Macrocyclic inhibitors of ATP citrate lyase

Abstract

The present invention provides, in part, a compound of formula (I), or a stereoisomer and / or pharmaceutically acceptable salt thereof, wherein the variables are as defined herein; pharmaceutical compositions comprising such compounds; and methods of using the compounds to treat conditions, diseases, and disorders associated with abnormal lipid levels. # imgabs0 #

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to and the benefit of U.S. Provisional Patent Application No. 63 / 337,344, filed on May 2, 2022, and U.S. Provisional Patent Application No. 63 / 481,045, filed on January 23, 2023, the contents of each of which are incorporated herein by reference in their entirety. Background Art

[0003] Human genetics, overnutrition, and a sedentary lifestyle contribute to disturbances in cholesterol and triglyceride metabolism. These disturbances can manifest as one or more risk factors associated with an increased likelihood of developing a variety of life-threatening metabolic and / or cardiovascular diseases. The importance of maintaining cholesterol homeostasis in humans is strongly supported by epidemiological cohort studies and meta-analyses of multiple Mendelian and statin randomized trials, which clearly demonstrate an association between elevated plasma low-density lipoprotein cholesterol (LDL-C) levels (hypercholesterolemia) and the risk of atherosclerotic cardiovascular disease (ASCVD). (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).

[0004] Although the association between ASCVD and circulating triglyceride levels is unclear (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), abnormal triglyceride metabolism also appears to be a risk factor for other metabolic 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, as one of the most common causes of chronic liver disease and hepatocellular carcinoma, NAFLD poses an independent health challenge and is the leading cause of liver-related morbidity and mortality in the Western world. (Loomba and Sanyal, (2013), The global NAFLD epidemic., Nat. Rev. Gastroenterol. Hepatol., 10, 686–690).

[0005] Currently available treatment options are inadequate for both ASCVD and NAFLD. Many patients experience lipid disorders that are ineffectively treated with current standard therapies, and ASCVD remains a leading cause of death and disability in the Western world. (Mendis, (2010), The contribution of the Framingham Heart Study to the prevention of cardiovascular disease: a global perspective., Prog. Cardiovasc. Dis., 53, 10–14). Therefore, new therapeutic strategies targeting cholesterol and triglyceride metabolism are needed. ATP-citrate lyase (ACLY) is a unique enzyme located at the intersection of nutrient catabolism and cholesterol and fatty acid biosynthesis, a metabolic relationship that has been shown to be dysregulated in a variety of disease states. Extensive evidence indicates that ACLY-derived acetyl-CoA (CoA) is not only a carbon precursor for cholesterol and fatty acid biosynthesis but also a key metabolic checkpoint used by multiple cell types to sense nutrient availability and coordinate metabolic adaptations for diverse effector functions. Therefore, there is an unmet need for the development of novel therapeutics that modulate (e.g., inhibit) ACLY activity to treat metabolic and / or cardiovascular diseases. Summary of the Invention

[0006] Provided herein are compounds designed as modulators (e.g., inhibitors) of ATP citrate lyase (ACLY). Such compounds can be used 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.

[0007] In one aspect, provided herein are compounds of formula (I)

[0008]

[0009] or a stereoisomer and / or pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0010] In another aspect, provided herein are compounds of formula (Ia)

[0011]

[0012] or a stereoisomer and / or pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0013] In certain embodiments, the compound of Formula (I) or Formula (Ia) is selected from the compounds of Table 1 or stereoisomers and / or pharmaceutically acceptable salts thereof.

[0014] 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.

[0015] The compounds of formula (I) of the present invention, or their stereoisomers and / or pharmaceutically acceptable salts; or pharmaceutical compositions can be used to treat various conditions, diseases, and disorders described herein. For example, treatment methods may include inhibiting ACLY, inhibiting cholesterol synthesis, and / or inhibiting fatty acid biosynthesis. In some embodiments, the condition, disease, or disorder may be a liver condition, disease, or disorder, such as NAFLD or NASH, and the method includes treating a liver condition, disease, or disorder, such as NAFLD or NASH. In some embodiments, the condition, disease, or disorder may be type 2 diabetes, and the method includes treating type 2 diabetes. In some embodiments, the condition, disease, or disorder may be inflammation, and the method includes treating inflammation. In some embodiments, the condition, disease, or disorder is chronic kidney disease, and the method includes treating chronic kidney disease. In some embodiments, the condition, disease, or disorder is autoimmunity, 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

[0017] As generally described herein, the present disclosure provides compounds of formula (I), such as compounds of formula (Ia), (Ib), or (II), or stereoisomers and / or pharmaceutically acceptable salts thereof, and pharmaceutical compositions containing them. The compounds and compositions described herein are used as regulators (e.g., inhibitors) of ACLY. The present disclosure also provides methods for treating various conditions, diseases, and disorders associated with abnormal metabolism using the compounds and compositions disclosed herein. Such conditions, diseases, and disorders include, but are not limited to, NAFLD, NASH, type 2 diabetes, chronic kidney disease, inflammation, autoimmunity, and cancer.

[0018] definition

[0019] To facilitate understanding of the present invention, certain terms and phrases are defined below.

[0020] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which the invention belongs. Abbreviations used herein have their conventional meanings in the fields of chemistry and biology. The chemical structures and formulas listed herein are constructed according to standard rules of chemical valence states known in the chemical art.

[0021] Throughout this specification, when compositions and kits are described as having, including, or comprising particular components, or when processes and methods are described as having, including, or comprising particular steps, it is also contemplated that the compositions and kits of the invention consist essentially of, or consist of, the components, and that the processes and methods of the invention consist essentially of, or consist of, the process steps.

[0022] In this application, where an element or component is referred to as being included in and / or selected from a list of enumerated elements or components, it should be understood that the element or component can be any one of the elements or components, or the element or component can be selected from a group consisting of two or more of the elements or components.

[0023] In addition, it should be understood that the elements and / or features of the compositions or methods described herein can be combined in various ways without departing from the spirit and scope of this teaching, whether it is clear or implicit in this application. For example, when referring to a particular compound, the compound can be used for various embodiments of the compositions of the present invention and / or the method of invention, unless otherwise understood from the context. In other words, in this application, the embodiments have been described and depicted in a clear and concise manner that enables writing and drawing of the application, but it is intended and will be understood that the embodiments can be variously combined or separated without departing from this teaching and the present invention. For example, it will be understood that all features described and depicted in this application are applicable to all aspects of the invention described and depicted in this application.

[0024] Unless the context is inappropriate, the articles "a" and "an" are used herein to refer to one or more (i.e., to at least one) of the grammatical object of the article. For example, "an element" means one element or a plurality of elements. By further example, "an analogue" means one analogue or a plurality of analogues.

[0025] As used herein, the term "and / or" means "and" or "or" unless stated otherwise.

[0026] It should be understood that, unless otherwise understood from the context and usage, the expression "at least one of..." includes each of the items represented by the ellipsis and various combinations of two or more of the items. Unless otherwise understood from the context, the expression "and / or" related to three or more items should be understood to have the same meaning.

[0027] The use of the terms "include," "includes," "including," "have," "has," "having," "contain," "contains," or "containing," including grammatical equivalents thereof, should generally be understood as open-ended and non-limiting, e.g., not excluding other unrecited elements or steps, unless otherwise specifically stated or understood from the context.

[0028] When the term "about" is used before a quantitative value, the present teachings also include the specific quantitative value itself unless otherwise expressly stated. The term "about" as used herein refers to a variation from the nominal value.

[0029] ±10%, ±5%, ±3%, ±2%, or ±1% unless otherwise stated or inferred.

[0030] Where reference is made to, for example, the molecular weight of a polymer rather than an absolute value, the molecular weight should be understood to be an average molecular weight unless otherwise indicated or understood from the context.

[0031] Should be understood that, as long as present teaching is still operable, the order of step or the order in which certain actions are performed is not important.In addition, two or more steps or actions can be performed simultaneously.

[0032] Throughout this specification, variables or parameters are disclosed in groups or ranges. Specifically, the description shall include each individual subcombination of the members of these groups and ranges. For example, "C 1–6 "Alkyl" shall include 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 C 5–6For another example, integers ranging from 0 to 40 are specifically intended to disclose individually 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 ranging from 1 to 20 are specifically intended to disclose individually 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20. Other examples include the phrase "optionally substituted with 1-5 substituents" which 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.

[0033] The use of any and all examples or exemplary language herein, e.g., "such as" or "including," is intended merely to illustrate the present invention and does not limit the scope of the invention unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention.

[0034] Chemical definition

[0035] The definitions of specific functional groups and chemical terms are described in more detail below. Chemical elements are identified according to the CAS version of the Periodic Table of the Elements on the inside cover of Handbook of Chemistry and Physics, 75th edition, and specific functional groups are generally defined as described therein. In addition, the general principles of organic chemistry and specific functional moieties and reactivity are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5th edition, John Wiley & Sons, New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3rd edition, Cambridge University Press, Cambridge, 1987.

[0036] The compounds of the present disclosure may contain one or more chiral centers and / or double bonds and may therefore exist as stereoisomers, such as geometric isomers, enantiomers, or diastereomers. The term "stereoisomer" as used herein includes all geometric isomers, enantiomers, and / or diastereomers of a compound. For example, when a compound is shown to have a particular chiral center, compounds depicted as having that position and other chiral centers of the compound that do not exhibit the chiral center 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 (e.g., with solid or dashed wedge-shaped bonds).

[0037] 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, such as enantiomers and / or diastereomers. For example, the compounds described herein may be in the form of individual enantiomers, diastereomers, or geometric isomers, or in the form of mixtures of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. Isomers can be separated 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. See, e.g., 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 (ELEliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). The present disclosure also includes the compounds described herein as individual isomers substantially free of other isomers, or as mixtures of various isomers.

[0038] As used herein, an enantiomerically pure compound is substantially free of the other enantiomer or stereoisomer of the compound (i.e., enantiomeric excess). In other words, the "S" form of the compound is substantially free of the "R" form of the compound and is therefore in enantiomeric excess of the "R" form. The term "enantiomerically pure" or "pure enantiomer" means that the compound contains greater than 75% by weight, greater than 80% by weight, greater than 85% by weight, greater than 90% by weight, greater than 91% by weight, greater than 92% by weight, greater than 93% by weight, greater than 94% by weight, greater than 95% by weight, greater than 96% by weight, greater than 97% by weight, greater than 98% by weight, greater than 98.5% by weight, greater than 99% by weight, greater than 99.2% by weight, greater than 99.5% by weight, greater than 99.6% by weight, greater than 99.7% by weight, greater than 99.8% by weight, or greater than 99.9% by weight of the enantiomer. In certain embodiments, the weight is based on the total weight of all enantiomers or stereoisomers of the compound.

[0039] Geometric isomers, arising from the arrangement of substituents around a carbon-carbon double bond or around a cycloalkyl or heterocycloalkyl group, may also exist in the compounds of the present disclosure. " represents a bond that can be a single bond, a double bond, or a triple bond as described herein. Substituents around a carbon-carbon double bond are designated as "Z" or "E" configuration, where the terms "Z" and "E" are used according to IUPAC standards. Unless otherwise indicated, structures depicting double bonds encompass both "E" and "Z" isomers.

[0040] Substituents around a carbon-carbon double bond may also be referred to as "cis" or "trans," where "cis" refers to substituents on the same side of the double bond and "trans" refers to substituents on opposite sides of the double bond. The arrangement of substituents around a carbon ring may also be designated as "cis" or "trans." The term "cis" refers to substituents on the same side of the ring plane, and the term "trans" refers to substituents on opposite sides of the ring plane. A mixture of compounds with substituents on both the same and opposite sides of the ring plane is designated "cis / trans."

[0041] The compounds described herein may also contain one or more isotopic substitutions. For example, H may be in any isotopic form, including 1 H, 2 H (D or deuterium) and 3 H (T or tritium); C can be in any isotopic form, including 12 C. 13 C and 14 C; O can be in any isotopic form, including 16 O and 18 O; F can be in any isotopic form, including 18 F and 19 F. Other examples of isotopes that can be incorporated into the compounds described herein include isotopes of nitrogen, phosphorus, and chlorine, for example,15 N, 31 P, 32 P, 35 S and 36 As an example of isotopic compounding, one or more H atoms of the compounds described herein may be replaced by deuterium.

[0042] The terms described herein are intended to have the meanings presented and can be used to understand the description and intended scope of the present disclosure. When describing the present disclosure, which may include compounds disclosed herein or stereoisomers thereof and / or pharmaceutically acceptable salts thereof, pharmaceutical compositions containing such compounds, and methods of using such compounds and compositions, defined terms, if any, have the meanings ascribed thereto unless otherwise indicated.

[0043] Unless otherwise indicated, the term "substituted" shall be defined as described herein. It is also to be understood that the terms "group" and "radical" as used herein may be considered interchangeable.

[0044] As used herein, "alkyl" refers to a straight-chain or branched saturated hydrocarbon group, for example, having 1 to 20 carbon atoms ("C 1–20 In another example, "C1-C4 alkyl" refers to a straight or branched saturated hydrocarbon containing 1 to 4 carbon atoms. Examples of C1-C4 alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, and neopentyl. In another example, "C1-C4 alkyl" refers to a straight or branched saturated hydrocarbon containing 1 to 4 carbon atoms. Examples of C1-C4 alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, isopentyl, and neopentyl. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 3-methyl-2-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, and hexyl.

[0045] As used herein, "carbocyclyl" or "carbocyclic" refers to a non-aromatic cyclic hydrocarbon group having from 3 to 10 ring carbon atoms ("C 3–10In some embodiments, a carbocyclyl group has 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 5–10 Carbocyclyl”). Exemplary C 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. Exemplary C 3–8 Carbocyclyl groups include, but are not limited to, the above-mentioned C 3–6 Carbocyclic groups and cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo [2.2.1] heptyl (C7), bicyclo [2.2.2] octyl (C8), etc. Exemplary C 3–10 Carbocyclyl groups include, but are not limited to, the above-mentioned C 3–8 Carbocyclic groups and cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthyl (C 10 ), spiro[4.5]decyl (C 10 ), etc. As shown in the foregoing examples, in certain embodiments, the carbocyclyl group is monocyclic ("monocyclic carbocyclyl"), or contains a fused, bridged or spiro ring system, such as a bicyclic ring system ("bicyclic carbocyclyl"), and can be saturated or partially unsaturated.

[0046] As used herein, "cycloalkyl" refers to a monovalent saturated cyclic, bicyclic or bridged cyclic (e.g., adamantyl) hydrocarbon group of 3-12, 3-8, 3-6, 4-8 or 4-6 carbon atoms derived from cycloalkane, referred to herein as, for example, "C 3-6 Exemplary cycloalkyl groups include, but are not limited to, cyclohexanes (e.g., cyclohexyl and cyclohexenyl), cyclopentanes (e.g., cyclopentyl and cyclopentenyl), cyclobutanes (e.g., cyclobutyl), and cyclopropanes (e.g., cyclopropyl).

[0047] As used herein, "heteroatom" refers to an atom of any element other than carbon or hydrogen, including, for example, nitrogen (N), oxygen (O), silicon (Si), sulfur (S), phosphorus (P), and selenium (Se).

[0048] As used herein, "heterocyclyl" or "heterocyclic" refers to a group of a 3 to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus and silicon ("3-10 membered heterocyclyl"). In some embodiments, the heterocyclyl is 5 to 10-membered ("5-10 membered heterocyclyl"). In heterocyclyls containing one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as long as the valence permits. The heterocyclyl group can be monocyclic ("monocyclic heterocyclyl") or a fused, bridged or spirocyclic ring system, such as a bicyclic ring system ("bicyclic heterocyclyl"), and can be saturated or can be partially unsaturated. The heterocyclyl bicyclic ring system 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, wherein the point of attachment is on the carbocyclyl ring or the heterocyclyl ring, or ring systems in which a heterocyclyl ring (as defined above) is fused to one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such cases, the number of ring members continues to refer to the number of ring members in the heterocyclyl ring system. The terms "heterocycle," "heterocyclyl," "heterocyclyl ring," "heterocyclic group," "heterocyclic moiety," and "heterocyclyl" are used interchangeably.

[0049] As used herein, "heteroaryl" refers to a radical of a 5-14 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., sharing 6 or 10 electrons in the cyclic array) having ring carbon atoms and 1-4 ring heteroatoms ("5-10 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 or nitrogen atom, as valence permits. Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings. "Heteroaryl" also includes ring systems in which a heteroaryl ring (as defined above) is fused to one or more aryl groups, wherein the point of attachment is on the aryl or heteroaryl ring, and in this case, the number of ring members represents the number of ring members in the fused (aryl / heteroaryl) ring system. Bicyclic heteroaryl groups, wherein one ring does not contain heteroatoms (e.g., indolyl, quinolyl, carbazolyl, etc.), the point of attachment can be on either ring, i.e., the ring with heteroatoms (e.g., 2-indolyl) or the ring without heteroatoms (e.g., 5-indolyl). Other non-limiting examples of heteroaryl groups include pyridyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, thienyl, furanyl, and isoquinolinyl.

[0050] As used herein, "=hetero" can be used to describe a compound or group present on a compound in which one or more carbon atoms in the compound or group have been replaced by a heteroatom. Hetero can apply to any of the above-mentioned hydrocarbon groups, such as alkyl, such as heteroalkyl; carbocyclic groups, such as heterocyclic groups; aryl groups, such as heteroaryl; and analogs having 1 to 5 heteroatoms, particularly 1 to 3 heteroatoms.

[0051] As used herein, "carbonyl" refers to the group -C(O)- or C=O.

[0052] As used herein, "cyano" refers to -CN.

[0053] As used herein, "hydroxy" and "hydroxyl" refer to the group -OH.

[0054] As used herein, "oxo" refers to the group =0 (doubly bonded oxygen).

[0055] As used herein, "halo" and "halogen" refer to an atom selected from fluorine (F, -F), chlorine (Cl, -Cl), bromine (Br, -Br) and iodine (I, -I). In certain embodiments, the halogen group is fluorine or chlorine.

[0056] As used herein, "alkoxy" refers to an alkyl group attached to another moiety through an oxygen atom (—O(alkyl)). Alkoxy groups can have 1-6 or 2-6 carbon atoms and are referred to herein as C1-C6 alkoxy and C2-C6 alkoxy, respectively. Exemplary alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, and tert-butoxy.

[0057] As used herein, "haloalkyl" refers to mono-, poly-, and perhaloalkyl groups substituted with one or more halogen atoms, wherein the halogens are independently selected from fluorine, chlorine, bromine, and iodine. In some embodiments, the haloalkyl group has 1 to 6 carbon atoms ("C 1-6 haloalkyl").

[0058] 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 group has 1 to 6 carbon atoms ("C 1-6 "haloalkoxy").

[0059] As generally used herein, "substituted," whether or not preceded by the term "optionally," means that at least one hydrogen present on a group (e.g., a carbon atom or a nitrogen atom) is replaced with a permitted substituent (e.g., a substituent that, upon substitution, results in a stable compound), e.g., a compound that does not spontaneously transform (e.g., by rearrangement, cyclization, elimination, or other reaction). Unless otherwise indicated, a "substituted" group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent at each position may be the same or different.

[0060] Nitrogen atoms are substituted or unsubstituted as valence permits, and include primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents include, but are not limited to, hydrogen, -OH, -OR aa 、–

[0061] N(R cc )2, –CN, –C(=O)R aa 、–C(=O)N(R cc 2. –CO2R aa ,–SO2R aa 、–

[0062] C(=NR bb )R aa 、–C(=NR cc )OR aa 、–C(=NR cc )N(R cc )2、–SO2N(R cc )2. –SO2R cc 、–

[0063] 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 Perhalogenated alkyl, C 2–10 Alkenyl, C 2–10 Alkynyl, C 3–10 Carbocyclic, 3–14 membered heterocyclic, C 6–14 Aryl and 5–14 membered heteroaryl groups, attached to the nitrogen atom or to the two R ccThe groups are connected to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl group is independently substituted with 0, 1, 2, 3, 4 or 5 R dd group, and wherein R aa , R bb ,

[0064] R cc and R dd As defined above.

[0065] These and other exemplary substituents are described in greater detail in the detailed description, examples, and claims.It is not intended that the present invention be limited in any manner by the foregoing list of exemplary substituents.

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

[0067] In addition, if a variable is not accompanied by a definition, the definition of the variable is the same as elsewhere in this disclosure unless it is understood to be different from the context. In addition, each variable and / or substituent (e.g., C1-C6 alkyl, R 2 、R b , w, etc.), when they occur more than once in any structure or compound, they may be independent of their definitions elsewhere in the same structure or compound.

[0068] The definitions of variables and / or substituents in the formulas and / or compounds herein encompass a plurality of 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 those described herein, ii) the definition is a collection of two or more chemical groups selected from those described herein, and iii) a compound is defined by a combination of variables and / or substituents, wherein the variable and / or substituent is defined by either (i) or (ii).

[0069] Other definitions

[0070] 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 properly administered to animals or humans. For human administration, formulations should meet sterility, pyrogenicity, general safety, and purity standards as required by the FDA Office of Biologics.

[0071] 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 drug administration. Pharmaceutically acceptable carriers can include phosphate buffered saline, water, emulsions (e.g., oil / water or water / oil emulsions), and various types of wetting agents. The composition may also include stabilizers and preservatives.

[0072] As used herein, "pharmaceutically acceptable salts" refers to any salt of an acidic or basic group that may be present in the compounds of the present invention, which salt is compatible with drug administration. As known to those skilled in the art, "salts" of the compounds of the present invention can be derived from inorganic or organic acids and bases. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66: 1-19. Pharmaceutically acceptable salts of the compounds of the present invention include salts derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, non-toxic acid addition salts are salts formed of an amino group with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid, or salts formed by using other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, dodecylsulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (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 cations formed, if appropriate, with counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

[0073] As used herein, "subjects" contemplated for administration include, but are not limited to, humans (i.e., males or females of any age group, such as pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young, middle-aged, or elderly)) and / or non-human animals, such as mammals, such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In certain embodiments, the subject is a human. In certain embodiments, the subject is a non-human animal. The terms "human," "patient," and "subject" are used interchangeably herein.

[0074] As used herein, and unless otherwise indicated, the terms "treat" and "treatment" refer to actions performed while a subject has a particular disease, disorder or condition that lessens the severity of, or delays or slows the progression of, the disease, disorder or condition ("therapeutic treatment"), and also refer to actions performed before a subject develops a particular disease, disorder or condition ("prophylactic treatment").

[0075] As used herein, an "effective amount" of a compound is an amount sufficient to elicit a desired biological response. Those skilled in the art will appreciate that an effective amount of a compound of the invention may vary depending on factors such as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the route of administration, and the age, health, and condition of the subject. An effective amount encompasses both therapeutic and prophylactic treatments.

[0076] As used herein, unless otherwise indicated, 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 treating a disease, disorder, or condition, or to delay or alleviate one or more symptoms associated with the disease, disorder, or condition. A therapeutically effective amount of a compound (e.g., a compound of the present invention) refers to an amount of a therapeutic agent that provides a therapeutic benefit when used alone or in combination with other therapies in treating a disease, disorder, or condition. The term "therapeutically effective amount" can include an amount that improves overall treatment, reduces or avoids symptoms or causes of a disease or condition, or enhances the therapeutic effect of another therapeutic agent.

[0077] As used herein, "disease," "disorder," "condition," or "affliction" are used interchangeably, unless otherwise indicated or understood from the context, to refer to a state or health condition of a patient or subject that can be treated with the compounds, pharmaceutical compositions, or methods provided herein. In some embodiments, the compounds and methods described herein include alleviating or eliminating one or more symptoms of a disease, disorder, condition, or affliction, for example, by administering a compound of Formula (I) or a stereoisomer and / or pharmaceutically acceptable salt thereof.

[0078] As used herein, "administering" refers to oral administration, administration as a suppository, topical contact, intravenous, parenteral, intraperitoneal, intramuscular, intralesional, intrathecal, intracranial, intranasal or subcutaneous administration, or implanting a sustained-release device, such as a mini-osmotic pump, to a subject. Administration can be carried out by any route, including parenteral and transmucosal (e.g., oral, sublingual, palate, gum, nasal cavity, vagina, rectal or transdermal). Parenteral administration includes, for example, intravenous, intramuscular, intraarterial, intradermal, subcutaneous, intraperitoneal, intraventricular and intracranial. Other modes of administration include, but are not limited to, the use of liposome formulations, intravenous infusions, transdermal patches, etc. "Co-administration" refers to administration of a composition described herein and one or more other therapies (e.g., anticancer agents, chemotherapeutics or neurodegenerative disease treatment) simultaneously, before or after. The compounds of the present invention can be administered alone or co-administered to a patient. Co-administration refers to the simultaneous or continuous administration of a single compound or a combination of compounds (one or more compounds or agents). Therefore, if desired, the preparation can also be combined with other active substances (e.g., in order to reduce metabolic degradation).

[0079] As used herein, "liver disease" generally refers to diseases, disorders, and / or conditions that affect the liver, which can range in severity and include, for example, simple accumulation of fat in hepatocytes (steatosis), macrovesicular steatosis, periportal and lobular inflammation (steatohepatitis), cirrhosis, fibrosis, liver cancer, and liver failure.

[0080] As used herein, "fatty liver disease" ("FLD"), also known as "steatosis," refers to a disease that results in liver damage caused by abnormal fat accumulation in liver cells. FLD can arise from a variety of sources, including excessive alcohol consumption and metabolic disorders, such as those associated with insulin resistance, obesity, and high blood pressure.

[0081] As used herein, "non-alcoholic fatty liver disease" ("NAFLD") refers to a group of diseases caused by 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.

[0082] As used herein, "drug-induced liver disease" or "toxic liver injury" refers to a disease or condition in which an active agent causes damage to the liver.

[0083] As used herein, "alcoholic liver disease," also known as "alcoholic liver damage," refers to a disease caused by the accumulation of fat in liver cells, at least in part due to alcohol consumption. Examples include, but are not limited to, diseases such as alcoholic simple fatty liver, alcoholic steatohepatitis ("ASH"), alcoholic liver fibrosis, alcoholic cirrhosis, and alcoholic fatty liver. It should be noted that alcoholic steatohepatitis, also known as alcoholic steatohepatitis, includes alcoholic liver fibrosis.

[0084] As used herein, "fatty liver of pregnancy" refers to an acute, potentially life-threatening fatty liver disorder that may occur during pregnancy.

[0085] As used herein, "altering lipid metabolism" refers to an observable (measurable) change in at least one aspect of lipid metabolism, including but not limited to total blood lipid content, blood HDL cholesterol, blood LDL cholesterol, blood VLDL cholesterol, blood triglycerides, blood Lp(a), blood apolipoprotein AI, blood apolipoprotein E (blood apo E), and blood non-esterified fatty acids.

[0086] As used herein, "altering glucose metabolism" refers to an observable (measurable) change in at least one aspect of glucose metabolism, including but not limited to total blood glucose levels, blood insulin, blood insulin to blood glucose ratio, insulin sensitivity, and oxygen consumption.

[0087] For clarity, various aspects of the present disclosure are listed herein in the form of headings and / or sections; however, it should be understood that all aspects, embodiments or features of the present disclosure described in a particular section are not limited to that particular section, but may apply to any aspect, embodiment or feature of the present disclosure.

[0088] Compound

[0089] In one aspect disclosed herein are compounds of formula (I):

[0090]

[0091] or a stereoisomer and / or a pharmaceutically acceptable salt thereof, wherein:

[0092] Ring A is phenyl or pyridone, wherein the nitrogen atom of the pyridone may be optionally substituted with C 1-6 alkyl;

[0093] Ring B is phenyl or a 5-10 membered heterocyclic group;

[0094] Ring C is phenyl, 5-10 membered heterocyclyl or 5-10 membered heteroaryl; or

[0095] Ring C is absent;

[0096] R 1 is independently selected at each occurrence from halogen, hydroxy, 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;

[0097] R 2 is independently selected at each occurrence from halogen, hydroxy, C 1-6 Halogenated alkyl, C 1-6 Alkoxy and COOH; R 3 is cyano, halogen or C 3-6 Cycloalkyl;

[0098] X 1 Selected from *-S(O)2N(R A )-**、-C(O)-、*-C(O)N(R A )-**、*-CH2N(R A )-** and *-S(O)2CH2-**, where * represents the point of attachment to Ring A and ** represents the point of attachment to Ring B;

[0099] X 2 is a bond or -O-;

[0100] X 3 For #-L 1 -L 2 -L 3 -##, where # represents the point of attachment to Ring A and ## represents the point of attachment to Ring C or, when Ring C is absent, to Ring B;

[0101] L 1 Selected from -CH2-, -O-, -C(O)-, -C(O)N(R B )-、-C(O)O-、C 1-6 Alkyl-O- and 5-6 membered heteroaryl;

[0102] L 2 C 1-6 Alkyl or 4-6 membered heterocyclic group, wherein the 4-6 membered heterocyclic group may be optionally substituted with oxo; L 3 Selected from bond, -O-, -OC 1-6 Alkyl, C 1-6 Alkyl-O- and 4-6 membered heterocyclic group; R A is hydrogen or C 1-6 Alkyl; R B is hydrogen or C 1-6alkyl; n is 0, 1 or 2; o is 1 or 2; and p is 0 or 1. In another aspect, provided herein are compounds of formula (I):

[0103]

[0104] or a stereoisomer and / or a pharmaceutically acceptable salt thereof, wherein:

[0105] Ring A is phenyl, pyridyl or pyridonyl, wherein the nitrogen atom of the pyridonyl group may be optionally substituted with C 1-6 alkyl;

[0106] Ring B is phenyl or a 5-10 membered heterocyclic group;

[0107] Ring C is phenyl, 5-10 membered heterocyclyl or 5-10 membered heteroaryl; or

[0108] Ring C is absent;

[0109] R 1 is independently selected at each occurrence from halogen, hydroxy, C 1-6 Alkyl, C 1-6 Halogenated alkyl, 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;

[0110] R 2 is independently selected at each occurrence from halogen, hydroxy, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl and COOH;

[0111] R 3 Selected from cyano, halogen, C 1-6 Alkyl and C 3-6 Cycloalkyl;

[0112] X 1 Selected from *-S(O)2N(R A )-**、-C(O)-、*-C(O)N(R A )-**、*-CH2N(R A )-** and *-S(O)2CH2-**, where * represents the point of attachment to Ring A and ** represents the point of attachment to Ring B;

[0113] X 2 is a bond or -O-;

[0114] X 3 For #-L 1 -L 2 -L 3 -##, where # represents the point of attachment to Ring A and ## represents the point of attachment to Ring C or, when Ring C is absent, to Ring B;

[0115] L 1 Selected from -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 Alkyl-O- and 5-6 membered heteroaryl;

[0116] L 2 C 1-6 alkyl or 4-6 membered heterocyclic group, wherein the 4-6 membered heterocyclic group may be optionally substituted with oxo; or

[0117] L 2 does not exist;

[0118] L 3 Selected from bond, -O-, -OC 1-6 Alkyl, C 1-6 Alkyl-O- and 4-6 membered heterocyclyl;

[0119] R A is hydrogen or C 1-6 alkyl;

[0120] R B is hydrogen or C 1-6 alkyl;

[0121] R E is independently hydrogen or C 1-6 alkyl;

[0122] n is 0, 1, or 2;

[0123] o is 1 or 2; and

[0124] p is 0 or 1.

[0125] In another aspect, provided herein are compounds of formula (I):

[0126]

[0127] or a stereoisomer and / or a pharmaceutically acceptable salt thereof, wherein:

[0128] Ring A is phenyl, pyridyl or pyridonyl, wherein the nitrogen atom of the pyridonyl group may be optionally substituted with C 1-6 alkyl;

[0129] Ring B is phenyl or a 5-10 membered heterocyclic group;

[0130] Ring C is phenyl, 5-10 membered heterocyclyl or 5-10 membered heteroaryl; or

[0131] Ring C is absent;

[0132] R 1 is independently selected at each occurrence from halogen, hydroxy, C 1-6 Alkyl, C 1-6 Halogenated alkyl, 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;

[0133] R 2 is independently selected at each occurrence from halogen, hydroxy, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl and COOH;

[0134] R 3 Selected from cyano, halogen, C 1-6 Alkyl and C 3-6 Cycloalkyl;

[0135] X 1 Selected from *-S(O)2N(R A )-**、-C(O)-、*-C(O)N(R A )-**、*-CH2N(R A )-** and *-S(O)2CH2-**, where * represents the point of attachment to Ring A and ** represents the point of attachment to Ring B;

[0136] X 2 is a bond or -O-;

[0137] X 3 For #-L 1 -L 2 -L 3 -##, where # represents the point of attachment to Ring A and ## represents the point of attachment to Ring C or, when Ring C is absent, to Ring B;

[0138] L 1 Selected from -CH2-, -C(O)-, -C(O)O-, -CH2-C(O)O-, -CH2-N(R B)C(O)-、C 1-6 Alkyl-O- and 5-6 membered heteroaryl;

[0139] L 2 C 1-6 alkyl or 4-6 membered heterocyclic group, wherein the 4-6 membered heterocyclic group may be optionally substituted with oxo; or

[0140] L 2 does not exist;

[0141] L 3 Selected from bond, -O-, -OC 1-6 Alkyl, C 1-6 Alkyl-O- and 4-6 membered heterocyclyl;

[0142] R A is hydrogen or C 1-6 alkyl;

[0143] R B is hydrogen or C 1-6 alkyl;

[0144] R E is independently hydrogen or C 1-6 alkyl;

[0145] n is 0, 1, or 2;

[0146] o is 1 or 2; and

[0147] p is 0 or 1.

[0148] In some embodiments, Ring A is phenyl or 2-pyridonyl, wherein the nitrogen atom of the 2-pyridonyl may be optionally substituted with C 1-6 In some embodiments, ring A is phenyl, pyridyl or 2-pyridonyl, wherein the nitrogen atom of the 2-pyridonyl group may be optionally substituted with C 1-6 alkyl.

[0149] In some embodiments, Ring A is phenyl or 2-pyridonyl, wherein the nitrogen atom of the 2-pyridonyl group may be optionally substituted with CH 3 . In some embodiments, Ring A is phenyl, pyridinyl or 2-pyridonyl, wherein the nitrogen atom of the 2-pyridonyl group may be optionally substituted with CH 3 .

[0150] In some embodiments, Ring A is Where Δ represents the difference between 1 The connection point and ΔΔ represents the connection with X 3 connection point.

[0151] In some embodiments, Ring A is selected from

[0152] Where Δ represents the difference between 1 The connection point and ΔΔ represents the connection with X 3 connection point.

[0153] In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2.

[0154] In some embodiments, R 1 In some embodiments, R 1 Selected from chlorine, hydroxyl, CH3, CHF2 and NH2.

[0155] In some embodiments, R 1 independently at each occurrence selected from chloro, hydroxy, CH3, -O-CH3, -O-CHF2, -OC(O)CH3 and In some embodiments, R 1 is independently selected at each occurrence from chloro, fluoro, hydroxy, CH3, CHF2, -O-CH3, -O-CHF2, -OC(O)CH3 and

[0156] In some embodiments, Ring B is phenyl or a 9-membered heterocyclyl.

[0157] In some embodiments, wherein Ring B is phenyl or

[0158] In some embodiments, Ring B is Among them, ● represents the 1 and ●● represents the connection point with X 2 connection point.

[0159] In some embodiments, o is 1. In some embodiments, o is 2.

[0160] In some embodiments, R 2 is selected from fluorine, hydroxyl, -O-CH3 and C(O)OH. In some embodiments, R 2 Selected from fluorine, hydroxy, cyclopropyl, CF3, -O-CH3, -O-CHF2, -O-CF3 and C(O)OH.

[0161] In some embodiments, R 2 is independently selected at each occurrence from chloro, fluoro, CF3, and -O-CH3. In some embodiments, R 2 is independently at each occurrence selected from chloro, fluoro, CH3, CF3 and -O-CH3.

[0162] In some embodiments, Ring C is absent.

[0163] In some embodiments, ring C is selected from phenyl, pyrrolidinyl, piperidinyl, pyridinyl,

[0164] In some embodiments, ring C is selected from phenyl, pyrrolidinyl, piperidinyl, pyridinyl,

[0165] In some embodiments, Ring C is selected from

[0166]

[0167] □ in the middle represents X 2 The connection point and □□ represents the connection point with X 3 connection point.

[0168] In some embodiments, Ring C is selected from

[0169] Where □ represents the 2 The connection point and □□ represents the connection point with X 3 connection point.

[0170] In some embodiments, p is 1. In some embodiments, p is 0.

[0171] In some embodiments, R 3 is selected from the group consisting of bromo, chloro, fluoro, cyano and cyclopropyl. 3 Selected from bromine, chlorine, fluorine, cyano, CH3 and cyclopropyl.

[0172] In some embodiments, X 1 Selected from *-S(O)2N(H)-**, *-S(O)2N(CH3)-**, -C(O)-, *-C(O)N(H)-**, *-CH2N(H)-** and *-S(O)2CH2-**, wherein * represents the point of attachment to ring A and ** represents the point of attachment to ring B.

[0173] In some embodiments, X 2 In some embodiments, X 2 It is -O-.

[0174] In some embodiments, L 1 Selected from -C(O)N(H)-, -C(O)N(CH3)-, -C(O)O-, -CH2-, -CH2-O-, -C(O)-, -O- and In some embodiments, L 1 Selected from -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 In some embodiments, L 1 Selected from -C(O)O-, -CH2-, -CH2-O-, -C(O)-, -CH2-C(O)O-, -CH2-N(CH3)C(O)- and

[0175] In some embodiments, L 2 Selected from -CH2CH2-, -(CH2)3-, -CH2-, -(CH2)4-, -CH(CH3)CH2-,

[0176] In some embodiments, L 2 Selected from -CH2CH2-, -(CH2)3-, -CH2-, -(CH2)4-, -CH(CH3)CH2-, -CH2CH2C(H)(CH3)-,

[0177]

[0178] In some embodiments, L 2 Does not exist.

[0179] In some embodiments, L 3 is the key.

[0180] In some embodiments, L 3 -O- or In some embodiments, L 3 -O-, -CH2-O- or

[0181] In some embodiments, X 3 Selected from

[0182]

[0183]

[0184] wherein # indicates the point of attachment to ring A and ## indicates the point of attachment to ring C.

[0185] In some embodiments, X 3 Selected from

[0186]

[0187] wherein # indicates the point of attachment to ring A and ## indicates the point of attachment to ring C.

[0188] In some embodiments, X 3 Selected from

[0189]

[0190] wherein # indicates the point of attachment to ring A and ## indicates the point of attachment to ring C.

[0191] Also disclosed herein, in various embodiments, are compounds of Formula (Ia):

[0192]

[0193] or a stereoisomer and / or a pharmaceutically acceptable salt thereof, wherein:

[0194] R 4 is hydrogen, halogen or C 1-6 alkyl;

[0195] R 5 Selected from hydrogen, hydroxyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -C(O)OC 1-6 Alkyl and -C(O)OC 1-6 Cycloalkyl;

[0196] R 6 Selected from hydrogen, halogen, hydroxyl, C 1-6 Alkoxy, C 1-6 Alkyl and C(O)OH;

[0197] R 7 Selected from hydrogen, halogen, C 1-6 Haloalkyl and C 1-6 alkoxy;

[0198] R 8 is hydrogen or halogen;

[0199] R 9 Selected from hydrogen, cyano, halogen and C 3-6 Cycloalkyl;

[0200] R 10 is hydrogen or halogen;

[0201] X 4Selected from *-S(O)2N(R C )-**、*-C(O)N(R C )-**、*-CH2N(R C )-** and *-S(O)2CH2-**, where * represents and ** indicates the connection point with connection points;

[0202] X 5 For #-L 4 -L 5 -L 6 -##, where # indicates The connection point and ## indicates connection points;

[0203] L 4 Selected from CH2, C 1-6 Alkyl-O-, -O-, -C(O)-, -C(O)N(R D )-, -C(O)O-, and 5-6 membered heteroaryl;

[0204] L 5 is a 4-6 membered heterocyclic group, wherein the 4-6 membered heterocyclic group may be optionally substituted with oxo;

[0205] L 6 Selected from bond, -O-, C 1-6 Alkyl-O- and 4-6 membered heterocyclyl;

[0206] R C is hydrogen or C 1-6 alkyl; and

[0207] R D is hydrogen or C 1-6 alkyl.

[0208] In various embodiments, provided herein are compounds of Formula (Ia):

[0209]

[0210] or a stereoisomer and / or a pharmaceutically acceptable salt thereof, wherein:

[0211] R 4 Selected from hydrogen, hydroxy, halogen and C 1-6 alkyl;

[0212] R 5 Selected from hydrogen, halogen, hydroxyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, -C(O)OC 1-6Alkyl and -C(O)OC 1-6 Cycloalkyl;

[0213] R 6 Selected from hydrogen, halogen, hydroxyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl and C(O)OH;

[0214] R 7 Selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl and C 1-6 alkoxy;

[0215] R 8 is hydrogen, halogen or C 1-6 alkyl;

[0216] R 9 Selected from hydrogen, cyano, halogen and C 3-6 Cycloalkyl;

[0217] R 10 is hydrogen, cyano, or halogen;

[0218] X 4 Selected from *-S(O)2N(R C )-**、*-C(O)N(R C )-**、*-CH2N(R C )-** and *-S(O)2CH2-**, where * represents and ** indicates the connection point with connection points;

[0219] X 5 For #-L 4 -L 5 -L 6 -##, where # indicates The connection point and ## indicates connection points;

[0220] L 4 Selected from 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 5-6 membered heteroaryl;

[0221] L 5 C 1-6alkyl or 4-6 membered heterocyclic group, wherein the 4-6 membered heterocyclic group may be optionally substituted with oxo;

[0222] L 6 Selected from bond, -O-, C 1-6 Alkyl-O- and 4-6 membered heterocyclyl;

[0223] R C is hydrogen or C 1-6 alkyl; and

[0224] R D is hydrogen or C 1-6 alkyl.

[0225] In various embodiments, provided herein are compounds of Formula (Ia):

[0226]

[0227] or a stereoisomer and / or a pharmaceutically acceptable salt thereof, wherein:

[0228] R 4 Selected from hydrogen, hydroxy, halogen and C 1-6 alkyl;

[0229] R 5 Selected from hydrogen, halogen, hydroxyl, C 1-6 Alkoxy, C 1-6 Haloalkyl and C 1-6 haloalkoxy;

[0230] R 6 Selected from halogen, hydroxyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Haloalkyl and C 3-6 Cycloalkyl;

[0231] R 7 Selected from hydrogen, halogen, C 1-6 Alkyl and C 1-6 alkoxy;

[0232] R 8 is hydrogen or C 1-6 alkyl;

[0233] R 9 Selected from hydrogen, cyano, halogen and C 3-6 Cycloalkyl;

[0234] R 10 is hydrogen, cyano, or halogen;

[0235] X 4 Selected from *-S(O)2N(R C )-**、*-C(O)N(RC )-**、*-CH2N(R C )-** and *-S(O)2CH2-**, where * represents and ** indicates the connection point with connection points;

[0236] X 5 For #-L 4 -L 5 -L 6 -##, where # indicates The connection point and ## indicates connection points;

[0237] L 4 Selected from 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 5-6 membered heteroaryl;

[0238] L 5 C 1-6 Alkyl or 4-6 membered heterocyclic group;

[0239] L 6 Selected from bond, -O-, C 1-6 Alkyl-O- and 4-6 membered heterocyclyl;

[0240] R C is hydrogen or C 1-6 alkyl; and

[0241] R D is hydrogen or C 1-6 alkyl.

[0242] In various embodiments, provided herein are compounds of Formula (Ia):

[0243]

[0244] or a stereoisomer and / or a pharmaceutically acceptable salt thereof, wherein:

[0245] R 4 Selected from hydrogen, hydroxy, halogen and C 1-6 alkyl;

[0246] R 5 Selected from hydrogen, halogen, hydroxyl, C 1-6 Alkoxy, C 1-6 Haloalkyl and C 1-6 haloalkoxy;

[0247] R 6Selected from halogen, hydroxyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Haloalkyl and C 3-6 Cycloalkyl;

[0248] R 7 Selected from hydrogen, halogen, C 1-6 Alkyl and C 1-6 alkoxy;

[0249] R 8 is hydrogen or C 1-6 alkyl;

[0250] R 9 Selected from hydrogen, cyano, halogen and C 3-6 Cycloalkyl;

[0251] R 10 is hydrogen, cyano, or halogen;

[0252] X 4 Selected from *-S(O)2N(R C )-**、*-C(O)N(R C )-**、*-CH2N(R C )-** and *-S(O)2CH2-**, where * represents and ** indicates the connection point with connection points;

[0253] X 5 For #-L 4 -L 5 -L 6 -##, where # indicates The connection point and ## indicates connection points;

[0254] L 4 Selected from C 1-6 Alkyl-O-, -C(O)-, -C(O)O-, -CH2-C(O)O-, -CH2-N(R D )C(O)- and 5-6 membered heteroaryl;

[0255] L 5 C 1-6 Alkyl or 4-6 membered heterocyclic group;

[0256] L 6 Selected from bond, -O-, C 1-6 Alkyl-O- and 4-6 membered heterocyclyl;

[0257] R C is hydrogen or C 1-6 alkyl; and

[0258] R D is hydrogen or C 1-6 alkyl.

[0259] In some embodiments, R 4 is hydrogen, chlorine, or CH3. In certain embodiments, R 4 It is hydrogen, hydroxy, chlorine or CH3.

[0260] In some embodiments, R 5 Selected from hydrogen, hydroxy, -O-CH3, -O-CHF2, -OC(O)CH3 and In some embodiments, R 5 Selected from hydrogen, fluorine, hydroxy, CHF2, -O-CH3, -O-CHF2, -OC(O)CH3 and In some embodiments, R 5 Selected from hydrogen, fluorine, hydroxy, CHF2, -O-CH3 and -O-CHF2.

[0261] In some embodiments, R 6 is selected from the group consisting of hydrogen, hydroxy, fluorine, chlorine, -O-CH3 and C(O)OH. 6 is selected from hydrogen, hydroxy, fluorine, chlorine, cyclopropyl, CF3, -O-CH3, -O-CHF2, -O-CF3 and C(O)OH. In some embodiments, R 6 Selected from hydroxy, fluoro, cyclopropyl, CF3, -O-CH3, -O-CHF2 and -O-CF3.

[0262] In some embodiments, R 7 is selected from hydrogen, chlorine, fluorine, -O-CH3 and CF3. In some embodiments, R 7 Selected from hydrogen, fluorine, -O-CH3 and CH3.

[0263] In some embodiments, R 8 In some embodiments, R 8 is hydrogen, CH3 or chlorine. In some embodiments, R 8 It is hydrogen or CH3.

[0264] In some embodiments, R 9 is selected from hydrogen, cyano, chlorine, bromine, fluorine and cyclopropyl. 9 is selected from hydrogen, cyano, chlorine, bromine, fluorine and cyclopropyl.

[0265] In some embodiments, R 10 is hydrogen, chlorine, or fluorine. 10 is selected from hydrogen, cyano, chlorine and fluorine.

[0266] In some embodiments, X 4 Selected from *-S(O)2N(H)-**, *-S(O)2N(CH3)-**, *-C(O)N(H)-**, *-CH2N(H)-** and *-S(O)2CH2-**, wherein * represents and ** indicates the connection point with connection point.

[0267] In some embodiments, L 4 Selected from -CH2-, -O-, -C(O)-, -C(O)N(H)-, -C(O)N(CH3)-, -C(O)O-, -CH2-O- and In some embodiments, L 4 Selected from -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 In some embodiments, L 4 Selected from -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 In some embodiments, L 4 Selected from -CH2-, -C(O)-, -C(O)O-, -CH2-C(O)O-, -CH2-N(CH3)C(O)-, -CH2-O- and

[0268] In some embodiments, L 5 Selected from -CH2-, -CH2CH2-, -(CH2)3-, -CH(CH3)CH2-, -(CH2)4-, In some embodiments, L 5 Selected from -CH2-, -CH2CH2-, -(CH2)3-, -C(H)(CH3)CH2-, -CH2CH2C(H)(CH3)-, -(CH2)4-,

[0269] In some embodiments, L 5 Selected from -CH2-, -CH2CH2-, -(CH2)3-, -C(H)(CH3)CH2-, -CH2CH2C(H)(CH3)- and

[0270] In some embodiments, L 6 is the key.

[0271] In some embodiments, L 6 -O- or In some embodiments, L 6 -O-, -CH2-O- or

[0272] In some embodiments, X 5 Selected from

[0273]

[0274]

[0275] The # indicates that The connection point and ## indicates connection point.

[0276] In some embodiments, X 5 Selected from

[0277]

[0278]

[0279] The # indicates that The connection point and ## indicates connection point.

[0280] In some embodiments, X 5 Selected from

[0281]

[0282]

[0283] The # indicates that The connection point and ## indicates connection point.

[0284] In some embodiments, X 5 Selected from

[0285]

[0286] The # indicates that The connection point and ## indicates connection point.

[0287] In various embodiments, provided herein are compounds of Formula (Ib):

[0288]

[0289] or a stereoisomer and / or a pharmaceutically acceptable salt thereof, wherein:

[0290] R 11 Selected from hydrogen, hydroxy, halogen and C 1-6 alkyl;

[0291] R 12 Selected from hydrogen, halogen, hydroxyl, C 1-6 Alkoxy, C 1-6 Haloalkyl and C 1-6 haloalkoxy;

[0292] R 13 Selected from halogen, hydroxyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Haloalkyl and C 3-6 Cycloalkyl;

[0293] R 14 is hydrogen or halogen;

[0294] R 15 Selected from hydrogen, halogen, C 1-6 Alkyl and C 1-6 alkoxy;

[0295] R 16 is hydrogen or halogen;

[0296] R 17 is hydrogen or C 1-6 alkyl;

[0297] R 18 Selected from hydrogen, cyano, halogen and C 3-6 Cycloalkyl;

[0298] R 19 is hydrogen, cyano, or halogen;

[0299] X 6 Selected from *-S(O)2N(R E )-**、*-C(O)N(R E )-**、*-CH2N(R E )-** and *-S(O)2CH2-**, where * represents and ** indicates the connection point with connection points;

[0300] X7 For #-L 7 -L 8 -L 9 -##, where # indicates The connection point and ## indicates connection points;

[0301] L 7 Selected from 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 5-6 membered heteroaryl;

[0302] L 8 C 1-6 Alkyl or 4-6 membered heterocyclic group;

[0303] L 9 Selected from bond, -O-, C 1-6 Alkyl-O- and 4-6 membered heterocyclyl;

[0304] R E is hydrogen or C 1-6 alkyl; and

[0305] R F is hydrogen or C 1-6 alkyl.

[0306] In various embodiments, provided herein are compounds of Formula (Ib):

[0307]

[0308] or a stereoisomer and / or a pharmaceutically acceptable salt thereof, wherein:

[0309] R 11 Selected from hydrogen, hydroxy, halogen and C 1-6 alkyl;

[0310] R 12 Selected from hydrogen, halogen, hydroxyl, C 1-6 Alkoxy, C 1-6 Haloalkyl and C 1-6 haloalkoxy;

[0311] R 13 Selected from halogen, hydroxyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Haloalkyl and C 3-6 Cycloalkyl;

[0312] R 14 is hydrogen or halogen;

[0313] R 15 Selected from hydrogen, halogen, C 1-6 Alkyl and C 1-6 alkoxy;

[0314] R 16 is hydrogen or halogen;

[0315] R 17 is hydrogen or C 1-6 alkyl;

[0316] R 18 Selected from hydrogen, cyano, halogen and C 3-6 Cycloalkyl;

[0317] R 19 is hydrogen, cyano, or halogen;

[0318] X 6 Selected from *-S(O)2N(R E )-**、*-C(O)N(R E )-**、*-CH2N(R E )-** and *-S(O)2CH2-**, where * represents and ** indicates the connection point with connection points;

[0319] X 7 For #-L 7 -L 8 -L 9 -##, where # indicates The connection point and ## indicates connection points;

[0320] L 7 Selected from C 1-6 Alkyl-O-, -C(O)-, -C(O)O-, -CH2-C(O)O-, -CH2-N(R F )C(O)- and 5-6 membered heteroaryl;

[0321] L 8 C 1-6 Alkyl or 4-6 membered heterocyclic group;

[0322] L 9 Selected from bond, -O-, C 1-6 Alkyl-O- and 4-6 membered heterocyclyl;

[0323] R E is hydrogen or C 1-6 alkyl; and

[0324] R F is hydrogen or C1-6 alkyl.

[0325] In certain embodiments, R 11 Selected from hydrogen, hydroxy, chlorine and CH3.

[0326] In some embodiments, R 12 Selected from hydrogen, fluorine, hydroxy, CHF2, -O-CH3 and -O-CHF2.

[0327] In some embodiments, R 13 Selected from hydroxy, fluoro, cyclopropyl, CF3, -O-CH3, -O-CHF2 and -O-CF3.

[0328] In some embodiments, R 14 is hydrogen or fluorine.

[0329] In some embodiments, R 15 Selected from hydrogen, chlorine, fluorine, -O-CH3, CH3 and CF3.

[0330] In some embodiments, R 16 is hydrogen or fluorine.

[0331] In some embodiments, R 17 It is hydrogen or CH3.

[0332] In some embodiments, R 18 is selected from hydrogen, cyano, chlorine, bromine, fluorine and cyclopropyl.

[0333] In some embodiments, R 19 is selected from hydrogen, cyano, chlorine and fluorine.

[0334] In some embodiments, X 6 Selected from *-S(O)2N(H)-**, *-S(O)2N(CH3)-**, *-C(O)N(H)-**, *-CH2N(H)-** and *-S(O)2CH2-**, wherein * represents and ** indicates the connection point with connection point.

[0335] In some embodiments, L 7 Selected from -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 In some embodiments, L 7 Selected from -CH2-, -C(O)-, -C(O)O-, -CH2-C(O)O-, -N(CH3)C(O)-, -CH2-O- and

[0336] In some embodiments, L 8 Selected from -CH2-, -CH2CH2-, -(CH2)3-, -C(H)(CH3)CH2-, -CH2CH2C(H)(CH3)- and

[0337] In some embodiments, L 9 is the key.

[0338] In some embodiments, L 9 -O-, -CH2-O- or In some embodiments, X 7 Selected from

[0339]

[0340] The # indicates that The connection point and ## indicates connection point.

[0341] In some embodiments, X 7 Selected from

[0342]

[0343] The # indicates that The connection point and ## indicates connection point.

[0344] In various embodiments, provided herein are compounds of formula (II):

[0345]

[0346] or a stereoisomer and / or a pharmaceutically acceptable salt thereof, wherein:

[0347] X1 and X2 are C(R G ),or

[0348] X1 is C=O and X2 is N(R H ),or

[0349] X1 is N(R H ) and X2 is C=O;

[0350] When X1 is C=O and X2 is N(RH), is a single bond, or

[0351] When X1 is C(R G )hour, is a double bond;

[0352] R 20 H or C 1-3 alkyl;

[0353] R 21 is independently selected at each occurrence from halogen, hydroxy, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl and COOH;

[0354] R 22 Selected from cyano, halogen, C 1-6 Alkyl and C 3-6 Cycloalkyl;

[0355] X 8 -C(O)C 1-6 Alkyl-, -C(O)-(C 1-6 alkyl)-O- or –(5-6 membered heteroaryl)-(C 1-6 alkyl)-O-;

[0356] R G is independently selected at each occurrence from halogen, hydroxy, 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;

[0357] R H H or C 1-3 alkyl;

[0358] r is 0, 1, or 2; and

[0359] s is 0 or 1.

[0360] In some embodiments, X1 and X2 are C(R G ). In some embodiments, R G is independently halogen or hydroxy at each occurrence. In some embodiments, R G is independently at each occurrence chloro or hydroxy.

[0361] In some embodiments, X1 is C=O and X2 is N(R H ). In some embodiments, R HIn some embodiments, R H C 1-3 alkyl.

[0362] In some embodiments, X1 is N(R H ) and X2 is C=O. In some embodiments, R H In some embodiments, R H C 1-3 alkyl.

[0363] In some embodiments, R 20 In some embodiments, R 20 C 1-3 alkyl.

[0364] In some embodiments, r is 0.

[0365] In some embodiments, r is 1. In some embodiments, R 21 C 1-6 In some embodiments, R 21 It is CF3.

[0366] In some embodiments, r is 2. In some embodiments, R 21 is independently halogen at each occurrence. In some embodiments, R 21 is independently fluorine at each occurrence.

[0367] In some embodiments, s is 0.

[0368] In some embodiments, s is 1. In some embodiments, R 22 In some embodiments, R 22 For fluorine.

[0369] In some embodiments, X 8 -C(O)CH2-, -C(O)(CH2)2O- or

[0370]

[0371] In some embodiments, X 8 is #-C(O)CH2-##, #-C(O)(CH2)2O-##, or The # indicates that The connection point and ## indicates connection point.

[0372] In some embodiments, the compound is selected from Table 1:

[0373] Table 1. List of compounds.

[0374]

[0375]

[0376]

[0377]

[0378]

[0379]

[0380]

[0381]

[0382]

[0383]

[0384]

[0385]

[0386]

[0387]

[0388]

[0389]

[0390]

[0391]

[0392]

[0393]

[0394]

[0395]

[0396]

[0397]

[0398] Pharmaceutical compositions and routes of administration

[0399] The compounds provided in accordance with the present disclosure are typically administered in the form of pharmaceutical compositions. Therefore, the present invention provides pharmaceutical compositions containing one or more compounds described herein or their stereoisomers and / or pharmaceutically acceptable salts as active ingredients, 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 in a manner well known in the pharmaceutical field (see, for example, Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa. 17th edition (1985); and Modern Pharmaceutics, Marcel Dekker, Inc. 3rd edition (G.S. Banker & C.T. Rhodes, Eds.)

[0400] The pharmaceutical compositions described herein can be administered in single or multiple doses by any accepted mode of administration of pharmaceutical agents with similar utility, for example, as described in those patents and patent applications incorporated by reference, including rectal, oral, intranasal, and transdermal routes, by intraarterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, as an inhalant, or by an impregnated or coated device (e.g., a stent or a cylindrical polymer inserted into an artery).

[0401] One mode of administration is parenteral administration, particularly by injection. The novel compositions of the present disclosure may be added to formulations comprising aqueous or oily suspensions or emulsions containing sesame oil, corn oil, cottonseed oil or peanut oil, as well as elixirs, mannitol, dextrose or sterile aqueous solutions and similar pharmaceutical carriers for administration by injection. Aqueous solutions in saline are also commonly used for injection, but are less preferred in the context of the present disclosure. Ethanol, glycerol, propylene glycol, liquid polyethylene glycols, etc. (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils may also be used. For example, suitable fluidity may be maintained by using a coating (e.g., lecithin), maintaining the desired particle size in the presence of dispersion, and by using a surfactant. Various antibacterial and antifungal agents may play a role in preventing the effects of microorganisms, such as parabens, chlorobutanol, phenol, sorbic acid, thimerosal, etc.

[0402] Sterile injectable solutions can be prepared by adding the desired amount of a compound of the present invention together with the various other ingredients listed above (as needed) in an appropriate solvent and then sterilizing by filtration. Typically, dispersions are prepared by adding the various sterilized active ingredients to a sterile carrier comprising a basic dispersion medium and the desired other ingredients listed above. For sterile powders for the preparation of sterile injectable solutions, preferred preparation methods are vacuum drying and freeze drying techniques, which can produce a powder of the active ingredient plus any additional desired ingredients from a previously sterile filtered solution.

[0403] Oral administration is another route of administration for the compounds of the present disclosure. Administration can be in the form of capsules or enteric-coated tablets, among others. When preparing a pharmaceutical composition comprising at least one compound described herein, the active ingredient is typically diluted with an excipient and / or encapsulated in a carrier, which can be in the form of a capsule, pouch, paper, or other container. When an excipient is used as a diluent, it can be in the form of a solid, semisolid, or liquid material (as described above) that serves as a vehicle, carrier, or medium for the active ingredient. Thus, the composition can be in the form of tablets, pills, powders, lozenges, pouches, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as solids or in liquid media), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injectable solutions, and sterile packaged powders.

[0404] Examples of some suitable excipients include, but are not limited to, lactose, glucose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginates, tragacanth gum, gelatin, calcium silicate, microcrystalline cellulose, polyvinyl pyrrolidone, cellulose, sterile water, syrup, and methylcellulose. The formulation may also include: lubricants, such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifiers and suspending agents; preservatives, such as methyl and propyl hydroxybenzoates; sweeteners; and flavoring agents.

[0405] The compositions of the present disclosure can be prepared using methods known in the art so that the quick, continuous or delayed release of active ingredients is provided after application to the patient. Controlled release drug delivery systems for oral administration include osmotic pump systems and dissolution systems containing polymer coating reservoirs or drug-polymer matrix formulations. The example of a controlled release system is provided in U.S. Patents 3,845,770, 4,326,525, 4,902,514 and 5,616,345. Another preparation for the disclosed method adopts a transdermal delivery device ("patch"). Such transdermal patches can be used for providing a continuous or discontinuous infusion of a controlled amount of the disclosed compound. The construction and use of transdermal patches for delivering medicaments are well known in the art. See, for example, U.S. Patents 5,023,252, 4,992,445 and 5,001,139. ​​Such patches can be configured to deliver medicaments continuously, pulsed or on demand.

[0406] The composition is preferably formulated in a unit dosage form. The term "unit dosage form" refers to physically discrete units suitable as unit doses for human subjects and other mammals, each unit containing a predetermined amount of active substance, which is calculated to produce the desired therapeutic effect and is combined with a suitable pharmaceutical excipient (e.g., tablets, capsules, ampoules). The compound is usually administered in a pharmaceutically effective amount. However, it should be understood that the amount of the compound actually administered will usually be determined by a doctor based on relevant circumstances, including the condition to be treated, the selected route of administration, the compound actually administered and its relative activity, the age, weight and response of the individual patient, the severity of the patient's symptoms, etc.

[0407] To prepare solid compositions (e.g., tablets), the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition comprising a homogeneous mixture of the disclosed compounds. When these preformulation compositions are referred to as homogeneous, it is meant that the active ingredient is evenly dispersed throughout the composition so that the composition can be easily subdivided into equally effective unit dosage forms, such as tablets, pills, and capsules.

[0408] Tablet of the present disclosure or pill can coating or otherwise mix to provide the dosage form with extended effect advantage, or protect it from the impact of the acidic conditions of the stomach.For example, tablet or pill can comprise inner dosage and outer dosage component, and the latter is the coating form that covers the former.These two components can be separated by enteric layer, and enteric layer is used to resist the disintegration in the stomach and allows inner component to enter duodenum or delay release intactly.Multiple materials can be used for this type of enteric layer or coating, and these materials comprise the mixture of multiple polymeric acid and polymeric acid and materials such as shellac, cetyl alcohol and cellulose acetate.

[0409] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents, or mixtures thereof, as well as powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. Preferably, the compositions are administered via the oral or nasal respiratory route for local or systemic effect. Preferably, compositions in pharmaceutically acceptable solvents can be aerosolized using an inert gas. Aerosolized solutions can be inhaled directly from the aerosolizing device, or the aerosolizing device can be connected to a face mask, oxygen tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions can be administered from a device that delivers the formulation in an appropriate manner, preferably orally or nasally.

[0410] In some embodiments, a pharmaceutical composition comprises a disclosed compound (e.g., a compound of Formula (I), Formula (la), Formula (lb), or Formula (II)) or a stereoisomer and / or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0411] Treatment

[0412] In various embodiments, the compounds disclosed herein (e.g., compounds of Formula (I), (Ia), (Ib), or (II)), or stereoisomers thereof, and / or pharmaceutically acceptable salts thereof, including pharmaceutical compositions, can be used to treat or prevent various conditions, diseases, and disorders. The methods of treating the conditions, diseases, or disorders described herein generally comprise administering to a patient in need thereof a therapeutically effective amount of a compound described herein (e.g., a compound of Formula (I), (Ia), (Ib), or (II)), or stereoisomers thereof, and / or pharmaceutically acceptable salts thereof, to treat the condition, disease, or disorder.

[0413] In typical embodiments, the present disclosure is intended to encompass compounds disclosed herein, or stereoisomers thereof, and / or pharmaceutically acceptable salts thereof. In some embodiments, the present disclosure includes enantiomers, mixtures of enantiomers, stereoisomers, or mixtures of stereoisomers (pure or racemic or non-racemic) of the compounds described herein (e.g., compounds of Formula (I), Formula (Ia), Formula (Ib), or Formula (II)).

[0414] Examples of conditions, diseases, or disorders include, but are not limited to, cardiovascular disease, atrial fibrillation, blood coagulation, coronary heart disease, hypercoagulability, 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 diseases (e.g., syndrome X), galactosemia, HIV infection, peroxisome proliferator-activated receptor-associated diseases, sepsis, thrombotic diseases, obesity, pancreatitis, hypertension, kidney disease, cancer, inflammation (e.g., liver inflammation), inflammatory muscle diseases (e.g., polymyalgia rheumatica, polymyositis, and fibrositis), impotence, gastrointestinal diseases, 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 (SLE), multiple sclerosis (MS), and autoimmune chronic hepatitis), arthritis (e.g., rheumatoid arthritis, juvenile rheumatoid arthritis, and osteoarthritis), osteoporosis, soft tissue rheumatic diseases (e.g., tendinitis), bursitis, autoimmune diseases (e.g., systemic lupus erythematosus and lupus erythematosus), scleroderma, ankylosing spondylitis, gout, pseudogout, non-insulin-dependent diabetes mellitus, diabetes (e.g., type 2), polycystic ovary disease, hyperlipidemia (e.g., primary hyperlipidemia, familial hypercholesterolemia (FH), Fredrickson type IIa hypercholesterolemia, Fredrickson type IIb hypercholesterolemia, familial combined hyperlipidemia (FCH)), lipoprotein lipase deficiency (e.g., hypertriglyceridemia, hypoalphalipoproteinemia, and hypercholesterolemia), dyslipidemia associated with diabetes, dyslipidemia associated with obesity, and dyslipidemia associated with Alzheimer's disease. In certain embodiments, the method comprises treating and / or preventing hyperlipidemia, such as primary hyperlipidemia. In some embodiments, the method comprises treating and / or preventing cardiovascular disease.

[0415] In certain embodiments, the compounds disclosed herein (e.g., compounds of Formula (I), (Ia), (Ib), or (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 lipid cholesterol (non-HDL-C), high levels of total serum cholesterol (TC), high levels of high-sensitivity C-reactive protein (hsCRP), high levels of fibrinogen, high levels of insulin, high levels of glucose, and low levels of high-density lipoprotein cholesterol (HDL-C). In other words, the methods of the present disclosure can 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 can include inhibiting ACLY, inhibiting cholesterol synthesis, and / or inhibiting fatty acid biosynthesis. In some embodiments, an effective amount of a compound described herein (e.g., a compound of Formula (I), (la), (lb), or (II)), or a stereoisomer thereof, and / or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure can be used as an adjunct to diet and maximally tolerated statin therapy to lower LDL-C in adults with heterozygous familial hypercholesterolemia or established atherosclerotic cardiovascular disease. In some embodiments, an effective amount of a compound described herein (e.g., a compound of Formula (I), (la), (lb), or (II)), or a stereoisomer thereof, and / or a 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.

[0416] In certain embodiments, the compounds disclosed herein (e.g., compounds of Formula (I), Formula (la), Formula (lb), or Formula (II)), or stereoisomers and / or pharmaceutically acceptable salts thereof, including pharmaceutical compositions, can be used to treat or prevent various diseases and conditions, including, but not limited to, aging, Alzheimer's disease, cancer, cardiovascular disease, diabetic nephropathy, diabetic retinopathy, glucose metabolism disorders, dyslipidemia, dyslipoproteinemia, enhanced bile production, hypertension, impotence, inflammation, insulin resistance, lipid elimination in bile, regulation of C-reactive protein, obesity, oxysterol elimination in bile, pancreatitis, pancreatitius, pancreatitis, Parkinson's disease, peroxisome proliferator-activated receptor-associated diseases, phospholipid elimination in bile, kidney disease, rhabdomyolysis, sepsis, sleep apnea, syndrome X, and thrombotic diseases.

[0417] In certain embodiments, provided herein is a method of treating a liver disease selected from steatohepatitis, alcoholic liver disease, fatty liver, hepatic steatosis, cirrhosis, liver fibrosis, and acute fatty liver of pregnancy. In some embodiments, the disease is steatohepatitis. In some embodiments, steatohepatitis is NASH. In some embodiments, steatohepatitis is NASH. In some embodiments, the disease is alcoholic liver disease. In some embodiments, the disease is fatty liver. In some embodiments, the disease is hepatic steatosis, cirrhosis, or liver fibrosis. In some embodiments, the disease is acute fatty liver of pregnancy. In some embodiments, the patient is an adult.

[0418] In certain embodiments, the present disclosure provides methods of treating or preventing aging, Alzheimer's disease, cancer, cardiovascular disease, diabetic nephropathy, diabetic retinopathy, glucose metabolism disorders, dyslipidemia, dyslipoproteinemia, enhancing bile production, enhancing reverse lipid transport, hypertension, impotence, inflammation, insulin resistance, lipid elimination in bile, regulating C-reactive protein, obesity, oxysterol elimination in bile, pancreatitis, pancreatitis, Parkinson's disease, peroxisome proliferator-activated receptor-associated disease, phospholipid elimination in bile, kidney disease, sepsis, metabolic syndrome disorders (e.g., syndrome X), or thrombotic disorders.

[0419] In certain embodiments, the disease is selected from the group consisting of lipodystrophy, lysosomal acid lipase deficiency, and glycogen storage disease. In some embodiments, the patient is an adult.

[0420] In certain embodiments, the disease is selected from hepatitis C, human immunodeficiency virus infection, alpha 1-antitrypsin deficiency, Bassen-Kornzweig syndrome, hypobetalipoproteinemia, celiac disease, Wilson's disease, and Weber-Christian syndrome. In some embodiments, the disease is hepatitis B. In some embodiments, the disease is hepatitis C. In some embodiments, the disease is human immunodeficiency virus infection. In some embodiments, the disease is alpha 1-antitrypsin deficiency. In some embodiments, the disease is Bassen-Kornzweig syndrome. In some embodiments, the disease is hypobetalipoproteinemia. In some embodiments, the disease is celiac disease or Wilson's disease. In some embodiments, the disease is Weber-Christian syndrome. In some embodiments, the patient is an adult.

[0421] In certain embodiments, the condition is selected from toxic liver injury, total parenteral nutrition, severe surgical weight loss, environmental toxicity, malnutrition, and starvation. In some embodiments, the condition is toxic liver injury. In some embodiments, the condition is total parenteral nutrition or severe surgical weight loss. In some embodiments, the condition is environmental toxicity. In some embodiments, the condition is malnutrition or starvation. In some embodiments, the patient is an adult.

[0422] In various embodiments, provided herein are methods for treating NAFLD in a subject in need thereof, which generally comprise 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 thereof and / or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein.

[0423] In various embodiments, provided herein are methods of treating NASH 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 thereof and / or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein.

[0424] In various embodiments, provided herein are methods for 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 thereof and / or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein.

[0425] 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 thereof and / or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein.

[0426] In various embodiments, provided herein are methods for treating chronic kidney disease 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 thereof and / or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein.

[0427] In various embodiments, provided herein are methods for treating an autoimmune disease 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 thereof and / or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein.

[0428] In various embodiments, provided herein are methods for treating cancer (e.g., liver cancer) in a subject in need thereof, which generally comprise administering to the subject a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula (I), (Ia), (Ib), or (II)), or a stereoisomer thereof and / or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein.

[0429] In certain embodiments, in order to prolong the effect of the drug, the compound described herein (e.g., a compound of Formula (I), Formula (la), Formula (lb), 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 oily vehicle.

[0430] In certain embodiments, the actual dosage level of the compounds described herein (e.g., compounds of Formula (I), (Ia), (Ib), or (II)), or stereoisomers and / or pharmaceutically acceptable salts thereof, in the pharmaceutical compositions of the present disclosure may be varied to obtain an amount of the compound (e.g., a compound of Formula (I), (Ia), (Ib), or (II)), or stereoisomers and / or pharmaceutically acceptable salts thereof, that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.

[0431] In certain embodiments, the selected dosage level will depend upon a variety of factors including the route of administration, the time of administration, the rate of excretion or metabolism of the particular compound being employed, the rate and extent of absorption, the duration of the treatment, other drugs, compounds and / or materials used in combination with the particular compound being employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.

[0432] 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.

[0433] In certain embodiments, a suitable daily dose of a compound described herein (e.g., a compound of Formula (I)-(II)), or a stereoisomer and / or pharmaceutically acceptable salt thereof) will be that amount that corresponds to the minimum effective dose that produces a therapeutic effect. In certain embodiments, when a compound described herein (e.g., a compound of Formula (I)-(II)), or a stereoisomer and / or pharmaceutically acceptable salt thereof) is co-administered with another therapeutic agent, the effective amount may be less than the effective amount when the compound (e.g., a compound of Formula (I)-(Ia)-(Ib) or (II)), or a stereoisomer and / or pharmaceutically acceptable salt thereof, is used alone.

[0434] In certain embodiments, the effective daily dose of a compound described herein (e.g., a compound of Formula (I), (Ia), (Ib), or (II)), or a stereoisomer and / or pharmaceutically acceptable salt thereof, can be administered in two, three, four, five, six, or more sub-doses. In certain embodiments, two, three, four, five, six, or more sub-doses 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), (Ia), (Ib), or (II)), or a stereoisomer and / or pharmaceutically acceptable salt thereof, is administered to a patient for 1 day, 5 days, 10 days, 20 days, 30 days, 1 week, 2 weeks, 3 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 1 year, 2 years, 3 years, 4 years, or 5 years. In some embodiments, a compound described herein (e.g., a compound of Formula (I), Formula (la), Formula (lb), or Formula (II)), or a stereoisomer and / or pharmaceutically acceptable salt thereof, is administered to a patient for the patient's lifetime.

[0435] Combination therapy

[0436] In various embodiments, the compounds disclosed herein (e.g., compounds of Formula (I), (Ia), (Ib), or (II)), or stereoisomers and / or pharmaceutically acceptable salts thereof, including pharmaceutical compositions 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), (Ia), (Ib), or (II)), or stereoisomers and / or pharmaceutically acceptable salts 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), (Ia), (Ib), or (II)), or stereoisomers and / or pharmaceutically acceptable salts thereof; and a second therapeutic agent.

[0437] In some embodiments, the second therapeutic agent is selected from lovastatin, a thiazolidinedione or fibrate, a bile acid binding resin, niacin, an anti-obesity drug, a hormone, an antiviral agent (e.g., for treating an underlying hepatitis C infection that causes the patient's liver disease), an anti-cancer agent (e.g., for treating hepatocellular carcinoma or other cancers that cause liver disease or fatty liver disease), an antioxidant, a drug that reduces insulin resistance or a drug that improves lipid metabolism (e.g., to treat hyperlipidemia), a tyrophostine inhibitor, a sulfonylurea drug, a biguanide, an α-glucosidase inhibitor, an apolipoprotein AI agonist, apolipoprotein E, a cardiovascular drug, a drug that raises HDL, an HDL enhancer, or a regulator of apolipoprotein AI, apolipoprotein A-IV, and / or apolipoprotein genes.

[0438] In various embodiments, the second therapeutic agent can be bepedoic acid, a statin, and / or ezetimibe.

[0439] In certain embodiments, the second therapeutic agent is bepedic 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.

[0440] In certain embodiments, administration of a pharmaceutical composition of the present disclosure comprising a compound described herein (e.g., a compound of Formula (I)-(C), (Ia)-(Ib)-(II)), or a stereoisomer thereof and / or a pharmaceutically acceptable salt thereof, and a second therapeutic agent is intended to provide a beneficial effect resulting from the combined action of the compound (e.g., a compound of Formula (I)-(C), (Ia)-(Ib)-(II)), or a stereoisomer thereof and / or a pharmaceutically acceptable salt thereof, and a second therapeutic agent. In some embodiments, the beneficial effect of the combination therapy may include a pharmacokinetic or pharmacodynamic co-action resulting from the combination of the compound (e.g., a compound of Formula (I)-(C), (Ia)-(Ib)-(II)), or a stereoisomer thereof and / or a pharmaceutically acceptable salt thereof, and a second therapeutic agent.

[0441] Reagent test kit

[0442] 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 a condition, disease, or disorder, e.g., as described herein, and ii) a compound described herein (e.g., a compound of Formula (I), (Ia), (Ib), or (II)) or a stereoisomer thereof and / or a pharmaceutically acceptable salt thereof (e.g., a pharmaceutical composition comprising an effective amount of a compound described herein (e.g., a compound of Formula (I), (Ia), (Ib), or (II)) or a stereoisomer thereof and / or a 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), (Ia), (Ib), or (II)) or a stereoisomer thereof and / or a pharmaceutically acceptable salt thereof, effective to treat a condition, disease, or disorder.

[0443] The description herein includes various aspects and embodiments of the present disclosure, including methods of making the compounds described herein (e.g., compounds of Formula (I)-(II)), or stereoisomers and / or pharmaceutically acceptable salts thereof; methods of using the compounds described herein (e.g., compounds of Formula (I)-(Ia)-(Ib) or (II)), or stereoisomers and / or pharmaceutically acceptable salts thereof; compositions comprising an effective amount of a compound described herein (e.g., a compound of Formula (I)-(Ia)-(Ib) or (II)), or stereoisomers and / or pharmaceutically acceptable salts thereof; and kits. The present disclosure specifically includes all combinations and permutations of the aspects and embodiments described herein. Example

[0444] The representative examples that follow are intended to help illustrate the present disclosure and are not intended to, nor should they be interpreted as, limiting the scope of the present disclosure.

[0445] The following general methods and procedures can be used to prepare the compounds provided herein from readily available starting materials. It should be understood that when typical or preferred process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.) are given, other process conditions may also be used, unless otherwise stated. Optimum reaction conditions may vary with the specific reactants or solvents used, but those skilled in the art can determine such conditions by conventional optimization.

[0446] In addition, as will be clear to those skilled in the art, conventional blocking groups may be necessary to prevent undesirable reactions in certain functional groups. It is well known in the art to select suitable blocking groups and suitable conditions for protection and deprotection for specific functional groups. For example, Protecting Groups in Organic Synthesis 2nd edition, TW Greene and PGM Wuts, Wiley, New York, 1991, and the references cited therein, have described many blocking groups and their introduction and removal.

[0447] The compounds provided herein can be separated and purified by known standard procedures. Such procedures include recrystallization, filtration, flash chromatography, grinding, high pressure liquid chromatography (HPLC) or supercritical fluid chromatography (SFC). Note that flash chromatography can be performed manually or by 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.

[0448] Analytical methods

[0449] Method A: Reversed-phase ultra-high-performance liquid chromatography-mass spectrometry (UHPLC-MS) was performed using a Phenomenex Kinetex-XB C18 column (2.1 mm × 100 mm, 1.7 μm; temperature: 40°C). The injection volume was 1 μL, the flow rate was 0.6 mL / min, and the gradient was 5–100% B over 5.30 minutes, followed by 100% B over 0.50 minutes, where A = 0.1% formic acid in water and B = 0.1% formic acid in acetonitrile. A second gradient of 100–5% B was then applied over 0.02 minutes and held for 1.18 minutes. UV spectra were recorded at 215 nm; the spectral range was 200–400 nm. Where reported, ELS data were collected on a Waters ELS detector. Mass spectra were acquired using a Waters SQD, SQD2, or QDA detector; ionization mode: positive or negative electrospray. Data were integrated and reported using Waters MassLynx and OpenLynx software.

[0450] Method B: UHPLC-MS performed in a reversed-phase system using UPLC TM BEH TM A C18 column (2.1 mm × 50 mm, 1.7 μm; temperature: 40°C) was used with an injection volume of 1 μL and a flow rate of 0.9 mL / min. The gradient was 5–100% B over 1.10 minutes, followed by 100% B over 0.25 minutes, where A = 0.1% formic acid in water and B = 0.1% formic acid in acetonitrile. A second gradient of 100–5% B over 0.05 minutes was then applied and held for 0.10 minutes. UV spectra were recorded at 215 nm; spectral range: 200–400 nm. Mass spectra were acquired using Waters SQD, SQD2, or QDA detectors; ionization modes: positive or negative electrospray. Data were integrated and reported using Waters MassLynx and OpenLynx software.

[0451] Method C: Using Waters UPLC™ CORTECS TMUHPLC-MS was performed in reverse phase on a C8 column (2.1 mm × 100 mm, 1.6 μm; temperature: 40°C) with a 1 μL injection volume and a flow rate of 0.6 mL / min. The gradient was 5–100% B over 5.30 minutes, followed by 100% B over 0.50 minutes, where A = 0.1% formic acid in water and B = 0.1% formic acid in acetonitrile. A second gradient of 100–5% B was then applied over 0.02 minutes and held for 1.18 minutes. UV spectra were recorded at 215 nm; the spectral range was 200–400 nm. ELS data were collected using a Waters ELS detector, where reported. Mass spectra were acquired using a Waters SQD, QD2, or QDA; ionization modes were electrospray positive or negative. Data were integrated and reported using Waters MassLynx and OpenLynx software.

[0452] Preparative HPLC method

[0453] Method P1: Using Waters Sunfire TM Reverse-phase liquid chromatography (LC) was performed on a C18 column (30 mm × 100 mm, 5 μm; room temperature) with an injection volume of 1500 μL at a flow rate of 40 mL / min. 30% B was applied over 1.90 minutes, followed by a gradient of 30–95% B over 9.60 minutes and held for 1.97 minutes, where A = 0.1% formic acid in water and B = 0.1% formic acid in acetonitrile. A second gradient of 95–30% B was then applied over 0.33 minutes and held for 1.65 minutes. UV spectra were recorded at 215 nm.

[0454] Method P2: Using Waters Sunfire TM Reverse-phase LC was performed on a C18 column (30 mm × 100 mm, 5 μm; room temperature) with an injection volume of 1500 μL at a flow rate of 40 mL / min. A gradient of 10% B was applied over 1.90 minutes, followed by a gradient of 10–95% B over 14.10 minutes and a hold of 2.0 minutes, where A = 0.1% formic acid in water and B = 0.1% formic acid in acetonitrile. A second gradient of 95–10% B was then applied over 0.20 minutes and held for an additional 1.25 minutes. UV spectra were recorded at 215 nm.

[0455] Method P3: Using Waters XBridge TMReverse-phase liquid chromatography was performed on a C18 column (30 mm × 100 mm, 5 μm; room temperature) with a 1500 μL injection volume and a flow rate of 40 mL / min. A gradient of 10% B over 2.00 minutes, followed by a 10–95% B gradient over 14.00 minutes and a 2.00-minute hold, was applied. A = 0.2% ammonium hydroxide in water; B = 0.2% ammonium hydroxide in acetonitrile. A second gradient of 95–10% B over 0.20 minutes was then applied and held for 1.25 minutes. UV spectra were recorded at 215 nm.

[0456] abbreviation

[0457] Aq. Aqueous / aqueous solution

[0458] Boc tert-butylcarbamoyl

[0459] Boc2O Di-tert-butyl dicarbonate

[0460] CDCl3 deuterated chloroform

[0461] CHCl3 chloroform

[0462] CO2 carbon dioxide

[0463] CV column volume

[0464] DAST Diethylaminosulfur trifluoride

[0465] DCC N,N′-dicyclohexylcarbodiimide

[0466] DCE dichloroethane

[0467] DCM dichloromethane

[0468] DIAD Diisopropyl azodicarboxylate

[0469] DIBAL Diisobutylaluminum hydride

[0470] DIPEA N,N-Diisopropylethylamine

[0471] DMAP 4-(dimethylamino)pyridine

[0472] DMF N,N-dimethylformamide

[0473] DMSO dimethyl sulfoxide

[0474] dppf 1,1'-bis(diphenylphosphino)ferrocene

[0475] ESI electrospray ionization

[0476] Et2O ether

[0477] EtOH

[0478] EtOAc

[0479] FCC flash column chromatography

[0480] HCl Hydrogen chloride

[0481] H2O water

[0482] HPLC high-performance liquid chromatography

[0483] IPA Isopropyl alcohol

[0484] K2CO3 potassium carbonate

[0485] LCMS liquid chromatography-mass spectrometry

[0486] LiAlH4 lithium aluminum hydride

[0487] LiHMDS lithium bis(trimethylsilyl)amide

[0488] M Moore

[0489] mCPBA m-Chloroperbenzoic acid

[0490] MeCN Acetonitrile

[0491] MeOH methanol

[0492] MgSO4 magnesium sulfate

[0493] MnO2 Manganese(IV) oxide

[0494] NaHCO3 sodium bicarbonate

[0495] Na2SO4 sodium sulfate

[0496] Na2S2O3 sodium thiosulfate

[0497] NH3 ammonia

[0498] NH4Cl ammonium chloride

[0499] NMR nuclear magnetic resonance

[0500] Pd2(dba)3 tris(dibenzylideneacetone)dipalladium(0)

[0501] Pd(dppf)Cl2 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)

[0502] RT retention time

[0503] rt room temperature

[0504] sat. .saturated

[0505] SCX Strong Cation Exchange Column (Benzenesulfonic Acid-Functionalized Silica)

[0506] SFC Supercritical Fluid Chromatography

[0507] SiO2 silicon dioxide (FCC silica gel)

[0508] T3P Propylphosphonic Anhydride

[0509] TBAF Tetrabutylammonium fluoride

[0510] TBME tert-butyl methyl ether

[0511] TBS tert-Butyldimethylsilyl

[0512] THF Tetrahydrofuran

[0513] UV

[0514] wt% weight percentage

[0515] In some embodiments, compounds of the present disclosure can be synthesized using the procedures outlined in General Scheme 1:

[0516] General Solution 1

[0517]

[0518] In general scheme 1, starting material A is reacted with alcohol starting material B containing R1' and R2', for example, using Mitsunobu reaction conditions (e.g., PPh3, DIAD, THF, 30-40°C).

[0519] C, 1-3 hours) to obtain intermediate D, wherein X is oxygen. In some embodiments, R1' and R2' are selected from hydrogen and lower alkyl, such as methyl. In some embodiments, m is 1-3.

[0520] Alternatively, the amine starting material C is protected by amine protection using Boc protection conditions (e.g., Boc2O, NaHCO3 (aqueous solution), THF, room temperature, 1 hour) to obtain intermediate D, wherein R1' and R2' are both hydrogen, X is CH2, and m is 0-1. Alternatively, the starting material C is protected by amine protection using Boc protection conditions (e.g., Boc2O, NaHCO3 (aqueous solution), THF, room temperature, 1 hour), and then the carbamate nitrogen is methylated using alkylation conditions (e.g., NaH, MeI, DMF, 1 hour) to obtain intermediate D, wherein R1' is methyl, R2' is hydrogen, X is CH2, and m is 0-1.

[0521] Intermediate D is reacted with a pinacol boronate intermediate E containing R3' using palladium-catalyzed cross-coupling conditions (e.g., Pd(dppf)Cl2, K2CO3, dioxane / water, 100°C, about 18 hours) to provide intermediate F. In some embodiments, R3' is selected from H or lower alkyl, such as methyl. Intermediate F is reacted with a sulfonyl chloride intermediate G containing R4' under basic conditions (e.g., pyridine, 50°C, 1-2.5 hours) to provide intermediate H. In some embodiments, R4' is selected from lower alkyl (e.g., methyl) or haloalkyl (e.g., -CHF2). Intermediate H is subjected to ester hydrolysis under basic conditions (e.g., NaOH (aq), THF, or THF / MeOH, room temperature, 2-18 hours) to provide intermediate I. Intermediate I is subjected to Boc deprotection under acidic conditions (4M HCl in dioxane, room temperature, 1-2.5 hours) to provide intermediate J. Intermediate J is then cyclized using amide coupling conditions (e.g., T3P, DIPEA, DMF, room temperature, about 0.5-1 hour) to provide product K. Optionally, when R4' is methyl, intermediate K is ether cleaved using (e.g., 1M BBr3 in DCM, DMF, 80°C, typically 18-24 hours or 1M BBr3 in DCM, room temperature, typically for 18 hours) to provide the final product L.

[0522] In some embodiments, the disclosed compounds can be synthesized using the procedure outlined in General Scheme 2:

[0523] General Solution 2

[0524]

[0525] In General Scheme 2, starting material A reacts 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 hydroxy or Br; and m is 1-2. When Q is hydroxy, starting material A reacts with starting material B under Mitsunobu reaction conditions (e.g., PPh3, DIAD, THF, 40°C, 1-3 hours) to produce intermediate D. When Q is Br, starting material A reacts with starting material B under alkylation conditions (e.g., base (K2CO3), acetonitrile, ~70°C, ~18 hours) to produce intermediate D. Alternatively, alcohol starting material C (where m is 0-1) is protected as an alcohol under silyl ether protection conditions (e.g., TBS-Cl, imidazole, DMF, RT, 4 hours) to produce intermediate D, where X is CH2.

[0526] Intermediate D reacts with a pinacol boronate intermediate E containing R2' and R3' under 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 a sulfonyl chloride intermediate G under basic conditions (e.g., pyridine, 50°C, 1-2.5 hours) to produce Intermediate H. Intermediate H undergoes ester hydrolysis under basic conditions (e.g., NaOH (aq.), THF, room temperature, 4 hours) to produce Intermediate I. Intermediate I is protected with a silyl ether using a fluoride source (e.g., TBAF, THF, room temperature, 18-72 hours) to produce Intermediate J. Intermediate J is then cyclized using ester coupling conditions, such as Yamaguchi esterification conditions (e.g., 2,4,6-trichlorobenzoyl chloride, DIPEA, DMAP, room temperature for 1 hour, then at 65°C for 3-18 hours. Purified by acidic reverse phase preparative HPLC) to give intermediate K. Finally, intermediate K is cyclized using, for example, 1M BBr3 in DCM, DMF, 80°C.

[0527] C, ether cleavage was performed for 20 hours to obtain the final product L.

[0528] In some embodiments, compounds of the present disclosure can be synthesized using the procedure outlined in General Scheme 3:

[0529] General Solution 3

[0530]

[0531] In general scheme 3, starting material A reacts with pinacol boronate intermediate B under palladium-catalyzed cross-coupling conditions (e.g., Pd(dppf)Cl2, base (K2CO3), dioxane, 100°C, 18 hours) to provide intermediate C. Intermediate C reacts with sulfonyl chloride intermediate D under basic conditions (e.g., pyridine, 50°C, 1 hour) to provide intermediate E. Intermediate E undergoes ester hydrolysis under basic conditions (e.g., NaOH (aq), THF, room temperature, 3 hours) to provide intermediate F. Intermediate F undergoes cyclization under ester coupling conditions (e.g., DCC, DMAP, DCM, room temperature, 24 hours) to provide intermediate G. Finally, intermediate G undergoes ether cleavage (using, for example, iodocyclohexane, anhydrous DMF, 120°C, 1-3 hours; or lithium iodide, anhydrous pyridine, 80°C, 6-18 hours) to provide the final product H.

[0532] Intermediate A may have additional substitutions or may incorporate heteroatoms into the aromatic ring.

[0533] Intermediate B may have different or additional substitutions and may incorporate heteroatoms in the aromatic ring.

[0534] Example 1 - Synthesis of 15-chloro-21,23-difluoro-16-methoxy-8-oxa-18λ6-thia-11,19-diazatetracyclo[18.3.1.1 13,17 .0 2,7 ]pentadecan-1(24),2,4,6,13,15,17(25),20,22-nonaene-12,18,18-trione (Compound 1)

[0535]

[0536] To a solution of DIPEA (0.13mL, 0.740mmol) and T3P in EtOAc (50mL) (50wt%, 0.44mL, 0.740mmol) was added a solution of intermediate 6 (253mg, 0.493mmol) in DMF-anhydrous (50mL) over 1.5 hours. The colorless solution was stirred at room temperature for 23 hours. T3P in EtOAc (50wt%, 0.44mL, 0.740mmol) and DIPEA (0.13mL, 0.740mmol) were added to the reaction mixture and the reaction mixture was stirred at room temperature for 2.5 hours. The reaction mixture was diluted with H2O (200mL) and extracted with EtOAc (4x 200mL). The combined organic extracts were washed with brine (4x 200mL), dried over MgSO4, filtered and concentrated in vacuo to give a yellow residue (530mg). The residue was triturated and sonicated with DCM / MeOH and the resulting white suspension was collected by suction filtration.The filter cake was washed with DCM and then dried in vacuo to afford the title compound as a white solid (180 mg, 72% yield, 98% purity).

[0537] 1 H NMR (400MHz, DMSO) δ10.39 (s, 1H), 8.16–8.07 (m, 1H), 8.01 (d, J = 1.7Hz, 1H), 7.52 (d, J = 2.1Hz, 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=5.0Hz, 2H), 3.99 (s, 3H), 3.53–3.44 (m, 2H).

[0538] 19F 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

[0539] Example 2 - Synthesis of 15-chloro-21,23-difluoro-16-hydroxy-8-oxa-18λ6-thia-11,19-diazatetracyclo[18.3.1.1 13,17 .0 2,7 ]Twenty-penta-1(24),2,4,6,13,15,17(25),20,22-nonaene-12,18,18-trione (Compound 2)

[0540]

[0541] To the suspension of compound 1 (140mg, 0.283mmol) in DCM-anhydrous (2.0mL) and toluene-anhydrous (2.0mL) was added dropwise 1M BBr DCM solution (0.85mL, 0.849mmol) at 0°C. The gained white suspension was heated at 60°C for 22 hours. The reaction mixture was cooled to room temperature, transferred to a larger bottle and diluted with anhydrous DCM (6mL) and anhydrous toluene (6mL). 1M BBr was added dropwise to the reaction mixture in DCM (0.85mL, 0.849mmol) and the reaction mixture was heated at 70°C for 0.5 hours, then at 80°C for 6 hours. The reaction mixture was cooled to room temperature, then slowly added to NaHCO saturated aqueous solution at 0°C. The separation layer and the organic matter were washed with salt water, dried with MgSO, filtered and concentrated in vacuo. Purification by FCC (10 g SiO2 column, 0-20% MeOH in DCM) afforded the title compound as an off-white solid (76 mg, 54% yield, 96% purity).

[0542] 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–

[0543] 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 not observed.

[0544] 19F NMR (376MHz, DMSO-d6) δ-109.64, -120.02.

[0545] LCMS: m / z=480.9 / 482.9 [M+H]+, (ESI+), RT=3.22, Method A

[0546] Example 3 - Synthesis of 11-chloro-3,5-difluoro-10-hydroxy-18-oxa-8λ6-thia-7,15-

[0547] Diazatetracyclic [17.3.1.1 2,6 .1 9,13 ]Twenty-penta-1(22),2(25),3,5,9(24),10,12,19(23),20-nonaene-8,8,14-trione (Compound 3)

[0548]

[0549] 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]pentacos-1(22),2(25),3,5,9(24),10,12,19(23),20-nonen-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) was added 1 M BBr3 in DCM (0.19 mL, 0.190 mmol) dropwise at room temperature. The resulting solution was heated at 80°C for 18 hours and then cooled to room temperature. To the reaction mixture was added 1M BBr solution (0.76mL, 0.760mmol) in DCM and the reaction mixture was heated at 80°C for 5 hours, which was then cooled to room temperature. The reaction mixture was slowly added to NaHCO saturated aqueous solution. The mixture was diluted with water and 1:3IPA / CHCl. ​​Separating layer and aqueous layer were extracted with 1:3IPA / CHCl. ​​Organic matter was combined and passed through a hydrophobic glassware. Purified by FCC (10g SiO , 0-30% MeOH in DCM), then ground with MeCN to obtain the title compound, which was a pale solid (47mg, 98% purity).

[0550] 1H NMR (500 MHz, DMSO) δ 8.72 (broad s, 1H), 8.36 (app s, 1H), 7.80 (app 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 (app s, 1H), 4.19–4.01 (m, 2H), 3.62–3.46 (m, 2H). 2H not observed.

[0551] LCMS: m / z=481.2 / 483.2 [M+H]+, (ESI+), RT=2.98, Method A

[0552] Example 4 - Synthesis of 15-chloro-21,23-difluoro-16-hydroxy-11-methyl-8-oxa-18λ6-thia-11,19-diazatetracyclo[18.3.1.1 13,17 .0 2,7 ]Twenty-penta-1(24),2,4,6,13,15,17(25),20,22-nonaene-12,18,18-trione (Compound 4)

[0553]

[0554] 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]pentacos-1(24),2,4,6,13,15,17(25),20,22-nonen-12-one (synthesized according to general scheme 1, 92%, 250 mg, 0.452 mmol) in DCE-anhydrous (6.0 mL) and DMF-anhydrous (3.0 mL) at 0° C. was added 1M BBr in DCM (2.0 mL, 2.0 mmol) dropwise. The resulting light yellow suspension was heated at 80° C. for 5 hours. The reaction mixture was cooled to 0° C. and additional 1M BBr in DCM (2.0 mL, 2.0 mmol) was added. In 4-nitro- 4- pyridine-2-yl 4- pyridine-2-yl 4- pyridine-3 ...

[0555] 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–

[0556] 7.05 (m, 1H), 4.12-3.93 (m, 2H), 2.90 (broad s, 3H). 2H not observed LCMS: m / z = 495.2 / 497.2 [M+H]+, (ESI+), RT = 3.11, Method A

[0557] Example 5 - Synthesis of 11-chloro-3,5-difluoro-10-hydroxy-19-oxa-8λ6-thia-7,15-

[0558] Diazatetracyclic [18.3.1.1 2,6 .1 9,13]Hexadecan-1(23),2(26),3,5,9(25),10,12,20(24),21-nonaene-8,8,14-trione (Compound 5)

[0559]

[0560] 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]hexaconazole-1(23),2(26),3,5,9(25),10,12,20(24),21-nonen-14-one (synthesized according to general scheme 1, 90%, 200 mg, 0.354 mmol) in anhydrous DMF (4.0 mL) at room temperature was added 1M BBr3 in DCM (0.71 mL, 0.710 mmol). The reaction mixture was heated at 80°C for 6 hours 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 hours. The reaction mixture is cooled to room temperature, then slowly added to NaHCO saturated aqueous solution. The mixture is extracted with DCM (3x) and the organic matter merged is passed through a hydrophobic glass. Residue is purified by preparative HPLC (method P2) to obtain title compound, is off-white solid (93mg, 53% yield, 100% purity).

[0561] 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 not observed

[0562] LCMS: m / z=495.0 / 496.9 [M+H]+, (ESI+), RT=3.24, Method A

[0563] Example 6 - Synthesis of 16-chloro-22,24-difluoro-17-hydroxy-8-oxa-19λ6-thia-12,20-diazatetracyclic [19.3.1.1 14,18 .0 2,7]Hexadecan-1(25),2,4,6,14,16,18(26),21,23-nonaene-13,19,19-trione (Compound 6)

[0564]

[0565] 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]twenty-sixa-1(25),2,4,6,14,16,18(26),21,23-nonen-13-one (synthesized according to General Scheme 1, 93%, 140 mg, 0.256 mmol) in anhydrous DMF (3.8 mL) was added 1MBBr in DCM (1.00 mL, 1.00 mmol) at room temperature. The resulting solution was heated at 80° C. for 18 hours and then cooled to room temperature. The reaction mixture was slowly added to a saturated aqueous solution of NaHCO and the mixture was extracted with DCM (3x). 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).

[0566] 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). 5H not observed

[0567] LCMS: m / z=495.2 / 497.2 [M+H]+, (ESI+), RT=3.36, Method A

[0568] Example 7 - Synthesis of 15-chloro-21,23-difluoro-16-hydroxy-8,11-dioxa-18λ6-thia-19-azatetracyclic [18.3.1.1 13,17 .0 2,7 ]Twenty-penta-1(24),2,4,6,13,15,17(25),20,22-nonaene-12,18,18-trione (Compound 7)

[0569]

[0570] To the suspension of intermediate 12 (98%, 60mg, 0.119mmol) in DMF-anhydrous (3.0mL) at 0 DEG C, 1M BBr was added dropwise DCM (2.0mL, 2.0mmol) solution. The gained light yellow solution was heated at 80 DEG C for 20 hours and then cooled to room temperature. The reaction mixture was added into NaHCO saturated aqueous solution (30mL) and DCM (2x 20mL) for water layer. Organic matter was merged, washed with salt water (50mL), used Na SO Drying, filtered and concentrated in vacuo. Purification (method P1) was performed using preparative HPLC to obtain the title compound as a white solid (42mg, 74% yield, 100% purity).

[0571] 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 not observed.

[0572] LCMS: m / z=480.2 / 482.2 [MH]-, (ESI-), RT=3.79, Method A

[0573] Example 8 - Synthesis of 15-chloro-21,23-difluoro-16-hydroxy-18λ6-thia-11,19-diazatetracyclic [18.3.1.1 13,17 .0 2,7 ]Twenty-penta-1(24),2,4,6,13,15,17(25),20,22-nonaene-12,18,18-trione (Compound 8)

[0574]

[0575] 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 BBr3 in DCM (1.1 mL, 1.10 mmol) at room temperature. The reaction mixture was heated at 80°C for 4 hours and then cooled to room temperature. To the reaction mixture was added 1 M BBr3 in DCM (1.1 mL, 1.10 mmol) and the reaction mixture was heated at 80°C for 16 hours and then cooled to room temperature. The reaction mixture was added to H2O (40 mL). The aqueous solution is extracted with DCM (3x 30mL) and the organic matter merged is passed through hydrophobic glassware and vacuum concentration.Purification (10g SiO , 0-30% MeOH in DCM) is carried out by FCC.The fraction comprising product is combined and vacuum concentration and gained solid are purified by preparative HPLC (method P1) to obtain title compound, it is white solid (55mg, 41% productive rate, 98% purity).

[0576] 1 H NMR (400MHz, DMSO) δ11.07–9.88 (m, 2H), 8.30–8.18 (m, 1H), 7.88 (d, J=2.1Hz, 1H), 7.60 (d, J=2.3Hz, 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).

[0577] LCMS: m / z=479.0 / 480.8 [M+H]+, (ESI+), RT=3.34, Method A

[0578] Example 9 - Synthesis of 15-chloro-21,23-difluoro-16-hydroxy-19-methyl-8-oxa-18λ6-thia-11,19-diazatetracyclo[18.3.1.1 13,17 .0 2,7 ]Twenty-penta-1(24),2,4,6,13,15,17(25),20,22-nonaene-12,18,18-trione (Compound 9)

[0579]

[0580] 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]twenty-five-1(24),2,4,6,13,15,17(25),20,22-nonen-12-one (synthesized according to General Scheme 1, 80%, 200 mg, 0.314 mmol) in anhydrous DMF (5.0 mL) was added dropwise 1M BBr3 in DCM (3.0 mL, 3.00 mmol) at 0°C. The resulting solution was heated at 80°C for 20 hours and then cooled to room temperature. The reaction mixture was added to a saturated aqueous solution of NaHCO3 (30 mL) at 0°C. The organics were extracted with DCM (2 x 20 mL). The organics were combined, washed with brine (50 mL), dried over Na2SO4, filtered and concentrated in vacuo. Purification by preparative HPLC (Method P1) gave the title compound as a white solid (66 mg, 40% yield, 95% purity).

[0581] 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).

[0582] LCMS: m / z=495.2 / 497.2 [M+H]+, (ESI+), RT=3.60, Method A

[0583] Example 10 - Synthesis of 15-chloro-21,23-difluoro-16-hydroxy-11-methyl-18λ6-thia-11,19-diazatetracyclo[18.3.1.1 13,17 .0 2,7 ]Twenty-penta-1(24),2,4,6,13,15,17(25),20,22-nonaene-12,18,18-trione (Compound 10)

[0584]

[0585] 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]pentacosyl-1(24),2,4,6,13,15,17(25),20,22-nonen-12-one (synthesized according to general scheme 1, 91%, 153 mg, 0.275 mmol) in anhydrous DMF (4.0 mL) was added 1M BBr in DCM (1.1 mL, 1.10 mmol) at room temperature. The reaction mixture was heated at 80° C. for 18 hours and then cooled to room temperature. The reaction mixture was added to H 2 O (40 mL) and the organics were extracted with DCM (3 x 30 mL), combined and passed through a hydrophobic glassware. Purification by preparative HPLC (Method P1 ) gave the title compound as a white solid (78 mg, 56% yield, 97% purity).

[0586] 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).

[0587] LCMS: m / z=493.2 / 495.3 [M+H]+, (ESI+), RT=3.17, Method A

[0588] Example 11 - Synthesis of 24-fluoro-16-hydroxy-8-oxa-11,19-diazapentacyclic [17.5.2.1 13,17 .0 2, 7 .0 22,26 ]Heptadecan-1(24),2,4,6,13,15,17(27),22,25-nonaene-12,18-dione (Compound 11)

[0589]

[0590] Step 1

[0591] A mixture of intermediate 2 (92%, 500 mg, 1.45 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis-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 bubbled with nitrogen for 20 minutes, then Pd(dppf)Cl2 (107 mg, 0.145 mmol) was added and the solution was bubbled for another 5 minutes. The reaction mixture was heated at 100 ° C for a total of about 20 minutes. The mixture was then filtered through diatomaceous earth and washed with EtOAc. Water was added to the filtrate, and the layers were separated. The aqueous phase was extracted with EtOAc. The combined organics were washed with water and then with brine, dried (Na2SO4), filtered and concentrated. The residue was purified by FCC (50 g SiO column, 0-100% EtOAc 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 light yellow oil.

[0592] 1 H NMR (500MHz, DMSO) δ7.52 (dd, J=7.3, 1.8Hz, 1H), 7.43 (ddd, J=8.2, 7.3, 1.8Hz, 1H), 6.99–6.91 (m , 2H), 6.49 (t, J=5.6Hz, 1H), 3.98 (t, J=5.6Hz, 2H), 3.39–3.34 (m, 2H), 1.40 (s, 9H), 1.31 (s, 12H).

[0593] Step 2

[0594] 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-fluoro-indoline (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 bubbled with nitrogen for 5 minutes. Pd(dppf)Cl2 (61 mg, 0.0833 mmol) was then added and the reaction mixture was bubbled for another 5 minutes. The container was sealed and the reaction mixture was heated at 100 ° C overnight. The mixture was filtered through celite, washed with EtOAc and the filtrate was concentrated under reduced pressure. The residue was purified by FCC (25 g SiO2 column, 0-100% EtOAc 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.

[0595] 1 H NMR (400MHz, DMSO) δ7.32 (ddd, J=8.3, 7.3, 1.8Hz, 1H), 7.20–7.15 (m, 1H), 7.08 (d d, J=8.4, 1.1Hz, 1H), 6.99 (td, J=7.4, 1.0Hz, 1H), 6.89 (d, J=9.7Hz, 1H), 6.71 (t, J =5.5Hz, 1H), 6.38 (d, J = 6.1Hz, 1H), 5.31 (d, J = 2.3Hz, 1H), 3.97–3.89 (m, 2H), 3.43 (td, J=8.5, 2.2Hz, 2H), 3.17 (q, J=6.3Hz, 2H), 2.93 (t, J=8.4Hz, 2H), 1.37 (s, 9H).

[0596] LCMS: m / z=373.1 [M+H]+, (ESI+), RT=0.74, Method B

[0597] Step 3

[0598] To 2-methoxy-5-methoxycarbonyl-benzoic acid (96%, 94mg, 0.429mmol), N-[2-[2-(5-fluoroindoline-6-yl)phenoxy]ethyl]t-butyl carbamate (74%, 180mg, 0.358mmol) and DIPEA (249 μ L, 1.43mmol) in anhydrous DMF (6.3mL) solution, add T3P (50% in EtOAc) (0.64mL, 1.07mmol).The mixture is stirred at room temperature for 1 hour.The mixture is diluted with water (40ml) and extracted with EtOAc (2x 40mL).The organic water (30mL) and salt solution (30mL) merged are washed, then use MgSO4 dry, filter and vacuum concentrate. The residue was purified by FCC (10 g SiO column, 0-100% EtOAc in heptane) to give methyl 3-[6-[2-[2-(tert-butoxycarbonylamino)ethoxy]phenyl]-5-fluoro-indoline-1-carbonyl]-4-methoxybenzoate (95.0%) (155 mg, 73% yield, 95% purity) as a white solid.

[0599] 1 H NMR (400MHz, DMSO) δ8.09 (d, J=6.7Hz, 1H), 8.06 (dd, J=8.8, 2.2Hz, 1H), 7.89 (d, J=2.3Hz, 1H), 7.43–7.34 (m, 1H), 7.29 (d, J=8.9Hz, 1H), 7.25 (dd, J=7.5, 1.8Hz, 1H), 7.15 (dd, J=11 .7, 8.8Hz, 2H), 7.05 (td, J=7.5, 1.0Hz, 1H), 6.73 (t, J=5.7Hz, 1H), 3.99 (t, J=6.3Hz, 2H), 3.92 (s, 3H), 3.87–3.76 (m, 5H), 3.20 (q, J=6.3Hz, 2H), 3.12 (t, J=8.4Hz, 2H), 1.36 (s, 9H).

[0600] LCMS: m / z=587.3 [M+Na]+, (ESI+), RT=1.05, Method B

[0601] Step 4

[0602] 3-[6-[2-[2-(tert-butoxycarbonylamino)ethoxy]phenyl]-5-fluoro-indoline-1-carbonyl]-4-methoxybenzoic acid methyl ester (95%, 155mg, 0.261mmol) is dissolved in THF (4mL) and 2M sodium hydroxide aqueous solution (1.0mL, 2.00mmol) is added. The reaction mixture is stirred at room temperature for 45 minutes. Then 6M sodium hydroxide aqueous solution (1.0mL, 6.00mmol) is added and the mixture is stirred at room temperature for 2.5 hours. Then MeOH (1.5mL) is added and the mixture is stirred at room temperature for 45 minutes. The mixture is then warmed to 40°C and kept for 3 hours. The mixture is concentrated in vacuo, and the remaining aqueous portion is diluted with water (20mL) and acidified with 1M HCl aqueous solution. The mixture was extracted with DCM (3 x 20 mL) and the combined organics passed through a phase separator then concentrated to give 3-[6-[2-[2-(tert-butoxycarbonylamino)ethoxy]phenyl]-5-fluoro-indoline-1-carbonyl]-4-methoxybenzoic acid (144 mg, 92% yield, 92% purity) as a pale yellow solid.

[0603] LCMS: m / z=549.2 [MH]-, (ESI-), RT=1.05, Method B

[0604] Step 5

[0605] 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 a solution of 4M HCl in dioxane (1.8 mL, 7.23 mmol). The mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in DCM and concentrated (3x) to obtain 3-[6-[2-(2-aminoethoxy)phenyl]-5-fluoro-indoline-1-carbonyl]-4-methoxybenzoic acid HCl (120 mg, 95% yield, 90% purity) as a light yellow solid.

[0606] LCMS: m / z=451.1 [M+H]+, (ESI+), RT=0.66, Method B

[0607] Step 6

[0608] To a solution of T3P (50% in EtOAc) (330 μL, 0.555 mmol) and DIPEA (128 μL, 0.739 mmol) in anhydrous DMF (8 mL) was added dropwise a solution of 3-[6-[2-(2-aminoethoxy)phenyl]-5-fluoro-indoline-1-carbonyl]-4-methoxybenzoic acid HCl (90%, 100 mg, 0.185 mmol) in anhydrous DMF (8 mL) over 5 minutes. The mixture was stirred at room temperature for 30 minutes. The mixture was concentrated in vacuo. The residue was dissolved in EtOAc and water and the layers were separated. The aqueous phase was extracted with additional EtOAc. The combined organic phases were washed with water and brine, then dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by reverse phase FCC (12 g C18 column, 10-100% MeCN (0.1% formic acid) in water (0.1% formic acid)) to give 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-nonaene-12,18-dione (17 mg, 24% yield, 100% purity) as a white solid.

[0609] 1 H NMR (400MHz, DMSO) δ8.06 (s, 1H), 7.91 (d, J=8.7Hz, 1H), 7.65–7.56 (m, 1H), 7.32–7.24 (m, 1H), 7.23–7.15 (m, 2H), 6.98 (d, J=8. 3Hz, 1H), 6.90–6.83 (m, 2H), 5.66 (d, J=6.2Hz, 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).

[0610] LCMS: m / z=433.0 [M+H]+, (ESI+), RT=0.78, Method B

[0611] Step 7

[0612] 24-Fluoro-16-methoxy-8-oxa-11,19-diazapentacyclo[17.5.2.113,17.02,7.022,26]heptadecene-1(24),2,4,6,13,15,17(27),22,25-nonaene-12,18-dione (18 mg, 95% purity) was dissolved in 2,4,6-trimethylpyridine (1.3 mL, 9.71 mmol). Lithium iodide (26 mg, 0.198 mmol) was added to the reaction mixture and the reaction mixture was heated at 80 ° C for 18 hours and then cooled to room temperature. The reaction was acidified by adding 1M HCl aqueous solution. The organic matter was extracted with DCM (3x), combined, passed through a hydrophobic glass and concentrated in vacuo. Purification was performed by acidic reverse phase FCC (6 g C18SiO2, 10-100% acetonitrile (0.1% formic acid) in water (0.1% formic acid)) to give the title compound as an off-white solid (8 mg, 48% yield, 99% purity).

[0613] 1 H NMR (500MHz, DMSO) δ11.07 (width s, 1H), 8.23 ​​(s, 1H), 7.83–7.76 (m, 2H), 7.29 (ddd, J=8.4, 7.1, 2.1Hz, 1H), 7.25 (d, J=8.7Hz, 1H), 6.99 (d .

[0614] LCMS: m / z=419.1 [M+H]+, (ESI+), RT=3.20, Method A

[0615] Example 12 - Synthesis of 21,23-difluoro-16-hydroxy-8-oxa-11,19-diazatetracyclic [18.3.1.1 13, 17 .0 2,7 ]pentadecan-1(23),2,4,6,13,15,17(25),20(24),21-nonaene-12,18-dione (Compound 12)

[0616]

[0617] Step 1

[0618] To a solution of 4-methoxy-3-methoxycarbonyl-benzoic acid (387 mg, 1.84 mmol), 2-(2-bromophenoxy)ethylamine hydrochloride (96%, 440 mg, 1.67 mmol) and DIPEA (1165 μ L, 6.69 mmol) in anhydrous DMF (10 mL) was added T3P (50% in EtOAc) (2.5 mL, 4.18 mmol). The mixture was stirred at room temperature for 1.5 hours. Additional T3P (50% in EtOAc) (1.5 mL, 2.51 mmol) was added and the mixture was stirred at room temperature for 2 hours. The mixture was diluted with H2O (40 mL) and extracted with EtOAc (2 x 40 mL). The combined organic layers were washed with water (30 mL) and brine (30 mL) then dried over MgSO 4 , filtered and concentrated in vacuo to give 5-[2-(2-bromophenoxy)ethylcarbamoyl]-2-methoxybenzoate (565 mg, 71% yield, 86% purity) as a yellow oil.

[0619] 1 H NMR (500MHz, DMSO) δ8.68 (t, J=5.4Hz, 1H), 8.19 (d, J=2.4Hz, 1H), 8.05 (dd, J=8.8, 2.4Hz, 1H), 7.57 (dd, J=7.9, 1.6Hz, 1H), 7.34 (ddd, J=8.2, 7.4, 1.6Hz, 1 H), 7.24 (d, J=8.9Hz, 1H), 7.18 (dd, J=8.3, 1.4Hz, 1H), 6.90 (td, J=7.6, 1.4Hz , 1H), 4.20 (t, J=6.1Hz, 2H), 3.88 (s, 3H), 3.81 (s, 3H), 3.64 (q, J=5.9Hz, 2H). LCMS: m / z=407.9 / 409.9 [M+H]+, (ESI+), RT=0.84, Method B

[0620] Step 2

[0621] To a solution of 5-[2-(2-bromophenoxy)ethylcarbamoyl]-2-methoxybenzoic acid methyl ester (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 bubbled with nitrogen for 5 minutes. Pd(dppf)Cl2 (85 mg, 0.116 mmol) was added and the reaction mixture was bubbled for another 5 minutes. The container 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 EtOAc. The filtrate was concentrated in vacuo. The residue was purified by FCC (25 g SiO2 column, 0-100% EtOAc in heptane) to give methyl 5-[2-[2-(5-amino-2,4-difluoro-phenyl)phenoxy]ethylcarbamoyl]-2-methoxybenzoate (425 mg, 76% yield, 95% purity) as a yellow solid.

[0622] 1 H NMR (400MHz, DMSO) δ8.50 (t, J=5.5Hz, 1H), 8.16 (d, J=2.3Hz, 1H), 8.00 (dd, J=8.8, 2.4Hz , 1H), 7.35 (ddd, J=9.0, 7.4, 1.8Hz, 1H), 7.24 (d, J=8.9Hz, 1H), 7.16 (td, J=7.2, 1.4Hz, 2 H), 7.01 (td, J=7.4, 1.1Hz, 1H), 6.88 (dd, J=11.3, 9.7Hz, 1H), 6.70 (dd, J=10.1, 7.5Hz, 1 H), 4.94 (s, 2H), 4.10 (t, J=6.3Hz, 2H), 3.89 (s, 3H), 3.81 (s, 3H), 3.51 (q, J=6.1Hz, 2H).

[0623] LCMS: m / z=457.1 [M+H]+, (ESI+), RT=0.83, Method B

[0624] Step 3

[0625] To a mixture of 5-[2-[2-(5-amino-2,4-difluoro-phenyl)phenoxy]ethylcarbamoyl]-2-methoxybenzoic acid methyl ester (95%, 200 mg, 0.421 mmol), THF (4.5 mL) and MeOH (1.8 mL) was added 4M aqueous sodium hydroxide solution (0.53 mL, 2.10 mmol) and the mixture was stirred at room temperature for 3.5 hours. THF was removed in vacuo, and the remaining aqueous portion was diluted with water (20 mL) and acidified with 1M HCl aqueous solution. The mixture was extracted with DCM (3 x 20 mL), the combined organic matter was passed through a phase separator, and then concentrated to obtain 5-[2-[2-(5-amino-2,4-difluoro-phenyl)phenoxy]ethylcarbamoyl]-2-methoxybenzoic acid (195 mg, quantitative yield, 100% purity), which was a light yellow solid. LCMS: m / z=443.1 [M+Na]+, (ESI+), RT=0.74, Method B

[0626] Step 4

[0627] To a solution of T3P (50% in EtOAc) (690 μL, 1.16 mmol) and DIPEA (269 μL, 1.55 mmol) in anhydrous DMF (35 mL) was added dropwise 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) over 10 minutes. The mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc and water and the layers were separated. The aqueous solution was extracted with additional EtOAc (3x). The combined organics were washed with 0.5 M aqueous sodium hydroxide solution, then brine, then dried (Na2SO4), filtered and concentrated to give 21,23-difluoro-16-methoxy-8-oxa-11,19-diazatetracyclo[18.3.1.113,17.02,7]pentacos-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.

[0628] LCMS: m / z=425.0 [M+H]+, (ESI+), RT=0.73, Method B

[0629] Step 5

[0630] A suspension of 21,23-difluoro-16-methoxy-8-oxa-11,19-diazatetracyclo[18.3.1.113,17.02,7]pentacosyl-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 hours 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 hours, then at 100° C. for 18 hours, then at 110° C. for 22.5 hours, and then cooled to room temperature. The reaction mixture was acidified with 1M aqueous HCl solution. The organic matter was extracted with DCM (3x), combined, passed through a hydrophobic glassware, and then concentrated in vacuo. Purification was carried out by acidic reverse phase FCC (6g C18SiO2, a solution of 10-100% MeCN (0.1% formic acid) in water (0.1% formic acid)), then lyophilized to obtain the title compound as a brown solid (2mg, 18% yield, 90% purity).

[0631] 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).

[0632] LCMS: m / z=411.0 [M+H]+, (ESI+), RT=2.86, Method A

[0633] Example 13 - Synthesis of 21,23-difluoro-16-hydroxy-8-oxa-11,19-diazatetracyclic [18.3.1.1 13, 17 .0 2,7 ]25-1(23),2,4,6,13,15,17(25),20(24),21-nonen-12-one (Compound 13)

[0634]

[0635] Step 1

[0636] To the solution of 5-bromo-2,4-difluoroaniline (500mg, 2.40mmol) and 4-benzyloxy-3-formyl-benzoic acid methyl ester (780mg, 2.88mmol) in DCE (30mL), acetic acid (688 μ L, 12.0mmol) is added and the mixture is stirred at 85 DEG C for 5 hours.The mixture is cooled to room temperature, STAB (1528mg, 7.21mmol) is added and the mixture is stirred at room temperature for 1 hour.The mixture is diluted with DCM (30mL) and saturated NaHCO aqueous solution (50mL).The mixture is stirred for 20 minutes and separated layer.The aqueous solution is extracted with additional DCM (2x 30mL), and the organic matter then merged is passed through a phase separator and concentrated. The residue was purified by FCC (50 g SiO2 column, 0-100% EtOAc in heptane) to give methyl 4-benzyloxy-3-[(5-bromo-2,4-difluoro-anilino)methyl]benzoate (885 mg, 79% yield, 99% purity) as a white solid.

[0637] 1 H NMR (500MHz, DMSO) δ7.94–7.83 (m, 2H), 7.55–7.49 (m, 2H), 7.44–7.39 (m, 2H), 7.37–7.30 (m, 2H), 7.23 (d, J=8.4H z, 1H), 6.72 (dd, J=9.1, 6.9Hz, 1H), 6.32 (td, J=6.2, 2.1Hz, 1H), 5.30 (s, 2H), 4.35 (d, J=6.2Hz, 2H), 3.77 (s, 3H).

[0638] LCMS: m / z=461.9 / 463.9 [M+H]+, (ESI+), RT=1.19, Method B

[0639] Step 2

[0640] 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, then warmed to 35 ° C and stirred 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% EtOAc 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.

[0641] 1 H NMR (500MHz, DMSO) δ7.52 (d, J=1.8Hz, 1H), 7.44 (ddd, J=8.3, 7.3, 1.9Hz, 1H), 6.99–6.85 (m, 2H ), 6.50 (t, J=5.6Hz, 1H), 3.98 (t, J=5.6Hz, 2H), 3.38–3.34 (m, 2H), 1.40 (s, 9H), 1.31 (s, 12H).

[0642] Step 3

[0643] 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-difluoro-anilino)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 bubbled with nitrogen for 5 minutes. Pd(dppf)Cl2 (48 mg, 0.0649 mmol) was added and the reaction mixture was degassed for another 5 minutes. The vessel was sealed and the reaction mixture was heated at 100 ° C. overnight. The mixture was filtered through celite, washed with EtOAc and the filtrate was concentrated under reduced pressure. The residue was purified by FCC (25 g SiO column, 0-100% EtOAc 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 light yellow oil.

[0644] 1 H NMR (500MHz, DMSO) δ7.96 (d, J=2.3Hz, 1H), 7.84 (dd, J=8.6, 2.3Hz, 1H), 7.40–7.24 (m, 6 H), 7.19 (d, J=8.7Hz, 1H), 7.13–7.00 (m, 3H), 6.95 (td, J=7.3, 1.0Hz, 1H), 6.65 (t, J=5. 7Hz, 1H), 6.47 (dd, J=9.8, 7.2Hz, 1H), 6.00 (td, J=6.4, 2.1Hz, 1H), 5.21 (s, 2H), 4.34 (d , J=6.2Hz, 2H), 3.85 (t, J=6.5Hz, 2H), 3.78 (s, 3H), 3.06 (q, J=6.2Hz, 2H), 1.34 (s, 9H).

[0645] LCMS: m / z=619.4 [M+H]+, (ESI+), RT=1.22, Method B

[0646] Step 4

[0647] To a mixture of methyl 4-benzyloxy-3-[[5-[2-[2-(tert-butoxycarbonylamino)ethoxy]phenyl]-2,4-difluoro-anilino]methyl]benzoate (81%, 356 mg, 0.466 mmol), THF (4.4367 mL) and MeOH (1.4789 mL) was added 4M aqueous sodium hydroxide solution (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 1M aqueous HCl. The mixture was extracted with DCM (4 x 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 light yellow oil.

[0648] LCMS: m / z=605.3 [M+H]+, (ESI+), RT=1.10, Method B

[0649] Step 5

[0650] 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 a solution of 4M HCl in dioxane (2.1 mL, 8.25 mmol). The mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure. The residue was sonicated in DCM and then concentrated (3x) 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.

[0651] LCMS: m / z=505.1 [M+H]+, (ESI+), RT=0.78, Method B

[0652] Step 6

[0653] To a solution of T3P (50% in EtOAc) (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 EtOAc (70 mL) and H2O (70 mL) and the layers were separated. The aqueous layer was extracted with additional EtOAc (70 mL). The combined organics were washed with H2O (70 mL) and 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]pentacos-1(23),2,4,6,13,15,17(25),20(24),21-nonen-12-one (208 mg, 79% yield, 84% purity) as a light brown solid.

[0654] LCMS: m / z=487.1 [M+H]+, (ESI+), RT=1.06, Method B

[0655] Step 7

[0656] To 16-benzyloxy-21,23-difluoro-8-oxa-11,19-diazatetracyclo[18.3.1.113,17.02,7]pentacosyl-1(23),2,4,6,13,15,17(25),20(24),21-nonen-12-one (84%, 60 mg, 0.104 mmol) was added 1M BBr in DCM (1.0 mL, 1.00 mmol) at room temperature. The reaction mixture was stirred at room temperature for 45 minutes. The reaction mixture was diluted with DCM (30 mL) and poured onto H2O (40 mL), and the layers were separated. The aqueous layer was extracted with DCM (2 x 30 mL). The organic phases were combined, passed through a hydrophobic glass and concentrated in vacuo. The residue was purified by preparative HPLC (Method P1) and then further purified by preparative HPLC (Method P2) to give the title compound as a white solid (20 mg, 49% yield, 100% purity).

[0657] 1H NMR (500MHz, DMSO) δ10.16 (s, 1H), 7.53 (d, J=2.4Hz, 1H), 7.44 (dd, J=8.3, 2.2 Hz, 1H), 7.37 (ddd, J=8.3, 7.4, 1.8Hz, 1H), 7.14 (dd, J=7.5, 1.8Hz, 1H), 7.13– 7.06(m, 2H), 7.03–6.98(m, 2H), 6.89(dd, J=9.8, 7.5Hz, 1H), 6.82(d, J=8.3Hz , 1H), 5.56 (td, J=7.0, 2.5Hz, 1H), 4.43–4.19 (m, 2H), 4.16–4.01 (m, 2H), 3.57–

[0658] 3.40 (m, 2H).

[0659] LCMS: m / z=397.1 [M+H]+, (ESI+), RT=2.97, Method A

[0660] Example 14 - Synthesis of 15-chloro-21,23-difluoro-16-hydroxy-8-oxa-18λ6-thia-11-azatetracyclic [18.3.1.1 13,17 .0 2,7 ]Twenty-penta-1(24),2,4,6,13,15,17(25),20,22-nonaene-12,18,18-trione (Compound 14)

[0661]

[0662] Step 1

[0663] To intermediate 2 (98%, 650mg, 2.01mmol) and [2,4-difluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanol (58%, 1.00g, 2.15mmol) in 1,4-dioxane (12mL) solution, potassium carbonate (550mg, 3.98mmol) and water (3mL) are added and the mixture is bubbled with nitrogen for 10 minutes. Pd (dppf) Cl2 (150mg, 0.204mmol) is added and the reaction mixture is degassed again for 5 minutes, then the container is sealed and the reaction mixture is stirred at reflux for 20 hours. The reaction mixture is cooled to room temperature, filtered through diatomaceous earth and washed with EtOAc and the filtrate is added to water (50mL). The separation layer and the aqueous phase are extracted with EtOAc (2x 50mL). The organic layers were combined, washed with brine (100 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by FCC (50 g SiO column, 0-100% EtOAc 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.

[0664] 1 H NMR (500MHz, DMSO) δ7.45–7.35 (m, 2H), 7.23 (dd, J=7.5, 1.5Hz, 1H), 7.18 (t, J=10.1Hz, 1H), 7.12 (d, J=8.2Hz, 1H), 7.04 (td, J=7.5, 0.9 Hz, 1H), 6.74 (t, J=5.5Hz, 1H), 5.26 (t, J=5.5Hz, 1H), 4.54 (d, J=5.1Hz, 2H), 3.96 (t, J=6.3Hz, 2H), 3.18 (q, J=6.1Hz, 2H), 1.35 (s, 9H).

[0665] LCMS: m / z=402.0 [M+Na]+, (ESI+), RT=0.94, Method B

[0666] Step 2

[0667] To N-[2-[2-[2,4-difluoro-5-(hydroxymethyl)phenyl]phenoxy]ethyl]t-butyl carbamate (95%, 620mg, 1.55mmol) and carbon tetrabromide (800mg, 2.41mmol) 0 DEG C of solution in anhydrous DCM (50mL) triphenylphosphine (620mg, 2.36mmol) is added.Gained mixture is stirred under nitrogen for 4 hours while being warmed to room temperature.Reactant mixture is concentrated under reduced pressure and passed through FCC purification (25g SiO column, 0-100% EtOAc in heptane solution) to obtain N-[2-[2-[5-(bromomethyl)-2,4-difluoro-phenyl]phenoxy]ethyl]t-butyl carbamate (630mg, 90% yield, 98% purity), it is light yellow oil.

[0668] 1 H NMR (500MHz, DMSO) δ7.60 (t, J=8.4Hz, 1H), 7.39 (ddd, J=8.4, 7.5, 1.7Hz, 1H), 7.31 (t, J=10.1Hz, 1H), 7.27–7.22 (m, 1H), 7.13 (d, J=8 .2Hz, 1H), 7.04 (td, J=7.5, 0.8Hz, 1H), 6.78 (t, J=5.4Hz, 1H), 4.72 (s, 2H), 3.98 (t, J=6.1Hz, 2H), 3.20 (q, J=6.0Hz, 2H), 1.36 (s, 9H).

[0669] LCMS: m / z=342.0 / 343.9 [M-Boc+H]+, (ESI+), RT=1.13, Method B

[0670] Step 3

[0671] 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 MeOH (60 mL) was added potassium carbonate (220 mg, 1.59 mmol). After stirring at room temperature for 30 minutes, additional potassium carbonate (220 mg, 1.59 mmol) was added and the reaction was stirred at room temperature for another 30 minutes. The reaction mixture was acidified with 1M aqueous HCl solution (to pH ~ 4 / 5), then the solution was diluted with water (20 mL) and extracted with DCM (3 x 30 mL). The organic phases were combined, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by FCC (50 g SiO2 column, 0-100% ethyl acetate in heptane) to give tert-butyl N-[2-[2-[2,4-difluoro-5-(thiomethyl)phenyl]phenoxy]ethyl]carbamate (316 mg, 60% yield, 99% purity) as a viscous colorless oil.

[0672] 1 H NMR (500MHz, DMSO) δ7.47 (t, J=8.6Hz, 1H), 7.38 (ddd, J=8.3, 7.5, 1.8Hz, 1H), 7.27–7.19 (m, 2H), 7.13 (d, J=8.2Hz, 1H), 7.04 (td , J=7.5, 0.9Hz, 1H), 6.76 (t, J=5.4Hz, 1H), 3.97 (t, J=6.2Hz, 2H), 3.75 (s, 2H), 3.20 (q, J=6.1Hz, 2H), 2.98 (s, 1H), 1.36 (s, 9H).

[0673] LCMS: m / z=296.0 [M-Boc+H]+, (ESI+), RT=1.11, Method B

[0674] Step 4

[0675] To a solution of 3-bromo-5-chloro-4-methoxy-benzoic acid methyl ester (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-(thiomethyl)phenyl]phenoxy]ethyl]carbamate (99%, 310 mg, 0.776 mmol). The solution was sparged with nitrogen for 5 minutes, then 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 EtOAc (3 x 50 mL). The combined organic layer was washed with brine (100 mL), dried over NaSO, filtered and concentrated. The residue was purified by FCC (100 g SiO column, 0-100% EtOAc in heptane) to give 3-[[5-[2-[2-(tert-butoxycarbonylamino)ethoxy]phenyl]-2,4-difluoro-phenyl]methylsulfanyl]-5-chloro-4-methoxy-benzoic acid methyl ester (357 mg, 88% yield, 99% purity) as a viscous light yellow oil.

[0676] 1 H NMR (500MHz, DMSO) δ7.86 (d, J=2.0Hz, 1H), 7.82 (d, J=2.0Hz, 1H), 7.45 (t, J=8.4Hz, 1H), 7.38 (ddd, J=8.4, 7.5, 1.7Hz, 1H), 7.25 (t, J=10.0Hz, 1H), 7. 16–7.10 (m, 2H), 7.06–6.98 (m, 1H), 6.73 (t, J=5.6Hz, 1H), 4.33 (s, 2H), 3. 94 (t, J=6.2Hz, 2H), 3.82–3.80 (m, 6H), 3.16 (q, J=6.1Hz, 2H), 1.34 (s, 9H).

[0677] LCMS: m / z=494.0 [M-Boc+H]+, (ESI+), RT=1.25, Method B

[0678] Step 5

[0679] To a solution of 3-[[5-[2-[2-(tert-butoxycarbonylamino)ethoxy]phenyl]-2,4-difluoro-phenyl]methylsulfanyl]-5-chloro-4-methoxybenzoic acid methyl ester (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 hours. The reaction was added to a two-phase mixture of DCM (20 mL) and aqueous sodium sulfite solution (30 mL) and thoroughly mixed in a separating funnel. The layers were then separated and the aqueous phase was extracted with additional DCM (20 mL). The combined organic layer was then washed with aqueous sodium bicarbonate solution (40 mL) and the aqueous portion was extracted a second time with additional DCM (20 mL). The organic phases were combined and finally washed with brine (50 mL), then dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by FCC (10 g SiO2 column, 0-100% EtOAc in heptane) to give 3-[[5-[2-[2-(tert-butoxycarbonylamino)ethoxy]phenyl]-2,4-difluoro-phenyl]methylsulfonyl]-5-chloro-4-methoxy-benzoic acid methyl ester (272 mg, 78% yield, 90% purity).

[0680] 1 H NMR (500MHz, DMSO) δ8.36 (d, J=2.1Hz, 1H), 8.09 (d, J=2.1Hz, 1H), 7.46–7.35 (m, 2H), 7.27 (t, J=9.9Hz, 1H), 7.14 (d, J=8.3Hz, 1H), 7.09 (dd, J=7.4, 1.4 Hz, 1H), 7.04 (t, J=7.3Hz, 1H), 6.75 (t, J=5.5Hz, 1H), 4.90 (s, 2H), 4.08 (s, 3H), 3.95 (t, J=6.2Hz, 2H), 3.87 (s, 3H), 3.19 (q, J=6.1Hz, 2H), 1.34 (s, 9H).

[0681] LCMS: m / z=526.0 [M-Boc+H]+, (ESI+), RT=1.15, Method B

[0682] Step 6

[0683] 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 2M aqueous sodium hydroxide solution (3.0 mL, 6.00 mmol) was added. The resulting solution was stirred at room temperature for 3 hours. THF was removed under reduced pressure and the remaining aqueous solution was added to DCM (30 mL) and acidified with 1M aqueous HCl solution (30 mL). The layers were separated and the aqueous phase was extracted with additional DCM (2 x 15 mL), then the combined organic phases were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give 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.

[0684] LCMS: m / z=512.0 [M-Boc+H]+, (ESI+), RT=1.07, Method B

[0685] Step 7

[0686] 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 a solution of 4M HCl in dioxane (6.0 mL, 24.0 mmol). The solution was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure, and the remaining residue was dissolved in DCM (ultrasonication) and concentrated (3 x 20 mL) to give 3-[[5-[2-(2-aminoethoxy)phenyl]-2,4-difluoro-phenyl]methylsulfonyl]-5-chloro-4-methoxybenzoic acid HCl (236 mg, 94% yield, 80% purity) as a golden solid.

[0687] LCMS: m / z=512.0 [M+H]+, (ESI+), RT=0.74, Method B

[0688] Step 8

[0689] To a solution of DIPEA (0.30mL, 1.72mmol) and T3P (50% in EtOAc) (0.70mL, 1.18mmol) in DMF (3mL) was added 3-[[5-[2-(2-aminoethoxy)phenyl]-2,4-difluoro-phenyl]methylsulfonyl]-5-chloro-4-methoxybenzoic acid hydrochloride (80%, 230mg, 0.336mmol) in DMF (4mL) by a pump syringe over 1 hour. After addition, the mixture was stirred at room temperature for 3 hours. The second aliquot of T3P (50% in EtOAc) (0.70mL, 1.18mmol) was added dropwise and the mixture was stirred for another 16 hours. Additional DIPEA (0.30mL, 1.72mmol) was then added and the reaction was stirred for the last 1 hour. The reaction was then diluted with water (100mL) and extracted with EtOAc (4x 50mL). The combined organic phases were washed with brine (100 mL), dried over Na2SO4, 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]pentacos-1(24),2,4,6,13,15,17(25),20,22-nonen-12-one (150 mg, 81% yield, 90% purity) as a light brown solid.

[0690] 1 H NMR (500MHz, DMSO) δ8.14 (t, J=4.3Hz, 1H), 8.09 (d, J=2.2Hz, 1H), 7.45 (td, J=8.2, 1.7Hz, 1H), 7.40 (d, J=2.2Hz, 1H), 7.36 (t, J=8.2H z, 1H), 7.20 (dd, J=7.4, 1.7Hz, 1H), 7.18–7.14 (m, 1H), 7.07 (td, J=7.4, 0.8Hz, 1H), 6.88 (t, J=9.9Hz, 1H), 4.65 (s, 2H), 4.01 (s, 3H).

[0691] Step 9

[0692] 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]twenty-five-1(24),2,4,6,13,15,17(25),20,22-nonen-12-one (90%, 120 mg, 0.22 mmol) in anhydrous DMF (4 mL) was added dropwise a solution of 1M BBr in DCM (2.4 mL, 2.40 mmol) at 0°C. The resulting solution was heated at 80°C for 20 hours. The reaction mixture was cooled to room temperature and then placed on ice before the addition of an additional 1M BBr in DCM (0.60 mL, 0.6 mmol). The reaction mixture was then reheated to 80°C and stirred for an additional 4 hours. The reaction mixture was quenched by addition to saturated NaHCO3 aqueous solution (30 mL) at 0°C and diluted in DCM (20 mL). The aqueous phase was extracted again with DCM (20 mL) and the combined organic layers were then washed with brine (50 mL), dried over Na2SO4, 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)

[0693] 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 not observed

[0694] LCMS: m / z=480.0 / 481.9 [M+H]+, (ESI+), RT=3.28, Method A

[0695] Example 15 - Synthesis of 15-chloro-16-(difluoromethoxy)-21,23-difluoro-8-oxa-18λ6-thia-11,19-diazatetracyclo[18.3.1.1 13,17 .0 2,7 ]Twenty-penta-1(24),2,4,6,13,15,17(25),20,22-nonaene-12,18,18-trione (Compound 15)

[0696]

[0697] To a solution of T3P in EtOAc (50 wt%, 0.52 mL, 0.871 mmol) and DIPEA (0.25 mL, 1.45 mmol) in DMF-anhydrous (12.0 mL) was added dropwise a solution of 3-[[5-[2-(2-aminoethoxy)phenyl]-2,4-difluoro-phenyl]sulfamoyl]-5-chloro-4-(difluoromethoxy)benzoic acid HCl (synthesized according to General Scheme 1, 170 mg, 0.290 mmol) in anhydrous DMF (4.0 mL) at room temperature over 5 minutes. The reaction mixture was stirred at room temperature for 0.5 hours and then diluted with H2O (40 mL). The organics were extracted with EtOAc (2 x 30 mL), combined, washed with water (2 x 30 mL) and then with brine (30 mL), dried over MgSO4, 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).

[0698] 1 H NMR (500MHz, DMSO) δ10.58 (s, 1H), 8.35–8.27 (m, 1H), 8.11 (d, J = 2.1Hz, 1H), 7.56 (d, J = 2.2Hz, 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, 1.7Hz, 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).

[0699] LCMS: m / z=531.0 / 532.9 [M+H]+, (ESI+), RT=3.61, Method A

[0700] Example 16 - Synthesis of 15-chloro-21,23-difluoro-16-hydroxy-11-oxa-18λ6-thia-19-azatetracyclic [18.3.1.1 13,17 .0 2,7 ]Twenty-penta-1(24),2,4,6,13,15,17(25),20,22-nonaene-12,18,18-trione (Compound 16)

[0701]

[0702] 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]pentacosyl-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 DMF-anhydrous (1.0 mL) was added dropwise 1MBBr3 in DCM (0.60 mL, 0.60 mmol) at 0°C. The resulting solution was heated at 80°C for 16 hours and then cooled to room temperature. The reaction mixture was added to a saturated aqueous solution of NaHCO3 (30 mL) at 0°C. The organics were extracted with DCM (2 x 20 mL), combined, washed with brine (50 mL), dried over Na2SO4, filtered and concentrated in vacuo. Purification by preparative HPLC (Method P1) gave the title compound as a white solid (10 mg, 44% yield, 99% purity).

[0703] 1 H NMR (500MHz, DMSO) δ8.00–7.95 (m, 1H), 7.66 (d, J=2.2Hz, 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).

[0704] LCMS: m / z=478.2 / 480.2 [MH]-, (ESI-), RT=4.05, Method A

[0705] Example 17 - Synthesis of (10S)-15-chloro-21,23-difluoro-16-hydroxy-10-methyl-8-oxa-18λ6-thia-11,19-diazatetracyclo[18.3.1.1 13,17 .0 2,7 ]Twenty-penta-1(24),2,4,6,13,15,17(25),20,22-nonaene-12,18,18-trione (Compound 17)

[0706]

[0707] To (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]pentacosyl-1(24),2,4,6,13,15,17(25),20,22-nonen-12-one (synthesized according to General Scheme 1, 75%, 120 mg, 0.177 mmol) was added 1M BBr in DCM (2.2 mL, 2.2 mmol) at room temperature. The reaction mixture was stirred at room temperature for 18 hours. H2O (120 mL) was added to the reaction mixture. The organics were extracted with DCM (3 x 120 mL), combined, passed through a hydrophobic glassware and concentrated in vacuo. Purification by preparative HPLC (Method P1 ) gave the title compound as a white solid (45 mg, 49% yield, 97% purity).

[0708] 1 H NMR (400MHz, DMSO) δ10.59–10.12 (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=2.2Hz, 1H), 7.34–7.25 (m, 1H), 7.25 ( dd, J=7.5, 1.7Hz, 1H), 7.17–7.08 (m, 2H), 7.09–7.01 (m, 1H), 4.31 (dd, J=9. 4, 4.0Hz, 1H), 4.15–4.03 (m, 1H), 3.82–3.72 (m, 1H), 1.10 (d, J=6.6Hz, 3H).

[0709] LCMS: m / z=495.0 / 497.0 [M+H]+, (ESI+), RT=3.62, Method A

[0710] Example 18 - Synthesis of 5,15-dichloro-21,23-difluoro-16-hydroxy-8,11-dioxa-18λ6-thia-19-azatetracyclic [18.3.1.1 13,17 .0 2,7 ]Twenty-penta-1(24),2,4,6,13,15,17(25),20,22-nonaene-12,18,18-trione (Compound 18)

[0711]

[0712] 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]pentacosyl-1(24),2,4,6,13,15,17(25),20,22-nonen-12-one (synthesized according to General Scheme 2, 92%, 60 mg, 0.104 mmol) was added 1M BBr3 in DCM (8.0 mL, 8.0 mmol) dropwise and the reaction mixture was stirred at room temperature for 2 hours. The reaction was added to a saturated aqueous solution of NaHCO3 (30 mL). The organics were extracted with DCM (20 mL then 2 x 30 mL), combined, washed with brine (50 mL), dried over Na2SO4, filtered and concentrated in vacuo. Purification by preparative HPLC (Method P1 ) gave the title compound as an off-white solid (30 mg, 55% yield, 99% purity).

[0713] 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 not observed

[0714] LCMS: m / z=514.0 / 516.0 [MH]-, (ESI-), RT=4.30, Method A

[0715] Example 19 - Synthesis of (10R)-15-chloro-21,23-difluoro-16-hydroxy-10-methyl-8-oxa-18λ6-thia-11,19-diazatetracyclo[18.3.1.1 13,17 .0 2,7 ]Twenty-penta-1(24),2,4,6,13,15,17(25),20,22-nonaene-12,18,18-trione (Compound 19)

[0716]

[0717] 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]pentacos-1(24),2,4,6,13,15,17(25),20,22-nonen-12-one (synthesized according to General Scheme 1, 85%, 123 mg, 0.205 mmol) was added 1M BBr in DCM (2.6 mL, 2.6 mmol) at room temperature. The reaction mixture was stirred at room temperature for 3.5 hours, then 1M BBr in DCM (1.00 mL, 1.00 mmol) was added and the reaction mixture was stirred at room temperature for 14 hours. H2O (140 mL) was added to the reaction mixture. The organics were extracted with DCM (3 x 140 mL), combined, passed through a hydrophobic glass filter and concentrated in vacuo. Purification by preparative HPLC (Method P1 ) gave the title compound as a white solid (50 mg, 48% yield, 97% purity).

[0718] 1 H NMR (500MHz, DMSO) δ10.77–9.91(m, 2H), 8.08–7.92(m, 1H), 7.92–7.89(m, 1H), 7.46–7.41(m, 1H), 7.32(d, J=2.2Hz, 1H), 7.32–7.27(m, 1H), 7.25(dd , J=7.4, 1.7Hz, 1H), 7.16–7.09 (m, 2H), 7.07–7.03 (m, 1H), 4.31 (dd, J=9.3 , 4.0Hz, 1H), 4.13–4.03 (m, 1H), 3.81–3.73 (m, 1H), 1.10 (d, J=6.6Hz, 3H).

[0719] LCMS: m / z=495.0 / 497.0 [M+H]+, (ESI+), RT=3.68, Method A

[0720] Example 20 - Synthesis of 16-chloro-22,24-difluoro-17-hydroxy-8,12-dioxa-19λ6-thia-20-azatetracyclic [19.3.1.1 14,18 .0 2,7 Hexadecene-1(25),2,4,6,14,16,18(26),21,23-nonaene-13,19,19-trione (Compound 20)

[0721]

[0722] To 16-chloro-22,24-difluoro-17-methoxy-19,19-dioxo-8,12-dioxa-19λ6-thia-20-azatetracyclo[19.3.1.114,18.02,7]hexaconazole-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 1M BBr in DCM (1.4 mL, 1.40 mmol) at room temperature. The reaction mixture was stirred at room temperature for 1 hour, then diluted with DCM (30 mL) and poured into a 5 wt% aqueous solution of NaHCO (40 mL). The layers were separated and the organics were extracted from the aqueous phase using DCM (2 x 30 mL). The organics were combined, passed through a hydrophobic glassware and concentrated in vacuo. Purification was performed by acidic reverse phase FCC (30 g C18 SiO2, 10-100% MeCN (0.1% formic acid) in water (0.1% formic acid)) followed by lyophilization to afford the title compound as an off-white solid (27 mg, 39% yield, 98% purity).

[0723] 1 H NMR (500MHz, DMSO) δ11.95–9.45 (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, 1.7Hz, 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=5.0Hz, 2H), 2.01–1.94 (m, 2H).

[0724] LCMS: m / z=494.0 / 496.0 [MH]-, (ESI-), RT=4.18, Method A

[0725] Example 21 - Synthesis of 14-chloro-20,22-difluoro-15-hydroxy-10-oxa-17λ6-thia-18-azatetracyclic [17.3.1.1 12,16 .0 2,7 ]Tetracosyl-1(23),2,4,6,12,14,16(24),19,21-nonaene-11,17,17-trione (Compound 21)

[0726]

[0727] 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]pentacos-1(24),2,4,6,13,15,17(25),20,22-nonen-12-one (synthesized according to general scheme 2, 60%, 30 mg, 0.0364 mmol) in anhydrous DCM (0.6 mL) at 0° C. was added a 1 M solution of BBr3 in DCM (0.30 mL, 0.30 mmol) and the reaction mixture was stirred at 0° C. for 1 hour and then poured into a 5 wt% aqueous NaHCO3 solution (30 mL). The organics were extracted with DCM (3×20 mL), combined, passed through a hydrophobic glass and concentrated in vacuo. Purification by basic reverse phase FCC (30 g C18 SiO2, 10-100% MeCN (0.1% NH3) in water (0.1% NH3)) followed by lyophilization gave the title compound as a white solid (64 mg, 40% yield, 97% purity).

[0728] 1 H NMR (400MHz, DMSO) δ11.03–9.63 (m, 2H), 7.93 (d, J=2.1Hz, 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, 1.4Hz, 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).

[0729] LCMS: m / z=464.0 / 466.0 [MH]-, (ESI-), RT=4.06, Method A

[0730] Example 22 - Synthesis of 18-chloro-24,26-difluoro-19-hydroxy-14-oxa-3,21λ6-dithia-22-azapentacyclic [21.3.1.1 16,20 .0 2,10 .0 4,9 ]Octadecene-1(27),2(10),4,6,8,16,18,20(28),23,25-decene-15,21,21-trione (Compound 22)

[0731]

[0732] Step 1

[0733] To 3-(benzothiophene-3-yl) methyl propionate (98%, 1.55g, 6.90mmol) in DCM (21mL) was added dropwise a solution of bromine (0.37mL, 7.22mmol) in DCM (4.5mL) at 0 ℃ over 5 minutes. The reaction mixture was stirred at 0 ℃ for 1.75 hours, then saturated Na was added to the reaction mixture SO The aqueous solution (20mL), NaHCO (20mL saturated aqueous solution) and water (5mL). Organic matter was separated and the water layer was extracted with DCM (3x 15mL). Organic matter was merged, and by hydrophobic glassware and vacuum concentration, it obtained 3-(2-bromobenzothiophene-3-yl) methyl propionate (97.0%) (2.09g, 98% productive rate, 97% purity), which was a light yellow oil.

[0734] 1 H NMR (400MHz, CDCl3) δ7.75–7.67 (m, 2H), 7.40–7.29 (m, 2H), 3.69 (s, 3H), 3.22–3.16 (m, 2H), 2.67–2.60 (m, 2H).

[0735] Step 2

[0736] To 3-(2-bromobenzothiophene-3-yl) methyl propionate (97%, 1.89g, 6.13mmol) in anhydrous THF (44mL) and anhydrous MeOH (5.8mL) was added lithium tetrahydroborate (430mg, 19.7mmol) in batches at 0°C over 1 minute. The resulting solution was stirred at room temperature for 30 minutes, then additional lithium tetrahydroborate (50mg, 2.30mmol) was added and the mixture was stirred at room temperature for 10 minutes. The reaction mixture was cooled to 0°C and quenched by slowly adding HCl (20mL 1M aqueous solution). Organic matter was diluted with EtOAc (150mL) and then separated. Organic matter was washed with NaHCO (50mL saturated aqueous solution) and then washed with salt water. The aqueous phase merged was extracted with EtOAc (70mL). The organics were combined, dried over MgSO4, filtered and concentrated in vacuo to afford 3-(2-bromobenzothiophen-3-yl)propan-1-ol (1.97 g, 97% yield, 90% purity) as a light yellow oil.

[0737] 1 H NMR (400MHz, DMSO) δ7.94–7.90 (m, 1H), 7.83–7.79 (m, 1H), 7.44–7.35 (m, 2H), 4 .59(t, J=5.1Hz, 1H), 3.49–3.43(m, 2H), 2.89–2.83(m, 2H), 1.75–1.66(m, 2H).

[0738] Step 3

[0739] 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 EtOAc (120 mL) and washed with water (150 mL), then with brine (2 x 150 mL), dried over MgSO , filtered and concentrated in vacuo. The residue was purified by FCC (50 g SiO2 column, 0-10% EtOAc in heptane) to afford 3-(2-bromobenzothiophen-3-yl)propoxy-tert-butyl-dimethylsilane (2.22 g, 5.47 mmol, 84% yield, 95% purity) as a colorless oil.

[0740] 1 H NMR (400MHz, CDCl3) δ7.74–7.69 (m, 2H), 7.37–7.28 (m, 2H), 3.69 (t, J=6.1Hz, 2H), 2.97–2.89 (m, 2H), 1.88–1.79 (m, 2H), 0.94 (s, 9H), 0.08 (s, 6H).

[0741] Step 4

[0742] 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 and then filtered through a pad of celite topped with silica, washing with EtOAc. The filtrate was concentrated in vacuo and the residue was purified by FCC (50 g SiO column, 0-25% acetone in heptane) to afford 5-[3-[3-[tert-butyl(dimethyl)silyl]oxypropyl]benzothiophen-2-yl]-2,4-difluoro-aniline (1.50 g, 73% yield, 75% purity) as a yellow oil.

[0743] 1 H NMR (400MHz, DMSO) δ7.98–7.92 (m, 1H), 7.87–7.82 (m, 1H), 7.47–7.35 (m, 2H), 7.17 (dd, J=11.2, 9.7Hz, 1H), 6.82 (dd, J =9.8, 7.6Hz, 1H), 5.19 (s, 2H), 3.55 (t, J = 6.0Hz, 2H), 2.79–2.73 (m, 2H), 1.71–1.63 (m, 2H), 0.81 (s, 9H), -0.03 (s, 6H).

[0744] Step 5

[0745] Intermediate 1 (50%, 1.56 g, 2.61 mmol) and 5-[3-[3-[tert-butyl(dimethyl)silyl]oxypropyl]benzothiophen-2-yl]-2,4-difluoro-phenylamine (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 and diluted with 1M aqueous HCl (230 mL) and extracted with EtOAc (3×50 mL). The combined organic extracts were washed with brine (70 mL), dried over MgSO , 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-difluoro-phenyl]sulfamoyl]-5-chloro-4-methoxybenzoate (1.12 g, 46% yield, 75% purity) as a yellow oil.

[0746] 1 H NMR (400MHz, DMSO) δ10.54 (s, 1H), 8.25 (d, J = 2.1Hz, 1H), 8.19 (d, J = 2.1Hz, 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=6.0Hz, 2H), 2.73–2.66 (m, 2H), 1.64–1.57 (m, 2H), 0.78 (s, 9H), -0.06 (s, 6H).

[0747] LCMS: m / z=694.3 / 696.3 [MH]-, (ESI-), RT=1.02, Method B

[0748] Step 6

[0749] To a solution of methyl 3-[[5-[3-[3-[tert-butyl(dimethyl)silyl]oxypropyl]benzothiophen-2-yl]-2,4-difluoro-phenyl]sulfamoyl]-5-chloro-4-methoxybenzoate (75%, 1.12 g, 1.21 mmol) in MeOH (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% EtOAc in heptane, then 0-30% MeOH in EtOAc) 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.

[0750] LCMS: m / z=580.0 / 582.0 [MH]-, (ESI-), RT=1.09, Method B

[0751] Step 7

[0752] 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 2M aqueous sodium hydroxide solution (2.0 mL, 4.00 mmol) at room temperature. The reaction mixture was stirred at room temperature for 15.5 hours, and then the organic matter was concentrated in vacuo. 1M aqueous HCl solution (15 mL) was added to the flask and the organic matter was extracted with DCM (4 x 15 mL), passed through a hydrophobic glass 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.

[0753] LCMS: m / z=566.0 / 568.0 [MH]-, (ESI-), RT=0.97, Method B

[0754] Step 8

[0755] 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 SiO2 column, 0-60% EtOAc in heptane) and then by FCC (25 g SiO2 column, 0-100% Et2O in heptane) to give 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-decen-15-one (253 mg, 60% yield, 88% purity) as a white solid.

[0756] 1 H NMR (400MHz, DMSO) δ10.79 (s, 1H), 8.17 (d, J = 2.1Hz, 1H), 8.04–7.97 (m, 2H), 7.82 (d, J = 2.1Hz, 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).

[0757] LCMS: m / z=548.0 / 550.0 [MH]-, (ESI-), RT=1.19, Method B

[0758] Step 9

[0759] 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-decene-15-one (87%, 80 mg, 0.127 mmol) in anhydrous DCM (4.0 mL) was added 1 M BBr in DCM (0.70 mL, 0.70 mmol) at -16°C. The reaction mixture was gradually warmed to 10°C over 4 hours. Saturated aqueous NaHCO3 (4 mL) was added to the reaction mixture. The aqueous phase was extracted with DCM (3 x 4 mL), and the organic phases were combined, passed through a hydrophobic glassware, 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).

[0760] 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). 2H not observed.

[0761] LCMS: m / z=534.0 / 536.0 [MH]-, (ESI-), RT=4.63, Method A

[0762] Example 23 - Synthesis of 15-chloro-21-fluoro-16-hydroxy-8,11-dioxa-18λ6-thia-19-azatetracyclic [18.3.1.1 13,17 .0 2,7 ]pentadecan-1(24),2,4,6,13,15,17(25),20,22-nonaene-12,18,18-trione (Compound 23)

[0763]

[0764] 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]pentacos-1(24),2,4,6,13,15,17(25),20,22-nonen-12-one (synthesized according to General Scheme 2, 92%, 180 mg, 0.347 mmol) in anhydrous DCM (3.0 mL) was added 1 M BBr3 in DCM (1.5 mL, 1.5 mmol) at 0°C and the reaction mixture was stirred at 0°C for 1.5 hours. The reaction mixture was poured into 5 wt% aqueous NaHCO3 (30 mL) at 0°C. The organics were extracted with DCM (3 x 20 mL), combined, dried over Na2SO4, 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).

[0765] 1 H NMR (500MHz, DMSO) δ11.64–9.76 (m, 2H), 8.04 (d, J=2.1Hz, 1H), 7.67 (d, J=2.1Hz, 1H), 7.42–7.33 (m, 2H), 7.25 (dd, J=7.5, 1.7Hz, 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).

[0766] LCMS: m / z=462.0 / 464.0 [MH]-, (ESI-), RT=4.04, Method A

[0767] Example 24 - Synthesis of 4-bromo-15-chloro-21,23-difluoro-16-hydroxy-8,11-dioxa-18λ6-thia-19-azatetracyclo[18.3.1.1 13,17 .0 2,7 ]pentadecan-1(24),2,4,6,13,15,17(25),20,22-nonaene-12,18,18-trione (Compound 24)

[0768]

[0769] To a solution of 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]pentacos-1(24),2,4,6,13,15,17(25),20,22-nonen-12-one (synthesized according to General Scheme 2, 95%, 100 mg, 0.165 mmol) in anhydrous DCM (1.5 mL) was added 1 M BBr3 in DCM (0.80 mL, 0.80 mmol) at 0°C and the reaction mixture was stirred at 0°C for 1.5 hours. The reaction mixture was poured into 5 wt% aqueous NaHCO3 (30 mL) at 0°C. The organics were extracted with DCM (3 x 20 mL), combined, dried over Na2SO4, filtered and concentrated in vacuo. Purification by preparative HPLC (Method P1 ) gave the title compound as a white solid (26 mg, 25% yield, 90% purity).

[0770] 1 H NMR (500MHz, DMSO) δ11.67–9.84 (m, 2H), 8.04 (d, J=2.1Hz, 1H), 7.63 (dd, J=8.8, 2.6Hz, 1H), 7.51 (d, J=2.5Hz , 1H), 7.47 (d, J=2.2Hz, 1H), 7.37–7.31 (m, 1H), 7.28–7.20 (m, 1H), 7.17 (d, J=8.8Hz, 1H), 4.36–4.28 (m, 4H).

[0771] LCMS: m / z=557.9 / 559.9 / 561.9 [MH]-, (ESI-), RT=4.29, Method A

[0772] Example 25 - Synthesis of 15-chloro-21-hydroxy-16-methoxy-8,11-dioxa-18λ6-thia-19-azatetracyclic [18.3.1.1 13,17 .0 2,7 ]Twenty-penta-1(24),2,4,6,13,15,17(25),20,22-nonaene-12,18,18-trione (Compound 25)

[0773] Example 26 - Synthesis of 15-chloro-16-hydroxy-21-methoxy-8,11-dioxa-18λ6-thia-19-azatetracyclic [18.3.1.1 13,17 .0 2,7 ]Twenty-penta-1(24),2,4,6,13,15,17(25),20,22-nonaene-12,18,18-trione (Compound 26)

[0774] 25: 26:

[0775] 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]pentacos-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 minutes. 1 M BBr (0.13 mL, 0.13 mmol) was added to the reaction mixture and the reaction mixture was stirred at 0° C. for 1 hour. H 2 O (65 mL) was added to the reaction mixture and the organics were extracted with DCM (3 x 70 mL). The combined organic matter was passed through a hydrophobic glassware and concentrated in vacuo. Purification by preparative HPLC (Method P1) gave the following product:

[0776] Compound 25: white solid (26 mg, 21% yield, 98% purity)

[0777] 1 H NMR (500MHz, DMSO) δ9.50 (s, 2H), 8.12 (d, J = 2.1Hz, 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=8.3Hz, 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

[0778] Compound 26: white solid (31 mg, 25% yield, 98% purity)

[0779] 1H NMR(500MHz, DMSO)δ10.89(br s, 1H), 9.45 (s, 1H), 8.00 (d, J=2.1Hz, 1H), 7.43 (d, J=2.2Hz, 1H), 7.39–7.34 (m, 1H), 7.28–7.27 (m, 1H), 7.27–7.24 (m, 1H), 7.2 0–7.17 (m, 1H), 7.17–7.14 (m, 1H), 7.08–7.04 (m, 1H), 6.79 (d, J=8.5Hz, 1H), 4.35–4.31 (m, 2H), 4.27–4.23 (m, 2H), 3.40 (s, 3H).

[0780] LCMS: m / z=474.0 / 476.0 [MH]-, (ESI-), RT=4.08, Method A

[0781] Example 27 - Synthesis of 18-chloro-24,26-difluoro-19-hydroxy-14-oxa-21λ6-thia-10,22-diazapentacyclic [21.3.1.1 16,20 .0 2,10 .0 4,9 ]Octadecene-1(27),2,4,6,8,16,18,20(28),23,25-decene-15,21,21-trione (Compound 27)

[0782]

[0783] Step 1

[0784] To a solution of 2-iodo-1H-indole (95%, 775 mg, 3.03 mmol) in anhydrous DMF (30.2 mL) was added NaH (60%, 140 mg, 3.50 mmol) in mineral oil at 0°C, followed by addition of 3-bromopropoxy-tert-butyl-dimethylsilane (96%, 822 μL, 3.19 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 3 hours. The reaction mixture was diluted with saturated NaHCO3 aqueous solution (80 mL) at 0°C and extracted with EtOAc (2 x 80 mL). The combined organic layers were washed with brine (40 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by FCC (100 g SiO2 column, 0-5% EtOAc in heptane) to give tert-butyl-[3-(2-iodoindol-1-yl)propoxy]-dimethyl-silane (933 mg, 70% yield, 95% purity).

[0785] 1H NMR (500MHz, DMSO) δ7.49–7.45 (m, 2H), 7.10–7.06 (m, 1H), 7.02–6.98 (m, 1H), 6.77 (d, J=0.8H z, 1H), 4.28–4.22 (m, 2H), 3.62 (t, J=6.0Hz, 2H), 1.87–1.80 (m, 2H), 0.90 (s, 9H), 0.05 (s, 6H).

[0786] Step 2

[0787] 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 KCO (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 EtOAc. The filtrate was concentrated in vacuo and the residue was purified by FCC (25 g SiO column, 0-20% EtOAc in heptane) to give 5-[1-[3-[tert-butyl(dimethyl)silyl]oxypropyl]indol-2-yl]-2,4-difluoro-phenylamine (188 mg, 45% yield, 95% purity) as a brown gum.

[0788] 1 H NMR (400MHz, DMSO) δ7.56 (d, J=7.8Hz, 1H), 7.51 (d, J=8.2Hz, 1H), 7.21–7.13 (m, 2H), 7.09–7.03 (m, 1H), 6.82 (dd, J=9.9, 7.5H z, 1H), 6.44 (s, 1H), 5.17 (s, 2H), 4.13 (t, J=7.5Hz, 2H), 3.45 (t, J=5.8Hz, 2H), 1.72–1.62 (m, 2H), 0.79 (s, 9H), -0.06 (s, 6H).

[0789] Step 3

[0790] Intermediate 1 (50%, 263 mg, 0.440 mmol) and 5-[1-[3-[tert-butyl(dimethyl)silyl]oxypropyl]indol-2-yl]-2,4-difluoro-phenylamine (95%, 188 mg, 0.429 mmol) were dissolved in anhydrous pyridine (2.3 mL) and the mixture was heated at 50 ° C for 1 hour. The reaction mixture was diluted with 1M aqueous HCl (5 mL) and extracted with EtOAc (3 x 10 mL). The combined organic extracts were washed with brine (10 mL), dried over Na SO , filtered and concentrated under reduced pressure. The residue was purified by FCC (25 g SiO column, 0-20% EtOAc 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.

[0791] 1 H NMR (400MHz, DMSO) δ10.55 (s, 1H), 8.24 (d, J = 2.1Hz, 1H), 8.19 (d, J = 2.1Hz, 1H), 7. 58(d, J=7.8Hz, 1H), 7.52(d, J=8.3Hz, 1H), 7.50–7.43(m, 1H), 7.35(t, J=8.2Hz, 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=6.6Hz, 2H), 0.76 (s, 9H), -0.10 (s, 6H).

[0792] LCMS: m / z=679.2 / 681.2 [M+H]+, (ESI+), RT=0.99, Method B

[0793] Step 4

[0794] To a solution of 3-[[5-[1-[3-[tert-butyl(dimethyl)silyl]oxypropyl]indol-2-yl]-2,4-difluoro-phenyl]sulfamoyl]-5-chloro-4-methoxybenzoic acid methyl ester (90%, 315 mg, 0.413 mmol) in anhydrous THF (3.3 mL) was added a solution of 1M TBAF in THF (1.5 mL, 1.50 mmol) at room temperature and the reaction mixture was stirred at room temperature for 60 hours. The reaction mixture was diluted with 1M HCl aqueous solution (5 mL) and extracted with EtOAc (3 x 10 mL). The combined organic extracts were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by FCC (25 g SiO column, 0-100% EtOAc 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 light yellow gum.

[0795] LCMS: m / z=563.1 / 565.0 [MH]-, (ESI-), RT=1.06, Method B

[0796] Step 5

[0797] 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 MeOH (0.52 mL), and 2 M aqueous sodium hydroxide solution (1.2 mL, 2.40 mmol) was added. The resulting solution was stirred at room temperature for 1 hour. 6.0 M aqueous NaOH solution (0.5 mL) was added and the reaction was stirred at room temperature for an additional 1 hour. THF was removed 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), then 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 light yellow solid.

[0798] LCMS: m / z=549.0 / 551.0 [MH]-, (ESI-), RT=0.93, Method B

[0799] Step 6

[0800] 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 SiO2 column, 0-100% EtOAc 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-decen-15-one (107 mg, 68% yield, 90% purity) as a white solid.

[0801] 1 H NMR (400MHz, DMSO) δ10.79 (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).

[0802] LCMS: m / z=531.1 / 533.0 [MH]-, (ESI-), RT=1.12, Method B

[0803] Step 7

[0804] To a solution of 18-chloro-24,26-difluoro-19-methoxy-21,21-dioxo-14-oxa-21λ-thia-10,22-diazapentacyclo[21.3.1.116,20.02,10.04,9]octacos-1(27),2,4,6,8,16,18,20(28),23,25-decen-15-one (90%, 95 mg, 0.160 mmol) in DCM-anhydrous (9.5 mL) was added 1 M BBr3 in DCM (1.0 mL, 1.00 mmol) and the reaction mixture was stirred at 0° C. for 1.5 hours. To the reaction mixture was added 1 M BBr3 in DCM (0.50 mL, 0.50 mmol) and the reaction was stirred at 0° C. for 1 hour. To the reaction mixture was added H2O (50 mL). The aqueous phase is extracted with DCM (3x 50mL), and organic phases are merged, through hydrophobic glassware and vacuum concentration. 20wt% crude material is purified by preparative HPLC (method P1). Remaining 80wt% crude material is purified by reversed-phase FCC (12g C18SiO2, with 0.1% NH3 in MeCN in H200% NH3 solution, 10-100% elution). Products therefrom are combined and most of MeCN is removed in vacuo. Organic matter is extracted with DCM (3x 50mL) from remaining aqueous phase, merged, through hydrophobic glassware and vacuum concentration, obtain title compound, be pale solid (14mg, 16% yield, 96% purity).

[0805] 1 H NMR (500MHz, DMSO) δ7.99–7.94(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, 1 H), 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).

[0806] LCMS: m / z=517.0 / 519.0 [MH]-, (ESI-), RT=4.34, Method A

[0807] Example 28 - Synthesis of 15-chloro-21,23-difluoro-16-hydroxy-12,18,18-trioxo-8,11-dioxa-18λ6-thia-19-azatetracyclo[18.3.1.1 13,17 .0 2,7]Twenty-five-1(24),2,4,6,13,15,17(25),20,22-nonaene-4-carbonitrile (Compound 28)

[0808]

[0809] 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-nona-carbonitrile (synthesized according to General Scheme 2, 92%, 100 mg, 0.177 mmol) in anhydrous DCM (1.6 mL) was added 1M BBr3 in DCM (0.80 mL, 0.800 mmol) at 0°C and the reaction mixture was stirred at 0°C for 3 hours. The reaction mixture was poured into a saturated aqueous solution of NaHCO3 (30 mL). The organics were extracted with DCM (3 x 30 mL), combined, dried over Na2SO4, filtered and concentrated in vacuo. Purified by acidic preparative HPLC (standard method). Product containing fractions were combined, concentrated in vacuo and dried in a vacuum oven (40°C) to afford the title compound as a white solid (35 mg, 39% yield, 100% purity).

[0810] 1 H NMR (500MHz, DMSO) δ8.07–7.99 (m, 1H), 7.96 (dd, J=8.6, 2.2Hz, 1H), 7.83 (d, J=2.1Hz, 1H), 7.4 7(d, J=2.2Hz, 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).

[0811] LCMS: m / z=505.0 / 507.0 [MH]-, (ESI-), RT=3.81, Method A

[0812] Example 29 - Synthesis of 16-chloro-5,22,24-trifluoro-17-hydroxy-8,12-dioxa-19λ6-thia-20-azatetracyclic [19.3.1.1 14,18 .0 2,7 Hexadecene-1(25),2,4,6,14,16,18(26),21,23-nonaene-13,19,19-trione (Compound 29)

[0813]

[0814] 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]hexaconazole-1(24),2(7),3,5,14,16,18(26),21(25),22-nonen-13-one (synthesized according to General Scheme 2, 93%, 230 mg, 0.405 mmol) in anhydrous DCM (4.3 mL) was added 1 M BBr3 in DCM (2.0 mL, 2.0 mmol) at 0 ° C. and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was added dropwise to an ice-cold saturated aqueous NaHCO3 solution. The organics were extracted with DCM (3 x 10 mL), combined, passed through a hydrophobic glassware and concentrated in vacuo. The crude material was purified by reverse phase column chromatography (12 g C18 silica gel, 10-100% MeCN in water (0.1% NH3)) and then by preparative HPLC (Method P3) to give the title compound (11 mg, 5% yield, 98% purity) as a white solid.

[0815] 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). 2H not observed

[0816] LCMS: m / z=512.1 / 514.1 [MH]-, (ESI-), RT=3.93, Method A

[0817] Example 30 - Synthesis of 14-chloro-20,22-difluoro-15-hydroxy-17λ6-thia-10,18-diazatetracyclic [17.3.1.1 12,16 .0 2,7 ]Tetracosyl-1(23),2,4,6,12,14,16(24),19,21-nonaene-11,17,17-trione (Compound 30)

[0818]

[0819] At 0 ° C, 14-chloro-20,22-difluoro-15-methoxy-17,17-dioxo-17λ6-thia-10,18-diazatetracyclo[17.3.1.112,16.02,7]twenty-four-1(23),2,4,6,12,14,16(24),19,21-nona-

[0820] 11-ketone (synthesized according to universal scheme 1, 75%, 270mg, 0.423mmol) adds 1M BBr in the solution in anhydrous DCM (4mL) Solution in DCM (2.1mL, 2.1mmol) and reaction mixture is stirred 5 minutes at 0 ℃, then continues 20 hours at room temperature.At 0 ℃, 1M BBr is added to reaction mixture Solution in DCM (0.85mL, 0.85mmol), then reaction mixture is stirred at room temperature 1 hour.Reaction mixture is poured into ice-water (60mL).Aqueous phase is extracted with DCM (3x 40mL), and merges organic phase, passes through hydrophobic glassware and vacuum concentration.By preparative HPLC purifying (method P1), then by FCC purifying (10g SiO Column, 0-20% MeOH in DCM) to obtain title compound (32mg, 16% productive rate, 99% purity), it is pale solid.

[0821] 1 H NMR (400MHz, DMSO) δ8.00–7.89 (m, 1H), 7.78 (s, 1H), 7.51–

[0822] 7.40 (m, 3H), 7.39–7.32 (m, 1H), 7.26–7.16 (m, 1H), 6.91 (d, J=7.7Hz, 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).

[0823] LCMS: m / z=463.0 / 465.0 [MH]-, (ESI-), RT=3.46, Method A

[0824] Example 31 - Synthesis of 15-chloro-4-cyclopropyl-21,23-difluoro-16-hydroxy-8,11-dioxa-18λ6-thia-19-azatetracyclo[18.3.1.1 13,17 .0 2,7 ]Twenty-penta-1(23),2,4,6,13(25),14,16,20(24),21-nonaene-12,18,18-trione (Compound 31)

[0825]

[0826] 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]pentacosyl-1(24),2,4,6,13,15,17(25),20,22-nonen-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 hours. The reaction mixture was cooled to room temperature and then added to water (50 mL). The organics were extracted with EtOAc (3 x 50 mL), combined, washed with brine (100 mL), dried over Na2SO4, filtered and concentrated in vacuo. Purification by preparative HPLC (Method P1 ) gave the title compound (27 mg, 27% yield, 96% purity) as a white solid.

[0827] 1 H NMR (400MHz, DMSO) δ8.03 (d, J=2.1Hz, 1H), 7.45 (d, J=2.2Hz, 1H), 7.36–7.26 (m, 1H), 7.23–7.11 (m, 2H), 7.06 (d, J=8.5Hz, 1H), 6.97 (d, J=2.3Hz, 1H), 4.35–4.29 (m, 2H), 4.27–4.20 (m, 2H), 1.92 (tt, J=8.5, 5.1Hz, 1H), 0.94–0.86 (m, 2H), 0.74–0.62 (m, 2H).

[0828] LCMS: m / z=520.2 / 522.1 [MH]-, (ESI-), RT=4.39, Method A

[0829] Example 32 - Synthesis of 15-chloro-21,23-difluoro-16-hydroxy-8,11-dioxa-18λ6-thia-6,19-diazatetracyclo[18.3.1.1 13,17 .0 2,7 ]pentadecan-1(24),2,4,6,13,15,17(25),20,22-nonaene-12,18,18-trione (Compound 32)

[0830]

[0831] 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]twenty-five-1(24),2,4,6,13,15,17(25),20,22-nonen-12-one (synthesized according to General Scheme 2, 95%, 110 mg, 0.210 mmol) in anhydrous DCM (2 mL) was added 1M BBr in DCM (1.1 mL, 1.1 mmol) at 0°C. The reaction mixture was stirred at 0°C for 10 minutes and then at room temperature for 3 hours. The reaction mixture was poured into a saturated aqueous solution of NaHCO (30 mL). The aqueous phase was extracted with DCM (3x30 mL), and the organic phases were combined, passed through a hydrophobic glassware 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.

[0832] 1 H NMR (500MHz, DMSO) δ8.27 (dd, J=5.0, 1.9Hz, 1H), 8.06–7.98 (m, 1H), 7.75 (dd, J=7.3, 1.9Hz, 1H), 7.68 ( d, J=2.2Hz, 1H), 7.40–7.26 (m, 2H), 7.15 (dd, J=7.3, 5.0Hz, 1H), 4.51–4.44 (m, 2H), 4.44–4.36 (m, 2H).

[0833] LCMS: m / z=481.0 / 483.0 [MH]-, (ESI-), RT=3.85, Method A

[0834] 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]heptaconic-1(25),2,4,6,14,16,18(26),21,23-nonaen-13-one (Compound 33)

[0835]

[0836] 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 Example 1, 95% purity, 50 mg, 0.09 mmol) in anhydrous DCM (2 mL) was cooled to 0° C., and then a solution of 1M BBr 3 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 an ice-cold saturated aqueous NaHCO 3 solution (30 mL), and then DCM (30 mL) was added. To 4-nitro- 4- ...

[0837] 1 H NMR (400MHz, DMSO) δ10.77 (br.s, 1H), 7.67 (s, 1H), 7.54–7.43 (m, 1H), 7.41–7.30 (m, 2H), 7.23 (d, J=7.9Hz, 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).

[0838] LCMS: m / z=507.0 / 509.0 [M+H]+, (ESI+), RT=3.40, Method A

[0839] 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]twentetra-1(22),3,5,7(24),10(23),11,13,18,20-nonen-15-one (Compound 34)

[0840]

[0841] Step 1

[0842] Methyl 3-iodobenzoate (500mg, 1.87mmol), 5-amino-2,4-difluorophenol (326mg, 2.24mmol), pyridine-2-carboxylic acid (23mg, 0.187mmol), cuprous (I) iodide (18mg, 0.09mmol) and tripotassium phosphate (794mg, 3.74mmol) are placed in a pressure bottle. The bottle is placed under nitrogen and three vacuum / nitrogen nitrogen cycles are used. Anhydrous DMSO (4mL) is added and the bottle is heated at 80°C for 24 hours. The reaction mixture is cooled to room temperature, then filtered through a silica gel pad and washed with EtOAc. H o (20mL) and separating layers are added to the filtrate. The water layer is extracted with additional EtOAc (2x 20mL). The combined organic layer is washed with brine, dried (Na sO ), filtered and concentrated. The residue was purified by FCC (25 g SiO2 column, 0-100% EtOAc in heptane) to give methyl 3-(5-amino-2,4-difluoro-phenoxy)benzoate (265 mg, 48% yield, 94% purity) as a light yellow oil.

[0843] 1 H NMR (400MHz, DMSO) δ7.72–7.67 (m, 1H), 7.57–7.49 (m, 1H), 7.38 (dd, J=2.8, 1.5Hz, 1H), 7.32–7.24(m, 2H), 6.64–6.56(m, 1H), 5.22(s, 2H), 3.84(s, 3H).

[0844] Step 2

[0845] To 3-(5-amino-2,4-difluoro-phenoxy) methyl benzoate (94% purity, 260mg, 0.875mmol) in anhydrous THF (6mL) solution, add lithium borohydride (95mg, 4.38mmol) and the mixture is stirred at 66 DEG C for 1 hour.The mixture is cooled to room temperature, then DCM (30mL) and saturated NaHCOaqueous solution (30mL) and separating layer are added.The aqueous solution is extracted with extra DCM (2x 20mL).The organic matter merged passes through phase separator, is then concentrated to obtain [3-(5-amino-2,4-difluoro-phenoxy) phenyl] methanol (214mg, 90% yield, 92% purity), it is light yellow oil.

[0846] 1H NMR (500MHz, DMSO) δ7.32–7.26 (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=5.8Hz, 1H), 5.15 (s, 2H), 4.46 (d, J=5.4Hz, 2H).

[0847] Step 3

[0848] Intermediate 1 (50% purity, 552 mg, 0.923 mmol) and [3-(5-amino-2,4-difluoro-phenoxy)phenyl]methanol (92% purity, 210 mg, 0.769 mmol) were dissolved in anhydrous pyridine (4 mL) and the mixture was stirred at 50 ° C for 1 hour. The reaction mixture was cooled to room temperature and diluted with 1M HCl aqueous solution (30 mL) and extracted with EtOAc (3 x 30 mL). The combined organic extracts were washed with brine (50 mL), dried over Na SO , filtered and concentrated under reduced pressure. The residue was purified by FCC (50 g SiO2 column, 0-100% EtOAc in heptane) to give 3-chloro-5-[[2,4-difluoro-5-[3-(hydroxymethyl)phenoxy]phenyl]sulfamoyl]-4-methoxy-benzoic acid methyl ester (270 mg, 65% yield, 95% purity) as a light yellow oil.

[0849] 1 H NMR (400MHz, DMSO) δ10.44 (s, 1H), 8.23 ​​(d, J = 2.1Hz, 1H), 8.11 (d, J = 2.1Hz, 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=5.7Hz, 1H), 4.46 (d, J=5.5Hz, 2H), 3.93 (s, 3H), 3.87 (s, 3H).

[0850] Step 4

[0851] 3- chloro-5-[[2,4-difluoro-5-[3-(hydroxymethyl)phenoxy]phenyl]sulfamoyl]-4-methoxy-benzoic acid methyl ester (95% purity, 270mg, 0.50mmol) is dissolved in THF (4mL) and 2M sodium hydroxide aqueous solution (1.2mL, 2.50mmol) is added. The reaction mixture is stirred at room temperature overnight. THF is removed in vacuo, and the remaining aqueous phase is diluted with water (30mL) and acidified with 1M HCl aqueous solution. The mixture is extracted with DCM (3x 30mL), and the combined organic phase is passed through a phase separator and then concentrated to obtain 3- chloro-5-[[2,4-difluoro-5-[3-(hydroxymethyl)phenoxy]phenyl]sulfamoyl]-4-methoxy-benzoic acid (240mg, 87% yield, 94% purity), which is a pale solid.

[0852] 1 H NMR (400MHz, DMSO) δ13.66 (br.s, 1H), 10.40 (br.s, 1H), 8.19 (d, J=2.1Hz, 1H), 8.10 (d, J=2.1Hz, 1H), 7.57–7.45 (m, 1H), 7.32–7. 25 (m, 1H), 7.08 (d, J=7.6Hz, 1H), 6.95–6.87 (m, 2H), 6.69 (dd, J=8.1, 2.7Hz, 1H), 5.22 (br.s, 1H), 4.53–4.38 (m, 2H), 3.92 (s, 3H).

[0853] LCMS: m / z=498.0 / 500.0 [MH]-, (ESI-), RT=0.87, Method B

[0854] Step 5

[0855] To a solution of 3-chloro-5-[[2,4-difluoro-5-[3-(hydroxymethyl)phenoxy]phenyl]sulfamoyl]-4-methoxy-benzoic acid (94% purity, 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 hours, then diluted with DCM (20 mL) and water (40 mL), and the layers were separated. The aqueous solution was extracted with DCM (2 x 30 mL), and the combined organic phases were passed through a phase separator and concentrated. The residue was purified by FCC (25 g SiO2 column, 0-100% EtOAc 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]tetracontac-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.

[0856] 1 H NMR (400MHz, DMSO) δ10.79 (s, 1H), 8.25 (d, J = 2.2Hz, 1H), 8.08 (d, J = 2.2Hz, 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).

[0857] LCMS: m / z=480.0 / 482.0 [MH]-, (ESI-), RT=1.12, Method B

[0858] Step 6

[0859] 12-Chloro-4,6-difluoro-11-methoxy-9,9-dioxo-2,16-dioxa-9λ6-thia-8-azatetracyclo[16.3.1.13,7.110,14]twenty-four-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 bottle. The bottle was sealed and heated at 100° C. for 3 hours. The reaction mixture was cooled to room temperature, and then saturated aqueous NaHCO solution (50 mL) was added, followed by extraction with EtOAc (3×50 mL). The combined organic extracts were washed with water (2×100 mL) and then with brine (100 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by FCC (10 g SiO2 column, 0-20% MeOH in DCM) to give the title compound (42 mg, 42% yield, 98% purity) as a white solid.

[0860] 1 H NMR (500MHz, DMSO) δ7.95 (d, J=2.5Hz, 1H), 7.71–7.60 (m, 1H), 7.51–7.30 (m, 3H), 7 .15 (dd, J=8.2, 2.6Hz, 1H), 7.06 (d, J=7.5Hz, 1H), 6.35–6.25 (m, 1H), 5.27 (s, 2H).

[0861] LCMS: m / z=466.0 / 468.0 [MH]-, (ESI-), RT=4.36, Method A

[0862] 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]pentacosyl-1(23),2(7),3,5,13,17(25),20(24),21-octaene-12,16-dione (Compound 35)

[0863]

[0864] Step 1

[0865] To a solution of 5-bromo-1-methyl-6-oxo-pyridine-3-carboxylic acid methyl ester (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. Phenylmethyl mercaptan (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 EtOAc (3x100 mL). The combined organic layers were washed with brine (100 mL), dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by FCC (0-100% EtOAc in heptane) to give 5-benzylsulfanyl-1-methyl-6-oxo-pyridine-3-carboxylic acid methyl ester (1.90 g, 82% yield, 100% purity) as a yellow solid.

[0866] 1 H NMR (400MHz, DMSO) δ8.37 (d, J=2.3Hz, 1H), 7.59 (d, J=2.3Hz, 1H), 7.46–7.37 (m, 2 H), 7.35–7.30(m, 2H), 7.28–7.22(m, 1H), 4.18(s, 2H), 3.78(s, 3H), 3.54(s, 3H).

[0867] LCMS: m / z=290.0 [M+H]+, (ESI+), RT=0.78, Method B

[0868] Step 2

[0869] 5-benzylsulfanyl-1-methyl-6-oxo-pyridine-3-formic acid methyl esters (500mg, 1.68mmol) are dissolved in a mixture of MeCN (10mL), acetic acid (0.5mL) and water (0.5mL). The resulting suspension is cooled to 0°C in an ice bath. 1,3-dichloro-5,5-dimethylhydantoin (673mg, 3.42mmol) is then added in batches (over about 15 minutes) and the reaction mixture is stirred at 0°C for 2 hours. MeCN is removed under reduced pressure and DCM (20mL) is added. The solution is cooled to 0°C and saturated NaHCO3 aqueous solution (20mL) is slowly added. The organic layer is separated, dried with MgSO4, filtered, and concentrated under reduced pressure to obtain 5-chlorosulfonyl-1-methyl-6-oxo-pyridine-3-formic acid methyl esters (800mg, 90% yield, 50% purity), which is a white solid.

[0870] LCMS: not ionized, RT=0.63, Method B

[0871] Step 3

[0872] 5-chlorosulfonyl-1-methyl-6-oxo-pyridine-3-formic acid methyl ester (50% purity, 600 mg, 1.13 mmol) is added to a stirred solution of intermediate 8 (95% purity, 450 mg, 1.13 mmol) in anhydrous pyridine (10 mL) at room temperature and the mixture is heated at 50 ° C for 1 hour. The reaction mixture is cooled to room temperature, quenched with 1M HCl aqueous solution (30 mL) and extracted with EtOAc (3x 30 mL). The combined organic layer is washed with salt water (30 mL), dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by FCC (0-100% EtOAc in heptane) to give 5-[[5-[2-[2-[tert-Butyl(dimethyl)silyl]oxyethoxy]phenyl]-2,4-difluoro-phenyl]sulfamoyl]-1-methyl-6-oxo-pyridine-3-carboxylic acid methyl ester (520 mg, 0.837 mmol, 74% yield, 98% purity) as a yellow glass.

[0873] 1 H NMR (400MHz, CDCl3) δ8.50 (d, J=2.5Hz, 1H), 8.42 (d, J=2.5Hz, 1H), 7.61 (brs, 1H), 7.54 (dd, J=8.9, 7.4Hz, 1H), 7.35 (ddd, J=8.3, 7.4, 1.8Hz, 1H), 7.18 (ddd , J=7.7, 1.8, 0.7Hz, 1H), 7.02–6.97 (m, 2H), 6.79 (dd, J=10.1, 9.0Hz, 1H), 4.0 4(t, J=5.3Hz, 2H), 3.89–3.82(m, 5H), 3.72(s, 3H), 0.81(s, 9H), -0.07(s, 6H).

[0874] Step 4

[0875] Toluenesulfonic acid hydrate (16 mg, 0.0837 mmol) was added to a stirred solution of 5-[[5-[2-[2-[tert-butyl(dimethyl)silyl]oxyethoxy]phenyl]-2,4-difluoro-phenyl]sulfamoyl]-1-methyl-6-oxo-pyridine-3-carboxylic acid methyl ester (98% purity, 520 mg, 0.837 mmol) in MeOH (10 mL) and the mixture was stirred for 1 hour. The reaction mixture was concentrated in vacuo and the residue was diluted with water (25 mL) and extracted with EtOAc (3 x 25 mL). The combined organic layers were washed with brine (25 mL), dried over MgSO , filtered and concentrated in vacuo. The residue was purified by FCC (0-100% EtOAc in heptane) to give 5-[[2,4-difluoro-5-[2-(2-hydroxyethoxy)phenyl]phenyl]sulfamoyl]-1-methyl-6-oxo-pyridine-3-carboxylic acid methyl ester (350 mg, 82% yield, 97% purity) as a yellow solid.

[0876] 1 H NMR (400MHz, CDCl3) δ8.52 (d, J=2.5Hz, 1H), 8.43 (d, J=2.5Hz, 1H), 7.68 (dd, J=8.9, 7.6Hz, 1H), 7.62 (br s, 1H), 7.37 (ddd, J=8.3, 7.4, 1.8Hz, 1H), 7.30–7.22 (m, 1H), 7.09–7.00 (m, 1H), 6.99 (dd, J=8.3, 1.1Hz, 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, 1.5Hz, 1H).

[0877] LCMS: m / z=495.1 [M+H]+, (ESI+), RT=0.75, Method B

[0878] Step 5

[0879] 2M aqueous sodium hydroxide solution (1.6mL, 3.14mmol) 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 methyl ester (97% purity, 320mg, 0.628mmol) in THF (10mL) at room temperature, and the mixture was stirred for 2 hours. THF was removed in vacuo, and the remaining aqueous phase was diluted with water (30mL). The diluted aqueous phase was acidified with 1M aqueous HCl solution. The mixture was extracted with DCM (3x 30mL). The combined organic layers were washed with brine (30 mL), dried over MgSO 4 , 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.

[0880] 1 H NMR (400MHz, DMSO) δ13.25 (br s, 1H), 9.96 (s, 1H), 8.82 (d, J=2.5Hz, 1H), 8.24 (d, J=2.5Hz, 1H), 7.38 (ddd, J=8.3 ,7.3, 1.8Hz, 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=5.4Hz, 2H), 3.64–3.54 (m, 5H).

[0881] LCMS: m / z=481.1 [M+H]+, (ESI+), RT=0.66, Method B

[0882] Step 6

[0883] DCC (86 mg, 0.416 mmol) is 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 is stirred for 5 hours. The reaction mixture is diluted with DCM (10 mL) and water (10 mL) to obtain a two-phase mixture. The two-phase mixture is separated and the aqueous layer is further extracted with DCM (2x10 mL). The combined organic layer is dried with MgSO4, filtered and concentrated in vacuo. The residue is purified by preparative HPLC (method P3), the fractions containing the target compound are combined and concentrated in vacuo, and the resulting solid is dissolved in DCM (10 mL) and washed with 1M HCl aqueous solution (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.

[0884] 1 H NMR(400MHz, DMSO)δ10.36(br s, 1H), 8.82 (d, J=2.6Hz, 1H), 7.68 (d, J=2.6Hz, 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).

[0885] LCMS: m / z=463.1 [M+H]+, (ESI+), RT=2.93, Method A

[0886] 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]pentacosyl-1(23),2(7),3,5,13,17(25),20(24),21-octaene-12,16-dione (Compound 36)

[0887]

[0888] Step 1

[0889] To a solution of 5-bromo-6-methoxy-pyridine-3-carboxylic acid methyl ester (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. Phenylmethylmercaptan (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 and diluted with H2O (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by FCC (0-100% EtOAc in heptane) to give 5-benzylsulfanyl-6-methoxy-pyridine-3-carboxylic acid methyl ester (1.45 g, 85% yield, 90% purity) as an orange solid.

[0890] 1 H NMR (500MHz, CDCl3) δ8.62 (d, J=2.1Hz, 1H), 8.04 (d, J=2.1Hz, 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).

[0891] LCMS: m / z=290.1 ​​[M+H]+, (ESI+), RT=1.00, Method B

[0892] Step 2

[0893] 5-benzylsulfanyl-6-methoxy-pyridine-3-carboxylic acid methyl ester (90% purity, 500mg, 1.56mmol) is dissolved in a mixture of MeCN (9mL), acetic acid (0.45mL) and water (0.45mL) and the resulting suspension is cooled to 0°C in an ice bath. 1,3-dichloro-5,5-dimethylhydantoin (613mg, 3.11mmol) is then added in portions (over about 15mins) and the reaction mixture is stirred at 0°C for 2 hours. MeCN is removed under reduced pressure and DCM (20mL) is added. The solution is cooled to 0°C and saturated NaHCO3 aqueous solution (20mL) is slowly added. The organic layer is separated, dried over MgSO4, filtered and concentrated under reduced pressure to obtain 5-chlorosulfonyl-6-methoxy-pyridine-3-carboxylic acid methyl ester (620mg, 99% yield, 66% purity) as a white solid.

[0894] LCMS: not ionized, RT=0.85, Method B

[0895] Step 3

[0896] 5- chlorosulfonyl -6- methoxy - pyridine -3- methyl formate (66% purity, 600mg, 1.49mmol) is added to a stirred solution of intermediate 8 (95% purity, 400mg, 1.00mmol) in anhydrous pyridine (10mL) at room temperature and the mixture is heated at 50 DEG C for 1 hour. The reaction mixture is cooled to room temperature and concentrated in vacuo. The residue is purified by FCC (0-100% EtOAc in heptane solution) to obtain 5- [ [5- [2- [2- [tert-butyl (dimethyl) silyl] oxyethoxy] phenyl] -2,4- difluoro- phenyl] sulfamoyl] -6- methoxy - pyridine -3- methyl formate (510mg, 70% yield, 84% purity), which is a yellow oil.

[0897] 1 H NMR (400MHz, CDCl3) δ8.96 (d, J=2.3Hz, 1H), 8.62 (d, J=2.2Hz, 1H), 7.58 (dd, J=9.0, 7.4Hz, 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, 8.9Hz, 1H), 4.23 (s, 3H), 4.04 (t, J=5.3Hz, 2H), 3.91 (s, 3H), 3.83 (t, J=5.3Hz, 2H), 0.81 (s, 9H), -0.09 (s, 6H).

[0898] Step 4

[0899] Toluenesulfonic acid hydrate (13 mg, 0.0690 mmol) was added to a stirred solution of 5-[[5-[2-[2-[tert-butyl(dimethyl)silyl]oxyethoxy]phenyl]-2,4-difluoro-phenyl]sulfamoyl]-6-methoxy-pyridine-3-carboxylic acid methyl ester (84% purity, 500 mg, 0.690 mmol) in MeOH (8 mL) and the mixture was stirred for 1 hour. The reaction mixture was concentrated in vacuo and the residue was diluted with saturated aqueous NaHCO solution (25 mL) and extracted with EtOAc (3 x 25 mL). The combined organic layers were washed with brine (25 mL), dried over MgSO, filtered and concentrated in vacuo. The residue was purified by FCC (0-100% EtOAc in heptane) to give 5-[[2,4-difluoro-5-[2-(2-hydroxyethoxy)phenyl]phenyl]sulfamoyl]-6-methoxy-pyridine-3-carboxylic acid methyl ester (340 mg, 93% yield, 93% purity) as a white solid.

[0900] 1 H NMR (400MHz, CDCl3) δ8.98 (d, J=2.2Hz, 1H), 8.64 (d, J=2.2Hz, 1H), 7.71 (dd, J=9. 0, 7.6Hz, 1H), 7.38 (ddd, J=8.3, 7.4, 1.7Hz, 1H), 7.27–7.22 (m, 1H), 7.16 (s, 1H), 7 .09–7.01 (m, 1H), 7.00 (dd, J=8.3, 1.0Hz, 1H), 6.81 (dd, J=10.2, 9.3Hz, 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=6.5Hz, 1H).

[0901] LCMS: m / z=495.1 [M+H]+, (ESI+), RT=0.85, Method B

[0902] Step 5

[0903] At room temperature, 2M aqueous sodium hydroxide solution (1.7mL, 3.40mmol) is added to a stirred solution of 5-[[2,4-difluoro-5-[2-(2-hydroxyethoxy)phenyl]phenyl]sulfamoyl]-6-methoxy-pyridine-3-carboxylic acid methyl ester (93% purity, 350mg, 0.658mmol) in THF (10mL) and the mixture is stirred for 1 hour.THF is removed in vacuo, the remaining aqueous portion is diluted with water (30mL) and carefully acidified with 1M HCl aqueous solution until pH 3 is reached.The mixture is extracted with DCM (3x30mL).The combined organic layer is washed with brine (30mL), dried over MgSO4, filtered and concentrated in vacuo to obtain 5-[[2,4-difluoro-5-[2-(2-hydroxyethoxy)phenyl]phenyl]sulfamoyl]-6-methoxy-pyridine-3-carboxylic acid (227mg, 68% yield, 95% purity).

[0904] LCMS: m / z=481.1 [M+H]+, (ESI+), RT=0.73, Method B

[0905] Step 6

[0906] DCC (180 mg, 0.870 mmol) was added to a stirred solution of 5-[[2,4-difluoro-5-[2-(2-hydroxyethoxy)phenyl]phenyl]sulfamoyl]-6-methoxy-pyridine-3-carboxylic acid (95% purity, 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 hours. The reaction mixture was diluted with DCM (10 mL) and water (10 mL) and the two-phase mixture was separated. The aqueous layer was further extracted with DCM (2 x 10 mL). The combined organic layers were dried with MgSO4, filtered and concentrated in vacuo. The residue was purified by FCC (0-100% EtOAc 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]pentacos-1(23),2(7),3,5,13,15,17(25),20(24),21-nonen-12-one (158 mg, 69% yield, 88% purity) as a white solid.

[0907] 1H NMR (400MHz, DMSO) δ10.60 (s, 1H), 8.88 (d, J = 2.3Hz, 1H), 7.77 (d, J = 2.3Hz, 1H), 7.46 (ddd, J = 8.3, 7.4, 1.8Hz, 1H), 7 .34–7.24 (m, 2H), 7.19 (dd, J=8.3, 1.0Hz, 1H), 7.17–7.06 (m, 2H), 4.41–4.33 (m, 2H), 4.33–4.26 (m, 2H), 4.11 (s, 3H).

[0908] LCMS: m / z=463.1 [M+H]+, (ESI+), RT=0.89, Method B

[0909] Step 7

[0910] Iodocyclohexane (320 μL, 2.47 mmol) was added 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]pentacos-1(23),2(7),3,5,13,15,17(25),20(24),21-nonen-12-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 hours. The reaction was cooled to room temperature and diluted with water (10 mL) and DCM (10 mL) and the resulting two-phase mixture was separated. The aqueous layer was extracted with DCM (2 x 10 mL) and the combined organic layers were washed with brine (10 mL), dried over MgSO 4 , filtered and concentrated in vacuo. The residue was purified by basic reverse phase FCC (C18 SiO 2 column, 10-100% MeCN in H 2 O (0.1% NH 3 )) to afford the title compound (84 mg, 0.182 mmol, 73% yield, 97% purity) as a white solid.

[0911] 1 H NMR (400MHz, DMSO) δ13.03 (br s, 1H), 10.33 (br s, 1H), 8.29 (d, J=2.7Hz, 1H), 7.64 (d, J=2.7Hz, 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).

[0912] LCMS: m / z=449.1 [M+H]+, (ESI+), RT=2.77, Method A

[0913] 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]pentacosyl-1(23),2(7),3,5,13,17(25),20(24),21-octaene-12,16-dione (Compound 37)

[0914]

[0915] The title compound was synthesized using a similar synthetic route as Example 36.

[0916] 1 H NMR (400MHz, DMSO) δ12.98 (br.s, 1H), 10.30 (br.s, 1H), 8.26 (d, J=2.7Hz, 1H), 7.74 (d, J=2.6 Hz, 1H), 7.35 (dd, J=7.6, 2.2Hz, 1H), 7.27–7.06 (m, 5H), 4.36–4.26 (m, 2H), 4.26–4.15 (m, 2H).

[0917] LCMS: m / z=449.0 [M+H]+, (ESI+), RT=2.93, Method A

[0918] 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]pentacosyl-1(23),2(7),3,5,13,17(25),20(24),21-octaene-12,15-dione (Compound 38)

[0919]

[0920] The title compound was synthesized using a similar synthetic route to Example 48.

[0921] 1 H NMR (500MHz, DMSO) δ12.40 (s, 1H), 10.25 (s, 1H), 7.48–7.43 (m, 1H), 7.29 (dd, J=7.5, 1.8Hz, 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).

[0922] LCMS: m / z=447.0 [MH]-, (ESI-), RT=3.17, Method A

[0923] 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]hexaconazole-1(23),2(7),3,5,13,15,17(25),20(24),21-nonen-12-one (Compound 39)

[0924]

[0925] Step 1

[0926] 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 hours. After cooling to room temperature, 1M HCl aqueous solution (50 mL) and Et2O (40 mL) were added, and the two phase mixture was separated. The aqueous layer was extracted with additional Et2O (40 mL). The combined organic layer was extracted with 1M NaOH aqueous solution (2 x 60 mL). The alkaline aqueous extracts were combined and acidified with 6M HCl aqueous solution. The aqueous phase was extracted with Et2O (2 x 80 mL). The resulting organic phases were then combined, washed with brine, dried over MgSO4, filtered and concentrated to obtain 2-allyl-6-bromophenol (2.74 g, 84% yield; 95% purity), which was a brown oil.

[0927] 1 H NMR (500MHz, DMSO) δ9.01 (s, 1H), 7.35 (dd, J=8.0, 1.6Hz, 1H), 7.06 (dd, J=7.5, 1.6Hz, 1H), 6. 78–6.65 (m, 1H), 5.93 (ddt, J=18.0, 9.1, 6.6Hz, 1H), 5.07–4.99 (m, 2H), 3.38 (d, J=6.6Hz, 2H).

[0928] Step 2

[0929] To a solution of 2-allyl-6-bromophenol (95% purity, 2.74 g, 12.2 mmol) in CHCl (120 mL) was added mCPBA (70% purity, 4.52 g, 18.3 mmol) and trifluoroacetic acid (0.093 mL, 1.22 mmol). The mixture was stirred at 65 ° C for 2.5 hours. Additional trifluoroacetic acid (0.093 mL, 1.22 mmol) was added and the mixture was stirred at 65 ° C for 2 hours. The mixture was cooled to room temperature, washed with NaHCO (2 x 70 mL) and then with brine (70 mL), dried over MgSO, filtered and concentrated. The residue was purified by FCC (100 g SiO2 column, 0-100% EtOAc in heptane) to give (7-bromo-2,3-dihydrobenzofuran-2-yl)methanol (1.73 g, 57% yield, 93% purity) as a light yellow oil.

[0930] 1 H NMR (500MHz, DMSO) δ7.26 (d, J=7.9Hz, 1H), 7.20–7.09 (m, 1H), 6.77–6.57 (m, 1H), 5.03 (dd, J=5.5, 5.5Hz, 1H), 4.93–

[0931] 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, 7.6Hz, 1H).

[0932] Step 3

[0933] A mixture of 2,4-difluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (85% purity, 670 mg, 2.23 mmol), (7-bromo-2,3-dihydrobenzofuran-2-yl)methanol (93% purity, 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)Cl (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 EtOAc, and the filtrate was concentrated. The residue was purified by FCC (50 g SiO2 column, 0-100% EtOAc 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.

[0934] 1 H NMR (400MHz, DMSO) δ7.22–7.17 (m, 1H), 7.06 (dd, J=11.4, 9.9Hz, 1H), 7.03–6.95 (m, 1H), 6.90–6.77 (m, 2H), 5.00 (s, 2H), 4.91 (dd, J=5.6, 5.6Hz, 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).

[0935] LCMS: m / z=278.0 [M+H]+, (ESI+), RT=0.78, Method B

[0936] Step 4

[0937] 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 1M HCl aqueous solution (30 mL) and extracted with EtOAc (3 x 30 mL). The combined organic extracts were washed with brine (50 mL), dried over Na SO , filtered and concentrated under reduced pressure. The residue was purified by FCC (50 g SiO column, 0-100% EtOAc in heptane) to give 3-chloro-5-[[2,4-difluoro-5-[2-(hydroxymethyl)-2,3-dihydrobenzofuran-7-yl]phenyl]sulfamoyl]-4-methoxy-benzoic acid methyl ester (790 mg, 66% yield, 85% purity) as a light yellow solid.

[0938] 1 H NMR (400MHz, DMSO) δ10.38 (s, 1H), 8.26 (d, J = 2.1Hz, 1H), 8.16 (d, J = 2.2Hz, 1H ), 7.38–7.28 (m, 2H), 7.24 (dd, J=7.3, 1.3Hz, 1H), 6.99 (d, J=7.7Hz, 1H), 6.91 –6.85 (m, 1H), 4.89 (dd, J=5.5, 5.5Hz, 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, 7.2Hz, 1H).

[0939] LCMS: m / z=538.1 / 540.1 [MH]-, (ESI-), RT=1.00, Method B

[0940] Step 5

[0941] 3-Chloro-5-[[2,4-difluoro-5-[2-(hydroxymethyl)-2,3-dihydrobenzofuran-7-yl]phenyl]sulfamoyl]-4-methoxy-benzoic acid methyl ester (85% purity, 785 mg, 1.24 mmol) was dissolved in THF (9 mL) and 2M aqueous sodium hydroxide solution (3.0 mL, 6.00 mmol) was added. The reaction mixture was stirred at room temperature for 4 hours. The THF was removed in vacuo, and the remaining aqueous portion was diluted with water (30 mL) and acidified with 1M aqueous HCl. The mixture was extracted with DCM (3 x 30 mL) and the combined organics passed through a phase separator then concentrated to give 3-chloro-5-[[2,4-difluoro-5-[2-(hydroxymethyl)-2,3-dihydrobenzofuran-7-yl]phenyl]sulfamoyl]-4-methoxy-benzoic acid (784 mg, quantitative yield, 86% purity) as an off-white solid.

[0942] 1 H NMR (500MHz, DMSO) δ13.66 (br.s, 1H), 10.34 (br.s, 1H), 8.22 (d, J=2.0Hz, 1H), 8. 15 (d, J=2.0Hz, 1H), 7.38–7.28 (m, 2H), 7.23 (dd, J=7.3, 1.3Hz, 1H), 6.97 (d, J=7. 7Hz, 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=4.7Hz, 2H), 3.25 (dd, J=15.9, 9.4Hz, 1H), 3.08 (dd, J=15.9, 7.2Hz, 1H).

[0943] LCMS: m / z=524.0 / 526.1 [MH]-, (ESI-), RT=0.87, Method B

[0944] Step 6

[0945] 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% purity, 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 hours. The mixture was diluted with water (40 mL) and the two phase mixture was separated. The aqueous solution was extracted with additional DCM (2 x 30 ml), and the combined organics were passed through a phase separator and concentrated. The residue was purified by FCC (25 g SiO2 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]hexacontac-1(23),2(7),3,5,13,15,17(25),20(24),21-nonen-12-one (451 mg, 70% yield, 93% purity) as a white solid.

[0946] Step 7

[0947] 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]hexaconazole-1(23),2(7),3,5,13,15,17(25),20(24),21-nonen-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 bottle. The bottle was sealed and heated at 120° C. for 1 hour and 45 minutes. The reaction mixture was cooled to room temperature, and saturated aqueous NaHCO 3 solution (30 mL) was added and the two phases were separated. The aqueous phase was extracted with EtOAc (2×30 mL). The organic extracts merged were washed with a saturated aqueous solution of Na2S2O3 (40 mL), a 1M HCl aqueous solution (40 mL), water (40 mL), then washed with salt water (40 mL), and dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by FCC (10 g SiO2 column, 0-20% MeOH in DCM) to give the title compound (105 mg, 77% yield, 99% purity) as a white solid.

[0948] 1H NMR (500MHz, DMSO) δ8.43–8.33 (m, 1H), 7.85–7.76 (m, 1H), 7.74 (dd, J=8.3, 8 .3Hz, 1H), 7.36 (dd, J=10.3, 10.3Hz, 1H), 7.27 (d, J=7.3Hz, 1H), 7.18–7.10( m, 1H), 6.92 (dd, J=7.5, 7.5Hz, 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, 9.1Hz, 1H), 2.97 (dd, J=15.9, 7.3Hz, 1H).

[0949] LCMS: m / z=492.0 / 494.0 [MH]-, (ESI-), RT=4.05, Method A

[0950] 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]hexaconestra-1(23),2(7),3,5,13,15,17(25),20(24),21-nonaen-12-one, Enantiomer 1 (Compound 40)

[0951] 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]hexaconestra-1(23),2(7),3,5,13,15,17(25),20(24),21-nonen-12-one, Enantiomer 2 (Compound 41)

[0952]

[0953] (7-Bromo-2,3-dihydrobenzofuran-2-yl)methanol (synthesized as in Example 39, Step 2; 977 mg, 4.2 mmol) was purified by chiral SFC (Chiralpak IG column, 21 x 250 mm, 5 μm; flow rate 50 mL / min; 20% MeOH / 80% CO2 (with 0.2% v / v NH3) as mobile phase) to give two components:

[0954] 7-Bromo-2,3-dihydrobenzofuran-2-yl)methanol, enantiomer 1 (355 mg, brown oil)

[0955] 1H NMR (500MHz, DMSO) δ7.28–7.24 (m, 1H), 7.19–7.16 (m, 1H), 6.74 (dd, J=8.0, 7.3Hz, 1H), 5.03 (t, J=5.4Hz , 1H), 4.88 (dddd, J=9.3, 7.7, 5.0, 4.1Hz, 1H), 3.67–3.55 (m, 2H), 3.31–3.27 (m, 1H), 3.15–3.09 (m, 1H).

[0956] Chiral analytical SFC: RT = 2.02 min (Chiralpak IG column, 4.6 x 250 mm, 5 μm; flow rate 4 mL / min; 20% MeOH / 80% CO2 containing 0.1% v / v NH3 as mobile phase)

[0957] 7-Bromo-2,3-dihydrobenzofuran-2-yl)methanol, enantiomer 2 (366 mg, brown oil)

[0958] 1 H NMR (500MHz, DMSO) δ7.28–7.24 (m, 1H), 7.19–7.16 (m, 1H), 6.74 (dd, J=8.0, 7.3Hz, 1H), 5.03 (t, J=5.5Hz , 1H), 4.88 (dddd, J=9.3, 7.7, 5.0, 4.1Hz, 1H), 3.67–3.55 (m, 2H), 3.31–3.26 (m, 1H), 3.15–3.09 (m, 1H).

[0959] Chiral analytical SFC: RT = 2.75 min (Chiralpak IG column, 4.6 x 250 mm, 5 μm; flow rate 4 mL / min; 20% MeOH / 80% CO2 containing 0.1% v / v NH3 as mobile phase)

[0960] 7-bromo-2,3-dihydrobenzofuran-2-yl)methanol, Enantiomer 1 (355 mg) was used in a similar synthetic sequence as described in Example 39 to give Example 40: 15-chloro-21,23-difluoro-16-hydroxy-

[0961] 18,18-Dioxo-8,11-dioxa-18λ6-thia-19-azapentacyclo[18.3.1.16,9.113,17.02,7]hexacones-1(23),2(7),3,5,13,15,17(25),20(24),21-nonen-12-one, Enantiomer 1 (60 mg, 99% purity) as a pink solid.

[0962] 1H NMR (500MHz, DMSO) δ8.47 (d, J=2.1Hz, 1H), 8.04 (d, J=2.1Hz, 1H), 7.83–7.76 (m, 1H), 7.48–7.40 (m, 1H), 7.30 (dd, J=

[0963] 7.4, 1.2Hz, 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, 3.7H z, 1H), 4.23 (dd, J=11.7, 10.7Hz, 1H), 3.40 (dd, J=16.0, 9.3Hz, 1H), 3.00 (dd, J=16.0, 6.2Hz, 1H).

[0964] LCMS: m / z=492.0 / 494.0 [MH]-, (ESI-), RT=3.97, Method A

[0965] 7-bromo-2,3-dihydrobenzofuran-2-yl)methanol, enantiomer 2 (366 mg) was used in a similar synthetic sequence as described in Example 39 to give Example 41: 15-chloro-21,23-difluoro-16-hydroxy-

[0966] 18,18-Dioxo-8,11-dioxa-18λ6-thia-19-azapentacyclo[18.3.1.16,9.113,17.02,7]hexaconac-1(23),2(7),3,5,13,15,17(25),20(24),21-nonen-12-one, Enantiomer 2 (37 mg, 100% purity) as a light brown solid.

[0967] 1 H NMR (500MHz, DMSO) δ8.47 (d, J=2.1Hz, 1H), 8.03 (d, J=2.1Hz, 1H), 7.82–7.75 (m, 1H), 7.48–7.40 (m, 1H), 7.29 (dd, J=

[0968] 7.3, 1.2Hz, 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, 3.7H z, 1H), 4.23 (dd, J=11.7, 10.7Hz, 1H), 3.39 (dd, J=16.2, 9.5Hz, 1H), 3.00 (dd, J=16.0, 6.2Hz, 1H).

[0969] LCMS: m / z=492.0 / 494.0 [MH]-, (ESI-), RT=3.98, Method A

[0970] 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]pentacosyl-1(23),2(7),3,5,13,15,17(25),20(24),21-nonen-12-one (Compound 42)

[0971]

[0972] 15-Chloro-21-fluoro-16-methoxy-18,18-dioxo-11-oxa-18λ6-thia-19-azatetracyclo[18.3.1.113,17.02,7]pentacosyl-1(23),2(7),3,5,13,15,17(25),20(24),21-nonen-12-one (synthesized using a similar method to intermediate 12, 95% purity, 100 mg, 0.20 mmol) and iodocyclohexane (210 mg, 1.00 mmol) were combined and the mixture was dissolved in anhydrous DMF (3 mL). The mixture was heated to 120° C. and stirred for 2 hours. The reaction mixture was cooled to room temperature and saturated aqueous Na2S2O3 (50 mL) was added. The two phase mixture was separated and the aqueous phase was extracted with DCM (3×50 mL). The combined organic extracts were washed with 1M HCl aqueous solution (50 mL), then washed with brine (50 mL) and dried over NaSO, 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.

[0973] 1 H NMR (500MHz, DMSO) δ7.97 (d, J=2.2Hz, 1H), 7.73 (d, J=2.2Hz, 1H), 7.42–7.36 (m, 3H), 7.29–7.24 (m, 1H), 7.16 (dd, J=7.5, 1.4Hz , 1H), 7.11 (dd, J=10.2, 8.4Hz, 1H), 7.00 (ddd, J=8.4, 4.7, 2.3Hz, 1H), 4.22–4.16 (m, 2H), 2.58–2.53 (m, 2H), 1.92–1.83 (m, 2H).

[0974] LCMS: m / z=460.1 / 462.1 [MH]-, (ESI-), RT=4.25, Method A

[0975] 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]pentacosyl-1(23),2(7),3,5,13,15,17(25),20(24),21-nonen-12-one (Compound 43)

[0976]

[0977] Step 1

[0978] At-15 ℃, thionyl chloride (1.8mL, 24.8mmol) is carefully added dropwise to a stirred solution of 3-(2-bromophenyl) butyric acid (500mg, 2.06mmol) in MeOH (15mL) and the mixture is stirred at room temperature for 16 hours. The mixture is concentrated in vacuo and gained material is dissolved in water (10mL) and EtOAc (10mL) and separated. Water layer is further extracted by EtOAc (2x 10mL) and the organic layer washed with salt water (10mL) merged, uses MgSO4 drying, filtration and vacuum concentration. Residue passes through FCC purifying (SiO2, the heptane solution of 0-100% EtOAc), to obtain 3-(2-bromophenyl) butyric acid methyl esters (470mg, 84% productive rate, 95% purity), it is colorless oil.

[0979] 1 H NMR (400MHz, DMSO) δ7.58 (dd, J=8.0, 1.3Hz, 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=6.9Hz, 3H).

[0980] LCMS: m / z=257.0 / 259.0 [M+H]+, (ESI+), RT=0.96, Method B

[0981] Step 2

[0982] The solution of 3-(2-bromophenyl) butyric acid methyl ester (95% purity, 450mg, 1.66mmol) in anhydrous THF (9.5mL) is cooled to 0 ℃ and DIBAL (1M in THF) (3.7mL, 3.70mmol) is added dropwise to the reaction solution.And the mixture is stirred for 2 hours.Saturated potassium sodium tartrate aqueous solution (20mL) and EtOAc (20mL) are added to the reaction and the gained mixture is stirred at room temperature for 1 hour.The mixture is separated and the water layer is further extracted with EtOAc (2x 20mL).The organic layer merged is washed with salt water (20mL), uses MgSO4 drying, filters and is concentrated in vacuo to obtain 3-(2-bromophenyl) butan-1-ol (360mg, 92% yield, 97% purity), it is colorless oil.

[0983] 1 H NMR (400MHz, DMSO) δ7.60–7.52 (m, 1H), 7.38–7.30 (m, 2H), 7.19–7.06 (m, 1H), 4. 40 (t, J=5.0Hz, 1H), 3.42–3.18 (m, 3H), 1.85–1.61 (m, 2H), 1.16 (d, J=6.9Hz, 3H).

[0984] Step 3

[0985] In room temperature, tert-butyldimethylsilyl chloride (490mg, 3.25mmol) is added to 3-(2-bromophenyl) butan-1-ol (97% purity, 350mg, 1.48mmol), N, N-diethylethylamine (0.45mL, 3.23mmol) and DMAP (18mg, 0.147mmol) in a stirred solution in anhydrous DCM (20mL) and the mixture is stirred for 16 hours. The mixture is quenched with water (20mL) and extracted with DCM (3x 20mL). The organic layer merged is washed with salt water (30mL), used MgSO4 is dried, filtered and concentrated in vacuo. Residue passes through FCC purifying (SiO2, the heptane solution of 0-100% EtOAc), to obtain 3-(2-bromophenyl) butoxy-tert-butyl-dimethylsilane (310mg, 60% productive rate, 98% purity), which is a colorless oil.

[0986] 1H NMR (400MHz, DMSO) δ7.60–7.53 (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=6.9Hz, 3H), 0.84 (s, 9H), -0.01–-0.06 (m, 6H).

[0987] Step 4

[0988] A stirred solution of 2,4-difluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (90% purity, 298 mg, 1.05 mmol), 3-(2-bromophenyl)butoxy-tert-butyl-dimethylsilane (97% purity, 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)Cl2 (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 EtOAc (3 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by FCC (SiO2, 0-50% EtOAc 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.

[0989] LCMS: m / z=392.3 [M+H]+, (ESI+), RT=1.20, Method C

[0990] Step 5

[0991] Intermediate 1 (50% purity, 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-phenylamine (97% purity, 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 (SiO , 0-100% EtOAc in heptane) to give 3-[[5-[2-[3-[tert-butyl(dimethyl)silyl]oxy-1-methyl-propyl]phenyl]-2,4-difluoro-phenyl]sulfamoyl]-5-chloro-4-methoxy-benzoic acid methyl ester (420 mg, 0.578 mmol, 78% yield, 90% purity) as a colorless oil.

[0992] LCMS: m / z=654.2 / 656.2 [M+H]+, (ESI+), RT=1.25, Method C

[0993] Step 6

[0994] To a stirred solution of methyl 3-[[5-[2-[3-[tert-butyl(dimethyl)silyl]oxy-1-methyl-propyl]phenyl]-2,4-difluoro-phenyl]sulfamoyl]-5-chloro-4-methoxy-benzoate (90% purity, 400 mg, 0.550 mmol) in methanol (10 mL) at room temperature was added p-toluenesulfonic acid hydrate (10 mg, 0.0550 mmol) 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 EtOAc (3 x 25 mL). The combined organic layers were washed with brine (25 mL), dried over MgSO , filtered and concentrated in vacuo. The residue was purified by FCC (SiO2, 0-100% EtOAc in heptane) to give 3-chloro-5-[[2,4-difluoro-5-[2-(3-hydroxy-1-methyl-propyl)phenyl]phenyl]sulfamoyl]-4-methoxy-benzoic acid methyl ester (310 mg, 79% yield, 76% purity) as a white solid.

[0995] 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 was not visible.

[0996] LCMS: m / z=540.1 / 541.9 [M+H]+, (ESI+), RT=0.99, Method B

[0997] Step 7

[0998] 2M aqueous sodium hydroxide solution (0.65 mL, 1.31 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-methoxy-benzoic acid methyl ester (76% purity, 310 mg, 0.436 mmol) in THF (10 mL) and the mixture was stirred for 2 hours. The mixture was concentrated in vacuo and then diluted with water (10 mL), acidified with 1M HCl (10 mL) and extracted with DCM (3 x 10 mL). The combined organic layers were washed with brine (10 mL), dried over MgSO 4 , filtered and concentrated in vacuo to give 3-chloro-5-[[2,4-difluoro-5-[2-(3-hydroxy-1-methyl-propyl)phenyl]phenyl]sulfamoyl]-4-methoxy-benzoic acid (210 mg, 71% yield, 78% purity) as a white solid.

[0999] LCMS (MSQ2, acidic 2 min): [M+H]+ m / z 526.0 / 528.0, RT 0.86 min.

[1000] 1 H 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 were not visible.

[1001] LCMS: m / z=526.0 / 528.0 [M+H]+, (ESI+), RT=0.86, Method B

[1002] Step 8

[1003] DCC (122 mg, 0.593 mmol) is 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 is stirred at room temperature for 2 hours. The mixture is diluted with water (20 mL) and DCM (10 mL) and the two-phase mixture is separated. The aqueous layer is further extracted with DCM (2 x 10 mL). The combined organic layer is washed with brine (20 mL), dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by FCC (SiO2, 0-100% EtOAc 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-nonen-12-one (120 mg, 72% yield, 90%) as a white solid.

[1004] 1 H NMR (400MHz, DMSO) δ10.71 (s, 1H), 8.16 (d, J = 2.2Hz, 1H), 7.78 (d, J = 2.2Hz, 1H), 7.59–7.36 (m, 3H), 7.36–7.25 (m, 2H), 7.26–7.1 3 (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=6.7Hz, 3H).

[1005] LCMS: m / z=506.1 / 508.2 [MH]-, (ESI-), RT=1.10, Method B

[1006] Step 9

[1007] 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]pentacos-1(23),2(7),3,5,13,15,17(25),20(24),21-nonen-12-one (90% purity, 120 mg, 0.213 mmol) in anhydrous DMF (5 mL) and the mixture was heated at 120° C. for 3 hours. The mixture was cooled to room temperature, diluted with H 2 O (20 mL) and DCM (20 mL), and separated. The aqueous layer was washed with DCM (2 x 20 mL) and the combined organic layers were washed with brine (30 mL), dried over MgSO , filtered and concentrated in vacuo. The residue was purified by FCC (C 18 -SiO 2 , 10-100% MeCN in H 2 O (0.1% NH 3 )), then dissolved in DCM (10 mL) and washed with 1 M HCl solution (3 x 10 mL), concentrated, and dried in a vacuum oven to give the title compound (65 mg, 61% yield, 99% purity) as a white solid.

[1008] 1 H NMR (500MHz, DMSO) δ8.04–7.93 (m, 1H), 7.73 (d, J=2.1Hz, 1H), 7.51–7.37 (m, 3H), 7.34–7.26 (m, 2H), 7.19 (d, J= 7.5Hz, 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=6.7Hz, 3H).

[1009] LCMS: m / z=492.0 / 494.0 [MH]-, (ESI-), RT=4.41, Method A

[1010] 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]pentacosyl-1(23),2(7),3,5,13,15,17(25),20(24),21-nonen-12-one, Enantiomer 1 (Compound 44)

[1011] 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]pentacosyl-1(23),2(7),3,5,13,15,17(25),20(24),21-nonen-12-one, Enantiomer 2 (Compound 45)

[1012]

[1013] 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% MeOH / 90% CO2 as mobile phase) to give two components:

[1014] Example 44: 13.2 mg, 99% purity, >99% ee

[1015] 1 H NMR (500MHz, DMSO) δ8.00–7.93 (m, 1H), 7.72 (d, J=2.2Hz, 1H), 7.50–7.37 (m, 3H), 7.33–7.24 (m, 2H), 7.18 (dd, J=7 .6, 1.3Hz, 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=6.7Hz, 3H).

[1016] LCMS: m / z=492.1 / 494.1 [MH]-, (ESI-), RT=4.38, Method A

[1017] Chiral analytical SFC: RT = 3.18 min (Chiralcel OJ-H column, 4.6 x 250 mm, 5 μm; flow rate 4 mL / min; 20% MeOH / 80% CO2 as mobile phase)

[1018] Example 45: 14.8 mg, 98% purity, 92% ee

[1019] 1H NMR (500MHz, DMSO) δ7.90–7.83 (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 , 1.3Hz, 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=6.8Hz, 3H).

[1020] LCMS: m / z=492.1 / 494.0 [MH]-, (ESI-), RT=4.39, Method A

[1021] Chiral analytical SFC: RT = 3.87 min (Chiralcel OJ-H column, 4.6 x 250 mm, 5 μm; flow rate 4 mL / min; 20% MeOH / 80% CO2 as mobile phase)

[1022] 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]pentacosyl-1(23),2(7),3,5,13,15,17(25),20(24),21-nonen-12-one (Compound 46)

[1023]

[1024] 15-Chloro-4,21-difluoro-16-methoxy-18,18-dioxo-8,11-dioxa-18λ6-thia-19-azatetracyclo[18.3.1.113,17.02,7]pentacosyl-1(23),2(7),3,5,13,15,17(25),20(24),21-nonen-12-one (synthesized using a similar method to Intermediate 12, 98% purity, 1.70 g, 3.36 mmol) and iodocyclohexane (3.50 g, 16.7 mmol) were combined and the mixture was dissolved in anhydrous DMF (50 mL). The mixture was heated to 120° C. and stirred for 3 hours. The reaction mixture was cooled to room temperature and saturated aqueous Na2S2O3 solution (100 mL) was added to the reaction mixture. The two phases were separated and the aqueous phase was extracted with DCM (3×100 mL). The combined organic extracts were washed with 1M HCl aqueous solution (100 mL), then washed with brine (100 mL) and dried over NaSO, filtered and concentrated in vacuo. The residue was purified by FCC (100 g SiO column, 0-100% gradient with DCM in heptane, then eluted with 0-40% MeOH in DCM) to give the title compound (820 mg, 1.68 mmol, 50% yield, 99% purity) as a white solid.

[1025] 1 H NMR (500MHz, DMSO) δ11.63–9.75 (m, 2H), 8.04 (d, J = 2.1Hz, 1H), 7.61 (d, J = 2.1Hz, 1H), 7.41 (dd, J = 7.5, 2.2Hz, 1H), 7.26–7.20 (m, 3H), 7.19–7.15 (m, 1H), 7.13 (dd, J=10.1, 8.5Hz, 1H), 4.38–4.32 (m, 2H), 4.28–4.23 (m, 2H).

[1026] LCMS: m / z=480.0 / 482.0 [MH]-, (ESI-), RT=4.04, Method A

[1027] 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]pentacosyl-1(23),2(7),3,5,13(25),14,16,20(24),21-nonen-12-one (Compound 47)

[1028]

[1029] 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]twenty-five-1(23),2(7),3,5,13(25),14,16,20(24),21-nonen-12-one (synthesized using a similar method to intermediate 12, 100% purity, 100 mg, 0.197 mmol) in DMF (2.5 mL). The reaction was heated to 80° C. for 40 hours. The reaction was cooled and quenched with saturated NaHCO3 aqueous solution (20 mL). The two phase mixture was separated and the aqueous layer was extracted into EtOAc (3×10 mL). The combined organics were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by FCC chromatography (10 g SiO2 column, 50-100% EtOAc in heptane) followed by preparative HPLC (Method P1) to afford the title compound (20 mg, 20% yield, 96% purity) as a white solid.

[1030] 1 H NMR (500MHz, DMSO) δ10.04 (s, 1H), 8.02 (s, 1H), 7.51 (d, J = 2.1Hz, 1H), 7.39–7.32 (m, 1H), 7.1 4(dd, J=7.5, 1.8Hz, 1H), 7.10–7.05(m, 2H), 7.03–6.98(m, 1H), 6.85(d, J=12.2Hz, 1H), 4.35–

[1031] 4.30 (m, 2H), 4.25–4.21 (m, 2H), 3.60 (s, 3H).

[1032] LCMS: m / z=492.0 / 494.0 [M+H]+, (ESI+), RT=3.88, Method A

[1033] 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]pentacosyl-1(23),2(7),3,5,13(25),14,16,20(24),21-nonen-12-one (Compound 48)

[1034]

[1035] 15-Chloro-5,21-difluoro-16-methoxy-18,18-dioxo-8,11-dioxa-18λ6-thia-19-azatetracyclo[18.3.1.113,17.02,7]pentacosyl-1(23),2(7),3,5,13(25),14,16,20(24),21-nonen-12-one (synthesized using a similar method 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 bottle. The bottle was sealed and heated at 120° C. for 1.5 hours. The reaction mixture was cooled to room temperature, and saturated aqueous NaHCO 3 solution (30 mL) was added, and the two phases were separated. The aqueous phase was extracted with EtOAc (2×30 mL). The organic extracts were saturated with Na2S2O3 aqueous solution (40 mL), 1M HCl aqueous solution (40 mL), water (40 mL), then washed with salt water (40 mL), and dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by FCC (10 g SiO2 column, 0-20% MeOH in DCM) to give the title compound (67 mg, 60% yield, 99% purity) as a white solid.

[1036] 1 H NMR (500MHz, DMSO) δ12.24–9.38 (m, 2H), 8.03 (d, J=2.2Hz, 1H), 7.71 (d, J=2.1Hz, 1H), 7.35 (dd, J=7.6, 2.1Hz, 1H), 7. 28 (dd, J=8.4, 6.9Hz, 1H), 7.21–7.07 (m, 3H), 6.88 (ddd, J=8.4, 8.4, 2.5Hz, 1H), 4.44–4.36 (m, 2H), 4.33–4.19 (m, 2H)

[1037] LCMS: m / z=480.0 / 482.0 [MH]-, (ESI-), RT=4.07, Method A

[1038] 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]pentacosyl-1(23),2(7),3,5,13(25),14,16,20(24),21-nonen-12-one (Compound 49)

[1039]

[1040] 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]pentacosyl-1(23),2(7),3,5,13(25),14,16,20(24),21-nonen-12-one (synthesized using a similar method 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 bottle. The bottle was sealed and heated at 120° C. for 1.25 hours and then cooled to room temperature. The mixture was purified by preparative HPLC (Method P1) to give a yellow solid. This was then triturated with Et2O (~5 mL) and filtered to give the title compound (61 mg, 65% yield, 99% purity) as a white solid.

[1041] 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). OH and NH were not observed.

[1042] LCMS: m / z=494.0 / 496.0 [MH]-, (ESI-), RT=4.12, Method A

[1043] 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]pentacosyl-1(23),2(7),3,5,13(25),14,16,20(24),21-nonen-12-one (Compound 50)

[1044]

[1045] 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]pentacos-1(23),2(7),3,5,13(25),14,16,20(24),21-nonen-12-one (synthesized using a similar method 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 bottle. The bottle was sealed and heated at 120° C. for 2 hours and then cooled to room temperature. To the 4-thiazolinyl methyl ester (50mg, 1.3mmol) of 4-nitropropane-2-ol (50mg, 2.5mmol) of 4-nitropropane-2-ol ...

[1046] 1 H NMR (400MHz, DMSO) δ8.02 (d, J=2.2Hz, 1H), 7.56 (d, J=2.1Hz, 1H), 7.40 (ddd, J=8.3, 7.4, 1.8Hz, 1H), 7.17–7.11 (m, 3 H), 7.08–7.03 (m, 1H), 6.99 (d, J=11.2Hz, 1H), 4.52–4.43 (m, 1H), 4.38–4.28 (m, 2H), 4.11–4.02 (m, 1H), 1.98 (s, 3H).

[1047] LCMS: m / z=476.1 / 478.1 [MH]-, (ESI-), RT=4.19, Method A

[1048] 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]pentacosyl-1(23),2(7),3,5,13(25),14,16,20(24),21-nonen-12-one (Compound 51)

[1049]

[1050] 15-Chloro-21,24-difluoro-16-methoxy-18,18-dioxo-8,11-dioxa-18λ6-thia-19-azatetracyclo[18.3.1.113,17.02,7]pentacos-1(23),2(7),3,5,13(25),14,16,20(24),21-nonen-12-one (synthesized using a similar method 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 bottle. The bottle was sealed and heated at 120° C. for 2 hours and then cooled to room temperature. To the 4-thiazolinyl methyl ester (50mg, 1.37mmol) of 4-nitropropene (2.5 ...

[1051] 1 H NMR (400MHz, DMSO) δ8.08 (d, J=2.1Hz, 1H), 7.90 (dd, J=2.2, 1.2Hz, 1H), 7.40 (ddd, J=8.3, 7.3, 1.8Hz, 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, 1.8Hz, 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).

[1052] LCMS: m / z=480.0 / 482.0 [MH]-, (ESI-), RT=3.91, Method A

[1053] 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]pentacosyl-1(23),2(7),3,5,13,15,17(25),20(24),21-nonen-12-one (Compound 52)

[1054]

[1055] 4,15-Dichloro-21-fluoro-16-methoxy-18,18-dioxo-8,11-dioxa-18λ6-thia-19-azatetracyclo[18.3.1.113,17.02,7]pentacos-1(23),2(7),3,5,13,15,17(25),20(24),21-nonen-12-one (synthesized using a similar method to Intermediate 12, 95% purity, 55 mg, 0.102 mmol) and iodocyclohexane (68 μL, 0.524 mmol) were added to a pressure bottle and the mixture was diluted to anhydrous DMF (2.5 mL). The bottle was sealed, heated to 120° C. and stirred for 3 hours. 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 salt water (100 mL), dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue was purified by FCC (10 g SiO 2 column, 0-100% MeOH in DCM) and then purified by preparative HPLC (method P2) to give the title compound (23 mg, 45% yield, 99% purity) as a white solid.

[1056] 1 H NMR (500MHz, DMSO) δ11.96–9.79 (m, 2H), 7.97 (d, J=2.2Hz, 1H), 7.59 (d, J=2.1Hz, 1H), 7.37 (dd, J=8.8, 2.7Hz, 1H), 7.32 (dd, J= 7.5, 2.2Hz, 1H), 7.26 (d, J=2.7Hz, 1H), 7.17–7.12 (m, 2H), 7.08 (dd, J=10.1, 8.5Hz, 1H), 4.33–4.27 (m, 2H), 4.24–4.17 (m, 2H).

[1057] LCMS: m / z=496.0 / 498.0 / 500.1 [MH]-, (ESI-), RT=4.29, Method A

[1058] 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-decene-15-one (Compound 53)

[1059]

[1060] 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-decene-15-one (synthesized using a similar method 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 solution (30 mL) and extracted with EtOAc (2×30 mL). The organic 10% aqueous citric acid solution (30mL) and salt solution (40mL) of merging are washed, then dried (NaSO), filtered and concentrated.Residue passes through FCC purification (10g SiO column, 0-20% MeOH in DCM), then passes through preparation HPLC purification (method P1) to obtain title compound (32mg, 43% yield, 99% purity), it is white solid.

[1061] 1 H NMR (500MHz, DMSO) δ13.09 (s, 1H), 11.75–9.80 (m, 2H), 8.06–8.00 (m, 2H), 7.47 (s, 1 H), 7.46 (d, J=2.2Hz, 1H), 7.43–7.35 (m, 2H), 7.26–7.17 (m, 1H), 4.39–4.22 (m, 4H).

[1062] LCMS: m / z=520.2 / 522.1 [MH]-, (ESI-), RT=3.44, Method A

[1063] 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]pentacosyl-1(23),2(7),3,5,13(25),14,16,20(24),21-nonen-12-one (Compound 54)

[1064]

[1065] To 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]pentacos-1(23),2(7),3,5,13(25),14,16,20(24),21-nonen-12-one (synthesized using a similar method to intermediate 12, 92% purity, 103 mg, 0.191 mmol) in anhydrous DMF (2.5 mL) was added iodocyclohexane (124 μL, 0.955 mmol) and then heated to 120°C in a pressure bottle for 1.5 hours. 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.

[1066] 1 H NMR (400MHz, DMSO) δ8.13–8.03 (m, 1H), 7.73 (d, J=2.1Hz, 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).

[1067] LCMS: m / z=480.2 / 482.2 [MH]-, (ESI-), RT=4.20, Method A

[1068] 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]pentacosyl-1(23),2(7),3,5,13(25),14,16,20(24),21-nonen-12-one (Compound 55)

[1069]

[1070] To a solution of 15-chloro-21-(difluoromethoxy)-16-methoxy-18,18-dioxo-8,11-dioxa-18λ-thia-19-azatetracyclo[18.3.1.113,17.02,7]pentacos-1(23),2(7),3,5,13(25),14,16,20(24),21-nonen-12-one (synthesized using a similar method to Intermediate 12, 100% purity, 123 mg, 0.234 mmol) in anhydrous DMF (3 mL) was added iodocyclohexane (151 μL, 1.17 mmol) and then heated to 120° C. in a pressure bottle for 1 hour. 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.

[1071] 1 H NMR (400MHz, DMSO) δ10.92 (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).

[1072] LCMS: m / z=510.3 / 512.3 [MH]-, (ESI-), RT=4.20, Method A

[1073] 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]pentacosyl-1(23),2(7),3,5,13(25),14,16,20(24),21-nonen-12-one (Compound 56)

[1074]

[1075] 15-Chloro-16-methoxy-18,18-dioxo-21-(trifluoromethoxy)-8,11-dioxa-18λ6-thia-19-azatetracyclo[18.3.1.113,17.02,7]pentacos-1(23),2(7),3,5,13(25),14,16,20(24),21-nonen-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 bottle. The bottle was sealed and heated at 120° C. for 2 hours and then cooled to room temperature. The organic matter was diluted with EtOAc (20 mL), washed with 1M HCl aqueous solution (10 mL), NaSO (10 mL saturated aqueous solution) and then with brine (10 mL), dried over MgSO, 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.

[1076] 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). OH and NH were not observed.

[1077] LCMS: m / z=528.1 / 530.1 [MH]-, (ESI-), RT=4.35, Method A

[1078] Example 57 - Synthesis of 15-chloro-21-cyclopropyl-16-hydroxy-18,18-dioxo-8,11-dioxa-18λ6-thia-19-azatetracyclo[18.3.1.113,17.02,7]pentacosyl-1(23),2(7),3,5,13(25),14,16,20(24),21-nonen-12-one (Compound 57)

[1079]

[1080] 15-Chloro-21-cyclopropyl-16-methoxy-18,18-dioxo-8,11-dioxa-18λ6-thia-19-azatetracyclo[18.3.1.113,17.02,7]pentacos-1(23),2(7),3,5,13(25),14,16,20(24),21-nonen-12-one (synthesized using a similar method 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 bottle. The bottle was sealed and heated at 120° C. for 2 hours and then cooled to room temperature. The organic matter was diluted with EtOAc (30 mL), washed with 1M HCl aqueous solution (20 mL), then Na SO (20 mL of 1M aqueous solution) washed, then washed with brine (20 mL), used Na SO dried, 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 a pale white solid.

[1081] 1 H NMR (500MHz, DMSO) δ10.99 (br.S, 1H), 10.04 (br.S, 1H), 7.99 (d, J=2.2Hz, 1H), 7.53 (d, J=2.2 Hz, 1H), 7.37 (ddd, J=8.2, 7.4, 1.8Hz, 1H), 7.30 (d, J=1.8Hz, 1H), 7.23 (dd, J=7.5, 1.8Hz, 1H) , 7.19–7.14 (m, 1H), 7.09 (dd, J=8.0, 1.8Hz, 1H), 7.07–7.03 (m, 1H), 6.64 (d, J=8.1Hz, 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).

[1082] LCMS: m / z=484.1 / 486.1 [MH]-, (ESI-), RT=4.34, Method A

[1083] 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]pentacosyl-1(24),2(7),3,5,13(25),14,16,20,22-nonaen-12-one (Compound 58)

[1084]

[1085] Step 1

[1086] A solution of 5-[2-[2-[tert-butyl(dimethyl)silyl]oxyethoxy]phenyl]-2-(trifluoromethyl)aniline (synthesized using a method 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 a solution of 1M LiHMDS in THF (1.2 mL, 1.20 mmol). The reaction was then stirred for 10 mins before adding a solution of intermediate 1 (50% purity, 550 mg, 0.919 mmol) in anhydrous THF (8.3 mL). The mixture was stirred for another 15 mins at -78 ° C, then warmed to room temperature, and stirred for 5 hours. The mixture was quenched with water (10 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (20 mL) and dried over MgSO , filtered, and concentrated in vacuo. The residue was purified by FCC (25 g SiO column, 0 to 100% EtOAc 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.

[1087] 1 H NMR (400MHz, CDCl3) δ8.41 (d, J=2.1Hz, 1H), 8.25 (d, J=2.1Hz, 1H), 7.78 (br.s, J=0.9Hz, 1H), 7.51 (d, J=0.9Hz, 1H), 7.36–7.31 (m, 2H ), 7.23 (dd, J=7.5, 1.8Hz, 1H), 7.05–6.98 (m, 2H), 4.14 (s, 3H), 4.06 (t, J=5.2Hz, 2H), 3.91–3.87 (m, 5H), 0.82 (s, 9H), -0.04 (s, 6H).

[1088] Step 2

[1089] A solution of 3-[[5-[2-[2-[tert-butyl(dimethyl)silyl]oxyethoxy]phenyl]-2-(trifluoromethyl)phenyl]sulfamoyl]-5-chloro-4-methoxybenzoic acid methyl ester (84% purity, 140 mg, 0.174 mmol) and 4-methylbenzenesulfonic acid hydrate (1:1) (3.3 mg, 0.0174 mmol) in MeOH (2 mL) was stirred at room temperature for 2 hours. The mixture was concentrated in vacuo and the residue was purified by FCC (10 g SiO column, 0 to 100% EtOAc in heptane) to give 3-chloro-5-[[5-[2-(2-hydroxyethoxy)phenyl]-2-(trifluoromethyl)phenyl]sulfamoyl]-4-methoxy-benzoic acid methyl ester (111 mg, 100% yield, 87% purity) as a white gum.

[1090] 1 H NMR (400MHz, DMSO) δ10.29 (s, 1H), 8.26 (d, J = 2.1Hz, 1H), 8.18 (d, J = 2.1Hz, 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, 1.8Hz, 1H), 6.99 (td, J=7.4, 1.0Hz, 1H), 4.74 (s , 1H), 4.03–3.97 (m, 2H), 3.94 (s, 3H), 3.85 (s, 3H), 3.65 (d, J=6.8Hz, 2H).

[1091] LCMS: m / z=558.1 / 560.1 [MH]-, (ESI-), RT=1.05, Method B

[1092] Step 3

[1093] By 3-chloro-5-[[5-[2-(2-hydroxyethoxy)phenyl]-2-(trifluoromethyl)phenyl]sulfamoyl]-4-methoxybenzoic acid methyl ester (87% purity, 111mg, 0.173mmol) in THF (3mL) and 2M sodium hydroxide aqueous solution (433 μ L, 0.865mmol) solution was stirred at room temperature for 4 hours.Mixture is diluted with EtOAc (10mL) and water (10mL) and separated layer.The water layer is acidified to~pH 2 using 1M HCl aqueous solution, then extracted with EtOAc (3x 10mL).The organic layer merged is filtered through phase separation filter paper and vacuum concentrated to obtain 3-chloro-5-[[5-[2-(2-hydroxyethoxy)phenyl]-2-(trifluoromethyl)phenyl]sulfamoyl]-4-methoxy-benzoic acid (102mg, 97% yield, 90% purity), it is a white powder.

[1094] 1 H NMR (400MHz, DMSO) δ10.25 (s, 1H), 8.25 (s, 1H), 8.13 (s, 1H), 7.85–7.42 (m, 2H), 7.33 (t, J=7.6Hz, 1H), 7.26 (s, 1H), 7.11 (d, J=8.4 Hz, 1H), 7.04 (dd, J=7.6, 1.9Hz, 1H), 6.96 (t, J=7.4Hz, 1H), 4.74 (s, 1H), 3.98 (t, J=5.1Hz, 2H), 3.91 (s, 3H), 3.63 (t, J=5.1Hz, 2H).

[1095] LCMS: m / z=544.0 / 546.0 [MH]-, (ESI-), RT=0.93, Method B

[1096] Step 4

[1097] A solution of 3-chloro-5-[[5-[2-(2-hydroxyethoxy)phenyl]-2-(trifluoromethyl)phenyl]sulfamoyl]-4-methoxybenzoic acid (90% purity, 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 hour. The mixture was diluted with water (30 mL) and extracted with DCM (3 x 30 mL), and 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 to 100%), then EtOAc in DCM (0 to 100%)) to give 15-chloro-16-methoxy-18,18-dioxo-21-(trifluoromethyl)-8,11-dioxa-18λ-thia-19-azatetracyclo[18.3.1.113,17.02,7]pentacos-1(24),2(7),3,5,13(25),14,16,20,22-nonen-12-one (40 mg, 42% yield, 93% purity) as a white powder.

[1098] 1 H NMR (400MHz, DMSO) δ10.50 (s, 1H), 8.33 (d, J=2.1Hz, 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, 1.8Hz, 1H), 7.31 (d, J=7.5Hz, 1H), 7.17 (d, J=8.3Hz, 1H), 7.07 (td, J=7.5, 1.0Hz, 1H), 4.60–4.50 (m, 2H), 4.29 (t, J=4.6Hz, 2H), 3.98 (s, 3H).

[1099] LCMS: m / z=526.3 / 528.3 [MH]-, (ESI-), RT=1.14, Method B

[1100] Step 5

[1101] 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]pentacos-1(24),2(7),3,5,13(25),14,16,20,22-nonen-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. in a sealed bottle for 2 hours. The mixture was cooled to room temperature and then purified by preparative HPLC (Method P1) to give the title compound as a white powder (19 mg, 53% yield, 100% purity).

[1102] 1 H NMR (400MHz, DMSO) δ8.11 (d, J=2.1Hz, 1H), 8.05 (d, J=2.1Hz, 1H), 7.72 (d, J=8.2Hz, 1H), 7.62 (s, 1H), 7.47–7.38 (m, 2H) , 7.28 (dd, J=7.5, 1.8Hz, 1H), 7.18 (d, J=8.5Hz, 1H), 7.07 (td, J=7.4, 1.0Hz, 1H), 4.49–4.44 (m, 2H), 4.30–4.24 (m, 2H).

[1103] LCMS: m / z=512.1 / 514.1 [MH]-, (ESI-), RT=4.15, Method A

[1104] 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]pentacosyl-1(24),2,4,6,13,15,17(25),20,22-nonaen-12-one (Compound 59)

[1105]

[1106] Step 1

[1107] Anhydrous THF (3mL) and anhydrous diisopropylamine (1.0mL, 7.14mmol) are added to a dry flask. The solution is cooled to -78°C, then a hexane solution (3.2mL, 8.00mmol) of 2.5M n-butyllithium is added dropwise over 2 minutes. The solution is stirred at -78°C for 1 hour. To a dry 2-neck flask equipped with a thermometer, 3-chloro-5-fluorobenzoic acid methyl ester (0.80mL, 5.62mmol) and anhydrous THF (20mL) are added. The solution is cooled to -78°C, then the solution prepared in the first step is added by cannula. The reaction mixture is stirred at -78°C for 40 minutes, then anhydrous DMF (1.3mL, 16.8mmol) is added. The reaction mixture is kept at -78°C for 1 hour, then it is warmed to -20°C, then saturated ammonium chloride solution (12mL) is added and the two-phase mixture is stirred for 10min. Water (20mL) is added to the two-phase mixture. The organic matter is extracted with EtOAc (3x 20mL), merged, washed with salt solution (30mL), used MgSO4 drying, filtered and concentrated in vacuo.The residue is purified by FCC (25g SiO2 column, 0-20% EtOAc in heptane) to obtain 3-chloro-5-fluoro-4-formylbenzoic acid methyl esters (463mg, 36% yield, 95% purity) as a light orange solid.

[1108] 1 H NMR (400MHz, DMSO) δ 10.35–10.29 (m, 1H), 7.91–7.88 (m, 1H), 7.83 (dd, J=10.6, 1.5Hz, 1H), 3.91 (s, 3H).

[1109] Step 2

[1110] To a suspension of potassium tert-butoxide (240 mg, 2.14 mmol) in anhydrous THF (15 mL) was added phenylmethyl mercaptan (0.22 mL, 1.88 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 5 minutes, then a cold (0° C.) solution of methyl 3-chloro-5-fluoro-4-formylbenzoate (95% purity, 435 mg, 1.91 mmol) in anhydrous THF (5 mL) was added. The reaction mixture was maintained at 0° C. for 1 minute, then allowed to warm to room temperature and stirred for an additional 2.5 hours. The mixture was concentrated in vacuo and purified by FCC (25 g SiO column, 0-40% EtOAc in heptanes) then by FCC (25 g SiO column, 0-20% EtO in heptanes) to give methyl 3-benzylsulfanyl-5-chloro-4-formylbenzoate (392 mg, 63% yield, 98% purity) as a yellow solid.

[1111] 1H NMR (400MHz, DMSO) δ10.47–10.46 (m, 1H), 8.02–7.98 (m, 1H), 7.78 (d, J=1.4Hz, 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).

[1112] LCMS: m / z=319.0 / 321.0 [MH]-, (ESI-), RT=1.12, Method B

[1113] Step 3

[1114] To a solution of 3-benzylthio-5-chloro-4-formylbenzoic acid methyl ester (98% purity, 387mg, 1.18mmol) in DCM (11mL) was added DAST (0.53mL, 4.01mmol) at room temperature. The reaction mixture was stirred at room temperature for 18.5 hours, then DAST (0.2mL, 1.51mmol) was added. The reaction mixture was stirred at room temperature for another 2 hours. Saturated NaHCO was carefully added to the reaction mixture at room temperature The aqueous solution (50mL) was stirred rapidly for 5 minutes, then fully shaken until gas evolution stopped. Separating layer, and organic matter was extracted with DCM (2x 20mL). Organic matter was merged, passed through a hydrophobic glass apparatus and vacuum concentration. The residue was purified by FCC (25 g SiO2 column, 0-10% EtOAc in heptane) to give methyl 3-benzylsulfanyl-5-chloro-4-(difluoromethyl)benzoate (350 mg, 86% yield, 100% purity) as a yellow oil.

[1115] 1 H NMR (400MHz, DMSO) δ7.98–7.96 (m, 1H), 7.85–7.83 (m, 1H), 7.43 (t, J=52.6Hz, 1H), 7.46–7.26 (m, 4H), 7.28–7.22 (m, 1H), 4.36 (s, 2H), 3.89 (s, 3H).

[1116] LCMS: m / z=341.1 / 343.1 [MH]-, (ESI-), RT=1.17, Method B

[1117] Step 4

[1118] 3-benzylthio-5-chloro-4-(difluoromethyl)benzoic acid methyl ester (350mg, 1.02mmol) is dissolved in a mixture of acetonitrile (4.5mL), acetic acid (0.23mL) and water (0.23mL) and the resulting suspension is cooled to 0°C in an ice bath. 1,3-dichloro-5,5-dimethylhydantoin (250mg, 1.27mmol) is then added portionwise and the reaction mixture is stirred at 0°C for 1 hour. The organic matter is concentrated in vacuo (water bath, at room temperature) and then diluted with DCM (20mL). The organic matter is washed with saturated NaHCO3 aqueous solution (20mL), separated, passed through a phase separator, and then concentrated under reduced pressure (water bath, at room temperature). A solution of intermediate 8 (90% purity, 319mg, 0.756mmol) in pyridine (3.6mL) is added and the mixture is stirred at 50°C for 50 minutes, then concentrated under reduced pressure. The residue was purified by FCC (25 g SiO column, 0-20% EtOAc 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.

[1119] 1 H NMR (500MHz, DMSO) δ11.13 (br.s, 1H), 8.33–8.29 (m, 2H), 7.78 (t, J=51.5Hz, 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).

[1120] LCMS: m / z=660.2 / 662.2 [MH]-, (ESI-), RT=1.33, Method B

[1121] Step 5

[1122] To 3-[[5-[2-[2-[tert-butyl(dimethyl)silyl]oxyethoxy]phenyl]-2,4-difluoro-phenyl]sulfamoyl]-5-chloro-4-(difluoromethyl)benzoic acid methyl esters (75% purity, 447mg, 0.506mmol) in methanol (12mL) in room temperature add p-toluenesulfonic acid hydrate (1:1) (20mg, 0.105mmol).Reactant mixture is stirred at room temperature for 1 hour, then concentrated in vacuo.Residue passes through FCC purification (25g SiO2 column, 0-100% EtOAc heptane solution) to obtain 3-chloro-5-[[2,4-difluoro-5-[2-(2-hydroxyethoxy)phenyl]phenyl]sulfamoyl]-4-(difluoromethyl)benzoic acid methyl esters (241mg, 78% yield, 90% pure), it is white solid.

[1123] 1 H NMR (500MHz, DMSO) δ11.08 (s, 1H), 8.32 (d, J = 1.7Hz, 1H), 8.29 (d, J = 1.6Hz, 1H), 7.76 (t, J = 51.5Hz, 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=5.6Hz, 2H), 3.90 (s, 3H), 3.59 (t, J=5.5Hz, 2H).

[1124] LCMS: m / z=546.1 / 548.1 [MH]-, (ESI-), RT=1.02, Method B

[1125] Step 6

[1126] To 3-chloro-5-[[2,4-difluoro-5-[2-(2-hydroxyethoxy)phenyl]phenyl]sulfamoyl]-4-(difluoromethyl)benzoic acid methyl ester (90% purity, 235mg, 0.386mmol) in THF (4.5mL) solution, add 2M sodium hydroxide aqueous solution (1.5mL, 3.00mmol).Reactant mixture is stirred at room temperature for 15.5 hours, then organic matter is removed in vacuo.To remaining aqueous phase, add 1M HCl aqueous solution (10mL).Mixture is extracted with DCM (3x 20mL), merge, pass through hydrophobic glassware and vacuum concentration to obtain 3-chloro-5-[[2,4-difluoro-5-[2-(2-hydroxyethoxy)phenyl]phenyl]sulfamoyl]-4-(difluoromethyl)benzoic acid (226mg, 91% yield, 83% purity), it is yellow oil / colloid.

[1127] 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). COOH and OH were not observed.

[1128] LCMS: m / z=532.0 / 534.0 [MH]-, (ESI-), RT=0.90, Method B

[1129] Step 7

[1130] To a solution of 3-chloro-5-[[2,4-difluoro-5-[2-(2-hydroxyethoxy)phenyl]phenyl]sulfamoyl]-4-(difluoromethyl)benzoic acid (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 hours and then concentrated in vacuo. The residue was purified by FCC (25 g SiO column, 20-100% DCM in heptane) to give the title compound as a white solid (96 mg, 53% yield, 99% purity).

[1131] 1 H NMR (500MHz, DMSO) δ11.02 (s, 1H), 8.27 (d, J=1.6Hz, 1H), 8.06 (t, J=51.8Hz, 1H), 7.63 (s, 1 H), 7.47 (ddd, J=8.2, 7.4, 1.7Hz, 1H), 7.39–7.35 (m, 1H), 7.31 (dd, J=7.5, 1.7Hz, 1H), 7.25–

[1132] 7.19(m, 2H), 7.13–7.09(m, 1H), 4.44–4.39(m, 2H), 4.35–4.29(m, 2H).

[1133] LCMS: m / z=514.2 / 516.2 [MH]-, (ESI-), RT=4.24, Method A

[1134] 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]pentacosyl-1(23),2(7),3,5,13(25),14,16,20(24),21-nonen-12-one (Compound 60)

[1135]

[1136] A suspension of Example 59 (99% purity, 60 mg, 0.115 mmol), potassium carbonate (48 mg, 0.347 mmol) and t-BuXPhosPd 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 pad of cotton wool and the residue was purified by preparative HPLC (Method P1) and then lyophilized to give the title compound (8.7 mg, 15% yield, 96% purity) as a white solid.

[1137] 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). NH was not observed.

[1138] LCMS: m / z=480.1 [MH]-, (ESI-), RT=3.91, Method A

[1139] 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]pentacosyl-1(24),2,4,6,13,15,17(25),20,22-nonaen-12-one (Compound 61)

[1140]

[1141] Step 1

[1142] To the suspension of potassium tert-butoxide (1.27g, 11.3mmol) in anhydrous THF (90mL) phenyl methyl mercaptan (1.1mL, 9.39mmol) was added at 0°C. The reaction mixture was stirred at 0°C for 10 minutes, then a solution of 2,6-dichloropyridine-4-methyl formates (2.50g, 12.1mmol) in anhydrous THF (20mL) was added. The reaction mixture was kept at 0°C for 1 minute, then warmed to room temperature and stirred for another 1 hour. The mixture was concentrated in vacuo and residue was purified by FCC (100g SiO2 column, 0-5% EtOAc in heptane solution) to obtain 2-benzylsulfanyl-6-chloropyridine-4-methyl formates (2.55g, 68% yield, 74% purity), which was a pink oil.

[1143] 1 H NMR (500MHz, DMSO) δ7.69 (d, J=1.1Hz, 1H), 7.54 (d, J=1.1Hz, 1H), 7.45–7.42 (m, 2H), 7.34–7.23 (m, 3H), 4.44 (s, 2H), 3.87 (s, 3H).

[1144] LCMS: m / z=294.0 / 296.0 [M+H]+, (ESI+), RT=1.17, Method B

[1145] Step 2

[1146] 2-benzylthio-6-chloropyridine-4-methyl formate (74% purity, 2.55g, 6.42mmol) is dissolved in a mixture of MeCN (24mL), acetic acid (1.2mL) and water (1.2mL) and the resulting suspension is cooled to 0°C in an ice bath. 1,3-dichloro-5,5-dimethylhydantoin (1.40g, 7.11mmol) is then added portionwise and the reaction mixture is stirred at 0°C for 30 minutes. The organic matter is concentrated under reduced pressure (water bath at room temperature) and then diluted with DCM (20mL). The organic matter is washed with saturated NaHCO3 aqueous solution (20mL), separated, passed through a phase separator, and then concentrated under reduced pressure (water bath at room temperature) to give a yellow oil. A solution of intermediate 8 (88% purity, 1.70g, 3.94mmol) in pyridine (18mL) is added and the mixture is stirred at 35°C for 1 hour. The mixture was concentrated in vacuo and the residue was purified by FCC (50 g SiO column, 0-40% EtOAc in heptane) to give methyl 2-[[5-[2-[2-[tert-butyl(dimethyl)silyl]oxyethoxy]phenyl]-2,4-difluoro-phenyl]sulfamoyl]-6-chloropicolinate (1.56 g, 55% yield, 85% purity) as a yellow oil.

[1147] 1 H NMR (500MHz, DMSO) δ10.77 (s, 1H), 8.19 (d, J = 1.2Hz, 1H), 8.15 (d, J = 1.2Hz, 1H), 7.38 (ddd, J = 8.3, 7.4, 1.8Hz, 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).

[1148] LCMS: m / z=611.2 / 613.2 [MH]-, (ESI-), RT=1.27, Method B

[1149] Step 3

[1150] To a solution of methyl 2-[[5-[2-[2-[tert-butyl(dimethyl)silyl]oxyethoxy]phenyl]-2,4-difluoro-phenyl]sulfamoyl]-6-chloropicolinate (85% purity, 1.56 g, 2.2 mmol) in methanol (25 mL) was added p-toluenesulfonic 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 SiO column, 0-100% EtOAc in heptane then 0-20% MeOH in EtOAc) 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.

[1151] 1 H NMR (400MHz, DMSO) δ10.74 (s, 1H), 8.18 (d, J = 1.2Hz, 1H), 8.14 (d, J = 1.2Hz, 1H), 7.39 (ddd, J = 8.4, 7.4, 1.8Hz, 1H), 7.36–7.2 6 (m, 2H), 7.17–7.12 (m, 2H), 7.05–6.99 (m, 1H), 4.66 (t, J=5.5Hz, 1H), 3.99 (t, J=5.5Hz, 2H), 3.92 (s, 3H), 3.61–3.56 (m, 2H).

[1152] LCMS: m / z=497.1 / 499.1 [MH]-, (ESI-), RT=0.93, Method B

[1153] Step 4

[1154] To a solution of 2-chloro-6-[[2,4-difluoro-5-[2-(2-hydroxyethoxy)phenyl]phenyl]sulfamoyl]pyridine-4-carboxylic acid methyl ester (96% purity, 945 mg, 1.82 mmol) in THF (20 mL) was added 2M aqueous sodium hydroxide solution (7.0 mL, 14.0 mmol). The reaction mixture was stirred at room temperature for 1.25 hours, then the organic matter was diluted with EtOAc (40 mL) and washed with 1M HCl aqueous solution (20 mL). The aqueous layer was extracted with EtOAc (20 mL), the organic layers were combined, washed with brine (20 mL), dried over MgSO and concentrated in vacuo to obtain 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.

[1155] 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). COOH was not observed.

[1156] LCMS: m / z=483.1 / 485.1 [MH]-, (ESI-), RT=0.77, Method B

[1157] Step 5

[1158] 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 hours and then concentrated in vacuo. The residue was purified by FCC (25 g SiO column, 40-100% DCM in EtOAc, then 0-20% EtOAc in DCM) to obtain 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).

[1159] 1 H NMR (500MHz, DMSO) δ10.62 (s, 1H), 8.17 (d, J=1.2Hz, 1H), 7.45 (ddd, J=8.2, 7.4, 1.8Hz, 1H), 7.41 (d, J=1. 2Hz, 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).

[1160] LCMS: m / z=465.3 / 467.3 [MH]-, (ESI-), RT=3.83, Method A

[1161] 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]pentacosyl-1(24),2,4,6,13,15,17(25),20,22-nonaen-12-one (Compound 62)

[1162]

[1163] The solution of 2M trimethylaluminum solution in toluene (0.11mL, 0.220mmol) is added to embodiment 61 (87% purity, 20mg, 0.0373mmol) and tetrakis (triphenylphosphine) palladium (0) (5.0mg, 4.33μmol) in anhydrous 1,4-dioxane (0.6mL) bubbling solution. The bottle is sealed and heated at 120 DEG C under microwave irradiation for 0.75 hour. Water (0.5mL) is carefully added to the reaction mixture. The mixture is extracted with DCM (3x 5mL), merged, passed through hydrophobic glassware and vacuum concentrated. Residue is then lyophilized to obtain title compound (7.8mg, 45% yield, 96% purity) by preparative HPLC purification (method P1), it is white solid.

[1164] 1 H NMR (500MHz, DMSO) δ10.38 (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).

[1165] LCMS: m / z=445.1 [MH]-, (ESI-), RT=3.42, Method A

[1166] 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]pentacosyl-1(23),2(7),3,5,13,15,17(25),20(24),21-nonen-12-one (Compound 63)

[1167]

[1168] A suspension of Example 61 (95% purity, 70 mg, 0.142 mmol), palladium (II) acetate (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, followed by the addition of cesium carbonate (95 mg, 0.292 mmol) and 1,1-diphenylmethane (40 μL, 0.238 mmol). 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, then redissolved in THF (1.5 mL), and 2M aqueous hydrogen chloride solution (0.18 mL, 0.360 mmol) was added. The resulting mixture was stirred at room temperature for 15 minutes, followed by the addition of saturated NaHCO3 aqueous solution (5 mL) and water (5 mL). The mixture was extracted with EtOAc (20 mL), the organic layer was washed with brine (10 mL), then dried over MgSO 4 , 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.

[1169] 1 H NMR (500MHz, DMSO) δ10.06 (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).

[1170] LCMS: m / z=448.0 [M+H]+, (ESI-), RT=3.16, Method A

[1171] 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]pentacosyl-1(23),2(7),3,5,13(25),14,16,20(24),21-nonen-12-one (Compound 64)

[1172]

[1173] Step 1

[1174] By 3- bromo -5- chloro- 4- fluorobenzoic acid methyl ester (70% purity, 2.00g, 5.23mmol), benzyl mercaptan (725 μ L, 6.19mmol), DIPEA (1.2mL, 6.89mmol), Pd2 (dba) 3 (160mg, 0.175mmol) and Xantphos (200mg, 0.346mmol) in 1,4- dioxane (40mL) by bubbling with nitrogen degassing. The reaction is heated to 100 DEG C and kept for 1 hour, then stirred at 80 DEG C for 18 hours. The reaction is cooled and the solid matter is removed by filtration and washed with EtOAc (solid discarded). The filtrate is distributed between water and EtOAc. The water layer is extracted with EtOAc (3x 10mL), and the combined organic matter is washed with brine, used MgSO4 and is dried and concentrated in vacuo. The residue was purified by FCC (100 g SiO2 column, 0-20% EtOAc in heptane) to give methyl 3-benzylsulfanyl-5-chloro-4-fluorobenzoate (2.20 g, 92% yield, 68% purity) as a yellow solid.

[1175] 1 H NMR (500MHz, CDCl3) δ7.92 (dd, J=6.6, 2.1Hz, 1H), 7.88 (dd, J=6.6, 2.1Hz, 1H), 7.31–7.28 (m, 4H), 7.26–7.23 (m, 1H), 4.17 (s, 2H), 3.90 (s, 3H).

[1176] LCMS: m / z=309.1 / 311.1 [MH]-, (ESI-), RT=1.19, Method B

[1177] Step 2

[1178] 1,3-dichloro-5,5-dimethylhydantoin (450 mg, 2.28 mmol) is added to an ice-cooled solution of methyl 3-benzylthio-5-chloro-4-fluorobenzoate (68% purity, 500 mg, 1.09 mmol) in MeCN (9 mL), water (1 mL) and acetic acid (1 mL). The reaction is stirred for 1 hour, then the solvent volume is reduced in vacuo and then diluted with DCM (~15 mL). The mixture is quenched with saturated NaHCO3 aqueous solution and the water layer is extracted with DCM (3 x 10 mL). The combined organics are washed with brine, dried over MgSO4 and concentrated in vacuo. A solution of intermediate 8 (315 mg, 0.830 mmol) in pyridine (4.5 mL) is added and the mixture is stirred for 2 hours. The mixture is quenched in a 1M HCl aqueous solution and the water layer is extracted into EtOAc (3 x 10 mL), the combined organics are washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by FCC (25 g SiO column, 0-100% EtOAc 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).

[1179] 1 H NMR (400MHz, DMSO) δ10.92 (s, 1H), 8.42–8.34 (m, 1H), 8.16 (dd, J=6.0, 2.2Hz, 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=4.7Hz, 2H), 3.87 (s, 3H), 3.77 (t, J=4.6Hz, 2H), 0.73 (s, 9H), -0.18 (s, 6H).

[1180] LCMS: m / z=628.2 / 630.2 [MH]-, (ESI-), RT=1.29, Method B

[1181] Step 3

[1182] Toluenesulfonic acid monohydrate (7.0 mg, 0.037 mmol) is added to a solution of 3-[[5-[2-[2-[tert-butyl(dimethyl)silyl]oxyethoxy]phenyl]-2,4-difluoro-phenyl]sulfamoyl]-5-chloro-4-fluorobenzoic acid methyl esters (84% purity, 250 mg, 0.333 mmol) in MeOH (10 mL). The mixture is stirred for 1 hour and then concentrated in vacuo. The residue passes through FCC purification (10 g, SiO2 column, 20-80% EtOAc in heptane solution) to obtain 3-chloro-5-[[2,4-difluoro-5-[2-(2-hydroxyethoxy)phenyl]phenyl]sulfamoyl]-4-fluorobenzoic acid methyl esters (143 mg, 72% yield, 86% purity), which is a white solid.

[1183] 1 H NMR (500MHz, DMSO) δ10.88 (s, 1H), 8.39–8.34 (m, 1H), 8.14 (dd, J=6.0, 2.2Hz, 1H), 7.41–7.36 (m, 1H), 7.36–7.28 (m, 0H), 7.13 (d dd, J=9.7, 7.9, 1.4Hz, 2H), 7.05–6.98 (m, 1H), 4.67 (t, J=5.5Hz, 1H), 3.98 (t, J=5.5Hz, 2H), 3.87 (s, 3H), 3.58 (q, J=5.4Hz, 2H).

[1184] LCMS: m / z=514.1 / 516.1 [MH]-, (ESI-), RT=0.97, Method B

[1185] Step 4

[1186] 2M sodium hydroxide aqueous solution (0.50mL, 1.00mmol) is added to a solution of 3-chloro-5-[[2,4-difluoro-5-[2-(2-hydroxyethoxy)phenyl]phenyl]sulfamoyl]-4-fluorobenzoic acid methyl esters (86% purity, 143mg, 0.238mmol) in THF (2mL).The mixture is stirred for 1 hour, then quenched in water / EtOAc.Separate layer and organic matter is discarded.The aqueous layer is acidified to pH 4 with HCl aqueous solution and extracted into EtOAc (3x 5mL).The organic matter merged is washed with salt water / HCl, used MgSO4 is dried and concentrated in vacuo to obtain 3-chloro-5-[[2,4-difluoro-5-[2-(2-hydroxyethoxy)phenyl]phenyl]sulfamoyl]-4-fluorobenzoic acid (115mg, 85% yield, 88% purity), which is a colorless oil.

[1187] LCMS: m / z=500.1 / 502.0 [MH]-, (ESI-), RT=0.86, Method B

[1188] Step 5

[1189] DMAP (2.0 mg, 0.0164 mmol) is added to a solution of 3-chloro-5-[[2,4-difluoro-5-[2-(2-hydroxyethoxy)phenyl]phenyl]sulfamoyl]-4-fluorobenzoic acid (88% purity, 105 mg, 0.184 mmol) and DCC (85 mg, 0.412 mmol) in DCM (20 mL). The mixture is stirred for 1 hour and then quenched in water. The aqueous layer is extracted with DCM (3 x 5 mL), and the combined organic matter is washed with salt water, dried over MgSO and concentrated in vacuo. The residue is purified by preparative HPLC (method P1) to obtain the title compound (30 mg, 33% yield, 98% purity) as a white solid.

[1190] 1 H NMR (500MHz, DMSO) δ10.93 (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).

[1191] LCMS: m / z=482.0, 484.0 [MH]-, (ESI-), RT=3.97, Method A

[1192] 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]pentacosyl-1(24),2,4,6,13,15,17(25),20,22-nonaen-12-one (Compound 65)

[1193]

[1194] To 21,23-difluoro-15-methoxy-18,18-dioxo-8,11-dioxa-18λ6-thia-19-azatetracyclo[18.3.1.113,17.02,7]twenty-five-1(24),2,4,6,13,15,17(25),20,22-nonen-12-one (synthesized using a similar method to intermediate 12, 90% purity, 90 mg, 0.176 mmol) was added 1MBBr3 in DCM (9.0 mL, 9.00 mmol) dropwise. The resulting solution was stirred at room temperature for 2 hours. The reaction mixture was slowly added to a stirred, ice-cooled, saturated aqueous NaHCO3 solution (50 mL) and extracted with DCM (3 x 50 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by preparative HPLC (Method P1 ) to give the title compound as a white solid (20 mg, 25% yield, 99% purity).

[1195] 1 H NMR (500MHz, DMSO) δ10.68 (s, 1H), 10.09 (s, 1H), 7.48–7.41 (m, 3H), 7.31–7.21 (m, 3H), 7 .20–7.16(m,1H), 7.11–7.06(m,1H), 6.99(s,1H), 4.38–4.34(m,2H), 4.33–4.29(m,2H).

[1196] LCMS: m / z=446.1 [MH]-, (ESI-), RT=3.32, Method A

[1197] Example 66 - Synthesis of 21-fluoro-16-hydroxy-18,18-dioxo-8,11-dioxa-18λ6-thia-14,19-diazatetracyclo[18.3.1.113,17.02,7]pentacosyl-1(24),2,4,6,13,15,17(25),20,22-nonaen-12-one (Compound 66)

[1198]

[1199] Step 1

[1200] To a solution of 4-chloro-5-methoxy-pyridine-2-formic acid methyl esters (860mg, 4.27mmol) in anhydrous 1,4-dioxanes (22mL) was added DIPEA (0.90mL, 5.17mmol) and the solution was bubbled with nitrogen for 10 minutes. Phenylmethyl mercaptan (0.45mL, 3.84mmol), Pd(dba) (115mg, 0.126mmol) and Xantphos (150mg, 0.259mmol) were added and the reaction mixture was sealed and heated at 100°C for 16 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was purified by FCC (50g SiO2 column, 0-50% acetone in heptane) to obtain 4-benzylsulfanyl-5-methoxy-pyridine-2-formic acid methyl esters (465mg, 40% yield, 95% purity), which was a light yellow solid.

[1201] 1 H NMR (500MHz, DMSO) δ 8.29 (s, 1H), 7.93 (s, 1H), 7.47–7.43 (m, 2H), 7.37–7.32 (m, 2H), 7.30–7.25 (m, 1H), 4.36 (s, 2H), 4.01 (s, 3H), 3.84 (s, 3H).

[1202] Step 2

[1203] 4-Benzylthio-5-methoxy-pyridine-2-carboxylic acid methyl ester (95% purity, 230 mg, 0.755 mmol) was dissolved in a mixture of MeCN (3.6 mL), acetic acid (0.28 mL) and water (0.28 mL) and the resulting suspension was cooled to 0° C. in an ice bath. 1,3-Dichloro-5,5-dimethylhydantoin (295 mg, 1.50 mmol) was then added portionwise and the reaction mixture was stirred at 0° C. for 1 minute before the addition of a solution of 5-[2-[2-[tert-butyl(dimethyl)silyl]oxyethoxy]phenyl]-2-fluoroaniline (synthesized using a similar method to Intermediate 8, 95% purity, 200 mg, 0.526 mmol) in pyridine (4 mL). The reaction mixture was heated at 50° C. for 20 minutes before being cooled to room temperature. The mixture was diluted with EtOAc (40 mL) and washed with 1 M aqueous HCl (40 mL), then with saturated aqueous NaHCO (30 mL), then with brine (20 mL), dried over MgSO, filtered and concentrated in vacuo. The residue was purified by FCC (25 g SiO column, 0-70% EtOAc in heptane) to give 4-[[5-[2-[2-[tert-butyl(dimethyl)silyl]oxyethoxy]phenyl]-2-fluoro-phenyl]sulfamoyl]-5-methoxy-pyridine-2-carboxylic acid methyl ester (175 mg) as an off-white solid.

[1204] LCMS: m / z=589.3 [MH]-, (ESI-), RT=1.21, Method B

[1205] Step 3

[1206] To a solution of 4-[[5-[2-[2-[tert-butyl(dimethyl)silyl]oxyethoxy]phenyl]-2-fluoro-phenyl]sulfamoyl]-5-methoxy-pyridine-2-formic acid methyl esters (30% purity, 170mg, 0.086mmol) in MeOH (1mL) in room temperature, p-methylbenzenesulfonic acid hydrate (1:1) (3.0mg, 0.0158mmol) is added. The reaction mixture is stirred at room temperature for 1.25 hours, then concentrated in vacuo. The residue is purified by FCC (10g SiO2 column, 20-100% EtOAc in heptane solution) to obtain 4-[[2-fluoro-5-[2-(2-hydroxyethoxy)phenyl]phenyl]sulfamoyl]-5-methoxy-pyridine-2-formic acid methyl esters (46mg, 73% yield, 65% purity), which is a yellow oil.

[1207] LCMS: m / z=475.2 [MH]-, (ESI-), RT=0.79, Method B

[1208] Step 4

[1209] To a solution of 4-[[2-fluoro-5-[2-(2-hydroxyethoxy)phenyl]phenyl]sulfamoyl]-5-methoxy-pyridine-2-carboxylic acid methyl ester (65% purity, 43 mg, 0.059 mmol) in THF (1 mL) was added 2M aqueous sodium hydroxide solution (0.25 mL, 0.50 mmol). The reaction mixture was stirred at room temperature for 2.25 hours, and then 1M aqueous HCl solution (8 mL) was added to the reaction mixture. The mixture was extracted with EtOAc (2 x 30 mL), and the organic layer was passed through a hydrophobic glassware and concentrated in vacuo to give 4-[[2-fluoro-5-[2-(2-hydroxyethoxy)phenyl]phenyl]sulfamoyl]-5-methoxy-pyridine-2-carboxylic acid (27 mg, quantitative yield) as a yellow oil.

[1210] LCMS: m / z=461.1 [MH]-, (ESI-), RT=0.70, Method B

[1211] Step 5

[1212] To a solution of 4-[[2-fluoro-5-[2-(2-hydroxyethoxy)phenyl]phenyl]sulfamoyl]-5-methoxy-pyridine-2-carboxylic acid (27 mg, 0.058 mmol) in DCM (10 mL) was added DMAP (3.0 mg, 0.0246 mmol) and DCC (30 mg, 0.145 mmol). The reaction mixture was stirred at room temperature for 1.5 hours and then concentrated in vacuo. The residue was purified by preparative HPLC (Method P3) followed by FCC (10 g SiO column, 0-100% acetone in heptane) to give 21-fluoro-16-methoxy-18,18-dioxo-8,11-dioxa-18λ6-thia-14,19-diazatetracyclo[18.3.1.113,17.02,7]pentacos-1(24),2,4,6,13,15,17(25),20,22-nonaen-12-one (10 mg, 35% yield, 90% purity) as a white solid.

[1213] 1H NMR (500MHz, CDCl3) δ8.61 (s, 1H), 7.83 (s, 1H), 7.61 (dd, J=7.6, 2.2Hz, 1H), 7 .37 (ddd, J=8.2, 7.4, 1.8Hz, 1H), 7.21 (ddd, J=7.5, 1.8Hz, 1H), 7.12 (ddd, J=8.4 , 5.1, 2.2Hz, 1H), 7.08–7.04 (m, 1H), 7.03–6.98 (m, 1H), 6.98–6.83 (m, 1H), 6. 77 (dd, J=10.1, 8.5Hz, 1H), 4.50–4.47 (m, 2H), 4.32–4.28 (m, 2H), 4.21 (s, 3H).

[1214] LCMS: m / z=445.3 [M+H]+, (ESI+), RT=0.87, Method B

[1215] Step 6

[1216] To a solution of 21-fluoro-16-methoxy-18,18-dioxo-8,11-dioxa-18λ6-thia-14,19-diazatetracyclo[18.3.1.113,17.02,7]pentacos-1(24),2,4,6,13,15,17(25),20,22-nonaen-12-one (90% purity, 10 mg, 0.0203 mmol) in anhydrous pyridine (1.2 mL) was added lithium iodide (30 mg, 0.224 mmol). The reaction mixture was heated at 80° C. for 50 hours and then cooled to room temperature. The mixture was diluted with EtOAc (30 mL), washed with 1 M aqueous HCl (2 x 30 mL), then with saturated aqueous Na2SO3 (10 mL), then with brine (2 x 20 mL), dried over MgSO4, filtered and concentrated in vacuo to give the title compound (5.5 mg, 56% yield, 89% purity) as an off-white solid.

[1217] 1 H NMR (500MHz, DMSO) δ8.07–7.92 (m, 1H), 7.75 (s, 1H), 7.39 (dd, J=7.8, 2.1Hz, 1H), 7.38–7.31 (m, 1H), 7. 20 (dd, J=7.4, 1.8Hz, 1H), 7.17–7.11 (m, 1H), 7.08–6.97 (m, 3H), 4.38–4.26 (m, 2H), 4.26–4.14 (m, 2H).

[1218] LCMS: m / z=431.0 [M+H]+, (ESI+), RT=3.04, Method A

[1219] Example 67 - Synthesis of 15-chloro-21,23-difluoro-18,18-dioxo-8,11-dioxa-18λ6-thia-19-azatetracyclo[18.3.1.113,17.02,7]pentacosyl-1(23),2(7),3,5,13,15,17(25),20(24),21-nonaen-16-ol (Compound 67)

[1220]

[1221] Step 1

[1222] To the solution of intermediate 9 (90% purity, 1.90g, 2.66mmol) in MeOH (15.5mL), p-toluenesulfonic acid hydrate (1:1) (50mg, 0.263mmol) is added in room temperature.Reactant mixture is stirred at room temperature for 1 hour, then concentrated in vacuo.Residue passes through FCC purifying (25g SiO2 post, 0-40% EtOAc heptane solution) to obtain 3-chloro-5-[[2,4-difluoro-5-[2-(2-hydroxyethoxy)phenyl]phenyl]sulfamoyl]-4-methoxybenzoic acid methyl esters (1.20g, 81% productive rate, 95% purity), it is white solid.

[1223] 1 H NMR (400MHz, DMSO) δ10.36 (s, 1H), 8.25 (d, J = 2.1Hz, 1H), 8.17 (d, J = 2.1Hz, 1H), 7.38 (ddd, J=8.3, 7.3, 1.8Hz, 1H), 7.34–7.27 (m, 1H), 7.24–7.18 (m, 1H) , 7.15–7.12 (m, 1H), 7.09 (dd, J=7.5, 1.8Hz, 1H), 7.01 (s, 1H), 4.66 (t...

Claims

1. Compounds of formula (I) or a stereoisomer and / or a pharmaceutically acceptable salt thereof, wherein: Ring A is phenyl, pyridyl or pyridone, wherein the nitrogen atom of the pyridone may be optionally substituted with C 1-6 alkyl; Ring B is phenyl or a 5-10 membered heterocyclic group; Ring C is phenyl, 5-10 membered heterocyclyl or 5-10 membered heteroaryl; or Ring C is absent; R 1 is independently selected at each occurrence from halogen, hydroxy, 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 selected at each occurrence from halogen, hydroxy, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-6 Cycloalkyl and COOH; R 3 Selected from cyano, halogen, C 1-6 Alkyl and C 3-6 Cycloalkyl; X 1 Selected from *-S(O)2N(R A )-**、-C(O)-、*-C(O)N(R A )-**、*-CH2N(R A )-** and *-S(O)2CH2-**, wherein * represents the point of attachment to Ring A and ** represents the point of attachment to Ring B; X 2 is a bond or -O-; X 3 For #-L 1 -L 2 -L 3 -##, wherein # indicates the point of attachment to ring A and ## indicates the point of attachment to ring C or, when ring C is absent, to ring B; L 1 Selected from -CH2-, -O-, -C(O)-, -C(O)N(R B )-、-C(O)O-、C 1-6 Alkyl-O-, -CH2-C(O)O-, -CH2-N(R B )C(O)- and 5-6 membered heteroaryl; L 2 C 1-6 alkyl or 4-6 membered heterocyclic group, wherein the 4-6 membered heterocyclic group may be optionally substituted with oxo; or L 2 does not exist; L 3 Selected from bond, -O-, -OC 1-6 Alkyl, C 1-6 Alkyl-O- and 4-6 membered heterocyclyl; R A is hydrogen or C 1-6 alkyl; R B is hydrogen or C 1-6 alkyl; R E is independently hydrogen or C 1-6 alkyl; n is 0, 1 or 2; o is 1 or 2; and p is 0 or 1.

2. The compound of claim 1, wherein ring A is phenyl, pyridyl or 2-pyridone, wherein the nitrogen atom of the 2-pyridone may be optionally substituted with C 1-6 alkyl.

3. The compound according to claim 1 or 2, wherein ring A is phenyl, pyridyl or 2-pyridonyl, wherein the nitrogen atom of the 2-pyridonyl may be optionally substituted with CH3.

4. The compound according to any one of claims 1 to 3, wherein ring A is selected from Where Δ represents the 1 The connection point and ΔΔ represent the connection with X 3 connection point.

5. The compound of any one of claims 1 to 4, wherein n is 0.

6. The compound of any one of claims 1 to 4, wherein n is 1.

7. The compound of claim 6, wherein R 1 Selected from chlorine, hydroxyl, CH3, CHF2 and NH2.

8. The compound of any one of claims 1 to 4, wherein n is 2.

9. The compound of claim 8, wherein R 1 is independently selected at each occurrence from chloro, fluoro, hydroxy, CH3, CHF2, -O-CH3, -O-CHF2, -OC(O)CH3 and 10. The compound according to any one of claims 1 to 9, wherein ring B is phenyl or a 9-membered heterocyclic group.

11. The compound according to any one of claims 1 to 10, wherein ring B is phenyl or 12. The compound according to any one of claims 1 to 10, wherein ring B is Among them, ● represents 1 and ●● indicates the connection point with X 2 connection point.

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

14. The compound of claim 13, wherein R 2 Selected from fluorine, hydroxy, cyclopropyl, CF3, -O-CH3, -O-CHF2, -O-CF3 and C(O)OH.

15. The compound of any one of claims 1-12, wherein o is 2.

16. The compound of claim 15, wherein R 2 is independently at each occurrence selected from chloro, fluoro, CH3, CF3 and -O-CH3.

17. The compound of any one of claims 1-16, wherein Ring C is absent.

18. The compound of any one of claims 1 to 16, wherein ring C is selected from phenyl, pyrrolidinyl, piperidinyl, pyridinyl, 19. The compound of any one of claims 1-16 or 18, wherein ring C is selected from Where □ represents the 2 The connection point of 3 connection point.

20. The compound of any one of claims 1-16, 18 and 19, wherein p is 1.

21. The compound of claim 20, wherein R 3 Selected from bromine, chlorine, fluorine, cyano, CH3 and cyclopropyl.

22. The compound of any one of claims 1-16, 18 and 19, wherein p is 0.

23. The compound of any one of claims 1 to 22, wherein X 1 Selected from *-S(O)2N(H)-**, *-S(O)2N(CH3)-**, -C(O)-, *-C(O)N(H)-**, *-CH2N(H)-** and *-S(O)2CH2-**, wherein * represents the point of attachment to ring A and ** represents the point of attachment to ring B.

24. The compound of any one of claims 1 to 23, wherein X 2 is the key.

25. The compound of any one of claims 1 to 23, wherein X 2 For -O-.

26. The compound of any one of claims 1 to 25, wherein L 1 Selected from -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 27. The compound of any one of claims 1 to 26, wherein L 2 Selected from -CH2CH2-, -(CH2)3-, -CH2-, -(CH2)4-, -CH(CH3)CH2-, -CH2CH2C(H)(CH3)-, 28. The compound of any one of claims 1 to 26, wherein L 2 Does not exist.

29. The compound of any one of claims 1 to 28, wherein L 3 is the key.

30. The compound of any one of claims 1 to 28, wherein L 3 is -O-, -CH2-O- or 31. The compound of any one of claims 1 to 25, wherein X 3 Selected from wherein # indicates the point of attachment to ring A and ## indicates the point of attachment to ring C.

32. Compounds of formula (Ia) or a stereoisomer and / or a pharmaceutically acceptable salt thereof, wherein: R 4 is selected from hydrogen, hydroxyl, halogen and C 1-6 alkyl; R 5 Selected from 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 Selected from hydrogen, halogen, hydroxyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl and C(O)OH; R 7 Selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl and C 1-6 Alkoxy; R 8 is hydrogen, halogen or C 1-6 alkyl; R 9 is selected from hydrogen, cyano, halogen and C 3-6 Cycloalkyl; R 10 is hydrogen, cyano, or halogen; X 4 Selected from *-S(O)2N(R C )-**、*-C(O)N(R C )-**、*-CH2N(R C )-** and *-S(O)2CH2-**, where * indicates and ** indicates the connection point with The connection point; X 5 For #-L 4 -L 5 -L 6 -##, where # indicates The connection point and ## indicates The connection point; L 4 Selected from 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 5-6 membered heteroaryl; L 5 C 1-6 Alkyl or 4-6 membered heterocyclic group, wherein the 4-6 membered heterocyclic group may be optionally substituted with oxo; L 6 Selected from bond, -O-, C 1-6 Alkyl-O- and 4-6 membered heterocyclyl; R C is hydrogen or C 1-6 alkyl; and R D is hydrogen or C 1-6 alkyl.

33. The compound of claim 32, wherein R 4 Selected from hydrogen, hydroxy, chlorine and CH3.

34. The compound of claim 32 or 33, wherein R 5 Selected from hydrogen, fluorine, hydroxyl, CHF2, -O-CH3, -O-CHF2, -OC(O)CH3 and 35. The compound of any one of claims 32-34, wherein R 6 Selected from hydrogen, hydroxy, fluorine, chlorine, cyclopropyl, CF3, -O-CH3, -O-CHF2, -O-CF3 and C(O)OH.

36. The compound of any one of claims 32-35, wherein R 7 Selected from hydrogen, chlorine, fluorine, -O-CH3, CH3 and CF3.

37. The compound of any one of claims 32-36, wherein R 8 It is hydrogen, CH3 or chlorine.

38. The compound of any one of claims 32-37, wherein R 9 is selected from hydrogen, cyano, chlorine, bromine, fluorine and cyclopropyl.

39. The compound of any one of claims 32-38, wherein R 10 is selected from hydrogen, cyano, chlorine and fluorine.

40. The compound of any one of claims 32-39, wherein X 4 Selected from *-S(O)2N(H)-**, *-S(O)2N(CH3)-**, *-C(O)N(H)-**, *-CH2N(H)-** and *-S(O)2CH2-**, wherein * represents and ** indicates the connection point with connection point.

41. The compound of any one of claims 32-40, wherein L 4 Selected from -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 42. The compound of any one of claims 32-41, wherein L 5 Selected from -CH2-, -CH2CH2-, -(CH2)3-, -C(H)(CH3)CH2-, -CH2CH2C(H)(CH3)-, -(CH2)4-, 43. The compound of any one of claims 32-42, wherein L 6 is the key.

44. The compound of any one of claims 32-42, wherein L 6 is -O-, -CH2-O- or 45. The compound of any one of claims 32-40, wherein X 5 Selected from The # indicates The connection point and ## indicates connection point.

46. ​​A compound selected from any one of the compounds shown in Table 1, or a pharmaceutically acceptable salt thereof.

47. A pharmaceutical composition comprising a compound according to any one of claims 1 to 46; and a pharmaceutically acceptable carrier.

48. A method of inhibiting ACLY in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-46 or a pharmaceutical composition of claim 47.

49. The method of claim 48, wherein the subject has a liver condition, disease or disorder.

50. The method of claim 49, wherein the liver condition, disease or disorder is NAFLD or NASH.

51. The method of claim 48, wherein the subject has type 2 diabetes.

52. The method of claim 48, wherein the subject suffers from inflammation.

53. The method of claim 48, wherein the subject has chronic kidney disease.

54. The method of claim 48, wherein the subject has an autoimmune disease.

55. The method of claim 48, wherein the subject has cancer.

56. A method of treating NAFLD in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-46 or a pharmaceutical composition of claim 47.

57. A method of treating NASH in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-46 or a pharmaceutical composition of claim 47.

58. A method of treating type 2 diabetes in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-46 or a pharmaceutical composition of claim 47.

59. A method of treating inflammation in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-46 or a pharmaceutical composition of claim 47.

60. A method of treating chronic kidney disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-46 or a pharmaceutical composition of claim 47.

61. A method of treating an autoimmune disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-46 or a pharmaceutical composition of claim 47.

62. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-46 or a pharmaceutical composition of claim 47.

63. A method of treating a condition, disease or disorder described herein in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-46 or a pharmaceutical composition of claim 47.

Images