 h. The reaction mixture was cooled to room temperature, saturated aqueous NaHCO3 (50 mL) was added, and the mixture was subsequently extracted with ethyl acetate (3 × 50 mL). The combined organic extracts were washed with water (2 × 100 mL), then brine (100 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by FCC (10 g SiO2 column, 0-20% methanol in DCM) to give the title compound (42 mg, 42% yield, 98% purity) as a white solid. 1 H NMR (500 MHz, DMSO) δ 7.95 (d, J = 2.5 Hz, 1H), 7.71 - 7.60 (m, 1H), 7.51 - 7.30 (m, 3H), 7.15 (dd, J = 8.2, 2.6 Hz, 1H), 7.06 (d, J = 7.5 Hz, 1H), 6.35 - 6.25 (m, 1H), 5.27 (s, 2H). LCMS: m / z = 466.0 / 468.0 [MH]-, (ESI-), RT = 4.36, Method A

[0295] Example 35: Synthesis of 21,23-difluoro-15-methyl-18,18-dioxo-8,11-dioxa-18λ6-thia-15,19-diazatetracyclo[18.3.1.113,17.02,7]pentacosa-1(23),2(7),3,5,13,17(25),20(24),21-octaene-12,16-dione (Compound 35) TIFF2025515002000465.tif5048 Step 1 To a solution of methyl 5-bromo-1-methyl-6-oxo-pyridine-3-carboxylate (2.0 g, 7.97 mmol) in anhydrous 1,4-dioxane (75 mL) was added DIPEA (1.7 mL, 9.97 mmol), and the solution was sparged with nitrogen for 10 minutes. Phenylmethanethiol (1.1 mL, 9.44 mmol), Pd2(dba)3 (234 mg, 0.256 mmol), and Xantphos (281 mg, 0.486 mmol) were added, and the reaction mixture was heated at 100 °C for 16 hours. The reaction was cooled to room temperature, diluted with water (100 mL), and extracted with ethyl acetate (3 × 100 mL). The combined organic layers were washed with brine (100 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by FCC (0-100% ethyl acetate in heptane) to give methyl 5-benzylsulfanyl-1-methyl-6-oxopyridine-3-carboxylate (1.90 g, 82% yield, 100% purity) as a yellow solid. 1 H NMR (400 MHz, DMSO) δ 8.37 (d, J = 2.3 Hz, 1H), 7.59 (d, J = 2.3 Hz, 1H), 7.46 - 7.37 (m, 2H), 7.35 - 7.30 (m, 2H), 7.28 - 7.22 (m, 1H), 4.18 (s, 2H), 3.78 (s, 3H), 3.54 (s, 3H). LCMS: m / z = 290.0 [M+H]+, (ESI+), RT = 0.78, Method B

[0296] Step 2 Methyl 5-benzylsulfanyl-1-methyl-6-oxo-pyridine-3-carboxylate (500 mg, 1.68 mmol) was dissolved in a mixture of acetonitrile (10 mL), acetic acid (0.5 mL), and water (0.5 mL). The resulting suspension was cooled to 0 °C in an ice bath. 1,3-Dichloro-5,5-dimethylhydantoin (673 mg, 3.42 mmol) was then added in portions (over approximately 15 min), and the reaction mixture was stirred at 0 °C for 2 h. The acetonitrile was removed under reduced pressure, and DCM (20 mL) was added. The solution was cooled to 0 °C, and saturated aqueous NaHCO3 (20 mL) was added slowly. The organic layer was separated, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give methyl 5-chlorosulfonyl-1-methyl-6-oxo-pyridine-3-carboxylate (800 mg, 90% yield, 50% purity) as a white solid. LCMS: Not ionized, RT = 0.63, Method B

[0297] Step 3 Methyl 5-chlorosulfonyl-1-methyl-6-oxo-pyridine-3-carboxylate (50% pure, 600 mg, 1.13 mmol) was added to a stirred solution of Intermediate 8 (95% pure, 450 mg, 1.13 mmol) in anhydrous pyridine (10 mL) at room temperature, and the mixture was heated at 50° C. for 1 h. The reaction mixture was cooled to room temperature, quenched with 1 M aqueous HCl (30 mL), and extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with brine (30 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by FCC (0-100% ethyl acetate in heptane) to give methyl 5-[[5-[2-[tert-butyl(dimethyl)silyl]oxyethoxy]phenyl]-2,4-difluoro-phenyl]sulfamoyl]-1-methyl-6-oxo-pyridine-3-carboxylate (520 mg, 0.837 mmol, 74% yield, 98% purity) as a yellow glass. 1H NMR (400 MHz, CDCl3) δ 8.50 (d, J = 2.5 Hz, 1H), 8.42 (d, J = 2.5 Hz, 1H), 7.61 (br s, 1H), 7.54 (dd, J = 8.9, 7.4 Hz, 1H), 7.35 (ddd, J = 8.3, 7.4, 1.8 Hz, 1H), 7.18 (ddd, J = 7.7, 1.8, 0.7 Hz, 1H), 7.02 - 6.97 (m, 2H), 6.79 (dd, J = 10.1, 9.0 Hz, 1H), 4.04 (t, J = 5.3 Hz, 2H), 3.89 - 3.82 (m, 5H), 3.72 (s, 3H), 0.81 (s, 9H), -0.07 (s, 6H).

[0298] Step 4 p-Methylbenzenesulfonic acid hydrate (16 mg, 0.0837 mmol) was added to a stirred solution of methyl 5-[[5-[2-[2-[tert-butyl(dimethyl)silyl]oxyethoxy]phenyl]-2,4-difluoro-phenyl]sulfamoyl]-1-methyl-6-oxo-pyridine-3-carboxylate (98% pure, 520 mg, 0.837 mmol) in methanol (10 mL), and the mixture was stirred for 1 h. The reaction mixture was concentrated in vacuo, and the residue was diluted with water (25 mL) and extracted with ethyl acetate (3 × 25 mL). The combined organic layers were washed with brine (25 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by FCC (0-100% ethyl acetate in heptane) to give methyl 5-[[2,4-difluoro-5-[2-(2-hydroxyethoxy)phenyl]phenyl]sulfamoyl]-1-methyl-6-oxo-pyridine-3-carboxylate (350 mg, 82% yield, 97% purity) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.52 (d, J = 2.5 Hz, 1H), 8.43 (d, J = 2.5 Hz, 1H), 7.68 (dd, J = 8.9, 7.6 Hz, 1H), 7.62 (br s, 1H), 7.37 (ddd, J = 8.3, 7.4, 1.8 Hz, 1H), 7.30 - 7.22 (m, 1H), 7.09 - 7.00 (m, 1H), 6.99 (dd, J = 8.3, 1.1 Hz, 1H), 6.88 - 6.77 (m, 1H), 4.11 - 4.08 (m, 2H), 3.92 - 3.85 (m, 5H), 3.73 (s, 3H), 2.49 (td, J = 6.6, 1.5 Hz, 1H). LCMS: m / z = 495.1 [M+H]+, (ESI+), RT = 0.75, Method B

[0299] Step 5 To a stirred solution of methyl 5-[[2,4-difluoro-5-[2-(2-hydroxyethoxy)phenyl]phenyl]sulfamoyl]-1-methyl-6-oxo-pyridine-3-carboxylate (97% pure, 320 mg, 0.628 mmol) in THF (10 mL) was added 2 M aqueous sodium hydroxide (1.6 mL, 3.14 mmol) at room temperature, and the mixture was stirred for 2 h. The THF was removed in vacuo, and the remaining aqueous phase was diluted with water (30 mL). The diluted aqueous phase was acidified with 1 M aqueous HCl. The mixture was extracted with DCM (3 × 30 mL). The combined organic layers were washed with brine (30 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to give 5-[[2,4-difluoro-5-[2-(2-hydroxyethoxy)phenyl]phenyl]sulfamoyl]-1-methyl-6-oxo-pyridine-3-carboxylic acid (250 mg, 83% yield, 100% purity) as a white solid. 1H NMR (400 MHz, DMSO) δ 13.25 (br s, 1H), 9.96 (s, 1H), 8.82 (d, J = 2.5 Hz, 1H), 8.24 (d, J = 2.5 Hz, 1H), 7.38 (ddd, J = 8.3, 7.3, 1.8 Hz, 1H), 7.33 - 7.19 (m, 2H), 7.17 - 7.06 (m, 2H), 7.06 - 6.97 (m, 1H), 4.66 (br s, 1H), 3.98 (t, J = 5.4 Hz, 2H), 3.64 - 3.54 (m, 5H). LCMS: m / z = 481.1 [M+H]+, (ESI+), RT = 0.66, Method B

[0300] Step 6 DCC (86 mg, 0.416 mmol) was added to a stirred solution of 5-[[2,4-difluoro-5-[2-(2-hydroxyethoxy)phenyl]phenyl]sulfamoyl]-1-methyl-6-oxo-pyridine-3-carboxylic acid (100 mg, 0.208 mmol) and DMAP (5.1 mg, 0.042 mmol) in anhydrous DCM (10 mL) at room temperature, and the mixture was stirred for 5 h. The reaction mixture was diluted with DCM (10 mL) and water (10 mL) to give a biphasic mixture. The biphasic mixture was separated, and the aqueous layer was further extracted with DCM (2 × 10 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (Method P3), and the fractions containing the target compound were combined and concentrated in vacuo. The resulting solid was dissolved in DCM (10 mL) and washed with 1 M aqueous HCl (10 mL). The organic layer was passed through a phase separator and concentrated to give the title compound (30 mg, 31% yield, 98% purity) as a white solid. 1H NMR (400 MHz, DMSO) δ 10.36 (br s, 1H), 8.82 (d, J = 2.6 Hz, 1H), 7.68 (d, J = 2.6 Hz, 1H), 7.44 (ddd, J = 8.3, 7.4, 1.8 Hz, 1H), 7.32 - 7.15 (m, 4H), 7.13 - 7.00 (m, 1H), 4.40 - 4.19 (m, 4H), 3.58 (s, 3H). LCMS: m / z = 463.1 [M+H]+, (ESI+), RT = 2.93, Method A

[0301] Example 36: Synthesis of 21,23-difluoro-18,18-dioxo-8,11-dioxa-18λ6-thia-15,19-diazatetracyclo[18.3.1.113,17.02,7]pentacosa-1(23),2(7),3,5,13,17(25),20(24),21-octaene-12,16-dione (Compound 36) TIFF2025515002000466.tif5046 Step 1 To a solution of methyl 5-bromo-6-methoxy-pyridine-3-carboxylate (1.30 g, 5.28 mmol) in anhydrous 1,4-dioxane (50 mL) was added DIPEA (1.2 mL, 6.89 mmol), and the solution was sparged with nitrogen for 10 minutes. Phenylmethanethiol (0.75 mL, 6.40 mmol), Pd(dba) (145 mg, 0.158 mmol), and Xantphos (183 mg, 0.317 mmol) were added, and the reaction mixture was heated at 100 °C for 16 hours. The reaction was cooled to room temperature, diluted with water (100 mL), and extracted with ethyl acetate (3 × 100 mL). The combined organic layers were washed with brine (100 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by FCC (0-100% ethyl acetate in heptane) to give methyl 5-benzylsulfanyl-6-methoxy-pyridine-3-carboxylate (1.45 g, 85% yield, 90% purity) as an orange solid. 1H NMR (500 MHz, CDCl3) δ 8.62 (d, J = 2.1 Hz, 1H), 8.04 (d, J = 2.1 Hz, 1H), 7.36 - 7.33 (m, 2H), 7.34 - 7.27 (m, 2H), 7.27 - 7.23 (m, 1H), 4.16 (s, 2H), 4.08 (s, 3H), 3.90 (s, 3H). LCMS: m / z = 290.1 ​​[M+H]+, (ESI+), RT = 1.00, Method B

[0302] Step 2 Methyl 5-benzylsulfanyl-6-methoxy-pyridine-3-carboxylate (90% pure, 500 mg, 1.56 mmol) was dissolved in a mixture of acetonitrile (9 mL), acetic acid (0.45 mL), and water (0.45 mL), and the resulting suspension was cooled to 0 °C in an ice bath. 1,3-Dichloro-5,5-dimethylhydantoin (613 mg, 3.11 mmol) was then added in portions (over approximately 15 min), and the reaction mixture was stirred at 0 °C for 2 h. The acetonitrile was removed under reduced pressure, and DCM (20 mL) was added. The solution was cooled to 0 °C, and saturated aqueous NaHCO3 (20 mL) was added slowly. The organic layer was separated, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give methyl 5-chlorosulfonyl-6-methoxy-pyridine-3-carboxylate (620 mg, 99% yield, 66% purity) as a white solid. LCMS: No ionization, RT = 0.85, Method B

[0303] Step 3 Methyl 5-chlorosulfonyl-6-methoxy-pyridine-3-carboxylate (66% purity, 600 mg, 1.49 mmol) was added to a stirred solution of Intermediate 8 (95% purity, 400 mg, 1.00 mmol) in anhydrous pyridine (10 mL) at room temperature, and the mixture was heated at 50 °C for 1 h. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was purified by FCC (0-100% ethyl acetate in heptane) to give methyl 5-[[5-[2-[2-[tert-butyl(dimethyl)silyl]oxyethoxy]phenyl]-2,4-difluoro-phenyl]sulfamoyl]-6-methoxy-pyridine-3-carboxylate (510 mg, 70% yield, 84% purity) as a yellow oil. 1 H NMR (400 MHz, CDCl3) δ 8.96 (d, J = 2.3 Hz, 1H), 8.62 (d, J = 2.2 Hz, 1H), 7.58 (dd, J = 9.0, 7.4 Hz, 1H), 7.39 - 7.32 (m, 1H), 7.18 - 7.11 (m, 2H), 7.05 - 6.96 (m, 2H), 6.76 (dd, J = 10.3, 8.9 Hz, 1H), 4.23 (s, 3H), 4.04 (t, J = 5.3 Hz, 2H), 3.91 (s, 3H), 3.83 (t, J = 5.3 Hz, 2H), 0.81 (s, 9H), -0.09 (s, 6H).

[0304] Step 4 p-Methylbenzenesulfonic acid hydrate (13 mg, 0.0690 mmol) was added to a stirred solution of methyl 5-[[5-[2-[2-[tert-butyl(dimethyl)silyl]oxyethoxy]phenyl]-2,4-difluoro-phenyl]sulfamoyl]-6-methoxy-pyridine-3-carboxylate (84% pure, 500 mg, 0.690 mmol) in methanol (8 mL), and the mixture was stirred for 1 h. The reaction mixture was concentrated in vacuo, and the residue was diluted with saturated aqueous NaHCO3 (25 mL) and extracted with ethyl acetate (3 × 25 mL). The combined organic layers were washed with brine (25 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by FCC (0-100% ethyl acetate in heptane) to give methyl 5-[[2,4-difluoro-5-[2-(2-hydroxyethoxy)phenyl]phenyl]sulfamoyl]-6-methoxy-pyridine-3-carboxylate (340 mg, 93% yield, 93% purity) as a white solid. 1 H NMR (400 MHz, CDCl3) δ 8.98 (d, J = 2.2 Hz, 1H), 8.64 (d, J = 2.2 Hz, 1H), 7.71 (dd, J = 9.0, 7.6 Hz, 1H), 7.38 (ddd, J = 8.3, 7.4, 1.7 Hz, 1H), 7.27 - 7.22 (m, 1H), 7.16 (s, 1H), 7.09 - 7.01 (m, 1H), 7.00 (dd, J = 8.3, 1.0 Hz, 1H), 6.81 (dd, J = 10.2, 9.3 Hz, 1H), 4.24 (s, 3H), 4.13 - 4.08 (m, 2H), 3.92 (s, 3H), 3.91 - 3.87 (m, 2H), 2.46 (t, J = 6.5 Hz, 1H). LCMS: m / z = 495.1 [M+H]+, (ESI+), RT = 0.85, Method B

[0305] Step 5 To a stirred solution of methyl 5-[[2,4-difluoro-5-[2-(2-hydroxyethoxy)phenyl]phenyl]sulfamoyl]-6-methoxy-pyridine-3-carboxylate (93% pure, 350 mg, 0.658 mmol) in THF (10 mL) was added 2 M aqueous sodium hydroxide (1.7 mL, 3.40 mmol) at room temperature, and the mixture was stirred for 1 h. The THF was removed in vacuo, and the remaining aqueous solution was diluted with water (30 mL) and carefully acidified with 1 M aqueous HCl to pH 3. The mixture was extracted with DCM (3 × 30 mL). The combined organic layers were washed with brine (30 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to give 5-[[2,4-difluoro-5-[2-(2-hydroxyethoxy)phenyl]phenyl]sulfamoyl]-6-methoxy-pyridine-3-carboxylic acid (227 mg, 68% yield, 95% purity). LCMS: m / z = 481.1 [M+H]+, (ESI+), RT = 0.73, Method B

[0306] Step 6 DCC (180 mg, 0.870 mmol) was added to a stirred solution of 5-[[2,4-difluoro-5-[2-(2hydroxyethoxy)phenyl]phenyl]sulfamoyl]-6-methoxy-pyridine-3-carboxylic acid (95% pure, 220 mg, 0.435 mmol) and DMAP (11 mg, 0.0870 mmol) in anhydrous DCM (20 mL) at room temperature, and the mixture was stirred for 3 h. The reaction mixture was diluted with DCM (10 mL) and water (10 mL), and the biphasic mixture was separated. The aqueous layer was further extracted with DCM (2 × 10 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by FCC (0-100% ethyl acetate in heptane) to give 21,23-difluoro-16-methoxy-18,18-dioxo-8,11-dioxa-18λ6-thia-15,19-diazatetracyclo[18.3.1.113,17.02,7]pentacosa-1(23),2(7),3,5,13,15,17(25),20(24),21-nonaen12-one (158 mg, 69% yield, 88% purity) as a white solid. 1H NMR (400 MHz, DMSO) δ 10.60 (s, 1H), 8.88 (d, J = 2.3 Hz, 1H), 7.77 (d, J = 2.3 Hz, 1H), 7.46 (ddd, J = 8.3, 7.4, 1.8 Hz, 1H), 7.34 - 7.24 (m, 2H), 7.19 (dd, J = 8.3, 1.0 Hz, 1H), 7.17 - 7.06 (m, 2H), 4.41 - 4.33 (m, 2H), 4.33 - 4.26 (m, 2H), 4.11 (s, 3H). LCMS: m / z = 463.1 [M+H]+, (ESI+), RT = 0.89, Method B

[0307] Step 7 Iodocyclohexane (320 μL, 2.47 mmol) was added dropwise to a stirred solution of 21,23-difluoro-16-methoxy-18,18-dioxo-8,11-dioxa-18λ6-thia-15,19-diazatetracyclo[18.3.1.113,17.02,7]pentacosa-1(23),2(7),3,5,13,15,17(25),20(24),21-nonaen12-one (88% purity, 130 mg, 0.247 mmol) in anhydrous DMF (5 mL) at room temperature, and the mixture was heated at 100 °C for 3 h. The reaction was cooled to room temperature, diluted with water (10 mL) and DCM (10 mL), and the resulting biphasic mixture was separated. The aqueous layer was extracted with DCM (2 × 10 mL), and the combined organic layers were washed with brine (10 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by basic reverse-phase FCC (C18SiO2 column, 10-100% acetonitrile (0.1% NH3) in water) to give the title compound (84 mg, 0.182 mmol, 73% yield, 97% purity) as a white solid. 1H NMR (400 MHz, DMSO) δ 13.03 (br s, 1H), 10.33 (br s, 1H), 8.29 (d, J = 2.7 Hz, 1H), 7.64 (d, J = 2.7 Hz, 1H), 7.49 - 7.40 (m, 1H), 7.32 - 7.15 (m, 4H), 7.13 - 7.04 (m, 1H), 4.36 - 4.16 (m, 4H). LCMS: m / z = 449.1 [M+H]+, (ESI+), RT = 2.77, Method A

[0308] Example 37: Synthesis of 4,21-difluoro-18,18-dioxo-8,11-dioxa-18λ6-thia-15,19-diazatetracyclo[18.3.1.113,17.02,7]pentacosa-1(23),2(7),3,5,13,17(25),20(24),21-octaene-12,16-dione (Compound 37) TIFF2025515002000467.tif5146 The title compound was synthesized using a synthetic route similar to that described for Example 36. 1 H NMR (400 MHz, DMSO) δ 12.98 (br. s, 1H), 10.30 (br. s, 1H), 8.26 (d, J = 2.7 Hz, 1H), 7.74 (d, J = 2.6 Hz, 1H), 7.35 (dd, J = 7.6, 2.2 Hz, 1H), 7.27 - 7.06 (m, 5H), 4.36 - 4.26 (m, 2H), 4.26 - 4.15 (m, 2H). LCMS: m / z = 449.0 [M+H]+, (ESI+), RT = 2.93, Method A

[0309] Example 38: Synthesis of 21,23-difluoro-18,18-dioxo-8,11-dioxa-18λ6-thia-16,19-diazatetracyclo[18.3.1.113,17.02,7]pentacosa-1(23),2(7),3,5,13,17(25),20(24),21-octaene-12,15-dione (Compound 38) TIFF2025515002000468.tif4651 The title compound was synthesized using a synthetic route similar to that described for Example 48. 1 H NMR (500 MHz, DMSO) δ 12.40 (s, 1H), 10.25 (s, 1H), 7.48 - 7.43 (m, 1H), 7.29 (dd, J = 7.5, 1.8 Hz, 1H), 7.28 - 7.20 (m, 3H), 7.20 - 7.17 (m, 1H), 7.11 - 7.07 (m, 1H), 6.94 (s, 1H), 4.44 - 4.38 (m, 2H), 4.37 - 4.29 (m, 2H). LCMS: m / z = 447.0 [MH]-, (ESI-), RT = 3.17, Method A

[0310] Example 39: Synthesis of 15-chloro-21,23-difluoro-16-hydroxy-18,18-dioxo-8,11-dioxa-18λ6-thia-19-azapentacyclo[18.3.1.16,9.113,17.02,7]hexacosa-1(23),2(7),3,5,13,15,17(25),20(24),21-nonaen12-one (Compound 39) TIFF2025515002000469.tif4749 Step 1 A mixture of 1-allyloxy-2-bromobenzene (3.10 g, 14.5 mmol) and N,N-diethylaniline (5.0 mL, 31.2 mmol) was heated to reflux at 220 °C for 4.5 h. After cooling to room temperature, 1 M aqueous HCl (50 mL) and diethyl ether (40 mL) were added, and the biphasic mixture was separated. The aqueous layer was further extracted with diethyl ether (40 mL). The combined organic layer was extracted with 1 M aqueous NaOH (2 × 60 mL). The basic aqueous extracts were combined and acidified with 6 M aqueous HCl. This aqueous layer was extracted with diethyl ether (2 × 80 mL). The resulting organic layers were combined, washed with brine, dried over magnesium sulfate, filtered, and concentrated to give 2-allyl-6-bromophenol (2.74 g, 84% yield; 95% purity) as a brown oil. 1 H NMR (500 MHz, DMSO) δ 9.01 (s, 1H), 7.35 (dd, J = 8.0, 1.6 Hz, 1H), 7.06 (dd, J = 7.5, 1.6 Hz, 1H), 6.78 - 6.65 (m, 1H), 5.93 (ddt, J = 18.0, 9.1, 6.6 Hz, 1H), 5.07 - 4.99 (m, 2H), 3.38 (d, J = 6.6 Hz, 2H).

[0311] Step 2 To a solution of 2-allyl-6-bromophenol (95% pure, 2.74 g, 12.2 mmol) in CHCl3 (120 mL) was added mCPBA (70% pure, 4.52 g, 18.3 mmol) and trifluoroacetic acid (0.093 mL, 1.22 mmol). The mixture was stirred at reflux at 65 °C for 2.5 h. Additional trifluoroacetic acid (0.093 mL, 1.22 mmol) was added, and the mixture was stirred at reflux at 65 °C for 2 h. The mixture was cooled to room temperature, washed with sodium bicarbonate (2 × 70 mL), then brine (70 mL), dried over magnesium sulfate, filtered, and concentrated. The residue was purified by FCC (100 g ethylene SiO2 column, 0-100% ethyl acetate in heptane) to give (7-bromo-2,3-dihydrobenzofuran-2-yl)methanol (1.73 g, 57% yield, 93% purity) as a pale yellow oil. 1 H NMR (500 MHz, DMSO) δ 7.26 (d, J = 7.9 Hz, 1H), 7.20 - 7.09 (m, 1H), 6.77 - 6.57 (m, 1H), 5.03 (dd, J = 5.5, 5.5 Hz, 1H), 4.93 - 4.77 (m, 1H), 3.67 - 3.61 (m, 1H), 3.61 - 3.53 (m, 1H), 3.32 - 3.24 (m, 1H), 3.12 (dd, J = 15.8, 7.6 Hz, 1H).

[0312] Step 3 A mixture of 2,4-difluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (85% pure, 670 mg, 2.23 mmol), (7-bromo-2,3-dihydrobenzofuran-2-yl)methanol (93% pure, 500 mg, 2.03 mmol), potassium carbonate (561 mg, 4.06 mmol), water (1 mL), and anhydrous 1,4-dioxane (10 mL) was sparged with nitrogen for 5 minutes. Pd(dppf)Cl2 (149 mg, 0.203 mmol) was added, and the mixture was sparged for an additional 5 minutes. The vessel was sealed, and the reaction mixture was heated at 100 °C for 6 hours. The reaction mixture was cooled to room temperature, filtered through Celite, washed with ethyl acetate, and the filtrate was concentrated. The residue was purified by FCC (50 g SiO2 column, 0-100% ethyl acetate in heptane) to give [7-(5-amino-2,4-difluoro-phenyl)-2,3-dihydrobenzofuran-2-yl]methanol (761 mg, 95% yield, 70% purity) as a yellow oil. 1H NMR (400 MHz, DMSO) δ 7.22 - 7.17 (m, 1H), 7.06 (dd, J = 11.4, 9.9 Hz, 1H), 7.03 - 6.95 (m, 1H), 6.90 - 6.77 (m, 2H), 5.00 (s, 2H), 4.91 (dd, J = 5.6, 5.6 Hz, 1H), 4.85 - 4.70 (m, 1H), 3.59 - 3.48 (m, 2H), 3.30 - 3.16 (m, 1H), 3.09 - 2.98 (m, 1H). LCMS: m / z = 278.0 [M+H]+, (ESI+), RT = 0.78, Method B

[0313] Step 4 Intermediate 1 (50% purity, 1.25 g, 2.08 mmol) and [7-(5-amino-2,4-difluoro-phenyl)-2,3-dihydrobenzofuran-2-yl]methanol (70% purity, 750 mg, 1.89 mmol) were dissolved in anhydrous pyridine (8 mL), and the mixture was stirred at 50 °C for 1 hour. The reaction mixture was cooled to room temperature, diluted with 1 M aqueous HCl (30 mL), and extracted with ethyl acetate (3 × 30 mL). The combined organic extracts were washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by FCC (50 g SiO column, 0-100% ethyl acetate in heptane) to give methyl 3-chloro-5-[[2,4-difluoro-5-[2-(hydroxymethyl)-2,3-dihydrobenzofuran-7-yl]phenyl]sulfamoyl]-4-methoxybenzoate (790 mg, 66% yield, 85% purity) as a pale yellow solid. 1H NMR (400 MHz, DMSO) δ 10.38 (s, 1H), 8.26 (d, J = 2.1 Hz, 1H), 8.16 (d, J = 2.2 Hz, 1H), 7.38 - 7.28 (m, 2H), 7.24 (dd, J = 7.3, 1.3 Hz, 1H), 6.99 (d, J = 7.7 Hz, 1H), 6.91 - 6.85 (m, 1H), 4.89 (dd, J = 5.5, 5.5 Hz, 1H), 4.83 - 4.67 (m, 1H), 3.99 (s, 3H), 3.87 (s, 3H), 3.56 - 3.47 (m, 2H), 3.30 - 3.20 (m, 1H), 3.08 (dd, J = 15.9, 7.2 Hz, 1H). LCMS: m / z = 538.1 / 540.1 [MH]-, (ESI-), RT = 1.00, Method B

[0314] Step 5 Methyl 3-chloro-5-[[2,4-difluoro-5-[2-(hydroxymethyl)-2,3-dihydrobenzofuran-7-yl]phenyl]sulfamoyl]-4-methoxybenzoate (85% pure, 785 mg, 1.24 mmol) was dissolved in THF (9 mL) and 2 M aqueous sodium hydroxide (3.0 mL, 6.00 mmol) was added. The reaction mixture was stirred at room temperature for 4 h. THF was removed in vacuo, and the remaining aqueous solution was diluted with water (30 mL) and acidified with 1 M aqueous HCl. The mixture was extracted with DCM (3 × 30 mL), and the combined organics were passed through a phase separator and concentrated to give 3-chloro-5-[[2,4-difluoro-5-[2-(hydroxymethyl)-2,3-dihydrobenzofuran-7-yl]phenyl]sulfamoyl]-4-methoxybenzoic acid (784 mg, quantitative yield, 86% pure) as an off-white solid. 1H NMR (500 MHz, DMSO) δ 13.66 (br. s, 1H), 10.34 (br. s, 1H), 8.22 (d, J = 2.0 Hz, 1H), 8.15 (d, J = 2.0 Hz, 1H), 7.38 - 7.28 (m, 2H), 7.23 (dd, J = 7.3, 1.3 Hz, 1H), 6.97 (d, J = 7.7 Hz, 1H), 6.91 - 6.79 (m, 1H), 4.99 - 4.83 (m, 1H), 4.81 - 4.70 (m, 1H), 3.96 (s, 3H), 3.51 (d, J = 4.7 Hz, 2H), 3.25 (dd, J = 15.9, 9.4 Hz, 1H), 3.08 (dd, J = 15.9, 7.2 Hz, 1H). LCMS: m / z = 524.0 / 526.1 [MH]-, (ESI-), RT = 0.87, Method B

[0315] Step 6 To a mixture of 3-chloro-5-[[2,4-difluoro-5-[2-(hydroxymethyl)-2,3-dihydrobenzofuran-7-yl]phenyl]sulfamoyl]-4-methoxy-benzoic acid (86% pure, 720 mg, 1.18 mmol), DMAP (29 mg, 0.235 mmol), and anhydrous DCM (40 mL) was added DCC (486 mg, 2.35 mmol). The reaction mixture was stirred at room temperature for 2 h. The mixture was diluted with water (40 mL), and the biphasic mixture was separated. The aqueous solution was further extracted with DCM (2 × 30 mL), and the combined organics were passed through a phase separator and concentrated. The residue was purified by FCC (25 g SiO column, 20-100% DCM in heptane) to give 15-chloro-21,23-difluoro-16-methoxy-18,18-dioxo-8,11-dioxa-18λ6-thia-19-azapentacyclo[18.3.1.16,9.113,17.02,7]hexacosa-1(23),2(7),3,5,13,15,17(25),20(24),21-nonaen-12-one (451 mg, 70% yield, 93% purity) as a white solid.

[0316] Step 7 15-Chloro-21,23-difluoro-16-methoxy-18,18-dioxo-8,11-dioxa-18λ6-thia-19-azapentacyclo[18.3.1.16,9.113,17.02,7]hexacosa-1(23),2(7),3,5,13,15,17(25),20(24),21-nonaen-12-one (93% purity, 150 mg, 0.275 mmol), anhydrous DMF (4 mL), and iodocyclohexane (178 μL, 1.37 mmol) were added to a pressure vial. The vial was sealed and heated at 120 °C for 1 h 45 min. The reaction mixture was cooled to room temperature, saturated aqueous NaHCO3 (30 mL) was added, and the biphasic mixture was separated. The aqueous phase was extracted with ethyl acetate (2 × 30 mL). The combined organic extracts were washed with saturated aqueous sodium thiosulfate (40 mL), 1 M aqueous HCl (40 mL), water (40 mL), then brine (40 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by FCC (10 g SiO column, 0-20% methanol in DCM) to give the title compound (105 mg, 77% yield, 99% purity) as a white solid. 1 H NMR (500 MHz, DMSO) δ 8.43 - 8.33 (m, 1H), 7.85 - 7.76 (m, 1H), 7.74 (dd, J = 8.3, 8.3 Hz, 1H), 7.36 (dd, J = 10.3, 10.3 Hz, 1H), 7.27 (d, J = 7.3 Hz, 1H), 7.18 - 7.10 (m, 1H), 6.92 (dd, J = 7.5, 7.5 Hz, 1H), 5.21 - 5.08 (m, 1H), 4.65 - 4.53 (m, 1H), 4.32 - 4.21 (m, 1H), 3.36 (dd, J = 15.9, 9.1 Hz, 1H), 2.97 (dd, J = 15.9, 7.3 Hz, 1H). LCMS: m / z = 492.0 / 494.0 [MH]-, (ESI-), RT = 4.05, Method A

[0317] Example 40: Synthesis of 15-chloro-21,23-difluoro-16-hydroxy-18,18-dioxo-8,11-dioxa-18λ6-thia-19-azapentacyclo[18.3.1.16,9.113,17.02,7]hexacosa-1(23),2(7),3,5,13,15,17(25),20(24),21-nonaen-12-one, enantiomer 1 (compound 40) Example 41: Synthesis of 15-chloro-21,23-difluoro-16-hydroxy-18,18-dioxo-8,11-dioxa-18λ6-thia-19-azapentacyclo[18.3.1.16,9.113,17.02,7]hexacosa-1(23),2(7),3,5,13,15,17(25),20(24),21-nonaen-12-one, enantiomer 2 (compound 41) TIFF2025515002000470.tif4749 (7-Bromo-2,3-dihydrobenzofuran-2-yl)methanol (synthesized in Example 39, Step 2; 977 mg, 4.2 mmol) was purified by chiral SFC (Chiralpak IG column, 21 × 250 mm, 5 μm; flow rate 50 mL / min; 20% methanol / 80% CO2, 0.2% v / v NH3 mobile phase) to give two components.

[0318] 7-Bromo-2,3-dihydrobenzofuran-2-yl)methanol, Enantiomer 1 (355 mg, brown oil) 1 H NMR (500 MHz, DMSO) δ 7.28 - 7.24 (m, 1H), 7.19 - 7.16 (m, 1H), 6.74 (dd, J = 8.0, 7.3 Hz, 1H), 5.03 (t, J = 5.4 Hz, 1H), 4.88 (dddd, J = 9.3, 7.7, 5.0, 4.1 Hz, 1H), 3.67 - 3.55 (m, 2H), 3.31 - 3.27 (m, 1H), 3.15 - 3.09 (m, 1H). Chiral analytical SFC: RT = 2.02 min (Chiralpak IG column, 4.6 x 250 mm, 5 μm; flow rate 4 mL / min; 20% methanol / 80% CO, 0.1% v / v NH mobile phase)

[0319] 7-Bromo-2,3-dihydrobenzofuran-2-yl)methanol, Enantiomer 2 (366 mg, brown oil) 1 H NMR (500 MHz, DMSO) δ 7.28 - 7.24 (m, 1H), 7.19 - 7.16 (m, 1H), 6.74 (dd, J = 8.0, 7.3 Hz, 1H), 5.03 (t, J = 5.5 Hz, 1H), 4.88 (dddd, J = 9.3, 7.7, 5.0, 4.1 Hz, 1H), 3.67 - 3.55 (m, 2H), 3.31 - 3.26 (m, 1H), 3.15 - 3.09 (m, 1H). Chiral analytical SFC: RT = 2.75 min (Chiralpak IG column, 4.6 x 250 mm, 5 μm; flow rate 4 mL / min; 20% methanol / 80% CO, 0.1% v / v NH mobile phase)

[0320] 7-Bromo-2,3-dihydrobenzofuran-2-yl)methanol, enantiomer 1 (355 mg) was used in a synthetic sequence similar to that described for Example 39 to give Example 40: 15-chloro-21,23-difluoro-16-hydroxy-18,18-dioxo-8,11-dioxa-18λ6-thia-19-azapentacyclo[18.3.1.16,9.113,17.02,7]hexacosa-1(23),2(7),3,5,13,15,17(25),20(24),21-nonaen-12-one, enantiomer 1 (60 mg, 99% purity) as a pink solid. 1H NMR (500 MHz, DMSO) δ 8.47 (d, J = 2.1 Hz, 1H), 8.04 (d, J = 2.1 Hz, 1H), 7.83 - 7.76 (m, 1H), 7.48 - 7.40 (m, 1H), 7.30 (dd, J = 7.4, 1.2 Hz, 1H), 7.24 - 7.18 (m, 1H), 6.97 - 6.91 (m, 1H), 5.19 - 5.10 (m, 1H), 4.76 (dd, J = 11.7, 3.7 Hz, 1H), 4.23 (dd, J = 11.7, 10.7 Hz, 1H), 3.40 (dd, J = 16.0, 9.3 Hz, 1H), 3.00 (dd, J = 16.0, 6.2 Hz, 1H). LCMS: m / z = 492.0 / 494.0 [MH]-, (ESI-), RT = 3.97, Method A

[0321] 7-Bromo-2,3-dihydrobenzofuran-2-yl)methanol, enantiomer 2 (366 mg) was used in a synthetic sequence similar to that described for Example 39 to give Example 41: 15-chloro-21,23-difluoro-16-hydroxy-18,18-dioxo-8,11-dioxa-18λ6-thia-19-azapentacyclo[18.3.1.16,9.113,17.02,7]hexacosa-1(23),2(7),3,5,13,15,17(25),20(24),21-nonaen-12-one, enantiomer 2 (37 mg, 100% purity) as a light brown solid. 1H NMR (500 MHz, DMSO) δ 8.47 (d, J = 2.1 Hz, 1H), 8.03 (d, J = 2.1 Hz, 1H), 7.82 - 7.75 (m, 1H), 7.48 - 7.40 (m, 1H), 7.29 (dd, J = 7.3, 1.2 Hz, 1H), 7.24 - 7.19 (m, 1H), 6.98 - 6.91 (m, 1H), 5.19 - 5.10 (m, 1H), 4.75 (dd, J = 11.6, 3.7 Hz, 1H), 4.23 (dd, J = 11.7, 10.7 Hz, 1H), 3.39 (dd, J = 16.2, 9.5 Hz, 1H), 3.00 (dd, J = 16.0, 6.2 Hz, 1H). LCMS: m / z = 492.0 / 494.0 [MH]-, (ESI-), RT = 3.98, Method A

[0322] Example 42: Synthesis of 15-chloro-21-fluoro-16-hydroxy-18,18-dioxo-11-oxa-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 (Compound 42) TIFF2025515002000471.tif4945 15-Chloro-21-fluoro-16-methoxy-18,18-dioxo-11-oxa-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 (synthesized in a similar manner to Intermediate 12, 95% purity, 100 mg, 0.20 mmol) and iodocyclohexane (210 mg, 1.00 mmol) were combined and dissolved in anhydrous DMF (3 mL). The mixture was heated to 120 °C and stirred for 2 h. The reaction mixture was cooled to room temperature, and saturated aqueous NaSO (50 mL) was added. The biphasic mixture was separated, and the aqueous phase was extracted with DCM (3 x 50 mL). The combined organic extracts were washed with 1M aqueous HCl (50 mL), then with brine (50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (Method P1) to give the title compound (60 mg, 64% yield, 99% purity) as an off-white solid. 1 H NMR (500 MHz, DMSO) δ 7.97 (d, J = 2.2 Hz, 1H), 7.73 (d, J = 2.2 Hz, 1H), 7.42 - 7.36 (m, 3H), 7.29 - 7.24 (m, 1H), 7.16 (dd, J = 7.5, 1.4 Hz, 1H), 7.11 (dd, J = 10.2, 8.4 Hz, 1H), 7.00 (ddd, J = 8.4, 4.7, 2.3 Hz, 1H), 4.22 - 4.16 (m, 2H), 2.58 - 2.53 (m, 2H), 1.92 - 1.83 (m, 2H). LCMS: m / z = 460.1 / 462.1 [MH]-, (ESI-), RT = 4.25, Method A

[0323] Example 43: Synthesis of 15-chloro-21,23-difluoro-16-hydroxy-8-methyl-18,18-dioxo-11-oxa-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 (Compound 43) TIFF2025515002000472.tif5049 Step 1 Thionyl dichloride (1.8 mL, 24.8 mmol) was carefully added dropwise to a stirred solution of 3-(2-bromophenyl)butanoic acid (500 mg, 2.06 mmol) in methanol (15 mL) at −15° C., and the mixture was stirred at room temperature for 16 h. The mixture was concentrated in vacuo, and the resultant was dissolved in water (10 mL) and ethyl acetate (10 mL) and separated. The aqueous layer was further extracted with ethyl acetate (2×10 mL), and the combined organic layers were washed with brine (10 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by FCC (silicon dioxide, 0–100% ethyl acetate in heptane) to give methyl 3-(2-bromophenyl)butanoate (470 mg, 84% yield, 95% purity) as a colorless oil. 1 H NMR (400 MHz, DMSO) δ 7.58 (dd, J = 8.0, 1.3 Hz, 1H), 7.43 - 7.37 (m, 1H), 7.39 - 7.30 (m, 1H), 7.20 - 7.09 (m, 1H), 3.67 - 3.55 (m, 1H), 3.55 (s, 3H), 2.75 - 2.58 (m, 2H), 1.18 (d, J = 6.9 Hz, 3H). LCMS: m / z = 257.0 / 259.0 [M+H]+, (ESI+), RT = 0.96, Method B

[0324] Step 2 A solution of methyl 3-(2-bromophenyl)butanoate (95% pure, 450 mg, 1.66 mmol) in anhydrous THF (9.5 mL) was cooled to 0 °C, and DIBAL (1 M in THF) (3.7 mL, 3.70 mmol) was added dropwise to the reaction mixture. The mixture was then stirred for 2 h. Saturated aqueous sodium potassium tartrate (20 mL) and ethyl acetate (20 mL) were added to the reaction mixture, and the resulting mixture was stirred at room temperature for 1 h. The mixture was separated, and the aqueous layer was further extracted with ethyl acetate (2 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to give 3-(2-bromophenyl)butan-1-ol (360 mg, 92% yield, 97% purity) as a colorless oil. 1 H NMR (400 MHz, DMSO) δ 7.60 - 7.52 (m, 1H), 7.38 - 7.30 (m, 2H), 7.19 - 7.06 (m, 1H), 4.40 (t, J = 5.0 Hz, 1H), 3.42 - 3.18 (m, 3H), 1.85 - 1.61 (m, 2H), 1.16 (d, J = 6.9 Hz, 3H).

[0325] Step 3 tert-Butyldimethylsilyl chloride (490 mg, 3.25 mmol) was added to a stirred solution of 3-(2-bromophenyl)butan-1-ol (97% purity, 350 mg, 1.48 mmol), N,N-diethylethanolamine (0.45 mL, 3.23 mmol), and DMAP (18 mg, 0.147 mmol) in anhydrous DCM (20 mL) at room temperature, and the mixture was stirred for 16 h. The mixture was quenched with water (20 mL) and extracted with DCM (3 × 20 mL). The combined organic layers were washed with brine (30 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by FCC (silicon dioxide, 0–100% ethyl acetate in heptane) to give 3-(2-bromophenyl)butoxy-tert-butyldimethylsilane (310 mg, 60% yield, 98% purity) as a colorless oil. 1H NMR (400 MHz, DMSO) δ 7.60 - 7.53 (m, 1H), 7.38 - 7.33 (m, 2H), 7.17 - 7.08 (m, 1H), 3.60 - 3.47 (m, 2H), 3.38 - 3.26 (m, 1H), 1.89 - 1.76 (m, 1H), 1.77 - 1.66 (m, 1H), 1.16 (d, J = 6.9 Hz, 3H), 0.84 (s, 9H), -0.01 - -0.06 (m, 6H).

[0326] Step 4 A stirred solution of 2,4-difluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (90% pure, 298 mg, 1.05 mmol), 3-(2-bromophenyl)butoxy-tert-butyldimethylsilane (97% pure, 310 mg, 0.876 mmol), and potassium carbonate (242 mg, 1.75 mmol) in 1,4-dioxane (5 mL) and water (0.5 mL) was sparged with nitrogen for 10 minutes. Pd(dppf)Cl (64 mg, 0.0875 mmol) was added, and the mixture was heated at 100 °C for 4 hours. The mixture was cooled to room temperature, quenched with water (50 mL), and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine (50 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by FCC (silicon dioxide, 0-50% ethyl acetate in heptane) to give 5-[2-[3-[tert-butyl(dimethyl)silyl]oxy-1-methyl-propyl]phenyl]-2,4-difluoro-aniline (301 mg, 85% yield, 97% purity) as a colorless oil. LCMS: m / z = 392.3 [M+H]+, (ESI+), RT = 1.20, Method C

[0327] Step 5 Intermediate 1 (50% pure, 444 mg, 0.742 mmol) was added to a stirred solution of 5-[2-[3-[tert-butyl(dimethyl)silyl]oxy-1-methyl-propyl]phenyl]-2,4-difluoro-aniline (97% pure, 300 mg, 0.743 mmol) in pyridine (10 mL) at room temperature, and the mixture was heated at 50° C. for 1 hour. The mixture was concentrated in vacuo, and the residue was purified by FCC (silicon dioxide, 0-100% ethyl acetate in heptane) to give methyl 3-[[5-[2-[3-[tert-butyl(dimethyl)silyl]oxy-1-methyl-propyl]phenyl]-2,4-difluoro-phenyl]sulfamoyl]-5-chloro-4-methoxybenzoate (420 mg, 0.578 mmol, 78% yield, 90% purity) as a colorless oil. LCMS: m / z = 654.2 / 656.2 [M+H]+, (ESI+), RT = 1.25, Method C

[0328] Step 6 p-Methylbenzenesulfonic acid hydrate (10 mg, 0.0550 mmol) and methyl 3-[[5-[2-[3-[tert-butyl(dimethyl)silyl]oxy-1-methyl-propyl]phenyl]-2,4-difluoro-phenyl]sulfamoyl]-5-chloro-4-methoxybenzoate (90% pure, 400 mg, 0.550 mmol) in methanol (10 mL) were added at room temperature, and the mixture was stirred for 1 hour. The mixture was concentrated in vacuo, and the residue was diluted with water (25 mL) and extracted with ethyl acetate (3 × 25 mL). The combined organic layers were washed with brine (25 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by FCC (silicon dioxide, 0-100% ethyl acetate in heptane) to give methyl 3-chloro-5-[[2,4-difluoro-5-[2-(3-hydroxy-1-methyl-propyl)phenyl]phenyl]sulfamoyl]-4-methoxybenzoate (310 mg, 79% yield, 76% purity) as a white solid. 1H NMR (400 MHz, DMSO) δ 10.11 (s, 1H), 8.29 - 8.11 (m, 2H), 7.47 - 7.33 (m, 2H), 7.33 - 7.16 (m, 2H), 7.16 - 6.92 (m, 2H), 3.99 (s, 3H), 3.88 (s, 3H), 3.18 - 3.10 (m, 2H), 2.64 - 2.54 (m, 1H), 1.74 - 1.55 (m, 2H), 1.10 - 0.98 (m, 3H). OH Not observed LCMS: m / z = 540.1 / 541.9 [M+H]+, (ESI+), RT = 0.99, Method B

[0329] Step 7 To a stirred solution of methyl 3-chloro-5-[[2,4-difluoro-5-[2-(3-hydroxy-1-methyl-propyl)phenyl]phenyl]sulfamoyl]-4-methoxybenzoate (76% purity, 310 mg, 0.436 mmol) in THF (10 mL) was added 2 M aqueous sodium hydroxide (0.65 mL, 1.31 mmol), and the mixture was stirred for 2 h. The mixture was concentrated in vacuo, diluted with water (10 mL), acidified with 1 M hydrochloric acid (10 mL), and extracted with DCM (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to give 3-chloro-5-[2,4-difluoro-5-[2-(3-hydroxy-1-methyl-propyl)phenyl]phenyl]sulfamoyl]-4-methoxybenzoic acid (210 mg, 71% yield, 78% purity) as a white solid. LCMS (MSQ2, acidic 2 min): [M+H]+ m / z 526.0 / 528.0, RT 0.86 min. 1H NMR (400 MHz, DMSO) δ 8.23 ​​- 8.15 (m, 2H), 7.50 - 7.36 (m, 3H), 7.32 - 7.17 (m, 2H), 7.12 - 6.95 (m, 2H), 3.99 (s, 3H), 3.20 - 3.11 (m, 2H), 2.63 - 2.53 (m, 1H), 1.73 - 1.55 (m, 2H), 1.18 - 0.94 (m, 3H). NH and acidic protons not observed. LCMS: m / z = 526.0 / 528.0 [M+H]+, (ESI+), RT = 0.86, Method B

[0330] Step 8 DCC (122 mg, 0.593 mmol) was added to a stirred solution of 3-chloro-5-[[2,4-difluoro-5-[2-(3-hydroxy-1-methyl-propyl)phenyl]phenyl]sulfamoyl]-4-methoxybenzoic acid (78%, 205 mg, 0.297 mmol) and DMAP (7.2 mg, 0.0593 mmol) in anhydrous DCM (15 mL), and the mixture was stirred at room temperature for 2 h. The mixture was diluted with water (20 mL) and DCM (10 mL), and the biphasic mixture was separated. The aqueous layer was further extracted with DCM (2 × 10 mL). The combined organic layers were washed with brine (20 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by FCC (silicon dioxide, 0-100% ethyl acetate in heptane) to give 15-chloro-21,23-difluoro-16-methoxy-8-methyl-18,18-dioxo-11-oxa-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-nonaen12-one (120 mg, 72% yield, 90%) as a white solid. 1H NMR (400 MHz, DMSO) δ 10.71 (s, 1H), 8.16 (d, J = 2.2 Hz, 1H), 7.78 (d, J = 2.2 Hz, 1H), 7.59 - 7.36 (m, 3H), 7.36 - 7.25 (m, 2H), 7.26 - 7.13 (m, 1H), 4.51 - 4.34 (m, 1H), 4.15 - 3.96 (m, 4H), 2.56 - 2.39 (m, 1H), 2.06 - 1.93 (m, 1H), 1.86 - 1.71 (m, 1H), 1.19 (d, J = 6.7 Hz, 3H). LCMS: m / z = 506.1 / 508.2 [MH]-, (ESI-), RT = 1.10, Method B

[0331] Step 9 Iodocyclohexane (275 μL, 2.13 mmol) was added to a solution of 15-chloro-21,23-difluoro-16-methoxy-8-methyl-18,18-dioxo-11-oxa-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-nonaen12-one (90% pure, 120 mg, 0.213 mmol) in anhydrous DMF (5 mL), and the mixture was heated at 120 °C for 3 h. The mixture was cooled to room temperature, diluted with water (20 mL) and DCM (20 mL), and separated. The aqueous layer was washed with DCM (2 × 20 mL), and the combined organic layers were washed with brine (30 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by FCC (C18-silicon dioxide, 10-100% acetonitrile in water (0.1% NH3)), dissolved in DCM (10 mL), washed with 1 M aqueous HCl (3 × 10 mL), concentrated, and dried in a vacuum oven to give the title compound (65 mg, 61% yield, 99% purity) as a white solid. 1H NMR (500 MHz, DMSO) δ 8.04 - 7.93 (m, 1H), 7.73 (d, J = 2.1 Hz, 1H), 7.51 - 7.37 (m, 3H), 7.34 - 7.26 (m, 2H), 7.19 (d, J = 7.5 Hz, 1H), 4.48 - 4.34 (m, 1H), 4.10 - 3.92 (m, 1H), 2.05 - 1.93 (m, 1H), 1.84 - 1.74 (m, 1H), 1.17 (d, J = 6.7 Hz, 3H). LCMS: m / z = 492.0 / 494.0 [MH]-, (ESI-), RT = 4.41, Method A

[0332] Example 44: Synthesis of 15-chloro-21,23-difluoro-16-hydroxy-8-methyl-18,18-dioxo-11-oxa-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, enantiomer 1 (compound 44) Example 45: Synthesis of 15-chloro-21,23-difluoro-16-hydroxy-8-methyl-18,18-dioxo-11-oxa-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, enantiomer 2 (compound 45) TIFF2025515002000473.tif5049 Example 43 (45 mg) was purified by chiral SFC (Chiralcel OJ-H column, 10 x 250 mm, 5 µm; flow rate 15 mL / min; 10% methanol / 90% CO2 mobile phase) to give two components. Example 44: 13.2 mg, purity 99%, >99% ee 1H NMR (500 MHz, DMSO) δ 8.00 - 7.93 (m, 1H), 7.72 (d, J = 2.2 Hz, 1H), 7.50 - 7.37 (m, 3H), 7.33 - 7.24 (m, 2H), 7.18 (dd, J = 7.6, 1.3 Hz, 1H), 4.56 - 4.27 (m, 1H), 4.09 - 3.89 (m, 1H), 2.04 - 1.90 (m, 1H), 1.88 - 1.74 (m, 1H), 1.16 (d, J = 6.7 Hz, 3H). LCMS: m / z = 492.1 / 494.1 [MH]-, (ESI-), RT = 4.38, Method A Chiralcel SFC analysis: RT = 3.18 minutes (Chiralcel OJ-H color, 4.6 x 250 mm, 5 μm; flow rate 4 mL / min; 20% methenol / 80% CO2 mobile phase) Example 45: 14.8mg, purity 98%, 92%ee 1 H NMR (500 MHz, DMSO) δ 7.90 - 7.83 (m, 1H), 7.74 - 7.66 (m, 1H), 7.49 - 7.38 (m, 3H), 7.34 - 7.22 (m, 2H), 7.17 (dd, J = 7.6, 1.3 Hz, 1H), 4.49 - 4.30 (m, 1H), 4.03 - 3.87 (m, 1H), 2.03 - 1.93 (m, 1H), 1.87 - 1.71 (m, 1H), 1.15 (d, J = 6.8 Hz, 3H). LCMS: m / z = 492.1 / 494.0 [MH]-, (ESI-), RT = 4.39, Method A Chiralcel SFC analysis: RT = 3.87 minutes (Chiralcel OJ-H color, 4.6 x 250 mm, 5 μm, flow rate 4 mL / min, 20% metalol / 80% CO2 mobile phase)

[0333] Example 46: Synthesis of 15-chloro-4,21-difluoro-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-nonaen12-one (Compound 46) TIFF2025515002000474.tif5051 15-Chloro-4,21-difluoro-16-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 (synthesized in a similar manner to Intermediate 12, 98% purity, 1.70 g, 3.36 mmol) and iodocyclohexane (3.50 g, 16.7 mmol) were combined and dissolved in anhydrous DMF (50 mL). The mixture was heated to 120 °C and stirred for 3 h. The reaction mixture was cooled to room temperature, and saturated aqueous NaSO (100 mL) was added to the reaction mixture. The biphasic mixture was separated, and the aqueous phase was extracted with DCM (3 × 100 mL). The combined organic extracts were washed with 1 M aqueous HCl (100 mL), then brine (100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by FCC (100 g SiO column, eluted with DCM in heptane, 0-100% gradient, then methanol in DCM, 0-40%) to give the title compound (820 mg, 1.68 mmol, 50% yield, 99% purity) as a white solid. 1 H NMR (500 MHz, DMSO) δ 11.63 - 9.75 (m, 2H), 8.04 (d, J = 2.1 Hz, 1H), 7.61 (d, J = 2.1 Hz, 1H), 7.41 (dd, J = 7.5, 2.2 Hz, 1H), 7.26 - 7.20 (m, 3H), 7.19 - 7.15 (m, 1H), 7.13 (dd, J = 10.1, 8.5 Hz, 1H), 4.38 - 4.32 (m, 2H), 4.28 - 4.23 (m, 2H). LCMS: m / z = 480.0 / 482.0 [MH]-, (ESI-), RT = 4.04, Method A

[0334] Example 47: Synthesis of 15-chloro-21-fluoro-16-hydroxy-23-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(25),14,16,20(24),21-nonaen-12-one (Compound 47) Iodocyclohexane (130 μL, 1.00 mmol) was added to a suspension of 15-chloro-21-fluoro-16,23-dimethoxy-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(25),14,16,20(24),21-nonaen12-one (synthesized in a manner similar to Intermediate 12, 100% purity, 100 mg, 0.197 mmol) in DMF (2.5 mL). The reaction was heated to 80 °C for 40 h. The reaction was cooled and quenched with saturated aqueous NaHCO (20 mL). The biphasic mixture was separated, and the aqueous layer was extracted with ethyl acetate (3 × 10 mL). The combined organics were washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by FCC chromatography (10 g SiO column, 50-100% ethyl acetate in heptane) followed by preparative HPLC (Method P1) to give the title compound (20 mg, 20% yield, 96% purity) as a white solid. 1H NMR (500 MHz, DMSO) δ 10.04 (s, 1H), 8.02 (s, 1H), 7.51 (d, J = 2.1 Hz, 1H), 7.39 - 7.32 (m, 1H), 7.14 (dd, J = 7.5, 1.8 Hz, 1H), 7.10 - 7.05 (m, 2H), 7.03 - 6.98 (m, 1H), 6.85 (d, J = 12.2 Hz, 1H), 4.35 - 4.30 (m, 2H), 4.25 - 4.21 (m, 2H), 3.60 (s, 3H). LCMS: m / z = 492.0 / 494.0 [M+H]+, (ESI+), RT = 3.88, Method A

[0335] Example 48: Synthesis of 15-chloro-5,21-difluoro-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(25),14,16,20(24),21-nonaen12-one (Compound 48) TIFF2025515002000476.tif564515-Chloro-5,21-difluoro-16-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(25),14,16,20(24),21-nonaen-12-one (synthesized in a manner similar to Intermediate 12, 99% purity, 115 mg, 0.230 mmol), anhydrous DMF (4 mL), and iodocyclohexane (148 µL, 1.15 mmol) were added to a pressure vial. The vial was sealed and heated at 120 °C for 1.5 h. The reaction mixture was cooled to room temperature, saturated aqueous NaHCO3 (30 mL) was added, and the biphasic mixture was separated. The aqueous phase was extracted with ethyl acetate (2 x 30 mL). The combined organic extracts were washed with saturated aqueous Na2S2O3 (40 mL), 1 M aqueous HCl (40 mL), water (40 mL), then brine (40 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by FCC (10 g SiO2 column, 0-20% methanol in DCM) to give the title compound (67 mg, 60% yield, 99% purity) as a white solid. 1 H NMR (500 MHz, DMSO) δ 12.24 - 9.38 (m, 2H), 8.03 (d, J = 2.2 Hz, 1H), 7.71 (d, J = 2.1 Hz, 1H), 7.35 (dd, J = 7.6, 2.1 Hz, 1H), 7.28 (dd, J = 8.4, 6.9 Hz, 1H), 7.21 - 7.07 (m, 3H), 6.88 (ddd, J = 8.4, 8.4, 2.5 Hz, 1H), 4.44 - 4.36 (m, 2H), 4.33 - 4.19 (m, 2H) LCMS: m / z = 480.0 / 482.0 [MH]-, (ESI-), RT = 4.07, Method A

[0336] Example 49: Synthesis of 15-chloro-21,23-difluoro-16-hydroxy-3-methyl-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(25),14,16,20(24),21-nonaen-12-one (Compound 49) TIFF2025515002000477.tif4951 15-Chloro-21,23-difluoro-16-methoxy-3-methyl-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(25),14,16,20(24),21-nonaen-12-one (synthesized using a method similar to Intermediate 12, 95% purity, 100 mg, 0.186 mmol), anhydrous DMF (2.5 mL), and iodocyclohexane (120 µL, 0.928 mmol) were added to a pressure vial. The vial was sealed and heated at 120 °C for 1.25 h and then cooled to room temperature. The mixture was purified by preparative HPLC (Method P1) to give a yellow solid, which was triturated with diethyl ether (~5 mL) and filtered to give the title compound (61 mg, 65% yield, 99% purity) as a white solid. 1 H NMR (500 MHz, DMSO) δ 8.06 (d, J = 2.2 Hz, 1H), 7.59 (d, J = 2.1 Hz, 1H), 7.34–7.30 (m, 1H), 7.29–7.24 (m, 1H), 7.24–7.19 (m, 1H), 6.99 (d, J = 8.3 Hz, 1H), 6.96 (d, J = 7.7 Hz, 1H), 4.44–4.35 (m, 2H), 4.32–4.25 (m, 1H), 4.10–4.02 (m, 1H), 2.02 (s, 3H). No OH or NH was observed. LCMS: m / z = 494.0 / 496.0 [MH]-, (ESI-), RT = 4.12, Method A

[0337] Example 50: Synthesis of 15-chloro-21-fluoro-16-hydroxy-23-methyl-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(25),14,16,20(24),21-nonaen-12-one (Compound 50) TIFF2025515002000478.tif5557 15-Chloro-21-fluoro-16-methoxy-23-methyl-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(25),14,16,20(24),21-nonaen-12-one (synthesized in a manner similar to Intermediate 12, 95% purity, 150 mg, 0.290 mmol), anhydrous DMF (3.9 mL), and iodocyclohexane (0.19 mL, 1.47 mmol) were added to a pressure vial. The vial was sealed and heated at 120 °C for 2 h, then cooled to room temperature. The organics were diluted with ethyl acetate (30 mL), washed with sodium sulfite (2 × 20 mL of saturated aqueous solution), then brine (20 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by FCC (10 g SiO column, 0-10% methanol in DCM) followed by preparative HPLC (Method P1) to give the title compound (53 mg, 38% yield, 100% purity) as a white solid. 1 H NMR (400 MHz, DMSO) δ 8.02 (d, J = 2.2 Hz, 1H), 7.56 (d, J = 2.1 Hz, 1H), 7.40 (ddd, J = 8.3, 7.4, 1.8 Hz, 1H), 7.17 - 7.11 (m, 3H), 7.08 - 7.03 (m, 1H), 6.99 (d, J = 11.2 Hz, 1H), 4.52 - 4.43 (m, 1H), 4.38 - 4.28 (m, 2H), 4.11 - 4.02 (m, 1H), 1.98 (s, 3H). LCMS: m / z = 476.1 / 478.1 [MH]-, (ESI-), RT = 4.19, Method A

[0338] Example 51: Synthesis of 15-chloro-21,24-difluoro-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(25),14,16,20(24),21-nonaen-12-one (Compound 51) TIFF2025515002000479.tif555115-Chloro-21,24-difluoro-16-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(25),14,16,20(24),21-nonaen-12-one (synthesized in a manner similar to Intermediate 12, 95% purity, 95 mg, 0.182 mmol), anhydrous DMF (2.4 mL), and iodocyclohexane (0.12 mL, 0.928 mmol) were added to a pressure vial. The vial was sealed and heated at 120 °C for 2 h, then cooled to room temperature. The organics were diluted with ethyl acetate (30 mL), washed with sodium sulfite (2 × 20 mL of saturated aqueous solution), then brine (20 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by FCC (10 g SiO column, 0-60% methanol in DCM) followed by preparative HPLC (Method P1) to give the title compound (53 mg, 60% yield, 100% purity) as a white solid. 1H NMR (400 MHz, DMSO) δ 8.08 (d, J = 2.1 Hz, 1H), 7.90 (dd, J = 2.2, 1.2 Hz, 1H), 7.40 (ddd, J = 8.3, 7.3, 1.8 Hz, 1H), 7.35 - 7.28 (m, 1H), 7.27 - 7.21 (m, 1H), 7.18 - 7.14 (m, 1H), 7.10 (dd, J = 7.5, 1.8 Hz, 1H), 7.03 - 6.98 (m, 1H), 4.74 - 4.62 (m, 1H), 4.42 - 4.22 (m, 2H), 4.22 - 4.09 (m, 1H). LCMS: m / z = 480.0 / 482.0 [MH]-, (ESI-), RT = 3.91, Method A

[0339] Example 52: Synthesis of 4,15-dichloro-21-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 (Compound 52) TIFF2025515002000480.tif57584, 15-Dichloro-21-fluoro-16-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 (synthesized in a manner similar to Intermediate 12, 95% purity, 55 mg, 0.102 mmol) and iodocyclohexane (68 µL, 0.524 mmol) were added to a pressure vial, and the mixture was diluted with anhydrous DMF (2.5 mL). The vial was sealed, heated to 120 °C, and stirred for 3 h. The reaction mixture was cooled to room temperature, added to water (50 mL), and extracted with DCM (3 × 30 mL). The combined organic extracts were washed with brine (100 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by FCC (10 g SiO column, 0-100% methanol in DCM) followed by preparative HPLC (Method P2) to give the title compound (23 mg, 45% yield, 99% purity) as a white solid. 1 H NMR (500 MHz, DMSO) δ 11.96 - 9.79 (m, 2H), 7.97 (d, J = 2.2 Hz, 1H), 7.59 (d, J = 2.1 Hz, 1H), 7.37 (dd, J = 8.8, 2.7 Hz, 1H), 7.32 (dd, J = 7.5, 2.2 Hz, 1H), 7.26 (d, J = 2.7 Hz, 1H), 7.17 - 7.12 (m, 2H), 7.08 (dd, J = 10.1, 8.5 Hz, 1H), 4.33 - 4.27 (m, 2H), 4.24 - 4.17 (m, 2H). LCMS: m / z = 496.0 / 498.0 / 500.1 [MH]-, (ESI-), RT = 4.29, Method A

[0340] Example 53: Synthesis of 18-chloro-24,26-difluoro-19-hydroxy-21,21-dioxo-11,14-dioxa-21λ6-thia-5,6,22-triazapentacyclo[21.3.1.116,20.02,10.04,8]octacosa-1(27),2(10),3,6,8,16(28),17,19,23,25-decaen-15-one (Compound 53) To a solution of 18-chloro-24,26-difluoro-19-methoxy-21,21-dioxo-11,14-dioxa-21λ6-thia-5,6,22-triazapentacyclo[21.3.1.116,20.02,10.04,8]octacosa-1(27),2(10),3,6,8,16(28),17,19,23,25-decaen-15-one (synthesized using a method similar to Intermediate 12, 75 mg, 0.140 mmol) in anhydrous pyridine (5 mL) was added lithium iodide (130 mg, 0.971 mmol). The reaction mixture was heated at 80 °C overnight. The mixture was diluted with 10% aqueous citric acid (30 mL) and extracted with ethyl acetate (2 × 30 mL). The combined organics were washed with 10% aqueous citric acid (30 mL) and brine (40 mL), dried (sodium sulfate), filtered, and concentrated. The residue was purified by FCC (10 g SiO column, 0-20% methanol in DCM) followed by preparative HPLC (Method P1) to afford the title compound (32 mg, 43% yield, 99% purity) as a white solid. 1 H NMR (500 MHz, DMSO) δ 13.09 (s, 1H), 11.75 - 9.80 (m, 2H), 8.06 - 8.00 (m, 2H), 7.47 (s, 1H), 7.46 (d, J = 2.2 Hz, 1H), 7.43 - 7.35 (m, 2H), 7.26 - 7.17 (m, 1H), 4.39 - 4.22 (m, 4H). LCMS: m / z = 520.2 / 522.1 [MH]-, (ESI-), RT = 3.44, Method A

[0341] Example 54: Synthesis of 15-chloro-21,22-difluoro-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(25),14,16,20(24),21-nonaen-12-one (Compound 54) A solution of 15-chloro-21,22-difluoro-16-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(25),14,16,20(24),21-nonaen-12-one (synthesized in a manner similar to Intermediate 12, 92% purity, 103 mg, 0.191 mmol) in anhydrous DMF (2.5 mL) was added to iodocyclohexane (124 μL, 0.955 mmol) and heated to 120 °C in a pressure vial for 1.5 h. The volume of the reaction mixture was reduced by approximately 50% and the residue was purified by preparative HPLC (Method P2) to give the title compound (68 mg, 73% yield, 99% purity) as a yellow solid. 1 H NMR (400 MHz, DMSO) δ 8.13 - 8.03 (m, 1H), 7.73 (d, J = 2.1 Hz, 1H), 7.46 - 7.36 (m, 1H), 7.33 - 7.23 (m, 2H), 7.22 - 7.14 (m, 2H), 7.11 - 7.00 (m, 1H), 4.44 - 4.37 (m, 2H), 4.32 - 4.23 (m, 2H). LCMS: m / z = 480.2 / 482.2 [MH]-, (ESI-), RT = 4.20, Method A

[0342] Example 55: Synthesis of 15-chloro-21-(difluoromethoxy)-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(25),14,16,20(24),21-nonaen-12-one (Compound 55) TIFF2025515002000483.tif5558 A solution of 15-chloro-21-(difluoromethoxy)-16-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(25),14,16,20(24),21-nonaen-12-one (synthesized in a manner similar to Intermediate 12, 100% purity, 123 mg, 0.234 mmol) in anhydrous DMF (3 mL) was added iodocyclohexane (151 μL, 1.17 mmol) and heated to 120 °C in a pressure vial for 1 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC (Method P1) to give the title compound (75 mg, 60% yield, 95% purity) as a beige solid. 1 H NMR (400 MHz, DMSO) δ 10.92 (s, 1H), 10.03 (s, 1H), 8.17 - 7.94 (m, 1H), 7.67 - 7.61 (m, 1H), 7.43 - 7.42 (m, 1H), 7.42 - 7.36 (m, 1H), 7.28 - 7.25 (m, 1H), 7.24 - 7.20 (m, 1H), 7.20 - 7.16 (m, 1H), 7.12 - 6.69 (m, 3H), 4.40 - 4.32 (m, 2H), 4.30 - 4.22 (m, 2H). LCMS: m / z = 510.3 / 512.3 [MH]-, (ESI-), RT = 4.20, Method A

[0343] Example 56: Synthesis of 15-chloro-16-hydroxy-18,18-dioxo-21-(trifluoromethoxy)-8,11-dioxa-18λ6-thia-19-azatetracyclo[18.3.1.113,17.02,7]pentacosa-1(23),2(7),3,5,13(25),14,16,20(24),21-nonaen-12-one (Compound 56) TIFF2025515002000484.tif5558 15-Chloro-16-methoxy-18,18-dioxo-21-(trifluoromethoxy)-8,11-dioxa-18λ6-thia-19-azatetracyclo[18.3.1.113,17.02,7]pentacosa-1(23),2(7),3,5,13(25),14,16,20(24),21-nonaen-12-one (synthesized using a similar method to Intermediate 12, 95% purity, 37 mg, 0.0646 mmol), anhydrous DMF (1 mL), and iodocyclohexane (70 µL, 0.541 mmol) were added to a pressure vial. The vial was sealed and heated at 120 °C for 2 h, then cooled to room temperature. The organics were diluted with ethyl acetate (20 mL) and washed sequentially with 1 M aqueous HCl (10 mL), saturated aqueous sodium sulfite (10 mL), then brine (10 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (Method P1) to give the title compound (21 mg, 61% yield, 99% purity) as a white solid. 1 H NMR (500 MHz, DMSO) δ 8.03 (d, J = 2.1 Hz, 1H), 7.75 (d, J = 2.1 Hz, 1H), 7.50 - 7.48 (m, 1H), 7.40 (ddd, J = 8.2, 7.4, 1.7 Hz, 1H), 7.28 - 7.25 (m, 3H), 7.20 - 7.17 (m, 1H), 7.09 - 7.04 (m, 1H), 4.41 - 4.36 (m, 2H), 4.29 - 4.25 (m, 2H). No OH or NH groups observed. LCMS: m / z = 528.1 / 530.1 [MH]-, (ESI-), RT = 4.35, Method A

[0344] Example 57: 15-chloro-21-cyclopropyl-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(25),14,16,20(24),21-nonaen-12-one (Compound 57) TIFF2025515002000485.tif555115-Chloro-21-cyclopropyl-16-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(25),14,16,20(24),21-nonaen-12-one (synthesized in a manner similar to Intermediate 12, 93% purity, 104 mg, 0.193 mmol), anhydrous DMF (2 mL), and iodocyclohexane (208 µL, 1.61 mmol) were added to a pressure vial. The vial was sealed and heated at 120 °C for 2 h, then cooled to room temperature. The organics were diluted with ethyl acetate (30 mL), washed sequentially with 1 M aqueous HCl (20 mL), sodium sulfite (20 mL of a 1 M solution in water), brine (20 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (Method P1) to give the title compound (51 mg, 52% yield, 97% purity) as an off-white solid. 1H NMR (500 MHz, DMSO) δ 10.99 (br. S, 1H), 10.04 (br. S, 1H), 7.99 (d, J = 2.2 Hz, 1H), 7.53 (d, J = 2.2 Hz, 1H), 7.37 (ddd, J = 8.2, 7.4, 1.8 Hz, 1H), 7.30 (d, J = 1.8 Hz, 1H), 7.23 (dd, J = 7.5, 1.8 Hz, 1H), 7.19 - 7.14 (m, 1H), 7.09 (dd, J = 8.0, 1.8 Hz, 1H), 7.07 - 7.03 (m, 1H), 6.64 (d, J = 8.1 Hz, 1H), 4.34 - 4.28 (m, 2H), 4.28 - 4.23 (m, 2H), 2.05 - 1.96 (m, 1H), 0.76 - 0.66 (m, 2H), 0.26 - 0.16 (m, 2H). LCMS: m / z = 484.1 / 486.1 [MH]-, (ESI-), RT = 4.34, Method A

[0345] Example 58: Synthesis of 15-chloro-16-hydroxy-18,18-dioxo-21-(trifluoromethyl)-8,11-dioxa-18λ6-thia-19-azatetracyclo[18.3.1.113,17.02,7]pentacosa-1(24),2(7),3,5,13(25),14,16,20,22-nonaen-12-one (Compound 58) TIFF2025515002000486.tif4946 Step 1 A solution of 5-[2-[2-[tert-butyl(dimethyl)silyl]oxyethoxy]phenyl]-2-(trifluoromethyl)aniline (synthesized in a manner similar to Intermediate 8, 96% purity, 344 mg, 0.80 mmol) in anhydrous THF (8.3 mL) was cooled to −78 °C and treated with 1 M LiHMDS in THF (1.2 mL, 1.20 mmol). The reaction was then stirred for 10 minutes, after which Intermediate 1 (50% purity, 550 mg, 0.919 mmol) in anhydrous THF (8.3 mL) was added. The mixture was stirred at −78 °C for an additional 15 minutes before being warmed to room temperature and stirred for 5 hours. The mixture was quenched with water (10 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic phase was washed with brine (20 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by FCC (25 g SiO column, 0–100% ethyl acetate in heptane) to give 3-[[5-[2-[2-[tert-butyl(dimethyl)silyl]oxyethoxy]phenyl]-2-(trifluoromethyl)phenyl]sulfamoyl]-5-chloro-4-methoxy-benzoate (140 mg, 22% yield, 84% purity) as a colorless gum. 1 H NMR (400 MHz, CDCl3) δ 8.41 (d, J = 2.1 Hz, 1H), 8.25 (d, J = 2.1 Hz, 1H), 7.78 (br. s, J = 0.9 Hz, 1H), 7.51 (d, J = 0.9 Hz, 1H), 7.36 - 7.31 (m, 2H), 7.23 (dd, J = 7.5, 1.8 Hz, 1H), 7.05 - 6.98 (m, 2H), 4.14 (s, 3H), 4.06 (t, J = 5.2 Hz, 2H), 3.91 - 3.87 (m, 5H), 0.82 (s, 9H), -0.04 (s, 6H).

[0346] Step 2 A solution of methyl 3-[[5-[2-[2-[tert-butyl(dimethyl)silyl]oxyethoxy]phenyl]-2-(trifluoromethyl)phenyl]sulfamoyl]-5-chloro-4-methoxybenzoate (84% purity, 140 mg, 0.174 mmol) and 4-methylbenzenesulfonic acid hydrate (1:1) (3.3 mg, 0.0174 mmol) in methanol (2 mL) was stirred at room temperature for 2 h. The mixture was concentrated in vacuo, and the residue was purified by FCC (10 g SiO column, 0-100% ethyl acetate in heptane) to give methyl 3-chloro-5-[[5-[2-(2-hydroxyethoxy)phenyl]-2-(trifluoromethyl)phenyl]sulfamoyl]-4-methoxybenzoate (111 mg, 100% yield, 87% purity) as a white gum. 1 H NMR (400 MHz, DMSO) δ 10.29 (s, 1H), 8.26 (d, J = 2.1 Hz, 1H), 8.18 (d, J = 2.1 Hz, 1H), 7.77 - 7.67 (m, 2H), 7.40 - 7.33 (m, 1H), 7.26 (s, 1H), 7.14 (d, J = 8.5 Hz, 1H), 7.08 (dd, J = 7.6, 1.8 Hz, 1H), 6.99 (td, J = 7.4, 1.0 Hz, 1H), 4.74 (s, 1H), 4.03 - 3.97 (m, 2H), 3.94 (s, 3H), 3.85 (s, 3H), 3.65 (d, J = 6.8 Hz, 2H). LCMS: m / z = 558.1 / 560.1 [MH]-, (ESI-), RT = 1.05, Method B

[0347] Step 3 A solution of methyl 3-chloro-5-[[5-[2-(2-hydroxyethoxy)phenyl]-2-(trifluoromethyl)phenyl]sulfamoyl]-4-methoxybenzoate (87% pure, 111 mg, 0.173 mmol) and 2 M aqueous sodium hydroxide (433 μL, 0.865 mmol) in THF (3 mL) was stirred at room temperature for 4 h. The mixture was diluted with ethyl acetate (10 mL) and water (10 mL), and the layers were separated. The aqueous layer was acidified to pH 2 with 1 M aqueous HCl and extracted with ethyl acetate (3 × 10 mL). The combined organic layers were filtered through phase separation filter paper and concentrated in vacuo to give 3-chloro-5-[[5-[2-(2-hydroxyethoxy)phenyl]-2-(trifluoromethyl)phenyl]sulfamoyl]-4-methoxybenzoate (102 mg, 97% yield, 90% purity) as a white powder. 1 H NMR (400 MHz, DMSO) δ 10.25 (s, 1H), 8.25 (s, 1H), 8.13 (s, 1H), 7.85 - 7.42 (m, 2H), 7.33 (t, J = 7.6 Hz, 1H), 7.26 (s, 1H), 7.11 (d, J = 8.4 Hz, 1H), 7.04 (dd, J = 7.6, 1.9 Hz, 1H), 6.96 (t, J = 7.4 Hz, 1H), 4.74 (s, 1H), 3.98 (t, J = 5.1 Hz, 2H), 3.91 (s, 3H), 3.63 (t, J = 5.1 Hz, 2H). LCMS: m / z = 544.0 / 546.0 [MH]-, (ESI-), RT = 0.93, Method B

[0348] Step 4 A solution of 3-chloro-5-[[5-[2-(2-hydroxyethoxy)phenyl]-2-(trifluoromethyl)phenyl]sulfamoyl]-4-methoxybenzoic acid (90% pure, 102 mg, 0.168 mmol), DMAP (4.1 mg, 0.034 mmol), and DCC (76 mg, 0.370 mmol) in DCM (10 mL) was stirred at room temperature for 1 h. The mixture was diluted with water (30 mL) and extracted with DCM (3 × 30 mL). The combined organic layers were filtered through a phase separation cartridge and concentrated in vacuo. The residue was purified by FCC (10 g SiO column, DCM in heptane (0–100%), followed by ethyl acetate in DCM (0–100%)) to give 15-chloro-16-methoxy-18,18-dioxo-21-(trifluoromethyl)-8,11-dioxa-18λ6-thia-19-azatetracyclo[18.3.1.113,17.02,7]pentacosa-1(24),2(7),3,5,13(25),14,16,20,22-nonaen-12-one (40 mg, 42% yield, 93% purity) as a white powder. 1 H NMR (400 MHz, DMSO) δ 10.50 (s, 1H), 8.33 (d, J = 2.1 Hz, 1H), 8.20 (s, 1H), 7.82 - 7.73 (m, 1H), 7.69 (s, 1H), 7.54 - 7.46 (m, 1H), 7.41 (ddd, J = 8.5, 7.3, 1.8 Hz, 1H), 7.31 (d, J = 7.5 Hz, 1H), 7.17 (d, J = 8.3 Hz, 1H), 7.07 (td, J = 7.5, 1.0 Hz, 1H), 4.60 - 4.50 (m, 2H), 4.29 (t, J = 4.6 Hz, 2H), 3.98 (s, 3H). LCMS: m / z = 526.3 / 528.3 [MH]-, (ESI-), RT = 1.14, Method B

[0349] Step 5 A solution of 15-chloro-16-methoxy-18,18-dioxo-21-(trifluoromethyl)-8,11-dioxa-18λ6-thia-19-azatetracyclo[18.3.1.113,17.02,7]pentacosa-1(24),2(7),3,5,13(25),14,16,20,22-nonaen-12-one (93% purity, 40 mg, 0.071 mmol) and iodocyclohexane (46 μL, 0.352 mmol) in DMF (1 mL) was heated to 120 °C for 2 h in a sealed vial. The mixture was cooled to room temperature and purified by preparative HPLC (Method P1) to give the title compound as a white powder (19 mg, 53% yield, 100% purity). 1 H NMR (400 MHz, DMSO) δ 8.11 (d, J = 2.1 Hz, 1H), 8.05 (d, J = 2.1 Hz, 1H), 7.72 (d, J = 8.2 Hz, 1H), 7.62 (s, 1H), 7.47 - 7.38 (m, 2H), 7.28 (dd, J = 7.5, 1.8 Hz, 1H), 7.18 (d, J = 8.5 Hz, 1H), 7.07 (td, J = 7.4, 1.0 Hz, 1H), 4.49 - 4.44 (m, 2H), 4.30 - 4.24 (m, 2H). LCMS: m / z = 512.1 / 514.1 [MH]-, (ESI-), RT = 4.15, Method A

[0350] Example 59: Synthesis of 15-chloro-16-(difluoromethyl)-21,23-difluoro-18,18-dioxo-8,11-dioxa-18λ6-thia-19-azatetracyclo[18.3.1.113,17.02,7]pentacosa-1(24),2,4,6,13,15,17(25),20,22-nonaen-12-one (Compound 59) TIFF2025515002000487.tif5251 Step 1 To a dry flask was added anhydrous THF (3 mL) and anhydrous diisopropylamine (1.0 mL, 7.14 mmol). The solution was cooled to -78 °C, and 2.5 M n-butyllithium in hexane (3.2 mL, 8.00 mmol) was added dropwise over 2 minutes. The solution was stirred at -78 °C for 1 hour. To a dry, two-necked flask equipped with a thermometer was added methyl 3-chloro-5-fluorobenzoate (0.80 mL, 5.62 mmol) and anhydrous THF (20 mL). The solution was cooled to -78 °C, and the solution prepared in the first step was added via cannula. The reaction mixture was stirred at -78 °C for 40 minutes, after which anhydrous DMF (1.3 mL, 16.8 mmol) was added. The reaction mixture was maintained at -78 °C for 1 hour, then warmed to -20 °C. Saturated ammonium chloride solution (12 mL) was added, and the biphasic mixture was stirred for 10 minutes. Water (20 mL) was added to the biphasic mixture. The organics were extracted with ethyl acetate (3 × 20 mL), combined, washed with brine (30 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by FCC (25 g SiO cartridge, 0–20% ethyl acetate in heptane) to give methyl 3-chloro-5-fluoro-4-formylbenzoate (463 mg, 36% yield, 95% purity) as a pale orange solid. 1 H NMR (400 MHz, DMSO) δ 10.35 - 10.29 (m, 1H), 7.91 - 7.88 (m, 1H), 7.83 (dd, J = 10.6, 1.5 Hz, 1H), 3.91 (s, 3H).

[0351] Step 2 To a suspension of potassium tert-butoxide (240 mg, 2.14 mmol) in anhydrous THF (15 mL) was added phenylmethanethiol (0.22 mL, 1.88 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 5 min, followed by the addition of a cooled (0 °C) solution of methyl 3-chloro-5-fluoro-4-formylbenzoate (95% pure, 435 mg, 1.91 mmol) in anhydrous THF (5 mL). The reaction mixture was held at 0 °C for 1 min, then warmed to room temperature and stirred for an additional 2.5 h. The mixture was concentrated in vacuo and purified by FCC (25 g SiO2 cartridge, 0-40% ethyl acetate in heptane) followed by FCC (25 g SiO2 cartridge, 0-20% diethyl ether in heptane) to give methyl 3-benzylsulfanyl-5-chloro-4-formylbenzoate (392 mg, 63% yield, 98% purity) as a yellow solid. 1 H NMR (400 MHz, DMSO) δ 10.47 - 10.46 (m, 1H), 8.02 - 7.98 (m, 1H), 7.78 (d, J = 1.4 Hz, 1H), 7.47 - 7.41 (m, 2H), 7.39 - 7.32 (m, 2H), 7.32 - 7.25 (m, 1H), 4.36 (s, 2H), 3.91 (s, 3H). LCMS: m / z = 319.0 / 321.0 [MH]-, (ESI-), RT = 1.12, Method B

[0352] Step 3 To a solution of methyl 3-benzylsulfanyl-5-chloro-4-formylbenzoate (98% purity, 387 mg, 1.18 mmol) in DCM (11 mL) at room temperature was added DAST (0.53 mL, 4.01 mmol). The reaction mixture was stirred at room temperature for 18.5 h, then DAST (0.2 mL, 1.51 mmol) was added. The reaction mixture was stirred at room temperature for an additional 2 h. Saturated aqueous NaHCO3 (50 mL) was carefully added to the reaction mixture at room temperature. The biphasic mixture was rapidly stirred for 5 min, then shaken thoroughly until gas evolution ceased. The layers were separated and the organics were extracted with DCM (2 x 20 mL). The organics were combined, passed through a hydrophobic frit, and concentrated in vacuo. The residue was purified by FCC (25 g SiO2 cartridge, 0-10% ethyl acetate in heptane) to give methyl 3-benzylsulfanyl-5-chloro-4-(difluoromethyl)benzoate (350 mg, 86% yield, 100% purity) as a yellow oil. 1 H NMR (400 MHz, DMSO) δ 7.98 - 7.96 (m, 1H), 7.85 - 7.83 (m, 1H), 7.43 (t, J = 52.6 Hz, 1H), 7.46 - 7.26 (m, 4H), 7.28 - 7.22 (m, 1H), 4.36 (s, 2H), 3.89 (s, 3H). LCMS: m / z = 341.1 / 343.1 [MH]-, (ESI-), RT = 1.17, Method B

[0353] Step 4 Methyl 3-benzylsulfanyl-5-chloro-4-(difluoromethyl)benzoate (350 mg, 1.02 mmol) was dissolved in a mixture of acetonitrile (4.5 mL), acetic acid (0.23 mL), and water (0.23 mL), and the resulting suspension was cooled to 0 °C in an ice bath. Next, 1,3-dichloro-5,5-dimethylhydantoin (250 mg, 1.27 mmol) was added portionwise, and the reaction mixture was stirred at 0 °C for 1 h. The organics were concentrated in vacuo (room temperature water bath) and then diluted with DCM (20 mL). The organics were washed with saturated aqueous NaHCO (20 mL), separated, passed through a phase separator, and then concentrated under reduced pressure (room temperature water bath). A solution of Intermediate 8 (90% pure, 319 mg, 0.756 mmol) in pyridine (3.6 mL) was added, and the mixture was stirred at 50 °C for 50 min before being concentrated under reduced pressure. The residue was purified by FCC (25 g SiO2 cartridge, 0–20% ethyl acetate in heptane) to give methyl 3-[[5-[2-[2-[tert-butyl(dimethyl)silyl]oxyethoxy]phenyl]-2,4-difluoro-phenyl]sulfamoyl]-5-chloro-4-(difluoromethyl)benzoate (453 mg, 68% yield, 75% purity) as a yellow oil. 1 H NMR (500 MHz, DMSO) δ 11.13 (br. s, 1H), 8.33 - 8.29 (m, 2H), 7.78 (t, J = 51.5 Hz, 1H), 7.41 - 7.37 (m, 1H), 7.35 - 7.32 (m, 1H), 7.28 - 7.23 (m, 1H), 7.14 - 7.10 (m, 2H), 7.04 - 7.00 (m, 1H), 4.02 - 3.99 (m, 2H), 3.89 (s, 3H), 3.78 - 3.74 (m, 2H), 0.73 (s, 9H), -0.18 (s, 6H). LCMS: m / z = 660.2 / 662.2 [MH]-, (ESI-), RT = 1.33, Method B

[0354] Step 5 To a solution of methyl 3-[[5-[2-[2-[tert-butyl(dimethyl)silyl]oxyethoxy]phenyl]-2,4-difluoro-phenyl]sulfamoyl]-5-chloro-4-(difluoromethyl)benzoate (75% purity, 447 mg, 0.506 mmol) in methanol (12 mL) at room temperature, p-methylbenzenesulfonic acid hydrate (1:1) (20 mg, 0.105 mmol) was added. The reaction mixture was stirred at room temperature for 1 h and then concentrated in vacuo. The residue was purified by FCC (25 g SiO2 cartridge, 0–100% ethyl acetate in heptane) to give methyl 3-chloro-5-[[2,4-difluoro-5-[2-(2-hydroxyethoxy)phenyl]phenyl]sulfamoyl]-4-(difluoromethyl)benzoate (241 mg, 78% yield, 90% purity) as a white solid. 1 H NMR (500 MHz, DMSO) δ 11.08 (s, 1H), 8.32 (d, J = 1.7 Hz, 1H), 8.29 (d, J = 1.6 Hz, 1H), 7.76 (t, J = 51.5 Hz, 1H), 7.42 - 7.33 (m, 2H), 7.32 - 7.27 (m, 1H), 7.17 - 7.11 (m, 2H), 7.05 - 7.01 (m, 1H), 4.67 (br. s, 1H), 3.99 (t, J = 5.6 Hz, 2H), 3.90 (s, 3H), 3.59 (t, J = 5.5Hz, 2H). LCMS: m / z = 546.1 / 548.1 [MH]-, (ESI-), RT = 1.02, Method B

[0355] Step 6 To a solution of methyl 3-chloro-5-[[2,4-difluoro-5-[2-(2-hydroxyethoxy)phenyl]phenyl]sulfamoyl]-4-(difluoromethyl)benzoate (90% pure, 235 mg, 0.386 mmol) in THF (4.5 mL) was added 2 M aqueous sodium hydroxide (1.5 mL, 3.00 mmol). The reaction mixture was stirred at room temperature for 15.5 h, after which the organics were removed in vacuo. To the remaining aqueous solution was added 1 M aqueous HCl (10 mL). The mixture was extracted with DCM (3 × 20 mL), combined, passed through a hydrophobic frit, and concentrated in vacuo to give 3-chloro-5-[[2,4-difluoro-5-[2-(2-hydroxyethoxy)phenyl]phenyl]sulfamoyl]-4-(difluoromethyl)benzoate (226 mg, 91% yield, 83% purity) as a yellow oil / gum. 1 H NMR (400 MHz, DMSO) δ 11.04 (br. s, 1H), 8.31 - 8.28 (m, 2H), 7.76 (t, J = 51.6 Hz, 1H), 7.43 - 7.34 (m, 2H), 7.31 - 7.26 (m, 1H), 7.18 - 7.11 (m, 2H), 7.05 - 7.00 (m, 1H), 4.00 (t, J = 5.5 Hz, 2H), 3.63 - 3.57 (m, 2H). No COOH or OH groups observed. LCMS: m / z = 532.0 / 534.0 [MH]-, (ESI-), RT = 0.90, Method B

[0356] Step 7 To a solution of 3-chloro-5-[[2,4-difluoro-5-[2-(2-hydroxyethoxy)phenyl]phenyl]sulfamoyl]-4-(difluoromethyl)benzoate (83% purity, 223 mg, 0.347 mmol) in anhydrous DCM (10.5 mL) was added DMAP (9.0 mg, 0.074 mmol) and DCC (140 mg, 0.679 mmol). The reaction mixture was stirred at room temperature for 1.5 h and then concentrated in vacuo. The residue was purified by FCC (25 g SiO2 cartridge, 20-100% DCM in heptane) to afford the title compound as a white solid (96 mg, 53% yield, 99% purity). 1 H NMR (500 MHz, DMSO) δ 11.02 (s, 1H), 8.27 (d, J = 1.6 Hz, 1H), 8.06 (t, J = 51.8 Hz, 1H), 7.63 (s, 1H), 7.47 (ddd, J = 8.2, 7.4, 1.7 Hz, 1H), 7.39 - 7.35 (m, 1H), 7.31 (dd, J = 7.5, 1.7 Hz, 1H), 7.25 - 7.19 (m, 2H), 7.13 - 7.09 (m, 1H), 4.44 - 4.39 (m, 2H), 4.35 - 4.29 (m, 2H). LCMS: m / z = 514.2 / 516.2 [MH]-, (ESI-), RT = 4.24, Method A

[0357] Example 60: Synthesis of 16-(difluoromethyl)-21,23-difluoro-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(25),14,16,20(24),21-nonaen-12-one (Compound 60) A suspension of Example 59 (99% pure, 60 mg, 0.115 mmol), potassium carbonate (48 mg, 0.347 mmol), and t-BuXPhos Pd G3 catalyst (5.0 mg, 6.29 μmol) in DMF (0.6 mL) and water (0.06 mL) was sparged with nitrogen for 2 minutes and then heated in a microwave at 115° C. for 40 minutes. The mixture was filtered through a cotton wool pad, and the residue was purified by preparative HPLC (Method P1) and lyophilized to give the title compound (8.7 mg, 15% yield, 96% purity) as a white solid. 1 H NMR (500 MHz, DMSO) δ 8.21–8.16 (m, 1H), 8.01–7.73 (m, 3H), 7.47–7.41 (m, 1H), 7.40–7.34 (m, 1H), 7.29–7.24 (m, 1H), 7.21–7.15 (m, 1H), 7.11–7.00 (m, 2H), 4.43–4.39 (m, 2H), 4.33–4.28 (m, 2H). No NH was observed. LCMS: m / z = 480.1 [MH]-, (ESI-), RT = 3.91, Method A

[0358] Example 61: Synthesis of 15-chloro-21,23-difluoro-18,18-dioxo-8,11-dioxa-18λ6-thia-16,19-diazatetracyclo[18.3.1.113,17.02,7]pentacosa-1(24),2,4,6,13,15,17(25),20,22-nonaen-12-one (Compound 61) TIFF2025515002000489.tif4651 Step 1 To a suspension of potassium tert-butoxide (1.27 g, 11.3 mmol) in anhydrous THF (90 mL) was added phenylmethanethiol (1.1 mL, 9.39 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 10 min, followed by the addition of a solution of methyl 2,6-dichloropyridine-4-carboxylate (2.50 g, 12.1 mmol) in anhydrous THF (20 mL). The reaction mixture was held at 0 °C for 1 min, then warmed to room temperature and stirred for an additional 1 h. The mixture was concentrated in vacuo, and the residue was purified by FCC (100 g SiO cartridge, 0–5% ethyl acetate in heptane) to give methyl 2-benzylsulfanyl-6-chloropyridine-4-carboxylate (2.55 g, 68% yield, 74% purity) as a pink oil. 1 H NMR (500 MHz, DMSO) δ 7.69 (d, J = 1.1 Hz, 1H), 7.54 (d, J = 1.1 Hz, 1H), 7.45 - 7.42 (m, 2H), 7.34 - 7.23 (m, 3H), 4.44 (s, 2H), 3.87 (s, 3H). LCMS: m / z = 294.0 / 296.0 [M+H]+, (ESI+), RT = 1.17, Method B

[0359] Step 2 Methyl 2-benzylsulfanyl-6-chloropyridine-4-carboxylate (74% purity, 2.55 g, 6.42 mmol) was dissolved in a mixture of acetonitrile (24 mL), acetic acid (1.2 mL), and water (1.2 mL), and the resulting suspension was cooled to 0 °C in an ice bath. 1,3-Dichloro-5,5-dimethylhydantoin (1.40 g, 7.11 mmol) was then added in portions, and the reaction mixture was stirred at 0 °C for 30 min. The organics were concentrated under reduced pressure (room temperature, water bath) and diluted with DCM (20 mL). The organics were washed with saturated aqueous NaHCO (20 mL), separated, passed through a phase separator, and concentrated under reduced pressure (room temperature, water bath) to give a yellow oil. A solution of Intermediate 8 (88% purity, 1.70 g, 3.94 mmol) in pyridine (18 mL) was added, and the mixture was stirred at 35 °C for 1 h. The mixture was concentrated in vacuo, and the residue was purified by FCC (50 g SiO2 cartridge, 0–40% ethyl acetate in heptane) to give methyl 2-[[5-[2-[2-[tert-butyl(dimethyl)silyl]oxyethoxy]phenyl]-2,4-difluoro-phenyl]sulfamoyl]-6-chloropyridine-4-carboxylate (1.56 g, 55% yield, 85% purity) as a yellow oil. 1 H NMR (500 MHz, DMSO) δ 10.77 (s, 1H), 8.19 (d, J = 1.2 Hz, 1H), 8.15 (d, J = 1.2 Hz, 1H), 7.38 (ddd, J = 8.3, 7.4, 1.8 Hz, 1H), 7.31 - 7.25 (m, 2H), 7.15 - 7.10 (m, 2H), 7.04 - 7.00 (m, 1H), 4.02 - 3.99 (m, 2H), 3.92 (s, 3H), 3.79 - 3.75 (m, 2H), 0.73 (s, 9H), -0.17 (s, 6H). LCMS: m / z = 611.2 / 613.2 [MH]-, (ESI-), RT = 1.27, Method B

[0360] Step 3 To a solution of methyl 2-[[5-[2-[2-[tert-butyl(dimethyl)silyl]oxyethoxy]phenyl]-2,4-difluoro-phenyl]sulfamoyl]-6-chloropyridine-4-carboxylate (85% purity, 1.56 g, 2.2 mmol) in methanol (25 mL) was added p-methylbenzenesulfonic acid hydrate (1:1) (50 mg, 0.263 mmol) at room temperature. The reaction mixture was stirred at room temperature for 17.5 hours and then concentrated in vacuo. The residue was purified by FCC (25 g SiO2 cartridge, 0–100% ethyl acetate in heptane, then 0–20% methanol in ethyl acetate) to give methyl 2-chloro-6-[[2,4-difluoro-5-[2-(2-hydroxyethoxy)phenyl]phenyl]sulfamoyl]pyridine-4-carboxylate (960 mg, 1.85 mmol, 83% yield, 96% purity) as an off-white solid. 1 H NMR (400 MHz, DMSO) δ 10.74 (s, 1H), 8.18 (d, J = 1.2 Hz, 1H), 8.14 (d, J = 1.2 Hz, 1H), 7.39 (ddd, J = 8.4, 7.4, 1.8 Hz, 1H), 7.36 - 7.26 (m, 2H), 7.17 - 7.12 (m, 2H), 7.05 - 6.99 (m, 1H), 4.66 (t, J = 5.5 Hz, 1H), 3.99 (t, J = 5.5 Hz, 2H), 3.92 (s, 3H), 3.61 - 3.56 (m, 2H). LCMS: m / z = 497.1 / 499.1 [MH]-, (ESI-), RT = 0.93, Method B

[0361] Step 4 To a solution of methyl 2-chloro-6-[[2,4-difluoro-5-[2-(2-hydroxyethoxy)phenyl]phenyl]sulfamoyl]pyridine-4-carboxylate (96% pure, 945 mg, 1.82 mmol) in THF (20 mL) was added 2 M aqueous sodium hydroxide (7.0 mL, 14.0 mmol). After stirring the reaction mixture at room temperature for 1.25 h, the organics were diluted with ethyl acetate (40 mL) and washed with 1 M aqueous HCl (20 mL). The aqueous layer was extracted with ethyl acetate (20 mL), and the organic layers were combined, washed with brine (20 mL), dried over magnesium sulfate, and concentrated in vacuo to give 2-chloro-6-[[2,4-difluoro-5-[2-(2-hydroxyethoxy)phenyl]phenyl]sulfamoyl]pyridine-4-carboxylic acid (1.25 g, 99% yield, 70% purity) as a yellow oil. 1 H NMR (400 MHz, DMSO) δ 10.70 (s, 1H), 8.14 (d, J = 1.2 Hz, 1H), 8.13 (d, J = 1.1 Hz, 1H), 7.39 (ddd, J = 8.4, 7.4, 1.8 Hz, 1H), 7.36 - 7.26 (m, 2H), 7.16 - 7.12 (m, 2H), 7.04 - 7.00 (m, 1H), 4.01 - 3.96 (m, 2H), 3.62 - 3.55 (m, 2H), 3.34 (br. s, 1H). No COOH was observed. LCMS: m / z = 483.1 / 485.1 [MH]-, (ESI-), RT = 0.77, Method B

[0362] Step 5 To a solution of 2-chloro-6-[[2,4-difluoro-5-[2-(2-hydroxyethoxy)phenyl]phenyl]sulfamoyl]pyridine-4-carboxylic acid (70% purity, 1.25 g, 1.80 mmol) in anhydrous DCM (57 mL) was added DMAP (47 mg, 0.385 mmol) and DCC (730 mg, 3.54 mmol). The reaction mixture was stirred at room temperature for 1.5 h and then concentrated in vacuo. The residue was purified by FCC (25 g SiO2 cartridge, 40-100% DCM in ethyl acetate, then 0-20% ethyl acetate in DCM) to give the title compound (63 mg, 7.4% yield, 99% purity) as a white solid. Additional product was isolated in lower purity and used in subsequent reactions (433 mg). 1 H NMR (500 MHz, DMSO) δ 10.62 (s, 1H), 8.17 (d, J = 1.2 Hz, 1H), 7.45 (ddd, J = 8.2, 7.4, 1.8 Hz, 1H), 7.41 (d, J = 1.2 Hz, 1H), 7.29 - 7.24 (m, 3H), 7.21 - 7.18 (m, 1H), 7.10 - 7.06 (m, 1H), 4.49 - 4.45 (m, 2H), 4.37 - 4.32 (m, 2H). LCMS: m / z = 465.3 / 467.3 [MH]-, (ESI-), RT = 3.83, Method A

[0363] Example 62: Synthesis of 21,23-difluoro-15-methyl-18,18-dioxo-8,11-dioxa-18λ6-thia-16,19-diazatetracyclo[18.3.1.113,17.02,7]pentacosa-1(24),2,4,6,13,15,17(25),20,22-nonaen-12-one (Compound 62) TIFF2025515002000490.tif4650 A 2 M solution of trimethylaluminum in toluene (0.11 mL, 0.220 mmol) was added to a sparged solution of Example 61 (87% pure, 20 mg, 0.0373 mmol) and tetrakis(triphenylphosphine)palladium(0) (5.0 mg, 4.33 μmol) in anhydrous 1,4-dioxane (0.6 mL). The vial was sealed and heated at 120 °C under microwave irradiation for 0.75 h. Water (0.5 mL) was carefully added to the reaction mixture. The mixture was extracted with DCM (3 × 5 mL), combined, passed through a hydrophobic frit, and concentrated in vacuo. The residue was purified by preparative HPLC (Method P1) and lyophilized to afford the title compound (7.8 mg, 45% yield, 96% purity) as a white solid. 1 H NMR (500 MHz, DMSO) δ 10.38 (s, 1H), 8.01 - 7.80 (m, 1H), 7.48 - 7.40 (m, 1H), 7.38 - 7.22 (m, 3H), 7.21 - 7.11 (m, 2H), 7.11 - 7.05 (m, 1H), 4.46 - 4.40 (m, 2H), 4.36 - 4.28 (m, 2H), 2.64 (s, 3H). LCMS: m / z = 445.1 [MH]-, (ESI-), RT = 3.42, Method A

[0364] Example 63: Synthesis of 15-amino-21,23-difluoro-18,18-dioxo-8,11-dioxa-18λ6-thia-16,19-diazatetracyclo[18.3.1.113,17.02,7]pentacosa-1(23),2(7),3,5,13,15,17(25),20(24),21-nonaen-12-one (Compound 63) A suspension of Example 61 (95% pure, 70 mg, 0.142 mmol), palladium(II) diacetate (4.0 mg, 0.018 mmol), and Xantphos (14 mg, 0.024 mmol) in 1,4-dioxane (1.5 mL) was sparged with nitrogen for 2 minutes, and cesium carbonate (95 mg, 0.292 mmol) and 1,1-diphenylmethanimine (40 μL, 0.238 mmol) were added. The reaction mixture was heated at 100 °C for 3 hours, then cooled to room temperature and filtered through Celite. The organics were concentrated in vacuo and redissolved in THF (1.5 mL), followed by the addition of 2 M aqueous hydrogen chloride (0.18 mL, 0.360 mmol). The resulting mixture was stirred at room temperature for 15 minutes, and then saturated aqueous NaHCO3 (5 mL) and water (5 mL) were added. The mixture was extracted with ethyl acetate (20 mL), and the organic layer was washed with brine (10 mL), then dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (Method P3) and then lyophilized to give the title compound (6.7 mg, 8.7% yield, 83% purity) as a white solid. 1 H NMR (500 MHz, DMSO) δ 10.06 (s, 1H), 7.47 - 7.42 (m, 1H), 7.31 - 7.26 (m, 1H), 7.25 - 7.20 (m, 2H), 7.19 - 7.16 (m, 1H), 7.10 - 7.06 (m, 2H), 7.00 - 6.96 (m, 2H), 6.57 (s, 1H), 4.39 - 4.36 (m, 2H), 4.33 - 4.27 (m, 2H). LCMS: m / z = 448.0 [M+H]+, (ESI-), RT = 3.16, Method A

[0365] Example 64: Synthesis of 15-chloro-16,21,23-trifluoro-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(25),14,16,20(24),21-nonaen-12-one (Compound 64) TIFF2025515002000492.tif4951 Step 1 A solution of methyl 3-bromo-5-chloro-4-fluorobenzoate (70% pure, 2.00 g, 5.23 mmol), benzyl mercaptan (725 μL, 6.19 mmol), DIPEA (1.2 mL, 6.89 mmol), Pd(dba) (160 mg, 0.175 mmol), and Xantphos (200 mg, 0.346 mmol) in 1,4-dioxane (40 mL) was degassed by sparging with nitrogen. The reaction was heated to 100 °C for 1 h and then stirred at 80 °C for 18 h. The reaction was cooled, and the solids were removed by filtration and washed with ethyl acetate (the solids were discarded). The filtrate was partitioned between water and ethyl acetate. The aqueous layer was extracted with ethyl acetate (3 × 10 mL), and the combined organics were washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by FCC (100 g SiO2 column, 0-20% ethyl acetate in heptane) to give methyl 3-benzylsulfanyl-5-chloro-4-fluorobenzoate (2.20 g, 92% yield, 68% purity) as a yellow solid. 1 H NMR (500 MHz, CDCl3) δ 7.92 (dd, J = 6.6, 2.1 Hz, 1H), 7.88 (dd, J = 6.6, 2.1 Hz, 1H), 7.31 - 7.28 (m, 4H), 7.26 - 7.23 (m, 1H), 4.17 (s, 2H), 3.90 (s, 3H). LCMS: m / z = 309.1 / 311.1 [MH]-, (ESI-), RT = 1.19, Method B

[0366] Step 2 1,3-Dichloro-5,5-dimethylhydantoin (450 mg, 2.28 mmol) was added to an ice-cold solution of methyl 3-benzylsulfanyl-5-chloro-4-fluorobenzoate (68% purity, 500 mg, 1.09 mmol) in acetonitrile (9 mL), water (1 mL), and acetic acid (1 mL). After stirring the reaction for 1 h, the solvent volume was reduced in vacuo and diluted with DCM (~15 mL). The mixture was quenched with saturated aqueous NaHCO3, and the aqueous layer was extracted with DCM (3 x 10 mL). The combined organics were washed with brine, dried over magnesium sulfate, and concentrated in vacuo. A solution of Intermediate 8 (315 mg, 0.830 mmol) in pyridine (4.5 mL) was added, and the mixture was stirred for 2 h. The mixture was quenched with 1 M aqueous HCl, the aqueous layer was extracted with ethyl acetate (3 × 10 mL), and the combined organics were washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by FCC (25 g SiO column, 0–100% ethyl acetate in heptane) to give methyl 3-[[5-[2-[2-[tert-butyl(dimethyl)silyl]oxyethoxy]phenyl]-2,4-difluoro-phenyl]sulfamoyl]-5-chloro-4-fluorobenzoate (243 mg, 39% yield, 84% purity). 1 H NMR (400 MHz, DMSO) δ 10.92 (s, 1H), 8.42 - 8.34 (m, 1H), 8.16 (dd, J = 6.0, 2.2 Hz, 1H), 7.42 - 7.33 (m, 1H), 7.34 - 7.26 (m, 1H), 7.26 - 7.18 (m, 1H), 7.16 - 7.09 (m, 2H), 7.05 - 6.97 (m, 1H), 4.00 (t, J = 4.7 Hz, 2H), 3.87 (s, 3H), 3.77 (t, J = 4.6 Hz, 2H), 0.73 (s, 9H), -0.18 (s, 6H). LCMS: m / z = 628.2 / 630.2 [MH]-, (ESI-), RT = 1.29, Method B

[0367] Step 3 p-Toluenesulfonic acid monohydrate (7.0 mg, 0.037 mmol) was added to a solution of methyl 3-[[5-[2-[2-[tert-butyl(dimethyl)silyl]oxyethoxy]phenyl]-2,4-difluoro-phenyl]sulfamoyl]-5-chloro-4-fluorobenzoate (84% purity, 250 mg, 0.333 mmol) in methanol (10 mL). The mixture was stirred for 1 h and then concentrated in vacuo. The residue was purified by FCC (10 g, SiO column, 20–80% ethyl acetate in heptane) to afford methyl 3-chloro-5-[[2,4-difluoro-5-[2-(2-hydroxyethoxy)phenyl]phenyl]sulfamoyl]-4-fluorobenzoate (143 mg, 72% yield, 86% purity) as a white solid. 1 H NMR (500 MHz, DMSO) δ 10.88 (s, 1H), 8.39 - 8.34 (m, 1H), 8.14 (dd, J = 6.0, 2.2 Hz, 1H), 7.41 - 7.36 (m, 1H), 7.36 - 7.28 (m, 0H), 7.13 (ddd, J = 9.7, 7.9, 1.4 Hz, 2H), 7.05 - 6.98 (m, 1H), 4.67 (t, J = 5.5 Hz, 1H), 3.98 (t, J = 5.5 Hz, 2H), 3.87 (s, 3H), 3.58 (q, J = 5.4 Hz, 2H). LCMS: m / z = 514.1 / 516.1 [MH]-, (ESI-), RT = 0.97, Method B

[0368] Step 4 To a solution of methyl 3-chloro-5-[[2,4-difluoro-5-[2-(2-hydroxyethoxy)phenyl]phenyl]sulfamoyl]-4-fluorobenzoate (86% purity, 143 mg, 0.238 mmol) in THF (2 mL) was added 2 M aqueous sodium hydroxide (0.50 mL, 1.00 mmol). The mixture was stirred for 1 h and then quenched with water / ethyl acetate. The layers were separated and the organics were discarded. The aqueous layer was acidified to pH 4 with aqueous HCl and extracted into ethyl acetate (3 × 5 mL). The combined organics were washed with brine / hydrochloric acid, dried over magnesium sulfate, and concentrated in vacuo to give 3-chloro-5-[[2,4-difluoro-5-[2-(2-hydroxyethoxy)phenyl]phenyl]sulfamoyl]-4-fluorobenzoate (115 mg, 85% yield, 88% purity) as a colorless oil. LCMS: m / z = 500.1 / 502.0 [MH]-, (ESI-), RT = 0.86, Method B

[0369] Step 5 To a solution of 3-chloro-5-[[2,4-difluoro-5-[2-(2-hydroxyethoxy)phenyl]phenyl]sulfamoyl]-4-fluorobenzoate (88% pure, 105 mg, 0.184 mmol) and DCC (85 mg, 0.412 mmol) in DCM (20 mL) was added DMAP (2.0 mg, 0.0164 mmol). The mixture was stirred for 1 h and then quenched with water. The aqueous layer was extracted with DCM (3 × 5 mL), and the combined organics were washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by preparative HPLC (Method P1) to give the title compound (30 mg, 33% yield, 98% purity) as a white solid. 1H NMR (500 MHz, DMSO) δ 10.93 (s, 1H), 8.34 - 8.29 (m, 1H), 7.52 - 7.42 (m, 2H), 7.34 - 7.26 (m, 2H), 7.26 - 7.16 (m, 2H), 7.14 - 7.06 (m, 1H), 4.43 - 4.38 (m, 2H), 4.34 - 4.28 (m, 2H). LCMS: m / z = 482.0,484.0 [MH]-, (ESI-), RT = 3.97, Method A

[0370] Example 65: Synthesis of 21,23-difluoro-15-hydroxy-18,18-dioxo-8,11-dioxa-18λ6-thia-19-azatetracyclo[18.3.1.113,17.02,7]pentacosa-1(24),2,4,6,13,15,17(25),20,22-nonaen-12-one (Compound 65) To 21,23-difluoro-15-methoxy-18,18-dioxo-8,11-dioxa-18λ6-thia-19-azatetracyclo[18.3.1.113,17.02,7]pentacosa-1(24),2,4,6,13,15,17(25),20,22-nonaen-12-one (synthesized using a method similar to Intermediate 12, 90% purity, 90 mg, 0.17...

Claims

1. A compound of formula (I) or its stereoisomers and / or pharmaceutically acceptable salts. [In the formula, Ring A is phenyl, pyridinyl, or pyridonyl, and the nitrogen atom of pyridonyl is optionally C １－６ It may also be substituted with alkyl groups. Ring B is a phenyl or 5-10 membered heterocyclyl. Ring C is either a phenyl molecule, a 5-10 membered heterocyclyl molecule, or a 5-10 membered heteroaryl molecule, or ring C is absent. R １ is, for each occurrence independently, halogen, hydroxyl, C １－６ alkyl, C １－６ haloalkyl, C １－６ alkoxy, C １－６ haloalkoxy, -O-C(O)C １－６ alkyl, -O-C(O)C ３－６ cycloalkyl and N(R Ｅ ) ２ selected from the group consisting of, R ２ For each occurrence, the halogen, hydroxyl, and C are independent. １－６ Alkyl, C １－６ Haloalkyl, C １－６ Alkoxy, C １－６ Haloalkoxy, C ３－６ Selected from the group consisting of cycloalkyl and COOH, R ３ These are cyano, halogen, and C １－６ Alkyl and C ３－６ Selected from the group consisting of cycloalkyl groups, X １ is *-S(O) ２ N(R) Ａ )-**, -C(O)-, *-C(O)N(R Ａ )-**, *-CH ２ N(R) Ａ )-** and *-S(O) ２ CH ２ - Selected from the group consisting of **, where * indicates a bond point to ring A, and ** indicates a bond point to ring B, X ２ is a bond or -O-, X ３ is, #-L １ -L ２ -L ３ -##, where # indicates a bond point to ring A, and ## indicates a bond point to ring C or, in the case of ring C not existing, to ring B. L １ is, -CH ２ -, -O-, -C(O)-, -C(O)N(R Ｂ )-, -C(O)O-,C １－６ Alkyl-O-,-CH ２ -C(O)O-, -CH ２ -N(R) Ｂ ) Selected from the group consisting of C(O)- and 5- to 6-membered heteroaryls, L ２ C １－６ Alkyl or 4-6 member heterocyclyl, where the 4-6 member heterocyclyl may be optionally substituted with an oxo, or L ２ It does not exist. L ３ The bonds are -O- and -O-C. １－６ Alkyl, C １－６ Selected from the group consisting of alkyl-O- and 4-6 membered heterocyclines, R Ａ is hydrogen or C １－６ It is alkyl, R Ｂ is hydrogen or C １－６ It is alkyl, R Ｅ For each occurrence, independently, hydrogen or C １－６ It is alkyl, n is 0, 1, or 2. о is either 1 or 2. p is either 0 or 1.

2. Ring A is phenyl, pyridinyl, or 2-pyridonyl, and the nitrogen atom of 2-pyridonyl is C １－６ The compound according to claim 1, which may be optionally substituted with an alkyl group.

3. Ring A is phenyl, pyridinyl, or 2-pyridonyl, and the nitrogen atom of 2-pyridonyl is CH ３ The compound according to claim 1, which may be optionally substituted by [the specified agent].

4. The compound according to claim 1, wherein ring A is selected from the group consisting of the following. [In the formula, Δ is X] １ The connection point to ΔΔ is X ３ [This indicates the connection point to...]

5. The compound according to claim 1, wherein n is 0.

6. The compound according to claim 1, wherein n is 1.

7. R １ However, chloro, hydroxyl, CH ３ CHF ２ and NH ２ A compound according to claim 6, selected from the group consisting of the following.

8. The compound according to claim 1, wherein n is 2.

9. R １ However, independently of each appearance, chloro, fluoro, hydroxyl, CH ３ CHF ２ , -O-CH ３ , -O-CHF ２ , -OC(O)CH ３ and the compound according to claim 8, selected from the group consisting of the following.

10. The compound according to claim 1, wherein ring B is a phenyl or a 9-membered heterocycline.

11. The compound according to claim 1, wherein ring B is phenyl or the following.

12. The compound according to claim 1, wherein ring B is as follows. or [In the formula, ● represents X] １ The connection point to, ●● is X ２ [This indicates the connection point to...]

13. The compound according to claim 1, wherein o is 1.

14. R ２ However, fluoro, hydroxyl, cyclopropyl, CF ３ , -O-CH ３ , -O-CHF ２ , -O-CF ３ The compound according to claim 13, selected from the group consisting of and C(O)OH.

15. The compound according to claim 1, wherein o is 2.

16. R ２ However, for each appearance, independently of chloro, fluoro, and CH, ３ CF ３ and -O-CH ３ A compound according to claim 15, selected from the group consisting of the following.

17. The compound according to claim 1, wherein the ring C is absent.

18. The compound according to claim 1, wherein ring C is selected from the group consisting of phenyl, pyrrolidinyl, piperidinyl, pyridinyl, and the following.

19. The compound according to claim 1, wherein ring C is selected from the group consisting of the following. [In the formula, □ represents X] ２ The connection point to □□ is X ３ [This indicates the connection point to...]

20. The compound according to any one of claims 1, 18, and 19, wherein p is 1.

21. R ３ However, bromo, chloro, fluoro, cyano, CH ３ The compound according to claim 20, selected from the group consisting of and cyclopropyl.

22. The compound according to any one of claims 1, 18, and 19, wherein p is 0.

23. X １ However, *-S(O) ２ N(H)-**, *-S(O) ２ N(CH ３ )-**, -C(O)-, *-C(O)N(H)-**, *-CH ２ N(H)-** and *-S(O) ２ CH ２ The compound according to claim 1, selected from the group consisting of -**, where * indicates a bond site to ring A and ** indicates a bond site to ring B.

24. X ２ The compound according to claim 1, wherein the compound is a bond.

25. X ２ The compound according to claim 1, wherein is -O-.

26. L １ is selected from the group consisting of -C(O)N(H)-, -C(O)N(CH ３ )-, -C(O)O-, -CH ２ -, -CH ２ -O-, -C(O)-, -CH ２ -C(O)O-, -CH ２ -N(CH ３ )C(O)-, -O- and the compound according to claim 1

27. L ２ is -CH ２ CH ２ -, -(CH ２ ) ３ -, -CH ２ -, -(CH ２ ) ４ -, -CH(CH ３ )CH ２ -, -CH ２ CH ２ C(H)(CH ３ ) - and the compound according to claim 1 selected from the group consisting of the following.

28. L ２ The compound according to claim 1, which does not exist.

29. L ３ The compound according to claim 1, wherein is a bond.

30. L ３ is -O-, -CH ２ The compound according to claim 1, wherein the compound is -O- or the following.

31. X ３ The compound according to claim 1, selected from the group consisting of the following. [In the formula, # represents a bond point to ring A, and ## represents a bond point to ring C.]

32. The compound of formula (Ia) or its stereoisomers and / or pharmaceutically acceptable salts. [In the formula, R ４ These are hydrogen, hydroxyl, halogen and C １－６ Selected from the group consisting of alkyl groups, R ５ is hydrogen, halogen, hydroxyl, C １－６ Alkoxy, C １－６ Haloalkyl, C １－６ Haloalkoxy, -C(O)OC １－６ Alkyl and C(O)OC １－６ Selected from the group consisting of cycloalkyl groups, R ６ is hydrogen, halogen, hydroxyl, C １－６ Alkoxy, C １－６ Haloalkoxy, C １－６ Alkyl, C １－６ Haloalkyl, C ３－６ Selected from the group consisting of cycloalkyl and C(O)OH, R ７ is hydrogen, halogen, C １－６ Alkyl, C １－６ Haloalkyl and CC １－６ Selected from the group consisting of alkoxys, R ８ is hydrogen, halogen or C １－６ It is alkyl, R ９ These are hydrogen, cyano, halogen and C ３－６ Selected from the group consisting of cycloalkyl groups, R １０ These are hydrogen, cyano, or halogen, X ４ is *-S(O) ２ N(R) Ｃ )-**, *-C(O)N(R Ｃ )-**, *-CH ２ N(R) Ｃ )-** and *-S(O) ２ CH ２ - Selected from the group consisting of **, where * is The connection point is indicated by **, This indicates the connection point with X ５ is, #-L ４ -L ５ -L ６ -##, where # is, The connection point is indicated by ##, This indicates the connection point with L ４ CH ２ , C １－６ Alkyl-O-,-O-,-C(O)-,-C(O)N(R) Ｄ )-, -C(O)O-, -CH ２ -C(O)O-, -CH ２ -N(R) Ｄ Selected from the group consisting of C(O)- and 5-6 member heteroaryls, L ５ C １－６ It is an alkyl or a 4- to 6-membered heterocycline, where the 4- to 6-membered heterocycline is optionally substituted with an oxo. L ６ is a bond, -O-, C １－６ Selected from the group consisting of alkyl-O- and 4-6 membered heterocyclines, R Ｃ is hydrogen or C １－６ It is alkyl, R Ｄ is hydrogen or C １－６ It is alkyl.

33. R ４ However, hydrogen, hydroxyl, chloro and CH ３ A compound according to claim 32, selected from the group consisting of the following.

34. R ５ However, hydrogen, fluoro, hydroxyl, CHF ２ , -O-CH ３ , -O-CHF ２ , -OC(O)CH ３ and the compound according to claim 32, selected from the group consisting of the following.

35. R ６ However, hydrogen, hydroxyl, fluoro, chloro, cyclopropyl, CF ３ , -O-CH ３ , -O-CHF ２ , -O-CF ３ The compound according to claim 32, selected from the group consisting of and C(O)OH.

36. R ７ However, hydrogen, chloro, fluoro, -O-CH ３ ,CH ３ and CF ３ A compound according to claim 32, selected from the group consisting of the following.

37. R ８ However, hydrogen, CH ３ The compound according to claim 32, or chloro.

38. R ９ The compound according to claim 32, selected from the group consisting of hydrogen, cyano, chloro, bromo, fluoro, or cyclopropyl.

39. R １０ The compound according to claim 32, selected from the group consisting of hydrogen, cyano, chloro, and fluoro.

40. X ４ However, *-S(O) ２ N(H)-**, *-S(O) ２ N(CH ３ )-**, *-C(O)N(H)-**, *-CH ２ N(H)-** and *-S(O) ２ CH ２ - Selected from the group consisting of **, where * indicates a connection point to the following: The compound according to claim 32, where ** indicates a bonding site to the following.

41. L ４ However, -CH ２ -, -O-, -C(O)-, -C(O)N(H)-, -C(O)N(CH ３ )-, -C(O)O-, -CH ２ -C(O)O-, -CH ２ -N(CH ３ )C(O)-,-CH ２ A compound according to claim 32, selected from the group consisting of -O- and the following.

42. L ５ However, -CH ２ -ien-CH ２ CH ２ -, - (CH ２ ) ３ -, -C(H)(CH ３ )CH ２ -ien-CH ２ CH ２ C(H)(CH ３ )-,-(CH ２ ) ４ - and the compound according to claim 32, selected from the group consisting of the following.

43. L ６ The compound according to claim 32, wherein the bond is

44. L ６ However, -O-, -CH ２ The compound according to claim 32, which is -O- or less.

45. X ５ The compound according to claim 32, selected from the group consisting of the following. Here, # is a connection point to the following: ## is a connection point to the following:

46. A compound selected from the compounds listed in Table 1 or their pharmaceutically acceptable salts. Table 1

47. A pharmaceutical composition for inhibiting ACLY, comprising a therapeutically effective amount of a compound according to any one of claims 1 to 46 and a pharmaceutically acceptable carrier.

48. The pharmaceutical composition according to claim 47 for a subject having symptoms, disease, or disorder of the liver.

49. The pharmaceutical composition according to claim 48, wherein the symptoms, disease, or disorder of the liver is NAFLD or NASH.

50. The pharmaceutical composition according to claim 47 for a subject having type 2 diabetes.

51. The pharmaceutical composition according to claim 47 for a subject having inflammation.

52. The pharmaceutical composition according to claim 47 for a subject with chronic kidney disease.

53. The pharmaceutical composition according to claim 47 for a subject having an autoimmune disease.

54. The pharmaceutical composition according to claim 47 for a subject having cancer.

55. A pharmaceutical composition for treating NAFLD, comprising a therapeutically effective amount of the compound described in any one of claims 1 to 46.

56. A pharmaceutical composition for treating NASH, comprising a therapeutically effective amount of the compound described in any one of claims 1 to 46.

57. A pharmaceutical composition for treating type 2 diabetes, comprising a therapeutically effective amount of the compound described in any one of claims 1 to 46.

58. A pharmaceutical composition for treating inflammation, comprising a therapeutically effective amount of the compound described in any one of claims 1 to 46.

59. A pharmaceutical composition for treating chronic kidney disease, comprising a therapeutically effective amount of the compound described in any one of claims 1 to 46.

60. A pharmaceutical composition for treating an autoimmune disease, comprising a therapeutically effective amount of the compound described in any one of claims 1 to 46.

61. A pharmaceutical composition for treating cancer, comprising a therapeutically effective amount of the compound described in any one of claims 1 to 46.

Images