Macrocyclic alpha4beta7 integrin inhibitors

Abstract

The present invention relates to compounds that are α4β7 integrin inhibitors, which have structural formula I, as defined herein. The present invention also relates to processes for the preparation of these compounds, pharmaceutical compositions containing them, and their use in the treatment of α4β7-related diseases or disorders.

Description

[Technical Field]

[0001] The present invention relates to compounds that inhibit the binding of the integrin receptor α4β7 to the mucosal addressin cell adhesion molecule-1 (MAdCAM-1) and exhibit selectivity over the closely related integrin receptor α4β1. The invention also relates to processes for the preparation of these compounds, pharmaceutical compositions containing them, and their use in the treatment of α4β7-associated diseases or disorders, such as inflammatory bowel diseases, including ulcerative colitis and Crohn's disease. [Background technology]

[0002] Integrins are a family of transmembrane adhesion receptors that facilitate adhesive connections between cells and their surrounding extracellular matrix or neighboring cells (DOI: 10.1007 / s00441-009-0834-6, DOI: 10.1016 / j.bbamem.2020.183206). They are composed of heterodimeric type I transmembrane proteins consisting of two noncovalently associated subunits: one alpha (α) subunit and one beta (β) subunit (DOI: 10.5483 / bmbrep.2014.47.12.241). These subunits contain a large extracellular domain, a single transmembrane domain, and a short cytoplasmic tail (DOI: 10.1242 / jcs.01014). The globular head domain creates the binding site for extracellular ligands, while the short cytoplasmic tail interacts with clusters of associated proteins, ultimately connecting them to the cytoskeleton. In mammals, there are 18 known alpha subunits and 8 known beta subunits, which combine to form 24 distinct integrin receptors, which play important roles in numerous biological processes, including leukocyte migration (DOI: 10.1242 / jcs.01014; DOI: 10.1016 / s0092-8674(02)00971-6). This is regulated by two mechanisms: first, differential expression of integrins, and second, chemokines that induce changes in integrin adhesion states (DOI: 10.1038 / 346425a). This allows different leukocyte populations to be recruited to specific organs in response to different inflammatory signals, which, if left unchecked, can lead to chronic inflammation and autoimmune disease (DOI:10.1007 / 978-88-470-2143-3_5).

[0003] The α4β7 integrin receptor, highly expressed on lymphocytes, including B and T lymphocytes, directs lymphocyte homing to the intestine via binding to its major ligand, MAdCAM-1, which is primarily expressed on intestinal endothelial cells (DOI:10.1046 / j.1365-2567.1996.d01-706.x, DOI:10.4049 / jimmunol.0902407, DOI:10.1111 / j.1365-2567.2005.02225.x PMCID:PMC1857942). Therefore, inhibiting α4β7 binding to MAdCAM-1 may be a useful method for treating intestinal inflammatory conditions. Indeed, monoclonal antibodies with high binding affinity to α4β7, such as natalizumab (Tysabri®) and vedolizumab (Entyvio®), have shown therapeutic benefit in gastrointestinal autoinflammatory / autoimmune diseases such as ulcerative colitis and Crohn's disease (DOI:10.1056 / NEJMoa1215734, DOI:10.1056 / NEJMoa1215739). However, there are potential concerns regarding the long-term administration of these therapies. For example, they are immunogenic, which leads to reduced drug efficacy and an increased risk of hypersensitivity reactions due to the development of persistent anti-drug antibodies (DOI:10.3748 / wjg.v24.i17.1868, DOI:10.3109 / 08830185.2012.690794, DOI:10.1038 / ni1275, DOI:10.1016 / j.jns.2008.08.003). Also, these therapies are administered by injection, which can result in infusion-related reactions (DOI:10.1016 / j.msard.2019.101523). Furthermore, one of these therapies, natalizumab, also inhibits the α4β1 integrin-ligand interaction and is associated with an increased risk of progressive multifocal leukoencephalopathy (PML), an opportunistic infection of the brain caused by reactivation of the John Cunningham virus (DOI:10.1111 / j.1527-3458.2007.00003.x).

[0004] Therefore, the development of effective and safe small molecule α4β7 integrin inhibitors that can be administered orally and have the potential to increase patient compliance would be an important addition to the armamentarium for α4β7-mediated pathologies such as inflammatory bowel disease, ulcerative colitis, and Crohn's disease. Indeed, clinical trials are underway with two selective small molecule α4β7 integrin inhibitors (NCT05291689; ACTRN12621000612819).

[0005] Therefore, given the role of α4β7 in inflammatory bowel disease, there is a continuing need for the development of effective and safe small molecule α4β7 integrin inhibitors. Summary of the Invention

[0006] In one aspect, the present invention provides a compound defined herein, or a pharmaceutically acceptable salt thereof.

[0007] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the invention as defined herein, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0008] In another aspect, the present invention relates to a compound of the invention as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, for use in therapy.

[0009] In another aspect, the invention relates to a compound of the invention as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, for use in the treatment of a disease or disorder mediated by α4β7.

[0010] In another aspect, the present invention relates to a method of treating a disease or disorder mediated by α4β7, the method comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of the invention as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein.

[0011] Examples of diseases or disorders mediated by α4β7 include inflammatory bowel diseases, including ulcerative colitis and Crohn's disease.

[0012] In another aspect, the present invention provides a compound as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition, for use in the treatment of inflammatory bowel disease, including ulcerative colitis and Crohn's disease.

[0013] In another aspect, the present invention provides a method of treating inflammatory bowel disease, including ulcerative colitis and Crohn's disease, the method comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition.

[0014] The present invention further provides methods for the synthesis of the compounds defined herein, or pharmaceutically acceptable salts thereof.

[0015] In another aspect, the present invention provides a compound, or a pharmaceutically acceptable salt thereof, obtainable by, or obtained directly by, a synthetic method as defined herein.

[0016] In another aspect, the present invention provides novel intermediates as defined herein that are suitable for use in any one of the synthetic methods presented herein.

[0017] The preferred, preferred, and optional features of any one particular embodiment of the present invention are also preferred, preferred, and optional features of any other embodiment. DETAILED DESCRIPTION OF THE INVENTION

[0018] definition Unless otherwise specified, the following terms used in the specification and claims have the following meanings, as defined below.

[0019] References to "treating" or "treatment" should be understood to include prevention of a condition as well as the alleviation of established symptoms of a condition. Thus, "treating" or "treatment" of a condition, disorder, or condition includes (1) preventing or delaying the onset of clinical symptoms of the condition, disorder, or condition in a person who may be suffering from or predisposed to the condition, disorder, or condition, but who has not yet experienced or exhibited clinical or subclinical symptoms of the condition, disorder, or condition; (2) inhibiting the condition, disorder, or condition, i.e., arresting, reducing, or delaying the onset of the disease or its recurrence (in the case of maintenance therapy) or at least one clinical or subclinical symptom thereof; or (3) palliating or alleviating the disease, i.e., causing regression of the condition, disorder, or condition, or at least one of its clinical or subclinical symptoms.

[0020] A "therapeutically effective amount" means the amount of a compound that, when administered to a mammal for treating a disease, is sufficient to effect such treatment for the disease. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity, and the age, weight, etc., of the mammal being treated.

[0021] As used herein, the term "alkyl" includes both straight-chain and branched-chain alkyl groups. References to individual alkyl groups, such as "propyl," are specific for the straight-chain version only, and references to individual branched-chain alkyl groups, such as "isopropyl," are specific for the branched-chain version only. For example, "(1-6C)alkyl" includes (1-4C)alkyl, (1-3C)alkyl, propyl, isopropyl, and t-butyl. A similar convention applies to other radicals, for example, "phenyl(1-6C)alkyl" includes phenyl(1-4C)alkyl, benzyl, 1-phenylethyl, and 2-phenylethyl.

[0022] As used herein, the term "alkylene" includes both straight-chain and branched-chain divalent alkyl groups. For example, "C1-4 "Alkylene" includes methylene (-CH2-), ethylene (-CH2CH2-), propylene, and butylene.

[0023] As used herein, the term "alkoxy" includes both straight and branched chain alkyl groups single-bonded to oxygen. For example, "C 1-4 "Alkoxy" includes methoxy, ethoxy, isopropoxy and t-butoxy.

[0024] The term "(m-nC)" or "(m-nC) group" used alone or as a prefix, refers to any group having m to n carbon atoms.

[0025] "Cycloalkyl" means a hydrocarbon monocyclic or bicyclic ring containing carbon atoms. Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Bicyclic rings may be fused or spiro-linked. Examples of bicyclic cycloalkyl groups include bicyclo[2.2.2]octane, bicyclo[2.1.1]hexane, bicyclo[1.1.1]pentane, spiro[2.4]heptane, bicyclo[4.1.0]heptane, and bicyclo[2.2.1]heptane.

[0026] The term "halo" refers to fluoro, chloro, bromo and iodo.

[0027] The term "haloalkyl" is used herein to refer to each alkyl group in which one or more hydrogen atoms have been replaced by a halogen (e.g., fluorine) atom. Examples of haloalkyl groups include fluoroalkyl groups such as -CHF2, -CH2CF3, or perfluoroalkyl / alkoxy groups such as -CF3, or -CF2CF3.

[0028] The terms "heterocyclyl," "heterocyclic," or "heterocycle" refer to non-aromatic, saturated or partially saturated, monocyclic, fused, bridged, or spiro bicyclic heterocyclic ring system(s). Monocyclic heterocyclic rings contain about 3 to 12 (preferably 3 to 7) ring atoms, including 1 to 5 (preferably 1, 2, or 3) heteroatoms selected from nitrogen, oxygen, or sulfur in the ring. Bicyclic heterocyclic rings contain 7 to 17 member atoms, preferably 7 to 12 member atoms in the ring. Bicyclic heterocyclic ring(s) can be fused, spiro, or bridged ring systems. Conveniently, the heterocyclic group is a 4- to 10-membered heterocyclyl. Preferred 4- to 10-membered heterocyclyl groups include monocyclic and bicyclic heterocycles. Advantageously, monocyclic heterocycles contain 4 to 6 ring atoms, including 1 to 3 heteroatoms selected from nitrogen, oxygen, or sulfur, in the ring. Advantageously, bicyclic heterocycles contain 8 to 10 ring atoms, including 1 to 3 heteroatoms selected from nitrogen, oxygen, or sulfur, in the ring. Suitable bicyclic heterocyclyl groups include 8- to 10-membered spiro-bicyclic heterocyclic ring systems, such as 2-azaspiro[4.5]decanyl, 2-azaspiro[4.4]nonanyl, 2,8-diazaspiro[4.5]decanyl, 8-oxa-2-azaspiro[4.5]decanyl, or 1,3-diazaspiro[4.5]decanyl. Examples of heterocyclic groups include oxiranyl, oxetanyl, tetrahydrofuranyl, dioxanyl, and cyclic ethers, such as substituted cyclic ethers. Nitrogen-containing heterocycles include, for example, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrotriazinyl, tetrahydropyrazolyl, 1,2-diazacyclohexanyl, etc. Typical sulfur-containing heterocycles include tetrahydrothienyl, dihydro-1,3-dithiol, tetrahydro-2H-thiopyran, and hexahydrothiepin.Other heterocycles include dihydrooxathiolyl, dihydroisoxazolyl (such as 4,5-dihydroisoxazolyl), dihydropyridinyl (such as 1,2-dihydropyridinyl or 1,6-dihydropyridinyl), tetrahydrooxazolyl, tetrahydrooxadiazolyl, tetrahydrodioxazolyl, tetrahydrooxathiazolyl, hexahydrotriazinyl, tetrahydrooxazinyl, morpholinyl, thiomorpholinyl, tetrahydropyrimidinyl, dioxolinyl, octahydrobenzofuranyl, octahydrobenzimidazolyl, and octahydrobenzothiazolyl. In the case of heterocycles containing sulfur, sulfur-oxidized heterocycles containing SO or SO groups are also included. Examples include sulfoxide and sulfone forms of tetrahydrothienyl and thiomorpholinyl, such as tetrahydrothienyl 1,1-dioxide and thiomorpholinyl 1,1-dioxide. Suitable values ​​for a heterocyclyl group bearing one or two oxo (=O) or thioxo (=S) substituents are, for example, 2-oxopyrrolidinyl, 2-thioxopyrrolidinyl, 2-oxoimidazolidinyl, 2-thioxoimidazolidinyl, 2-oxopiperidinyl, 2,5-dioxopyrrolidinyl, 2,5-dioxoimidazolidinyl or 2,6-dioxopiperidinyl. Specific heterocyclyl groups are saturated monocyclic 3- to 7-membered heterocyclyls containing one, two, or three heteroatoms selected from nitrogen, oxygen, or sulfur, such as azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, morpholinyl, tetrahydrothienyl, tetrahydrothienyl 1,1-dioxide, thiomorpholinyl, thiomorpholinyl 1,1-dioxide, piperidinyl, homopiperidinyl, piperazinyl, or homopiperazinyl. As will be appreciated by those skilled in the art, any heterocycle may be linked to another group through any suitable atom, for example, a carbon or nitrogen atom. Preferably, the terms "heterocyclyl," "heterocyclic," or "heterocycle" refer to a 4-, 5-, 6-, or 7-membered monocyclic ring as defined above, unless otherwise specified.

[0029] The term "heteroaryl" or "heteroaromatic" refers to an aromatic monocyclic, bicyclic, or polycyclic ring incorporating one or more (e.g., 1 to 4, particularly 1, 2, or 3) heteroatoms selected from nitrogen, oxygen, or sulfur. Examples of heteroaryl groups are monocyclic and bicyclic groups containing 5 to 12 ring members, more usually 5 to 10 ring members. A heteroaryl group can be, for example, a 5- or 6-membered monocyclic ring or a 9- or 10-membered bicyclic ring, e.g., a fused 5-membered and 6-membered ring, or a bicyclic structure formed from two fused 6-membered rings. Each ring may contain up to about four heteroatoms, typically selected from nitrogen, sulfur, and oxygen. Typically, a heteroaryl ring will contain up to three heteroatoms, more usually up to two, e.g., a single heteroatom. In one embodiment, a heteroaryl ring contains at least one ring nitrogen atom. The nitrogen atoms in a heteroaryl ring can be basic, as in the case of an imidazole or pyridine, or essentially non-basic, as in the case of an indole or pyrrole nitrogen. Generally, the number of basic nitrogen atoms present in a heteroaryl group, including any amino group substituents on the ring, will be less than five. Preferably, the term "heteroaryl" or "heteroaromatic" refers to a 5- or 6-membered monocyclic heteroaryl ring as defined above.

[0030] Non-limiting examples of heteroaryl include furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazenyl, benzofuranyl, indolyl, isoindolyl, benzothienyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, indazolyl, purinyl, benzofurazanyl, quinolyl, and isoquinolyl. , quinazolinyl, quinoxalinyl, cinnolinyl, pteridinyl, naphthyridinyl, carbazolyl, phenazinyl, benzisoquinolinyl, pyridopyrazinyl, thieno[2,3-b]furanyl, 2H-furo[3,2-b]-pyranyl, 5H-pyrido[2,3-d]-o-oxazinyl, 1H-pyrazolo[4,3-d]-oxazolyl, 4H-imidazo[4,5-d]thiazolyl, pyrazino[2,3-d]pyridazinyl, imidazo[2,1-b]thiazolyl, and imidazo[1,2-b][1,2,4]triazinyl. "Heteroaryl" also includes partially aromatic bicyclic or polycyclic ring systems in which at least one ring is aromatic and one or more of the other ring(s) is non-aromatic, saturated or partially saturated, provided that at least one ring contains one or more heteroatoms selected from nitrogen, oxygen, or sulfur.Examples of partially aromatic heteroaryl groups include, for example, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 2-oxo-1,2,3,4-tetrahydroquinolinyl, dihydrobenzothienyl, dihydrobenzofuranyl, 2,3-dihydro-benzo[1,4]dioxinyl, benzo[1,3]dioxolyl, 2,2-dioxo-1,3-dihydro-2-benzothienyl, 4,5,6,7-tetrahydrobenzofuranyl, indolinyl, 1,2,3,4-tetrahydro-1,8-naphthyridinyl, 1,2,3,4-tetrahydropyrido[2,3-b]pyrazinyl, 3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl, 4,5,6,7-tetrahydrobenzofuranyl, indolinyl, benzo[d]isoxazolyl, 4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridinyl, 5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazinyl, 5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazolyl, 6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazolyl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridinyl, 6,7-dihydro-4H-[1,2,3]triazolo[5,1-c][1,4]-oxazinyl, and 1,4,5,6-tetrahydrocyclopenta[d][1,2,3]-triazol-5-yl.

[0031] Non-limiting examples of 5-membered heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thienyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, and tetrazolyl groups.

[0032] Non-limiting examples of 6-membered heteroaryl groups include, but are not limited to, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, and triazinyl.

[0033] Specific non-limiting examples of bicyclic heteroaryl groups containing a 6-membered ring fused to a 5-membered ring include, but are not limited to, benzofuranyl, benzothiophenyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, isobenzofuranyl, indolyl, isoindolyl, indolizinyl, indolinyl, isoindolinyl, purinyl (e.g., adeninyl, guaninyl), indazolyl, benzodioxolyl, pyrrolopyridine, and pyrazolopyridinyl groups.

[0034] Specific non-limiting examples of bicyclic heteroaryl groups containing two fused six-membered rings include, but are not limited to, quinolinyl, isoquinolinyl, chromanyl, thiochromanyl, chromenyl, isochromenyl, chromanyl, isochromanyl, benzodioxanyl, quinolidinyl, benzoxazinyl, benzodiazinyl, pyridopyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl, and pteridinyl groups.

[0035] Specific non-limiting examples of bicyclic heteroaryl groups containing a 5-membered ring fused to a 5-membered ring include, but are not limited to, 6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazolyl and 1,4,5,6-tetrahydrocyclopenta[d][1,2,3]triazol-5-yl.

[0036] The term "aryl" refers to a cyclic or polycyclic aromatic ring having 6 to 12 carbon atoms. The term aryl includes both monovalent and divalent species. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, and the like. In this particular embodiment, aryl is phenyl or naphthyl, especially phenyl.

[0037] The term "optionally substituted" refers to groups, structures, or molecules that are substituted and to groups, structures, or molecules that are not substituted.

[0038] Where optional substituents are selected from "one or more" groups, this definition is understood to include all substituents being selected from one of the specified groups, or substituents being selected from two or more of the specified groups.

[0039] The phrase "compounds of the invention" means compounds disclosed herein both generically and specifically.

[0040] Compounds of the Invention In a first aspect, the present invention provides a compound of formula I, or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, A is an aromatic ring, and Z 1 , Z 2 , Z 3 and Z 4 are independently N or CR 2 and B is aryl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl, or 4- to 10-membered heterocyclyl, where B is C 1-5 Alkyl, halo, cyano, hydroxyl, NR 3 R 4 , C 1-5 Alkoxy, C 1-5 Haloalkyl, C 1-5 Haloalkoxy, C 1-4 Alkylene-OC 1-4 Alkyl, C 3-10 optionally substituted by 1 to 5 substituents independently selected from cycloalkyl, and 4- to 10-membered heterocyclyl; L is C 3-8 Alkylene, C 3-8 Alkenylene, or C 3-8 Alkynylene, where one, two or three methylene groups in L are —O—, —S—, —C(O)—, or —N(R 5 )-, and L is C 1-5 Alkyl, halo, hydroxyl, C 1-5Alkoxy, C 1-5 Haloalkyl, C 1-5 Haloalkoxy and NR 6 R 7 and optionally substituted with 1 to 5 substituents independently selected from R 1 4- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, aryl, C 3-10 cycloalkyl, or -NR 8 C(O)R 9 where: i) the 4- to 10-membered heterocyclyl, the 5- to 10-membered heteroaryl, the aryl, and the C 3-10 Each cycloalkyl is C 1-5 Alkyl, halo, oxo, cyano, C 1-5 Alkoxy, C 1-5 Haloalkyl, C 1-5 Haloalkoxy, C 1-4 Alkylene-OC 1-4 Alkyl, C 1-4 Alkylene-OH, C 3-6 Cycloalkyl, 4- to 6-membered heterocyclyl, and C 1-4 Alkylene-NR 10 R 11 and optionally substituted with 1 to 5 substituents independently selected from ii) the 4- to 10-membered heterocyclyl group optionally contains one or two carbon-carbon double bonds and is optionally fused to a 5- or 6-membered heteroaryl ring, or a phenyl ring; R 2 is independently selected for each occurrence as H, halo, cyano, hydroxyl, C 1-5 Alkyl, C 1-5 Alkoxy, C 1-5 Haloalkyl, C 1-5 Haloalkoxy, C 1-4 Alkylene-OC 1-4 Alkyl, C 3-6 selected from cycloalkyl and 4- to 6-membered heterocyclyl; R 3 and R 4 are independent, H, C 1-5 Alkyl, C 1-5Haloalkyl, and C 3-10 cycloalkyl; R 5 , R 6 and R 7 are independently H or C 1-5 is alkyl, R 8 But H, C 1-6 Alkyl, C 2-6 Haloalkyl, C 2-4 Alkylene-OC 1-4 Alkyl; C 3-6 Cycloalkyl, 4- to 6-membered heterocyclyl, or C 2-5 Alkylene-NR 12 R 13 and R 9 But C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, C 2-4 Alkylene-OC 1-4 Alkyl, C 3-6 Cycloalkyl, 4- to 6-membered heterocyclyl, NR 14 R 15 or C 1-5 Alkylene-NR 16 R 17 and R 10 and R 11 are independent, H, C 1-5 Alkyl, C 1-5 Haloalkyl or -C 1-4 Alkylene-OC 1-4 alkyl, or R 10 and R 11 together with the nitrogen attached to them, form halo, C 1-5 Alkyl, C 1-5 Alkoxy, C 1-5 Haloalkyl, and C 1-5 forming a 4- to 6-membered heterocyclyl ring optionally substituted with 1 to 4 groups independently selected from haloalkoxy; R 12 , R 13 , R 14, R 15 , R 16 , and R 17 are independent, H, C 1-5 Alkyl, or C 1-5 haloalkyl, or R 12 and R 13 , R 14 and R 15 , or R 16 and R 17 independently, together with the nitrogen atom to which they are attached, halo and C 1-5 Forms a 4- to 6-membered heterocyclyl ring optionally substituted with 1 to 4 groups independently selected from alkyl.

[0041] Particular compounds of the present invention include, for example, compounds of Formula I, or a pharmaceutically acceptable salt thereof, wherein, unless otherwise specified, Z 1 , Z 2 , Z 3 , Z 4 , A, B, L, R 1 , R 2 , R 10 , and R 11 each has any of the meanings defined herein above or in any of items (1) to (60) herein below. For the avoidance of doubt, the scope of the present invention includes compounds of formula I, or a pharmaceutically acceptable salt thereof, wherein any of the substituent definitions defined herein may be combined with any of the other substituent definitions also defined herein. (1)Z 1 , Z 2 , Z 3 and Z 4 All are CR 2 That is, (2) Z 1 , Z 2 , Z 3 and Z 4 Two of them are N and the other two are CR 2 That is, (3) Z 1 , Z 2 , Z 3 and Z4 One of them is N, and the other three are CR 2 That is, (4) Z 2 is N and Z 1 , Z 3 and Z 4 is CR 2 That is, (5)R 2 is independently for each occurrence H, halo, cyano, hydroxyl, C 1-5 Alkyl, C 1-5 Alkoxy, C 1-5 Haloalkyl, and C 3-6 cycloalkyl, (6)R 2 is independently H, halo, C for each occurrence. 1-5 Alkyl, C 1-5 Haloalkyl, and C 3-6 cycloalkyl, (7)R 2 is independently selected at each occurrence from H, fluoro, chloro, methyl, ethyl, trifluoromethyl, and cyclopropyl; (8)R 2 is independently selected at each occurrence from H, fluoro, methyl, trifluoromethyl, and cyclopropyl; (9)R 2 is H for each occurrence, (10) A is [ka] wherein "b" is the point of attachment to the B ring; (11) A is [ka] wherein "b" is the point of attachment to the B ring; (12) A is [ka] wherein "b" is the point of attachment to the B ring; (13) B is aryl, 5- to 6-membered heteroaryl, C 3-8 cycloalkyl, or 4- to 8-membered heterocyclyl, where B is C 1-5 Alkyl, halo, cyano, hydroxyl, NR 3 R 4 , C 1-5 Alkoxy, C 1-5 Haloalkyl, C 1-5 Haloalkoxy, C 1-4 Alkylene-OC 1-4 Alkyl, C 3-10 optionally substituted by 1 to 5 substituents independently selected from cycloalkyl, and 4- to 10-membered heterocyclyl; (14) B is aryl or 5- to 6-membered heteroaryl, where B is C 1-3 Alkyl, halo, cyano, hydroxyl, NR 3 R 4 , C 1-5 Alkoxy, C 1-5 Haloalkyl, C 1-5 Haloalkoxy, C 1-4 Alkylene-OC 1-4 Alkyl, C 3-7 optionally substituted by 1 to 4 substituents independently selected from cycloalkyl, and 4- to 10-membered heterocyclyl; (15) B is aryl, C 1-3 Alkyl, halo, cyano, hydroxyl, NR 3 R 4 , C 1-5 Alkoxy, C 1-5 Haloalkyl, C 1-5 Haloalkoxy, C 1-4 Alkylene-OC 1-4 Alkyl, C 3-7 optionally substituted by 1 to 4 substituents independently selected from cycloalkyl, and 4- to 10-membered heterocyclyl; (16) B is phenyl, C 1-3 Alkyl, halo, cyano, C 1-5 Alkoxy, C 1-5 Haloalkyl, C 3-7optionally substituted by 1 to 4 substituents independently selected from cycloalkyl, and 4- to 10-membered heterocyclyl; (17) B is C 1-3 Alkyl, Halo, C 3-7 phenyl optionally substituted by 1 to 3 substituents independently selected from cycloalkyl, and 4- to 10-membered heterocyclyl; (18) B is phenyl optionally substituted with 1 to 3 substituents independently selected from methyl, fluoro, cyclopropyl, and 5- to 6-membered heterocyclyl; (19)B is [ka] wherein "a" is the point of attachment to the A ring and "l" is the point of attachment to the linker L; (20)B is [ka] wherein "a" is the point of attachment to the A ring and "l" is the point of attachment to the linker L; (21)B is [ka] wherein "a" is the point of attachment to the A ring and "l" is the point of attachment to the linker L; (22) L is C 3-8 Alkylene, or C 3-8 alkenylene, where one, two, or three methylene groups in L are —O—, —S—, —C(O)—, or —N(R 5 )-, and L is C 1-5 Alkyl, halo, hydroxyl, C 1-5 Alkoxy, C 1-5 Haloalkyl, C 1-5 Haloalkoxy and NR 6 R 7 optionally substituted with 1 to 5 substituents independently selected from (23) L is C 5-8Alkylene, or C 5-8 alkenylene, where one, two, or three methylene groups in L are —O—, —S—, —C(O)—, or —N(R 5 )-, and L is C 1-5 Alkyl, halo, hydroxyl, C 1-5 Alkoxy, C 1-5 Haloalkyl, C 1-5 Haloalkoxy and NR 6 R 7 optionally substituted with 1 to 5 substituents independently selected from (24) L is C 5-8 Alkylene, or C 5-8 alkenylene, where one, two, or three methylene groups in L are —O—, —C(O)—, or —N(R 5 )-, and L is C 1-5 Alkyl, halo, hydroxyl, C 1-5 Alkoxy, and C 1-5 optionally substituted with 1 to 5 substituents independently selected from haloalkyl; (25)L is C 5-8 Alkylene, or C 5-8 alkenylene, where one or two methylene groups in L are —O—, —C(O)—, or —N(R 5 )-, and L is C 1-5 Alkyl, halo, hydroxyl, C 1-5 Alkoxy, and C 1-5 optionally substituted with 1 to 3 substituents independently selected from haloalkyl; (26) L is C 5-8 alkylene, where one or two methylene groups in L are —O—, —C(O)—, or —N(R 5 )-, and L is selected from 1 to 3 independently selected C 1-5 optionally substituted with alkyl substituents; (27) L is C 5-8alkylene, where one or two methylene groups in L are —O—, —C(O)—, or —N(R 5 )-, and L is optionally substituted with 1 to 3 methyl substituents; (28)L is [ka] wherein "b" is the point of attachment to the B ring; (29)L is [ka] wherein "b" is the point of attachment to the B ring; (30)L is [ka] wherein "b" is the point of attachment to the B ring; (31)R 1 is a 4- to 10-membered heterocyclyl, a 5- to 10-membered heteroaryl, an aryl, C 3-10 cycloalkyl, or -NR 8 C(O)R 9 where: i) the 4- to 10-membered heterocyclyl, the 5- to 10-membered heteroaryl, the aryl, and the C 3-10 Each cycloalkyl is C 1-5 Alkyl, halo, oxo, cyano, C 1-5 Alkoxy, C 1-5 Haloalkyl, C 1-5 Haloalkoxy, C 1-4 Alkylene-OC 1-4 Alkyl, C 3-6 Cycloalkyl, 4- to 6-membered heterocyclyl, and C 1-4 Alkylene-NR 10 R 11 and optionally substituted with 1 to 5 substituents independently selected from ii) the 4- to 10-membered heterocyclyl group optionally contains one or two carbon-carbon double bonds and is optionally fused to a 5- or 6-membered heteroaryl ring, or a phenyl ring; (32)R 1 is a 4- to 10-membered heterocyclyl, a 5- to 10-membered heteroaryl, or -NR 8 C(O)R 9 where: i) each of the 4- to 10-membered heterocyclyl and the 5- to 10-membered heteroaryl is C 1-5 Alkyl, halo, oxo, cyano, C 1-5 Alkoxy, C 1-5 Haloalkyl, C 1-5 Haloalkoxy, C 1-4 Alkylene-OC 1-4 Alkyl, C 3-6 Cycloalkyl, 4- to 6-membered heterocyclyl, and C 1-4 Alkylene-NR 10 R 11 and optionally substituted with 1 to 5 substituents independently selected from ii) the 4- to 10-membered heterocyclyl group optionally contains one or two carbon-carbon double bonds and is optionally fused to a 5- or 6-membered heteroaryl ring, or a phenyl ring; (33)R 1 is a 4- to 10-membered heterocyclyl, or -NR 8 C(O)R 9 wherein the 4- to 10-membered heterocyclyl is I C 1-5 Alkyl, halo, oxo, cyano, C 1-5 Alkoxy, C 1-5 Haloalkyl, C 1-5 Haloalkoxy, C 1-4 Alkylene-OC 1-4 Alkyl, C 3-6 Cycloalkyl, 4- to 6-membered heterocyclyl, and C 1-4 Alkylene-NR 10 R 11 and optionally substituted with 1 to 5 substituents independently selected from ii) optionally containing one or two carbon-carbon double bonds and optionally fused to a 5- or 6-membered heteroaryl ring, or a phenyl ring; (34)R 1 is a 5- to 6-membered heterocyclyl, C 1-5 Alkyl, halo, oxo, cyano, C 1-5 Alkoxy, C 1-5 Haloalkyl, C 1-5 Haloalkoxy, C 1-4 Alkylene-OC 1-4 Alkyl, C 3-6 Cycloalkyl, 4- to 6-membered heterocyclyl, and C 1-4 Alkylene-NR 10 R 11 and optionally containing 1 or 2 carbon-carbon double bonds, and optionally fused to a phenyl ring; (35)R 1 is a 5- to 6-membered heterocyclyl, C 1-5 Alkyl, halo, oxo, cyano, C 1-5 Haloalkyl, and C 1-4 Alkylene-NR 10 R 11 and optionally containing 1 or 2 carbon-carbon double bonds, and optionally fused to a phenyl ring; (36)R 1 is -NR 8 C(O)R 9 That is, (37)R 1 is -NR 8 C(O)R 9 and R 8 is H or C 1-6 is alkyl, (38)R 1 is -NR 8 C(O)R 9 and R 9 is C 1-6 is alkyl, (39)R 1is -NR 8 C(O)R 9 and R 8 is H or C 1-6 alkyl, and R 9 is C 1-6 is alkyl, (40)R 1 teeth, [ka] is selected from, which is C 1-5 Alkyl, halo, oxo, cyano, C 1-5 Alkoxy, C 1-5 Haloalkyl, C 1-5 Haloalkoxy, C 1-4 Alkylene-OC 1-4 Alkyl, C 1-4 Alkylene-OH, C 3-6 Cycloalkyl, 4- to 6-membered heterocyclyl, and C 1-4 Alkylene-NR 10 R 11 optionally substituted with 1 to 3 substituents independently selected from (41)R 1 teeth, [ka] is selected from, which is C 1-5 Alkyl, halo, oxo, cyano, C 1-5 Alkoxy, C 1-5 Haloalkyl, C 1-5 Haloalkoxy, C 1-4 Alkylene-OC 1-4 Alkyl, C 3-6 Cycloalkyl, 4- to 6-membered heterocyclyl, and C 1-4 Alkylene-NR 10 R 11 optionally substituted with 1 to 3 substituents independently selected from (42)R 1 teeth, [ka] is selected from, which is C 1-5Alkyl, Halo, C 1-5 Haloalkyl, and C 1-4 Alkylene-NR 10 R 11 optionally substituted with 1 to 3 substituents independently selected from (43)R 1 teeth, [ka] is selected from methyl, fluoro, trifluoromethyl, and C 2-3 Alkylene-NR 10 R 11 optionally substituted with 1 to 3 substituents independently selected from (44)R 1 teeth, [ka] is selected from, which is C 1-5 Alkyl, halo, oxo, cyano, C 1-5 Alkoxy, C 1-5 Haloalkyl, C 1-5 Haloalkoxy, C 1-4 Alkylene-OC 1-4 Alkyl, C 1-4 Alkylene-OH, C 3-6 Cycloalkyl, 4- to 6-membered heterocyclyl, and C 1-4 Alkylene-NR 10 R 11 optionally substituted with 1 to 3 substituents independently selected from (45)R 1 teeth, [ka] is selected from, which is C 1-5 Alkyl, Halo, C 1-5 Alkoxy, C 1-5 Haloalkyl, C 1-4 Alkylene-OH, C 3-6 Cycloalkyl, and C 1-4 Alkylene-NR 10 R 11optionally substituted with 1 to 3 substituents independently selected from (46)R 1 teeth, [ka] is selected from, which is C 1-3 Alkyl, fluoro, chloro, methoxy, C 1-2 Haloalkyl, C 1-4 Alkylene-OH, C 3-4 Cycloalkyl, and C 1-4 Alkylene-NR 10 R 11 optionally substituted with 1 to 3 substituents independently selected from (47)R 1 teeth, [ka] wherein R 18 But hydrogen, C 1-5 Alkyl, Halo, C 1-5 Alkoxy, C 1-5 Haloalkyl, and C 3-6 cycloalkyl, R 19 But hydrogen, halo, C 1-4 Alkylene-OC 1-4 Alkyl, C 1-4 Alkylene-OH and C 1-4 Alkylene-NR 10 R 11 Selected from: (48)R 1 teeth, [ka] wherein R 18 is hydrogen, methyl, halo, methoxy, C 1-2 Haloalkyl, and C 3-4 cycloalkyl, R 19 But hydrogen, C 1-4 Alkylene-OC 1-4 Alkyl, C 1-4 Alkylene-H and C 1-4 Alkylene-NR10 R 11 Selected from: (49)R 1 teeth, [ka] wherein R 18 is selected from hydrogen, methyl, fluoro, trifluoromethyl, methoxy, and cyclopropyl; R 19 is hydrogen, and C 2-3 Alkylene-NR 10 R 11 Selected from: (50)R 1 teeth, [ka] Selected from: (51)R 10 and R 11 are independently H or C 1-5 is alkyl, (52)R 10 and R 11 are independently H or methyl; (53)R 10 and R 11 Both are C 1-5 is alkyl, (54)R 10 and R 11 are both methyl, (55)R 10 and R 11 together with the nitrogen attached to them form halo, C 1-5 Alkyl, C 1-5 Alkoxy, and C 1-5 forming a 4- to 6-membered heterocyclyl ring optionally substituted with 1 to 4 groups independently selected from haloalkyl; (56)R 10 and R 11 together with the nitrogen attached to them, form halo and C 1-5 forming a 4- to 6-membered heterocyclyl ring optionally substituted with 1 to 4 groups independently selected from alkoxy; (57)R 10 and R 11 together with the nitrogen attached to them, form halo and C 1-5 forming a 4- to 5-membered heterocyclyl ring optionally substituted with 1 to 3 groups independently selected from alkoxy; (58)R 10 and R 11 together with the nitrogen to which they are attached form a 4- to 5-membered heterocyclyl ring optionally substituted with one or two groups independently selected from fluoro and methoxy; (59)R 10 and R 11 taken together with the nitrogen to which they are attached form an azetidinyl, pyrrolidinyl, or morpholinyl ring, each of which is optionally substituted with one or two groups independently selected from fluoro and methoxy; (60)R 10 and R 11 taken together with the nitrogen to which they are attached form an azetidinyl ring, optionally substituted with one or two groups independently selected from fluoro and methoxy.

[0042] Preferably, Z 1 , Z 2 , Z 3 and Z 4 is as defined in any one of the above items (1) to (4). Preferably, Z 1 , Z 2 , Z 3 and Z 4 is as defined in item (1) or item (4) above.

[0043] Preferably, R 2 is as defined in any one of items (5) to (9) above.

[0044] Suitably, A is as defined in any one of the above items (10) to (12). Preferably, A is as defined in the above item (12).

[0045] Preferably, B is as defined in any one of the above items (13) to (21). Preferably, B is as defined in the above item (20) or item (21).

[0046] Preferably, L is as defined in any one of items (22) to (30) above. In some embodiments, L is as defined in any one of items (27) to (30) above. In some embodiments, L is as defined in item (30) above.

[0047] Preferably, R 1 is as defined in any one of items (31) to (50) above. In some embodiments, R 1 is as defined in any one of items (44) to (49) above. In some embodiments, R 1 is as defined above in item (49).

[0048] Preferably, R 10 and R 11 is as defined in any one of the above items (51) to (60). Preferably, R 10 and R 11 is as defined in item (59) or item (60) above.

[0049] Conveniently, the compound of formula (I) has one of the substructures (IA) to (IF) set out herein below.

[0050] In one embodiment, a compound of formula IA or IB, or a pharmaceutically acceptable salt thereof, is provided, wherein Z 1 , Z 2 , Z 3 , Z 4 , B, L and R 1 is as defined herein. [ka]

[0051] In one embodiment, a compound according to any one of formulas IC-IL, or a pharmaceutically acceptable salt thereof, is provided, wherein Z 1 , Z 2 , Z 3 , Z 4 , L and R 1 is as defined herein; [ka] The A ring in formulas ID, IE, IG, IH, IK, and IL can be selected from halo, cyano, hydroxyl, C 1-5 Alkyl, C 1-5 Alkoxy, C 1-5 Haloalkyl, C 1-5 Haloalkoxy, C 1-4 Alkylene-OC 1-4 Alkyl, C 3-6 and optionally substituted with 1 to 3 groups independently selected from cycloalkyl and 4- to 6-membered heterocyclyl; and the B ring in formulas IC to IL is C 1-5 Alkyl, halo, cyano, hydroxyl, NR 3 R 4 , C 1-5 Alkoxy, C 1-5 Haloalkyl, C 1-5 Haloalkoxy, C 1-4 Alkylene-OC 1-4 Alkyl, C 3-10 and optionally substituted with 1 to 4 groups independently selected from cycloalkyl, and 4- to 10-membered heterocyclyl, and the C ring in formulae IF, IG, IH, IJ, IK, and IL is C 1-5 Alkyl, halo, cyano, C 1-5 Alkoxy, C 1-5 Haloalkyl, C 1-5 Haloalkoxy, C 1-4 Alkylene-OC 1-4 Alkyl, C 3-6 Cycloalkyl, 4- to 6-membered heterocyclyl, and C 1-4 Alkylene-NR 10 R 11is optionally substituted with 1 to 3 groups independently selected from

[0052] In a further group of compounds, the compounds have the above structural formulae IC to IL, wherein L is as defined in any one of items (27) to (30) above, and R in formulae IC, ID, and IE 1 is as defined in any one of items (44) to (46), and the A ring in formulas ID, IE, IG, IH, IK, and IL is selected from halo, C 1-5 Alkyl, C 1-5 Haloalkyl, and C 3-6 cycloalkyl; and the B ring in formulas IC-IL is optionally substituted with 1 to 3 groups independently selected from C 1-3 Alkyl, Halo, C 3-7 and optionally substituted with 1 to 3 groups independently selected from cycloalkyl, and 4- to 10-membered heterocyclyl, and the C ring in formulae IF, IG, IH, IJ, IK, and IL is C 1-5 Alkyl, Halo, C 1-5 Haloalkyl, and C 1-4 Alkylene-NR 10 R 11 is optionally substituted with 1 to 3 groups independently selected from

[0053] In a further group of compounds, the compounds have the above structural formulae IC to IL, wherein L is as defined in item (30) above, and R in formulae IC, ID and IE 1 is as defined in the above item (46), wherein the A ring in formulae ID, IE, IG, IH, IK, and IL is optionally substituted with 1 to 3 groups independently selected from fluoro, methyl, trifluoromethyl, and cyclopropyl; the B ring in formulae IC to IL is optionally substituted with 1 to 3 groups independently selected from methyl, fluoro, cyclopropyl, and 5- to 6-membered heterocyclyl; and the C ring in formulae IF, IG, IH, IJ, IK, and IL is optionally substituted with methyl, fluoro, trifluoromethyl, and C 2-3 Alkylene-NR 10 R 11is optionally substituted with 1 to 3 groups independently selected from

[0054] In certain embodiments, the compound according to Formula I is the following compound: 2-((9S,12S)-9-acetamido-2 6 -methyl-10-oxo-3-oxa-11-aza-1(1,3),2(1,2)-dibenzeneacyclododecaphan-12-yl)acetic acid, 2-((8S,11S)-8-acetamido-2 6 -methyl-9-oxo-3-oxa-10-aza-1(1,3),2(1,2)-dibenzeneacycloundecaphan-11-yl)acetic acid, 2-((10S,13S)-10-acetamido-2 6 -methyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetic acid, 2-((10S,13S)-10-acetamido-2 6 ,8-dimethyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetic acid, 2-((10S,13S)-10-acetamido-2 6 -methyl-11-oxo-3-oxa-12-aza-1,2(1,3)-dibenzeneacyclotridecaphan-13-yl)acetic acid, 2-((8S,11S)-8-acetamido-2 6 ,6-dimethyl-9-oxo-3-oxa-10-aza-1(1,3),2(1,2)-dibenzeneacycloundecaphan-11-yl)acetic acid, 2-((10S,13S)-2 6 -methyl-10-(N-methylacetamido)-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetic acid, 2-((3S,6S)-1 6-methyl-6-(N-methylacetamido)-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((10S,13S)-2 6 -methyl-11-oxo-10-(2-oxopyridin-1(2H)-yl)-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetic acid, 2-((10S,13S)-2 6 -methyl-11-oxo-10-(2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetic acid, 2-((10S,13S)-2 6 -methyl-11-oxo-10-(2-oxopiperidin-1-yl)-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetic acid, 2-((9S,12S)-2 6 -methyl-10-oxo-9-(2-oxopiperidin-1-yl)-3-oxa-11-aza-1(1,3),2(1,2)-dibenzeneacyclododecaphan-12-yl)acetic acid, 2-((10S,13S)-2 6 -methyl-11-oxo-10-(2-oxopyrrolidin-1-yl)-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetic acid, 2-((8S,11S)-2 6 -methyl-9-oxo-8-(2-oxopyridin-1(2H)-yl)-3-oxa-10-aza-1(1,3),2(1,2)-dibenzeneacycloundecaphan-11-yl)acetic acid, 2-((10S,13S)-2 4 -Fluoro-2 6 -methyl-11-oxo-10-(2-oxopyridin-1(2H)-yl)-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetic acid, 2-((10S,13S)-10-(5-fluoro-2-oxopyridin-1(2H)-yl)-2 6 -methyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetic acid, 2-((10S,13S)-2 6 -methyl-11-oxo-10-(2-oxopiperidin-1-yl)-3-oxa-12-aza-1(3,5)-pyridin-2(1,2)-benzeneacyclotridecaphan-13-yl)acetic acid, 2-((10S,13S)-2 4 -Fluoro-2 6 -methyl-11-oxo-10-(2-oxopyridin-1(2H)-yl)-3-oxa-12-aza-1(3,5)-pyridin-2(1,2)-benzeneacyclotridecaphan-13-yl)acetic acid, 2-((10S,13S)-10-(4-fluoro-2-oxopyridin-1(2H)-yl)-2 6 -methyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetic acid, 2-((10S,13S)-2 6 -methyl-11-oxo-10-(2-oxo-5-(trifluoromethyl)pyridin-1(2H)-yl)-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetic acid, 2-((10S,13S)-1 4 -Fluoro-1 5 ,2 6 -dimethyl-11-oxo-10-(2-oxopyridin-1(2H)-yl)-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetic acid, 2-((10S,13S)-10-(5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-2 6 -methyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetic acid, 2-((8S,11S)-8-(5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-2 6 -methyl-9-oxo-3-oxa-10-aza-1(1,3),2(1,2)-dibenzeneacycloundecaphan-11-yl)acetic acid, 2-((10S,13S)-2 6 -methyl-11-oxo-10-(2-oxopyridin-1(2H)-yl)-2 4 -(tetrahydro-2H-pyran-4-yl)-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetic acid, 2-((3S,6S)-6-acetamido-1 6 -methyl-5,12-dioxo-4,11-diaza-1(1,2),2(1,3)-dibenzeneacyclododecaphan-3-yl)acetic acid, 2-((3S,6S)-6-acetamido-1 6 -methyl-5,13-dioxo-4,12-diaza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((11S,14S,E)-11-acetamido-2 6 -methyl-12-oxo-3-oxa-13-aza-1(1,3),2(1,2)-dibenzeneacyclotetradecaphan-8-en-14-yl)acetic acid, 2-((11S,14S)-11-acetamido-2 6 -methyl-12-oxo-3-oxa-13-aza-1(1,3),2(1,2)-dibenzeneacyclotetradecaphan-14-yl)acetic acid, 2-((10S,13S)-2 4 -Fluoro-2 6 -methyl-10-(N-methylacetamido)-11-oxo-3-oxa-12-aza-1(3,5)-pyridin-2(1,2)-benzeneacyclotridecaphan-13-yl)acetic acid, 2-((10S,13S)-10-(5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-2 4 -Fluoro-26 -methyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetic acid, 2-((10S,13S)-2 6 -methyl-11-oxo-10-(2-oxo-5-(2-(pyrrolidin-1-yl)ethyl)pyridin-1(2H)-yl)-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetic acid, 2-((10S,13S)-2 4 -Fluoro-2 6 -methyl-10-(N-methylacetamido)-11-oxo-3-oxa-12-aza-1(3,5)-pyridin-2(1,2)-benzeneacyclotridecaphan-13-yl)acetic acid, 2-((10S,13S)-2 6 -methyl-11-oxo-10-(4-oxoquinazolin-3(4H)-yl)-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetic acid, 2-((10S,13S)-10-(5-(2-(dimethylamino)ethyl)-3-fluoro-2-oxopyridin-1(2H)-yl)-2 6 -methyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetic acid, 2-((10S,13S)-10-(5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-1 4 -Fluoro-1 5 ,2 6 -dimethyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetic acid, 2-((10S,13S)-10-(5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-2 4 ,2 6 -dimethyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetic acid, 2-((10S,13S)-10-(5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-1 4 -Fluoro-2 6 -methyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetic acid, 2-((10S,13S)-10-(5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-1 4 ,2 4 -difluoro-1 5 ,2 6 -dimethyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetic acid, 2-((10S,13S)-10-(5-(2-(3-fluoroazetidin-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-2 6 -methyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetic acid, 2-((10S,13S)-10-(5-(2-((R)-3-fluoropyrrolidin-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-2 6 -methyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetic acid, 2-((10S,13S)-10-(5-(2-(3-methoxyazetidin-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-2 6 -methyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetic acid, 2-((10S,13S)-10-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-2 6 -methyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetic acid, 2-((10S,13S)-10-(5-(2-(azetidin-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-1 5 ,2 6 -dimethyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetic acid, 2-((10S,13S)-1 4 ,2 4 -difluoro-10-(3-fluoro-5-(2-((R)-3-fluoropyrrolidin-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-1 5 ,2 6 -dimethyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetic acid, 2-((10S,13S)-1 4 -fluoro-10-(3-fluoro-5-(2-(3-fluoroazetidin-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-1 5 ,2 4 ,2 6 -trimethyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetic acid, 2-((10S,13S)-1 4 ,2 4 -difluoro-10-(3-fluoro-5-(2-(3-fluoroazetidin-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-1 5 ,2 6 -dimethyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetic acid, 2-((10S,13S)-10-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 4 -Fluoro-1 5 ,2 4 ,2 6-trimethyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetic acid, 2-((10S,13S)-1 4 ,2 4 -difluoro-10-(5-(2-(3-methoxyazetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 5 ,2 6 -dimethyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetic acid, 2-((10S,13S)-10-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 4 ,2 4 -difluoro-1 5 ,2 6 -Dimethyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetic acid 2-((10S,13S)-1 5 -cyclopropyl-10-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 2 ,1 4 -difluoro-2 4 ,2 6 -dimethyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetic acid, 2-((10S,13S)-1 4 -Fluoro-1 5 ,2 4 ,2 6 -trimethyl-11-oxo-10-(2-oxo-5-(2-(pyrrolidin-1-yl)ethyl)-4-(trifluoromethyl)pyridin-1(2H)-yl)-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetic acid, 2-((10S,13S)-1 4 ,24 -difluoro-1 5 ,2 6 -dimethyl-11-oxo-10-(2-oxo-5-(2-(pyrrolidin-1-yl)ethyl)-4-(trifluoromethyl)pyridin-1(2H)-yl)-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetic acid, 2-((10S,13S)-10-(5-(2-(dimethylamino)ethyl)-4-methyl-2-oxopyridin-1(2H)-yl)-1 4 -Fluoro-1 5 ,2 4 ,2 6 -trimethyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetic acid, 2-((10S,13S)-24-cyclopropyl-10-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 4 -Fluoro-1 5 ,2 6 -dimethyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetic acid, 2-((10S,13S)-10-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 4 -Fluoro-2 4 ,2 6 -dimethyl-11-oxo-1 5 -(trifluoromethyl)-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetic acid, 2-((8S,11S)-8-(5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-2 4 -Fluoro-2 6 -methyl-9-oxo-3-oxa-10-aza-1(1,3),2(1,2)-dibenzeneacycloundecaphan-11-yl)acetic acid, 2-((10S,13S)-10-(5-(2-(azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 5 -cyclopropyl-1 2 ,1 4 -difluoro-2 4 ,2 6 -dimethyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetic acid, 2-((10S,13S)-10-(5-(3-(dimethylamino)propyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 4 -Fluoro-1 5 ,2 4 ,2 6 -trimethyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetic acid, 2-((10S,13S)-1 5 -cyclopropyl-10-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 4 -Fluoro-2 4 ,2 6 -dimethyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetic acid, 2-((10S,13S)-1 4 -Fluoro-1 5 ,2 4 ,2 6 -trimethyl-11-oxo-10-(2-oxo-5-(3-(pyrrolidin-1-yl)propyl)-4-(trifluoromethyl)pyridin-1(2H)-yl)-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetic acid, 2-((10S,13S)-1 5 -cyclopropyl-10-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 4 ,25 -difluoro-2 4 ,2 6 -dimethyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetic acid, 2-((10S,13S)-10-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 2 ,1 4 -difluoro-1 5 ,2 4 ,2 6 -trimethyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetic acid, 2-((10S,13S)-1 5 -cyclopropyl-10-(5-(3-(dimethylamino)propyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 2 ,1 4 -difluoro-2 4 ,2 6 -dimethyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetic acid, 2-((3S,6S)-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-2 4 -Fluoro-1 4 ,1 6 -Dimethyl-5-oxo-2 5 -(trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzeneacyclotetradecaphan-3-yl)acetic acid, 2-((3S,6S)-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-2 4 -Fluoro-1 4 ,1 6 -Dimethyl-5-oxo-2 5-(trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-2 4 -Fluoro-1 4 ,1 6 -Dimethyl-5-oxo-2 5 -(trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzeneacyclododecaphan-3-yl)acetic acid, 2-((10S,13S)-1 5 -cyclopropyl-1 4 -Fluoro-2 4 ,2 6 -dimethyl-11-oxo-10-(2-oxo-5-(2-(pyrrolidin-1-yl)ethyl)-4-(trifluoromethyl)pyridin-1(2H)-yl)-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetic acid, 2-((10S,13S)-1 5 -cyclopropyl-10-(5-(3-(dimethylamino)propyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 4 -Fluoro-2 4 ,2 6 -dimethyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetic acid, 2-((10S,13S)-1 5 -cyclopropyl-10-(5-(2-(diethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 4 -Fluoro-2 4 ,2 6 -dimethyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetic acid, 2-((3S,6S)-2 5-cyclopropyl-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-2 4 -Fluoro-1 4 ,1 6 -dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-2 5 -cyclopropyl-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-2 4 -Fluoro-1 4 ,1 6 -dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclododecaphan-3-yl)acetic acid, 2-((10S,13S)-1 4 ,2 4 -difluoro-2 6 -methyl-11-oxo-10-(2-oxo-5-(2-(pyrrolidin-1-yl)ethyl)-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 5 -(trifluoromethyl)-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetic acid, 2-((10S,13S)-2 4 -cyclopentyl-1 5 -cyclopropyl-10-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 4 -Fluoro-2 6 -methyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetic acid, 2-((10S,13S)-1 5 -cyclopropyl-10-(5-(3-(diethylamino)propyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 4 -Fluoro-2 4 ,2 6-dimethyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetic acid, 2-((3S,6S)-2 5 -cyclopropyl-6-(5-(3-(dimethylamino)propyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-2 4 -Fluoro-1 4 ,1 6 -dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-1 4 -cyclopropyl-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-2 4 -Fluoro-1 6 ,2 5 -dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-1 4 -cyclopropyl-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-2 4 -Fluoro-1 6 ,2 5 -dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclododecaphan-3-yl)acetic acid, 2-((3S,6S)-2 5 -cyclopropyl-6-(5-(2-(dimethylamino)ethyl)-3-fluoro-2-oxopyridin-1(2H)-yl)-2 4 -Fluoro-1 4 ,1 6 -dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((10S,13S)-1 5 ,2 4-dicyclopropyl-10-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 4 -Fluoro-2 6 -methyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetic acid, 2-((9S,12S)-1 5 ,2 4 -dicyclopropyl-9-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 4 -Fluoro-2 6 -methyl-10-oxo-3-oxa-11-aza-1(1,3),2(1,2)-dibenzeneacyclododecaphan-12-yl)acetic acid, 2-((10S,13S)-1 5 -cyclopropyl-10-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 4 -Fluoro-2 4 ,2 5 ,2 6 -trimethyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetic acid, 2-((9S,12S)-1 5 -cyclopropyl-9-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 4 -Fluoro-2 4 ,2 5 ,2 6 -trimethyl-10-oxo-3-oxa-11-aza-1(1,3),2(1,2)-dibenzeneacyclododecaphan-12-yl)acetic acid, 2-((3S,6S)-2 5 -cyclopropyl-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 4 -Fluoro-1 6 ,2 4-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-2 5 -cyclopropyl-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 4 ,2 4 -difluoro-1 6 -methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclododecaphan-3-yl)acetic acid, 2-((10S,13S)-1 5 -cyclopropyl-10-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 4 -Fluoro-2 6 -methyl-11-oxo-2 4 -(trifluoromethyl)-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetic acid, 2-((9S,12S)-1 5 -cyclopropyl-9-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 4 -Fluoro-2 6 -methyl-10-oxo-2 4 -(trifluoromethyl)-3-oxa-11-aza-1(1,3),2(1,2)-dibenzeneacyclododecaphan-12-yl)acetic acid, 2-((3S,6S)-6-(5-(2-(azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-2 4 -Fluoro-1 4 ,1 6 -Dimethyl-5-oxo-2 5 -(trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-2 5 -cyclopropyl-1 4 ,24 -difluoro-6-(5-(2-(3-fluoroazetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 6 -methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-2 5 -cyclopropyl-1 4 ,2 4 -difluoro-6-(5-(2-(3-fluoroazetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 6 -methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclododecaphan-3-yl)acetic acid, 2-((3S,6S)-1 4 -cyclopropyl-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-2 4 -Fluoro-1 6 -methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-1 4 -cyclopropyl-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-2 4 -Fluoro-1 6 -methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclododecaphan-3-yl)acetic acid, 2-((3S,6S)-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-2 4 -Fluoro-1 4 ,1 6 -dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-2 4 -Fluoro-1 4 ,1 6 -dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclododecaphan-3-yl)acetic acid, 2-((3S,6S)-2 5 -cyclopropyl-6-(5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-2 4 -Fluoro-1 4 ,1 6 -dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-2 5 -cyclopropyl-6-(5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-2 4 -Fluoro-1 4 ,1 6 -dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclododecaphan-3-yl)acetic acid, 2-((3S,6S)-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-2 4 -Fluoro-1 4 ,1 6 ,2 5 -trimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-2 4 -Fluoro-1 4 ,1 6 ,2 5 -trimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclododecaphan-3-yl)acetic acid, 2-((10S,13S)-10-(5-(3-(dimethylamino)propyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 4 -Fluoro-2 4 ,2 6 -dimethyl-11-oxo-1 5 -(trifluoromethyl)-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetic acid, 2-((3S,6S)-2 5 -cyclopropyl-2 4 -fluoro-6-(5-(2-(3-fluoroazetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 4 ,1 6 -dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((10S,13S)-10-(5-(2-(azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 4 -Fluoro-2 4 ,2 6 -dimethyl-11-oxo-1 5 -(trifluoromethyl)-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetic acid, 2-((3S,6S)-6-(5-(3-(dimethylamino)propyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-2 4 -Fluoro-1 4 ,1 6 -Dimethyl-5-oxo-2 5 -(trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((10S,13S)-10-(5-(2-(azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 5 -cyclopropyl-1 4 -Fluoro-24 ,2 6 -dimethyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetic acid, 2-((3S,6S)-6-(5-(2-(azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-2 5 -cyclopropyl-2 4 -Fluoro-1 4 ,1 6 -dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-6-(5-(2-(azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-2 5 -cyclopropyl-1 4 ,2 4 -difluoro-1 6 -methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-6-(5-(2-(azetidin-1-yl)ethyl)-3-fluoro-2-oxopyridin-1(2H)-yl)-2 5 -cyclopropyl-2 4 -Fluoro-1 4 ,1 6 -dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-2 5 -cyclopropyl-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-2 4 -Fluoro-1 4 -methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-2 5-cyclopropyl-6-(5-(3-(dimethylamino)propyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 4 ,2 4 -difluoro-1 6 -methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-2 5 -cyclopropyl-6-(5-(2-(dimethylamino)ethyl)-3-fluoro-2-oxopyridin-1(2H)-yl)-1 4 ,2 4 -difluoro-1 6 -methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-2 5 -cyclopropyl-6-(5-(2-(dimethylamino)ethyl)-4-methyl-2-oxopyridin-1(2H)-yl)-1 4 ,2 4 -difluoro-1 6 -methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-2 5 -cyclopropyl-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-2 4 -Fluoro-1 6 -methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-2 5 -cyclopropyl-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-2 4 -Fluoro-1 6 -methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclododecaphan-3-yl)acetic acid, 2-((3S,6S)-2 5-cyclopropyl-2 4 -fluoro-6-(3-fluoro-5-(2-(3-fluoroazetidin-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-1 4 ,1 6 -dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((10S,13S)-1 5 -cyclopropyl-1 4 -fluoro-10-(4-methoxy-2-oxopyridin-1(2H)-yl)-2 4 ,2 6 -dimethyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetic acid, 2-((3S,6S)-6-(5-(2-(azetidin-1-yl)ethyl)-4-methyl-2-oxopyridin-1(2H)-yl)-2 5 -cyclopropyl-2 4 -Fluoro-1 4 ,1 6 -dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 4 ,2 4 -difluoro-1 6 -methyl-5-oxo-2 5 -(trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 4 ,2 4 -difluoro-1 6 -methyl-5-oxo-2 5 -(trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzeneacyclododecaphan-3-yl)acetic acid, 2-((3S,6S)-2 5 -cyclopropyl-1 4 ,2 4 -difluoro-6-(5-(3-(3-fluoroazetidin-1-yl)propyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 6 -methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-6-(5-(2-(azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-2 4 -Fluoro-1 4 ,1 6 ,2 5 -trimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-6-(5-(3-(dimethylamino)propyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-2 4 -Fluoro-1 4 ,1 6 ,2 5 -trimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-2 5 -cyclopropyl-1 4 ,2 4 -difluoro-6-(5-(2-(3-methoxyazetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 6 -methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-2 5 -cyclopropyl-1 4 ,2 4 -difluoro-6-(5-(2-(3-methoxyazetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 6-methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclododecaphan-3-yl)acetic acid, 2-((3S,6S)-6-(5-(2-(azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-2 5 -cyclopropyl-2 4 -Fluoro-1 6 -methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-2 5 -cyclopropyl-6-(5-(2-(dimethylamino)ethyl)-4-methyl-2-oxopyridin-1(2H)-yl)-2 4 -Fluoro-1 4 ,1 6 -dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-2 5 -cyclopropyl-6-(5-(2-(dimethylamino)ethyl)-4-methyl-2-oxopyridin-1(2H)-yl)-2 4 -Fluoro-1 4 ,1 6 -dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclododecaphan-3-yl)acetic acid, 2-((10S,13S)-1 5 -cyclopropyl-1 4 -fluoro-10-(4-fluoro-2-oxopyridin-1(2H)-yl)-2 4 ,2 6 -dimethyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetic acid, 2-((3S,6S)-2 5 -cyclopropyl-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 4 ,1 6-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-6-(5-(2-(azetidin-1-yl)ethyl)-4-methyl-2-oxopyridin-1(2H)-yl)-2 5 -cyclopropyl-1 4 ,2 4 -difluoro-1 6 -methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-2 5 -cyclopropyl-1 4 ,2 4 -difluoro-1 6 -methyl-6-(4-methyl-2-oxopyridin-1(2H)-yl)-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-2 4 -chloro-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 4 ,1 6 -dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-2 5 -cyclopropyl-6-(5-(3-(dimethylamino)propyl)-4-methyl-2-oxopyridin-1(2H)-yl)-1 4 ,2 4 -difluoro-1 6 -methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-6-(5-(2-(azetidin-1-yl)ethyl)-3-fluoro-2-oxopyridin-1(2H)-yl)-2 5 -cyclopropyl-1 4 ,2 4 -difluoro-1 6-methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-2 5 -cyclopropyl-6-(4-cyclopropyl-5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-2 4 -Fluoro-1 4 ,1 6 -dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-1 4 ,2 4 -difluoro-6-(3-(2-(3-fluoroazetidin-1-yl)ethyl)-6-oxo-4-(trifluoromethyl)pyridazin-1(6H)-yl)-1 6 ,2 5 -dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-2 5 -cyclopropyl-6-(5-(3-(dimethylamino)propyl)-4-methyl-2-oxopyridin-1(2H)-yl)-2 4 -Fluoro-1 4 ,1 6 -dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-2 5 -cyclopropyl-6-(5-(3-(dimethylamino)propyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-2 4 -Fluoro-1 6 -methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-2 5 -cyclopropyl-6-(5-(3-(dimethylamino)propyl)-3-fluoro-2-oxopyridin-1(2H)-yl)-2 4 -Fluoro-1 4 ,16 -dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-2 5 -cyclopropyl-6-(4-cyclopropyl-5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-1 4 ,2 4 -difluoro-1 6 -methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-2 5 -cyclopropyl-6-(5-(3-(dimethylamino)propyl)-3-fluoro-2-oxopyridin-1(2H)-yl)-1 4 ,2 4 -difluoro-1 6 -methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-2 5 -cyclopropyl-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 4 ,1 6 ,2 4 -trifluoro-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-2 5 -cyclopropyl-2 4 -fluoro-6-(5-(3-(3-fluoroazetidin-1-yl)propyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 4 ,1 6 -dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-6-(5-(2-(azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 4 ,24 -difluoro-1 6 -methyl-5-oxo-2 5 -(trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-6-(5-(2-(diethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 4 ,2 4 -difluoro-1 6 -methyl-5-oxo-2 5 -(trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-6-(5-(3-(dimethylamino)propyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 4 ,2 4 -difluoro-1 6 -methyl-5-oxo-2 5 -(trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-6-(5-(3-(azetidin-1-yl)propyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-2 5 -cyclopropyl-1 4 ,2 4 -difluoro-1 6 -methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-2 5 -cyclopropyl-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 4 ,2 2 ,2 4 -trifluoro-1 6 -methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 4 ,2 4 -difluoro-1 6 ,2 5 -dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-6-(5-(2-(diethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 4 ,2 4 -difluoro-1 6 ,2 5 -dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-6-(5-(2-(azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 4 ,2 4 -difluoro-1 6 ,2 5 -dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-1 6 -chloro-2 5 -cyclopropyl-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-2 4 -fluoro-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-2 5 -cyclopropyl-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 4 -Fluoro-1 6 -methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-6-(5-(3-(azetidin-1-yl)propyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 4 ,2 4 -difluoro-1 6 -methyl-5-oxo-2 5 -(trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-2 4 -Fluoro-1 4 ,1 6 ,2 5 -trimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-8-en-3-yl)acetic acid, 2-((3S,6S)-6-(4-(difluoromethyl)-5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-1 4 ,2 4 -difluoro-1 6 -methyl-5-oxo-2 5 -(trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 4 ,2 4 ,2 5 -trifluoro-1 6 -methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-2 5 -chloro-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 4 ,2 4 -difluoro-1 6-methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-6-(5-(2-(azetidin-1-yl)ethyl)-3-methyl-2-oxopyridin-1(2H)-yl)-2 5 -cyclopropyl-1 4 ,2 4 -difluoro-1 6 -methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((10S,13S)-1 4 ,2 4 -difluoro-1 5 ,2 6 -dimethyl-11-oxo-10-(3-oxo-2-azaspiro[4.5]decan-2-yl)-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetic acid, 2-((10S,13S)-1 5 -cyclopropyl-10-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 4 -Fluoro-2 3 ,2 4 ,2 6 -trimethyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetic acid, 2-((3S,6S)-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 4 -Fluoro-1 6 -methyl-5-oxo-2 5 -(trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 4 ,1 6 ,2 4-trifluoro-2 6 -methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 4 -Fluoro-1 6 ,2 5 -dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 4 ,2 2 -difluoro-1 6 -methyl-5-oxo-2 5 -(trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((10S,13S)-1 5 -cyclopropyl-10-(5-(3-(dimethylamino)propyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 4 ,2 3 ,2 4 -trifluoro-2 6 -methyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetic acid, 2-((3S,6S)-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 4 ,2 4 -difluoro-1 6 ,8-Dimethyl-5-oxo-2 5 -(trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 4 ,2 4 -difluoro-1 6 ,8-Dimethyl-5-oxo-2 5 -(trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzeneacyclododecaphan-3-yl)acetic acid, 2-((3S,6S)-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 4 ,2 4 -difluoro-1 6 ,2 6 -dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((10S,13S)-1 4 ,2 4 -difluoro-1 5 ,2 6 -dimethyl-10-(3-methyl-2-oxotetrahydropyrimidin-1(2H)-yl)-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetic acid, 2-((3S,6S)-1 4 ,2 4 -difluoro-6-(5-(2-(3-methoxyazetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 6 -methyl-5-oxo-2 5 -(trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-6-(5-(2-(ethyl(methyl)amino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 4 ,2 4 -difluoro-1 6 -methyl-5-oxo-2 5-(trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-6-(5-(3-(dimethylamino)propyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 4 ,2 4 -difluoro-1 6 ,2 5 -dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-1 4 ,2 4 -difluoro-6-(5-(2-(3-fluoroazetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 6 -methyl-5-oxo-2 5 -(trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-6-(5-(3-(azetidin-1-yl)propyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 4 ,2 4 -difluoro-1 6 ,2 5 -dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 4 ,1 6 ,2 4 ,2 5 -tetrafluoro-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 4 ,1 6 ,24 ,2 5 -tetrafluoro-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclododecaphan-3-yl)acetic acid, 2-((3S,6S)-1 4 ,2 4 -difluoro-1 6 -methyl-5-oxo-6-(2-oxo-5-(2-(pyrrolidin-1-yl)ethyl)-4-(trifluoromethyl)pyridin-1(2H)-yl)-2 5 -(trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-1 4 ,2 4 -difluoro-1 6 -methyl-5-oxo-6-(3-oxo-3,4-dihydroisoquinolin-2(1H)-yl)-2 5 -(trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-1 4 ,2 4 -difluoro-1 6 ,2 5 -dimethyl-5-oxo-6-(3-oxo-2-azaspiro[4.5]decan-2-yl)-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 4 ,2 4 -difluoro-1 6 ,9-Dimethyl-5-oxo-2 5 -(trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 4 ,1 6 ,24 -trifluoro-5-oxo-2 5 -(trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-1 4 ,2 4 ,2 5 -trifluoro-1 6 -methyl-5-oxo-6-(3-oxo-2-azaspiro[4.5]decan-2-yl)-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((10S,13S)-10-(4,4-dimethyl-2-oxopyrrolidin-1-yl)-1 4 ,2 4 -difluoro-1 5 ,2 6 -dimethyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetic acid, 2-((3S,6S)-1 4 ,2 4 -difluoro-1 6 -methyl-5-oxo-6-(3-oxo-2-azaspiro[4.4]nonan-2-yl)-2 5 -(trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-2 5 -cyclopropyl-1 4 ,2 4 -difluoro-1 6 -methyl-5-oxo-6-(3-oxo-2,8-diazaspiro[4.5]decan-2-yl)-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-2 5 -cyclopropyl-1 4 ,2 4 -difluoro-1 6-methyl-5-oxo-6-(8-methyl-3-oxo-2,8-diazaspiro[4.5]decan-2-yl)-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-1 4 ,2 4 -difluoro-6-(3-fluoro-5-(2-(3-fluoroazetidin-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-1 6 -methyl-5-oxo-2 5 -(trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-1 4 ,2 4 -difluoro-6-(5-(2-(3-methoxyazetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 6 ,2 5 -dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-6-(5-bromo-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 4 ,2 4 -difluoro-1 6 -methyl-5-oxo-2 5 -(trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-6-(5-(3-(dimethylamino)propyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 4 ,2 4 ,2 5 -trifluoro-1 6 -methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-6-(5-(3-(dimethylamino)propyl)-2-oxopyridin-1(2H)-yl)-1 4,2 4 -difluoro-1 6 -methyl-5-oxo-2 5 -(trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-6-(5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-1 6 -methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-1 4 ,2 4 -difluoro-1 6 -methyl-5-oxo-6-(3-oxo-8-oxa-2-azaspiro[4.5]decan-2-yl)-2 5 -(trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 6 -ethyl-1 4 ,2 4 -difluoro-5-oxo-2 5 -(trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-6-(5-(3-(dimethylamino)propyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 4 ,1 6 ,2 4 -trifluoro-5-oxo-2 5 -(trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-1 4 ,2 4 ,2 5 -trifluoro-1 6-methyl-6-(1-methyl-2-oxo-1,3-diazaspiro[4.5]decan-3-yl)-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-2 5 -cyclopropyl-2 4 -Fluoro-1 4 ,1 6 -dimethyl-5-oxo-6-(2-oxo-5-(2-(pyrrolidin-1-yl)ethyl)-4-(trifluoromethyl)pyridin-1(2H)-yl)-12-oxa-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((10S,13S)-10-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 4 ,2 4 -difluoro-2 6 ,7-Dimethyl-11-oxo-1 5 -(trifluoromethyl)-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetic acid, 2-((10S,13S)-10-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 4 ,2 4 -difluoro-2 6 ,4-Dimethyl-11-oxo-1 5 -(trifluoromethyl)-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetic acid, 2-((3S,6S)-1 4 ,2 4 -difluoro-1 6 -methyl-6-(5-(2-morpholinoethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-5-oxo-2 5 -(trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-6-(3-(2-(azetidin-1-yl)ethyl)-6-oxo-5-(trifluoromethyl)pyridazin-1(6H)-yl)-2 5 -cyclopropyl-1 4 ,2 4 -difluoro-1 6 -methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-2 5 -cyclopropyl-1 4 ,2 4 -difluoro-6-(3-(2-(3-fluoroazetidin-1-yl)ethyl)-6-oxo-5-(trifluoromethyl)pyridazin-1(6H)-yl)-1 6 -methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-6-(3-(2-(azetidin-1-yl)ethyl)-6-oxo-5-(trifluoromethyl)pyridazin-1(6H)-yl)-1 4 ,2 4 -difluoro-1 6 -methyl-5-oxo-2 5 -(trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-6-(3-(2-(azetidin-1-yl)ethyl)-5-methyl-6-oxopyridazin-1(6H)-yl)-2 5 -cyclopropyl-1 4 ,2 4 -difluoro-1 6 -methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-6-(3-(3-(dimethylamino)propyl)-6-oxo-5-(trifluoromethyl)pyridazin-1(6H)-yl)-1 4 ,2 4 -difluoro-1 6 -methyl-5-oxo-2 5-(trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-1 4 ,2 4 -difluoro-6-(3-(2-(3-fluoroazetidin-1-yl)ethyl)-5-methyl-6-oxopyridazin-1(6H)-yl)-1 6 -methyl-5-oxo-2 5 -(trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-1 4 ,2 4 -difluoro-6-(3-(2-(3-methoxyazetidin-1-yl)ethyl)-5-methyl-6-oxopyridazin-1(6H)-yl)-1 6 -methyl-5-oxo-2 5 -(trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-6-(3-(2-(azetidin-1-yl)ethyl)-5-methyl-6-oxopyridazin-1(6H)-yl)-1 4 ,2 4 -difluoro-1 6 -methyl-5-oxo-2 5 -(trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-6-(3-(3-(dimethylamino)propyl)-5-methyl-6-oxopyridazin-1(6H)-yl)-1 4 ,2 4 -difluoro-1 6 -methyl-5-oxo-2 5 -(trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-6-(3-(3-(dimethylamino)propyl)-6-oxo-4-(trifluoromethyl)pyridazin-1(6H)-yl)-1 4 ,24 -difluoro-1 6 -methyl-5-oxo-2 5 -(trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-1 4 ,2 4 -difluoro-6-(3-(2-(3-fluoroazetidin-1-yl)ethyl)-6-oxo-4-(trifluoromethyl)pyridazin-1(6H)-yl)-1 6 -methyl-5-oxo-2 5 -(trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-6-(3-(3-(dimethylamino)propyl)-6-oxo-4-(trifluoromethyl)pyridazin-1(6H)-yl)-1 4 ,2 4 -difluoro-1 6 ,2 5 -dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-2 5 -cyclopropyl-6-(3-(3-(dimethylamino)propyl)-6-oxo-4-(trifluoromethyl)pyridazin-1(6H)-yl)-1 4 ,2 4 -difluoro-1 6 -methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-6-(3-(3-(azetidin-1-yl)propyl)-6-oxo-4-(trifluoromethyl)pyridazin-1(6H)-yl)-1 4 ,2 4 -difluoro-1 6 -methyl-5-oxo-2 5 -(trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-25 -cyclopropyl-1 4 ,2 4 -difluoro-6-(3-(2-(3-methoxyazetidin-1-yl)ethyl)-6-oxo-4-(trifluoromethyl)pyridazin-1(6H)-yl)-1 6 -methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-2 5 -cyclopropyl-1 4 ,2 4 -difluoro-6-(3-(2-(3-fluoroazetidin-1-yl)ethyl)-6-oxo-4-(trifluoromethyl)pyridazin-1(6H)-yl)-1 6 -methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-2 5 -cyclopropyl-1 4 ,2 4 -difluoro-6-(5-(3-hydroxypropyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 6 -methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-1 4 ,2 4 -difluoro-6-(3-(2-(3-methoxyazetidin-1-yl)ethyl)-6-oxo-4-(trifluoromethyl)pyridazin-1(6H)-yl)-1 6 -methyl-5-oxo-2 5 -(trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-1 4 ,1 6 ,2 4 -trifluoro-6-(5-(2-morpholinoethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-5-oxo-2 5-(trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-6-(5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-1 4 ,2 4 -difluoro-1 6 -methyl-5-oxo-2 5 -(trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-6-(3-(2-(dimethylamino)ethyl)-6-oxo-4-(trifluoromethyl)pyridazin-1(6H)-yl)-1 4 ,2 4 -difluoro-1 6 -methyl-5-oxo-2 5 -(trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-2 5 -cyclopropyl-1 4 ,2 4 -difluoro-6-(3-(2-(3-fluoroazetidin-1-yl)ethyl)-5-methyl-6-oxopyridazin-1(6H)-yl)-1 6 -methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-1 4 ,2 4 -difluoro-6-(3-(2-(3-methoxyazetidin-1-yl)ethyl)-6-oxo-4-(trifluoromethyl)pyridazin-1(6H)-yl)-1 6 ,2 5 -dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-2 5 -cyclopropyl-1 4 ,1 6 ,2 4-trifluoro-6-(5-(2-(3-methoxyazetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-6-(3-(3-(dimethylamino)propyl)-6-oxo-4-(trifluoromethyl)pyridazin-1(6H)-yl)-1 4 ,2 4 ,2 5 -trifluoro-1 6 -methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-2 5 -cyclopropyl-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 3 ,1 4 ,2 4 -trifluoro-1 6 -methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-6-(3-(2-(azetidin-1-yl)ethyl)-6-oxo-4-(trifluoromethyl)pyridazin-1(6H)-yl)-1 4 ,2 4 -difluoro-1 6 -methyl-5-oxo-2 5 -(trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-2 5 -cyclopropyl-6-(3-(2-(dimethylamino)ethyl)-6-oxo-4-(trifluoromethyl)pyridazin-1(6H)-yl)-1 4 ,1 6 ,2 4 -trifluoro-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-6-(3-(2-(azetidin-1-yl)ethyl)-6-oxo-4-(trifluoromethyl)pyridazin-1(6H)-yl)-1 4 ,2 4 -difluoro-1 6 ,2 5 -dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-2 5 -cyclopropyl-6-(5-(2-(dimethylamino)ethyl)-4-methyl-2-oxopyrimidin-1(2H)-yl)-1 4 ,2 4 -difluoro-1 6 -methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-6-(5-(2-(3-methoxyazetidin-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-1 6 -methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, and 2-((3S,6S)-6-(5-(2-(3-fluoroazetidin-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-1 6 -methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, or a pharmaceutically acceptable salt thereof.

[0055] The various functional groups and substituents that comprise the compounds of the invention are typically selected so that the molecular weight of the compound does not exceed 1000. More usually, the molecular weight of the compound will be less than 800, for example, less than 750, or less than 700.

[0056] Suitable or preferred features of any compound of the invention are also suitable features of any other embodiment.

[0057] Suitable pharmaceutically acceptable salts of the compounds of the present invention are, for example, acid addition salts of compounds of the present invention that are sufficiently basic, for example, acid addition salts with inorganic or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, formic acid, citric acid, or maleic acid. In addition, suitable pharmaceutically acceptable salts of compounds of the present invention that are sufficiently acidic are alkali metal salts, for example, sodium or potassium salts, alkaline earth metal salts, for example, calcium or magnesium salts, ammonium salts, or salts with organic bases that provide physiologically acceptable cations, for example, salts with methylamine, dimethylamine, trimethylamine, piperidine, morpholine, or tris-(2-hydroxyethyl)amine.

[0058] Compounds that have the same molecular formula but differ in the nature or bonding order of their atoms or the spatial arrangement of their atoms are called "isomers." Isomers that differ in the spatial arrangement of their atoms are called "stereoisomers." Stereoisomers that are not mirror images of each other are called "diastereomers," and stereoisomers that are non-superimposable mirror images of each other are called "enantiomers." When a compound has an asymmetric center, e.g., it is bonded to four different groups, a pair of enantiomers is possible. Enantiomers can be characterized by the absolute configuration of their asymmetric center, described by Cahn-Prelog's R- and S-sequencing rules, or by the way the molecule rotates the plane of polarized light, and are designated as dextrorotatory or levorotatory (i.e., (+) or (-) isomers, respectively). Chiral compounds can exist as either individual enantiomers or mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture."

[0059] The compounds of the present invention typically have one or more asymmetric centers, and therefore, such compounds can be produced as individual (R)- or (S)-stereoisomers or mixtures thereof. Unless otherwise indicated, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers, diastereoisomers, and mixtures thereof (racemic or not). Methods for determining the stereochemical structure of stereoisomers and separating stereoisomers are well known in the art, for example, by synthesis from optically active starting materials or by resolution of racemates (see the discussion in Chapter 4 of "Advanced Organic Chemistry," 4th edition, J. March, John Wiley & Sons, New York, 2001). Some of the compounds of the present invention may have geometric isomer centers (E- and Z-isomers). It should be understood that the present invention encompasses all optical isomers, diastereoisomers, and geometric isomers, as well as mixtures thereof, that possess a4b7 inhibitory activity.

[0060] The present invention also includes compounds of the invention as defined herein that contain one or more isotopic substitutions. For example, H is 1 H, 2 H(D) and 3 H(T), and C may be in any isotopic form, including 12 C. 13 C, and 14 C may be in any isotopic form, including O 16 O and 18 In certain embodiments, the present invention also encompasses deuterated analogs of the compounds of the present invention defined by Formula I.

[0061] It is also understood that certain compounds of the present invention can exist in solvated as well as unsolvated forms, such as, for example, hydrated forms, and it is understood that the present invention encompasses all such solvated forms that possess a4b7 inhibitory activity.

[0062] It is also to be understood that certain compounds of the present invention may exhibit polymorphism, and that the present invention encompasses all such forms that possess a4b7 inhibitory activity.

[0063] The compounds of the present invention may exist in several different tautomeric forms, and reference to a compound of the present invention includes all such forms. For the avoidance of doubt, where a compound can exist in one of several tautomeric forms and only one is specifically described or shown, all others are still encompassed by the compound of the present invention. Examples of tautomeric forms include keto, enol, and enolate forms, for example, as in the following tautomeric pairs: keto / enol (illustrated below), imine / enamine, amide / iminoalcohol, amidine / amidine, nitroso / oxime, thioketone / enethiol, and nitro / aci-nitro. [ka]

[0064] The compounds of the present invention containing an amine function may also form N-oxides. In this specification, a reference to a compound of formula I containing an amine function also includes N-oxides. When a compound contains several amine functions, one or more nitrogen atoms may be oxidized to form N-oxides. Specific examples of N-oxides are N-oxides of tertiary amines or nitrogen atoms of nitrogen-containing heterocycles. N-oxides can be formed by treating the corresponding amine with an oxidizing agent such as hydrogen peroxide or a peracid (e.g., peroxycarboxylic acid). For example, see Advanced Organic Chemistry, by Jerry March, 4 th Edition, Wiley Interscience, pages 1977. More specifically, N-oxides can be made by the procedure of L.W. Ready (Syn. Comm. 1977, 7, 509-514), in which an amine compound is reacted with m-chloroperbenzoic acid (MCPBA) in an inert solvent such as dichloromethane.

[0065] The compounds of the present invention may be administered in the form of prodrugs, which are broken down in the human or animal body to release the compounds of the present invention. Prodrugs may be used to alter the physical properties and / or pharmacokinetic properties of the compounds of the present invention. Prodrugs can be formed when the compounds of the present invention contain a suitable group or substituent to which a property-modifying group can be attached. Examples of prodrugs include in vivo cleavable ester derivatives that can be formed at a carboxy or hydroxy group in the compounds of the present invention, and in vivo cleavable amide derivatives that can be formed at a carboxy or amino group in the compounds of the present invention.

[0066] Thus, the present invention includes compounds of formula I as defined hereinabove when made available by organic synthesis, and compounds of formula I as defined hereinabove when made available in the human or animal body via cleavage of a prodrug thereof. Thus, the present invention includes compounds of formula I produced by means of organic synthesis, and also such compounds produced in the human or animal body via metabolism of a precursor compound, i.e., compounds of formula I may be synthetically produced compounds or metabolically produced compounds.

[0067] Suitable pharmaceutically acceptable prodrugs of compounds of Formula I are those that are, based on sound medical judgment, suitable for administration to the human or animal body without undesirable pharmacological activity and without undue toxicity.

[0068] Various forms of prodrugs are described, for example, in the following documents: a) Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al. (Academic Press, 1985), b) Design of Pro-drugs, edited by H. Bundgaard, (Elsevier, 1985), c)A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H.Bundgaard,Chapter 5 “Design and Application of Pro-drugs”, by H.Bundgaard p.113-191(1991), d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992), e) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988), f) N. Kakeya, et al., Chem. Pharm. Bull., 32, 692 (1984), g) T. Higuchi and V. Stella, “Pro-Drugs as Novel Delivery Systems”, ACSSymposium Series, Volume 14, and h) E. Roche (editor), “Bioreversible Carriers in Drug Design”, Pergamon Press, 1987.

[0069] Suitable pharmaceutically acceptable prodrugs of compounds of formula I with a carboxy group are, for example, in vivo cleavable esters thereof. In vivo cleavable esters of compounds of formula I containing a carboxy group are, for example, pharmaceutically acceptable esters that are cleaved in the human or animal body to produce the parent acid. Suitable pharmaceutically acceptable esters for carboxy include C groups such as methyl, ethyl, and tert-butyl. 1-6 C such as alkyl esters and methoxymethyl esters 1-6 C such as alkoxymethyl ester, pivaloyloxymethyl ester, 3-phthalidyl ester 1-6 C such as alkanoyloxymethyl esters, cyclopentylcarbonyloxymethyl and 1-cyclohexylcarbonyloxyethyl esters 3-8Cycloalkylcarbonyloxy-C 1-6 alkyl esters, 2-oxo-1,3-dioxolenylmethyl esters such as 5-methyl-2-oxo-1,3-dioxolen-4-ylmethyl ester, and C esters such as methoxycarbonyloxymethyl and 1-methoxycarbonyloxyethyl esters 1-6 Alkoxycarbonyloxy-C 1-6 Contains alkyl esters.

[0070] Suitable pharmaceutically acceptable prodrugs of a compound of formula I having a hydroxy group are, for example, in vivo cleavable esters or ethers thereof. An in vivo cleavable ester or ether of a compound of formula I containing a hydroxy group is, for example, a pharmaceutically acceptable ester or ether that is cleaved in the human or animal body to generate the parent hydroxy compound. Suitable pharmaceutically acceptable ester-forming groups for a hydroxy group include inorganic esters such as phosphate esters (including cyclic phosphoramidate esters). Further suitable pharmaceutically acceptable ester-forming groups for a hydroxy group include C groups such as acetyl, benzoyl, phenylacetyl, and substituted benzoyl and phenylacetyl groups. 1-10 Alkanoyl group, ethoxycarbonyl, N,N-(C 1-6 ) C 2 carbamoyl, 2-dialkylaminoacetyl and 2-carboxyacetyl groups 1-10 Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl, and 4-(C 1-4 Suitable pharmaceutically acceptable ether forming groups for a hydroxy group include α-acyloxyalkyl groups, such as acetoxymethyl and pivaloyloxymethyl groups.

[0071] Suitable pharmaceutically acceptable prodrugs of compounds of formula I bearing a carboxy group include, for example, in vivo cleavable amides thereof, amines such as ammonia, C groups such as methylamine, etc. 1-4 (C) such as alkylamine, dimethylamine, N-ethyl-N-methylamine or diethylamine 1-4 C alkyl) 2-amine, 2-methoxyethylamine, etc. 1-4 Alkoxy-C 2-4 Phenyl-C such as alkylamines and benzylamines 1-4 Amides formed with alkylamines and amino acids such as glycine or its esters.

[0072] Suitable pharmaceutically acceptable prodrugs of compounds of formula I bearing an amino group are, for example, in vivo cleavable amide derivatives thereof. Suitable pharmaceutically acceptable amides derived from an amino group include, for example, C acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups. 1-10 Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl, and 4-(C 1-4 alkyl)piperazin-1-ylmethyl.

[0073] The in vivo effects of the compounds of formula I may be exerted, in part, by one or more metabolic products formed in the human or animal body following administration of the compounds of formula I. As noted hereinabove, the in vivo effects of the compounds of formula I may also be exerted through metabolism of a precursor compound (prodrug).

[0074] It will also be understood that the compounds of Formula I may also be covalently linked (at any suitable position) to other groups, such as, for example, solubilizing moieties (e.g., PEG polymers), moieties that allow them to be bound to solid supports (e.g., biotin-containing moieties, etc.), and targeting ligands (e.g., antibodies or antibody fragments, etc.).

[0075] synthesis The compounds of the present disclosure may be prepared using the methods disclosed herein, as well as routine variations thereof that will become apparent in light of the disclosures herein and methods well known in the art. In addition to the teachings herein, conventional and well-known synthetic methods may be used. The synthesis of exemplary compounds of formula (I), for example, compounds having a structure described by formula (I), or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, or deuterated analog thereof, may be accomplished as described in the following examples.

[0076] In the descriptions of synthetic methods set forth below, and in the referenced synthetic methods used to prepare starting materials, it is understood that all proposed reaction conditions, including the choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment, and work-up procedures, can be selected by one skilled in the art.

[0077] It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule must be compatible with the reagents and reaction conditions employed.

[0078] Necessary starting materials may be obtained by standard procedures of organic chemistry. The preparation of such starting materials is described in conjunction with the following representative process variants and within the accompanying examples. Alternatively, necessary starting materials can be obtained by analogous procedures to those exemplified, which are within the ordinary skill of an organic chemist.

[0079] It will be understood that during the synthesis of the compounds of the invention in the processes set out below, or during the synthesis of certain starting materials, it may be desirable to protect certain substituents to prevent their undesired reactions. The skilled chemist will understand when such protection is required and how such protecting groups may be placed and subsequently removed.

[0080] For examples of protecting groups, see one of the many general textbooks on the subject, e.g., "Protecting Groups in Organic Synthesis" (3 rd See, "Protective Groups: The Art of Protecting Groups," by T. Greene and P. Wuts, "Protective Groups: The Art of Protecting Groups," Ed., John Wiley & Sons, NY (1999)." Protecting groups may be removed by any convenient method described in the literature or known to the skilled chemist, as appropriate for the removal of the protecting group, such method being chosen to accomplish the removal of the protecting group while minimizing disturbance to groups elsewhere in the molecule.

[0081] Thus, if reactants include groups such as amino, carboxy or hydroxy, it may be desirable to protect the group in some of the reactions mentioned herein.

[0082] For example, suitable protecting groups for amino or alkylamino groups include, for example, acyl groups, e.g., alkanoyl groups such as acetyl; alkoxycarbonyl groups, e.g., methoxycarbonyl, ethoxycarbonyl, or tert-butoxycarbonyl; arylmethoxycarbonyl groups, e.g., benzyloxycarbonyl; or aroyl groups, e.g., benzoyl. The deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group. Thus, for example, acyl groups, e.g., alkanoyl, or alkoxycarbonyl or aroyl groups, may be removed by hydrolysis with a suitable base, e.g., an alkali metal hydroxide, e.g., lithium or sodium hydroxide. Alternatively, acyl groups, e.g., tert-butoxycarbonyl groups, may be removed by treatment with a suitable acid, e.g., hydrochloric acid, sulfuric acid, or phosphoric acid, or trifluoroacetic acid; and arylmethoxycarbonyl groups, e.g., benzyloxycarbonyl groups, may be removed by hydrogenation over a catalyst, e.g., palladium on carbon, or by treatment with a Lewis acid, e.g., BF3.OEt2. A suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or with hydrazine.

[0083] Those skilled in the art will recognize that the compounds of the present invention may be prepared in a variety of ways in a known manner. Compounds of Formula I can be prepared by the methods provided below, by the methods provided in the experimental section, or by analogous methods. The routes described are merely illustrative of some of the methods that may be used to synthesize compounds of Formula I, and those skilled in the art will understand that the order of reaction steps is not limited to that described. It will also be understood that the assignment of nucleophiles and electrophiles is not limited to that described herein, and that in some cases it may be appropriate to reverse the assignment. Various approaches to synthetic chemistry strategies are discussed in "Organic Synthesis: The Disconnection Approach," 2 nd edition, S. Warren and P. Wyatt (2008).

[0084] General method The compound of formula (I) is first deprotected, i.e., cleaved of the ester group, followed optionally by conversion to a compound of formula (A1), where E is C 1-6 The compounds may be prepared by a process involving conversion of a hydroxy group to a salt of an alkyl group, such as tert-butyl or methyl, and all other variables being defined in accordance with the scope of the present invention. [ka]

[0085] Deprotection of compounds of formula (A1) where E is tert-butyl may be accomplished by acid hydrolysis using, for example, hydrochloric acid, sulfuric acid or trifluoroacetic acid in a suitable solvent such as dichloromethane, tetrahydrofuran or 1,4-dioxane. When E is methyl, deprotection may be accomplished by base hydrolysis using, for example, lithium or sodium hydroxide in the presence of water and a suitable solvent such as methanol, ethanol, tetrahydrofuran or 1,4-dioxane.

[0086] After cleavage of the ester group, the resulting product may be converted into the required salt by methods well known to those skilled in the art.

[0087] L is -C 3-8 alkenylene-group, where n and m are 0 to 6 (provided that n and m together are 1 to 6), -C 3-8 One, two or three methylene groups in the alkenylene group may be —O—, —S—, —C(O)— or —N(R 5 Compounds of formula (A1), optionally substituted with )-, which are compounds of formula (A2), may be prepared from intermediates of formula (A3) via olefin metathesis in the presence of a suitable metal catalyst, such as the ruthenium-based catalysts reported by Robert H. Grubbs and Amir H. Hoveyda (DOI: 10.1021 / ja952676d, DOI: 10.1021 / ja983222u, DOI: 10.1021 / ol990909q and DOI: 10.1021 / ja001179g). The metathesis reaction may be carried out in a suitable solvent, such as tetrahydrofuran, 1,4-dioxane, dichloromethane, 1,2-dichloroethane or toluene, under a nitrogen atmosphere at elevated temperatures. [ka]

[0088] L is -C 3-8 The alkylene-containing compound of formula (A1), which is a compound of formula (A4), may be prepared from a compound of formula (A2) by reduction of the double bond. The reduction may be accomplished by catalytic hydrogenation using hydrogen in the presence of a noble metal catalyst such as Pt, Pd, Rh, Ru, or Raney nickel. The hydrogenation reaction is carried out in a solvent such as methanol, ethanol, tetrahydrofuran, or a mixture thereof. [ka]

[0089] L is -C 3-8alkylene-, where two adjacent methylene groups are —C(O)— and —N(R 5 A compound of formula (A1) (which is a compound of formula (A5)), wherein n is substituted with )- and n and m are 0 to 6 (provided that n and m taken together are 1 to 6), may be prepared from an intermediate of formula (A6) by amide coupling. The amide coupling may be accomplished according to the procedure for amide bond formation described herein below. Specifically, the intermediate of formula (A6) may be reacted with a coupling agent, such as N,N'-carbonyldiimidazole (CDI), 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI), or benzotriazol-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (commercially available as PyBOP), in a solvent such as tetrahydrofuran, dichloromethane, chloroform, or 1,2-dichloroethane. The reaction is preferably carried out in the presence of a base such as triethylamine, diisopropylethylamine or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). [ka]

[0090] The intermediate of formula (A6) can also be converted to an activated form (A9) where Y represents halo or the residue of an activated ester, for example Y is an aryloxy group such as phenoxy, p-nitrophenoxy, pentafluorophenoxy, etc., or Y can be the residue of a mixed anhydride. Activation of the carboxylic acid in (A6) can lead to an intramolecular cyclization reaction to give compounds of formula (A5). [ka]

[0091] The activated intermediate of formula (A9) can be prepared from the intermediate of formula (A6) as outlined in the scheme above. The amine functionality in (A6) is protected with PG1 (where PG1 represents a suitable amine protecting group (as defined above)) to give the intermediate of formula (A7). The carboxylic acid functionality in (A7) can then be activated as described above to give the intermediate of formula (A8). The amine protecting group (PG 1 Removal of (A9), which can be done according to art-known procedures, gives intermediates of formula (A9), which undergo an intramolecular cyclization reaction to give compounds of formula (A5).

[0092] R 1 But NR 8 C(O)R 9 or an N-linked group such as an N-linked heterocyclyl group (such as pyrrolidin-2-onyl, piperidin-2-onyl, or 2-oxopyridin-1(2H)-yl), wherein n, m, and E are as defined above, may be prepared from an intermediate of formula (A14) (wherein LG1 represents a suitable leaving group such as mesylate, triflate, tosylate, bromide, chloride, etc.). The reaction between the intermediate of formula (A14) and the N-linked heterocyclyl group may be carried out in the presence of a base such as sodium hydride, sodium methoxide, potassium tert-butoxide, or potassium carbonate, and an inert solvent such as dimethylacetamide, dimethylformamide, acetonitrile, etc. [ka]

[0093] The intermediate of formula (A14) can be obtained from the intermediate of formula (A13) using methods well known to those skilled in the art. For example, mesylate, triflate, tosylate, bromine and chlorine leaving groups can be introduced by reacting the alcohol functional group in (A13) with mesyl chloride, trifluoromesyl chloride, tosyl chloride, phosphorus tribromide and thionyl chloride, respectively, in the presence of a base such as triethylamine, diisopropylethylamine or pyridine in a solvent such as diethyl ether, tetrahydrofuran, toluene or cyclohexane or a mixture thereof.

[0094] The intermediate of formula (A13) can be prepared by forming an amide bond between the intermediate of formula (A11) and the intermediate of formula (A12) using the conditions described above for the preparation of the intermediate of formula (A5) from the intermediate of formula (A6). The intermediate of formula (A12) is commercially available or can be prepared according to procedures known to those skilled in the art.

[0095] The intermediate of formula (A11), in which the methylene group attached to B is replaced with -O-, and n and E are defined above, (which is an intermediate of formula (A15)), may be prepared from intermediates of formula (A16) and (A17) by subsequent deprotection of the amine protecting group (PG2) in the intermediate of formula (A18). [ka]

[0096] In the procedure of the above scheme, an intermediate of formula (A16) (wherein LG2 represents a suitable leaving group such as mesylate, triflate, tosylate, bromine, or chlorine) is coupled to an alcohol function in an intermediate of formula (A17) (wherein PG2 represents a suitable amine-protecting group) to form an ether bond. The reaction may be carried out in an inert solvent such as dimethylacetamide, dimethylformamide, acetonitrile, or the like, in the presence of a base such as potassium carbonate, sodium hydride, or potassium tert-butoxide. Removal of the amine-protecting group (PG2) in an intermediate of formula (A18) to obtain an intermediate of formula (A15) can be accomplished according to procedures known in the art. For example, when a Boc group is used, the preferred methods are trifluoroacetic acid in dichloromethane or hydrochloric acid in 1,4-dioxane.

[0097] Intermediates of formula (A16) are either commercially available or can be prepared from intermediates of formula (A19) using the conditions described above for the preparation of intermediates of formula (A14) from intermediates of formula (A13). Intermediates of formula (A19) are either commercially available or readily available by synthetic procedures known in the art. [ka]

[0098] The intermediate of formula (A17) (wherein E and PG2 are defined above) can be prepared by reacting an intermediate of formula (A20) with an intermediate of formula (A21) (wherein X 1 and X 2 X can be prepared by a transition metal catalyzed cross-coupling reaction between X and X (representing a pair of reactive moieties capable of undergoing a transition metal catalyzed cross-coupling reaction). Exemplary reactive moieties include, but are not limited to, halides, triflates, and boron-containing functional groups. 1 or X 2 When one of X is a halide or triflate, the other X 1 or X 2is a boron-containing functional group of formula -B(OR)2, where each R can independently be hydrogen or alkyl. When R is alkyl, it is preferred that the two R substituents and the boron atom form a ring (e.g., pinacol boronic ester). [ka]

[0099] The cross-coupling reaction can be carried out at elevated temperatures in a suitable solvent such as 1,4-dioxane, toluene, ethanol, water, and mixtures thereof, in the presence of a suitable catalyst such as Pd(PPh), Pd(dba), or Pd(dppf)Cl, and a weak base such as KCO and NaCO. The selection of catalyst, base, solvent, and reaction conditions (i.e., time, temperature, pressure, atmosphere selection, etc.) are known to those skilled in the art.

[0100] The intermediate of formula (A11), in which n is 0 and E is as defined above (which is an intermediate of formula (A24)), may be prepared from intermediates of formula (A20) and (A22) by subsequent deprotection of the amine protecting group (PG2) in the intermediate of formula (A23). [ka]

[0101] In the procedures of the above schemes, cross-coupling of intermediates of formula (A20) and (A22) to give intermediates of formula (A23) can be accomplished using the conditions described above for cross-coupling of intermediates of formula (A20) and (A21) to give intermediates of formula (A17). Removal of the amine protecting group (PG2) in intermediates of formula (A23) to give intermediates of formula (A24) can be accomplished using the conditions described above for deprotecting intermediates of formula (A18) to give intermediates of formula (A15).

[0102] Intermediates of formula (A21) and (A22) (wherein X 2represents reactive moieties (e.g., halides, triflates, boronic acids and boronic esters) capable of undergoing transition metal catalyzed cross-coupling reactions, and B is defined in accordance with the scope of the present invention) are commercially available or can be prepared according to procedures known to those skilled in the art.

[0103] X 1 The intermediate of formula (A20), in which represents a pinacolboronic acid ester, (which is an intermediate of formula (A25)) can be prepared from an intermediate of formula (A26) by a process which involves first protecting the acid functionality with a suitable protecting group (E) to give an intermediate of formula (A27), followed by protecting the amine functionality in (A27) with a suitable protecting group (PG2) to give an intermediate of formula (A28), and then cross-coupling reaction with bis(pinacolato)diboron to give an intermediate of formula (A25). [ka]

[0104] In the procedure of the above scheme, protecting the acid functionality in the intermediate of formula (A26) with a suitable protecting group (E) to give the intermediate of formula (A27) can be carried out by removing water either physically, for example by azeotropic removal of water, or chemically by using a dehydrating agent, to give the intermediate of formula (A26) and C 1-6 This can be accomplished by reacting an alkyl alcohol (e.g., methanol or ethanol) with the intermediate of formula (A27). Protection of the amine functionality in the intermediate of formula (A27) with a suitable protecting group (PG2) to give the intermediate of formula (A28) can be accomplished using the conditions described above for protecting the amine functionality in the intermediate of formula (A6) to give the intermediate of formula (A7). Conversion of the bromine functionality in the intermediate of formula (A28) to the pinacolboronic ester functionality in (A25) can be accomplished using the conditions described above for cross-coupling of intermediates of formula (A20) and (A21) to give the intermediate of formula (A17).

[0105] The synthesis of the intermediate β-amino acid of formula (A26) can be accomplished using well-known procedures described in literature such as Enantioselective Synthesis of β-Amino Acids, (John Wiley & Sons, 2005), Ellman et al., Acc. Chem. Res. 2002, 35, 984-995, Franklin A. Davis and Bang-Chi, Chen Chem. Soc. Rev., 1998, 27, 13-18, Mikkel F. Jacobsen and Troels Skrydstrup, J. Org. Chem. 2003, 68, 7122, Tony P. Tang and Jonathan A. Ellman, J. Org. Chem. 2002, 67, 7819, and Tony P. Tang and Jonathan A. Ellman, J. Org. Chem. 1999, 64, 12.

[0106] 2-oxopyridin-1(2H)-yl (Z) used in the synthesis of intermediates of formula (A10) 5 and Z 6 is C), pyridazin-3(2H)-one (Z 5 is N and Z 6 is C) and pyrimidin-2(1H)-one (Z 5 is C and Z 6 is N) intermediates are commercially available or can be readily prepared according to procedures known to those skilled in the art. For example, substituted intermediates of formula (A29) can be prepared from intermediates of formula (A30), where the ring can be further substituted with one or more optional substituents described herein. [ka]

[0107] In the procedure of the above scheme, the aldehyde functionality in the intermediate of formula (A30) may be subjected to a Wittig reaction using the Wittig reagent (methoxymethyl)triphenylphosphonium chloride in the presence of a strong base such as sodium hydride or potassium tert-butoxide in an inert solvent such as dimethoxyethane or tetrahydrofuran at or about room temperature to give an intermediate of formula (A31). Cleavage of the enol ether functionality in the intermediate of formula (A31) can be accomplished by acid hydrolysis using, for example, trifluoroacetic acid or formic acid in a suitable solvent such as dichloromethane, to give an intermediate of formula (A32). Reductive amination of the aldehyde functionality in the intermediate of formula (A32) with the amine functionality in the intermediate of formula (A33) gives an intermediate of formula (A29). The reductive amination may be carried out under acidic or neutral conditions (i.e., with or without the presence of an acid, e.g., acetic acid) in the presence of a suitable reducing agent, such as sodium triacetoxyborohydride, in a suitable solvent, such as dichloromethane, 1,2-dichloroethane, tetrahydrofuran, or a mixture thereof.

[0108] Intermediates of formula (A30) and (A33) are either commercially available or readily accessible by synthetic procedures known in the art.

[0109] The intermediate of formula (A32) can also be converted into an intermediate of formula (A33) 3 represents a triflate or halide group) to obtain an intermediate of formula (A17) by a transition metal catalyzed cross-coupling reaction with trans-2-ethoxyvinylboronic acid pinacol ester to obtain an intermediate of formula (A34), using the conditions described above for the cross-coupling of intermediates of formula (A20) and (A21) to obtain an intermediate of formula (A17), followed by cleavage of the enol ether functionality in the intermediate of formula (A34) to obtain an intermediate of formula (A32), using the conditions described above for the conversion of the intermediate of formula (A31) to the intermediate of formula (A32). [ka]

[0110] Intermediates of formula (A33) are either commercially available or readily accessible by synthetic procedures known in the art.

[0111] Substituted 2-oxopyridin-1(2H)-yl (Z) of formula (A35) 5 and Z 6 is C), pyridazin-3(2H)-one (Z 5 is N and Z 6 is C) and pyrimidin-2(1H)-one (Z 5 is C and Z 6 is N) intermediate can be converted to an intermediate of formula (A33) (wherein the ring may be further substituted with one or more optional substituents described herein, and X 3 may be prepared from a triflate or halide group). [ka]

[0112] In the procedure of the above scheme, cross-coupling of intermediates of formula (A33) and (A36) to obtain intermediate of formula (A37) can be carried out in the presence of a suitable catalyst such as Pd(PPh3)4 or Pd(PPh3)2Cl2, a copper salt, typically copper(I) iodide, and a base such as triethylamine. The reaction is carried out in a solvent such as THF or 1,4-dioxane at elevated temperature. The intermediate of formula (A35) can be prepared from the intermediate of formula (A37) by reduction of the triple bond. The reduction can be carried out by catalytic hydrogenation using hydrogen in the presence of a noble metal catalyst such as Pt, Pd, Rh, Ru, or Raney nickel. The hydrogenation reaction is carried out in a solvent such as methanol, ethanol, tetrahydrofuran, or a mixture thereof.

[0113] Intermediates of formula (A36) are either commercially available or readily accessible by synthetic procedures known in the art.

[0114] Pharmaceutical Composition The compounds of the present invention are usually, but not necessarily, formulated into pharmaceutical compositions prior to administration to a patient. Thus, according to a further aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of formula I, as defined hereinabove, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0115] The pharmaceutical compositions of the present invention may be prepared and packaged in bulk form, from which a safe and effective amount of the compound of the present invention can be extracted and then administered to a patient, such as in a powder or syrup. Alternatively, the pharmaceutical compositions of the present invention may be prepared and packaged in unit dosage form, each physically discrete unit containing a safe and effective amount of the compound of the present invention. When prepared in unit dosage form, the pharmaceutical compositions of the present invention typically contain 1 mg to 1000 mg.

[0116] The compositions of the present invention may be in a form suitable for oral use (e.g., as tablets, capsules, caplets, pills, lozenges, powders, syrups, elixirs, suspensions, solutions, emulsions, sachets, and cachets), topical use (e.g., as creams, ointments, lotions, solutions, pastes, sprays, foams, and gels), transdermal administration such as via a transdermal patch, administration by inhalation (e.g., as dry powders, aerosols, suspensions, and solutions), administration by insufflation (e.g., as a finely divided powder), or parenteral administration (e.g., as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular, intraperitoneal, or intramuscular administration, or as a suppository for rectal administration).

[0117] In a preferred embodiment, the pharmaceutical composition of the present invention is in a form suitable for parenteral administration, such as intravenous or intraperitoneal administration. Solutions or suspensions used for parenteral administration may contain one or more of the following additives: a sterile diluent (e.g., water, saline, oil, glycerin, propylene glycol, polyethylene polyglycol, or other pharmaceutically acceptable solvents), a buffer (e.g., acetate, citrate, phosphate, or an isotonic agent such as sodium chloride or dextrose), a chelating agent (e.g., EDTA), an antibacterial agent (e.g., methylparaben or benzyl alcohol), or an antioxidant (e.g., ascorbic acid or sodium bisulfite). In a preferred embodiment, the pharmaceutical composition of the present invention is in a form suitable for intravenous or intraperitoneal administration and comprises phosphate-buffered saline or normal saline. Conveniently, parenteral compositions are enclosed in ampoules, vials, or syringes made of glass or plastic.

[0118] As used herein, "pharmaceutically acceptable excipient" refers to a pharmaceutically acceptable material, composition, or vehicle that is involved in providing a pharmaceutical composition with a shape or consistency. Each excipient must be compatible with the other components of the pharmaceutical composition when mixed to avoid interactions that would substantially reduce the effectiveness of the compound of the present invention when administered to a patient and interactions that would result in a pharmaceutical composition that is not pharmaceutically acceptable. In addition, each excipient must be of sufficient purity to make it pharmaceutically acceptable.

[0119] Suitable pharmaceutically acceptable additives will vary depending on the specific dosage form selected. In addition, suitable pharmaceutically acceptable additives may be selected for the specific function they may perform in the composition. For example, certain pharmaceutically acceptable additives may be selected for their ability to facilitate the production of a uniform dosage form. Certain pharmaceutically acceptable additives may be selected for their ability to facilitate the production of a stable dosage form. Certain pharmaceutically acceptable additives may be selected for their ability to facilitate the transport or transportation of the compound(s) of the present invention from one organ or part of the body to another organ or part of the body once administered to a patient. Certain pharmaceutically acceptable additives may be selected for their ability to improve patient compliance.

[0120] Suitable pharmaceutically acceptable excipients include the following types of excipients: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweeteners, flavoring agents, flavor-masking agents, colorants, anti-caking agents, humectants, chelating agents, plasticizers, thickeners, antioxidants, preservatives, stabilizers, surfactants, and buffers. One of ordinary skill in the art will understand that a particular pharmaceutically acceptable excipient may serve more than one function, or may serve alternative functions, depending on how much of the excipient is present in the formulation and what other ingredients are present in the formulation.

[0121] Those skilled in the art possess the knowledge and skill to select suitable pharmaceutically acceptable excipients in appropriate amounts for use in the present invention. In addition, several resources describing pharmaceutically acceptable excipients are available to those skilled in the art and may be useful in selecting suitable pharmaceutically acceptable excipients. Examples include Remington's Pharmaceutical Sciences (Mack Publishing Company), The Handbook of Pharmaceutical Additives (Gower Publishing Limited), and The Handbook of Pharmaceutical Excipients (the American Pharmaceutical Association and the Pharmaceutical Press).

[0122] The pharmaceutical compositions of the present invention are prepared using techniques and methods known to those skilled in the art. Some of the methods commonly used in the art are described in Remington's Pharmaceutical Sciences (Mack Publishing Company).

[0123] The amount of active ingredient that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the host treated and the particular route of administration. For example, a formulation intended for oral administration to humans will generally contain, for example, 0.5 mg to 0.5 g of active agent (more preferably 0.5 to 100 mg, e.g., 1 to 30 mg), compounded with an appropriate and convenient amount of excipient, which may vary from about 5 to about 98 percent by weight of the total composition.

[0124] The size of a therapeutic or prophylactic dose of a compound of formula I will, of course, vary with the nature and severity of the condition, the age and sex of the animal or patient, and the route of administration, in accordance with well-known principles of medicine.

[0125] When using the compounds of the present invention for therapeutic or prophylactic purposes, they will generally be administered so that a daily dose ranging, for example, from 0.1 mg / kg to 75 mg / kg of body weight is given (given in divided doses if necessary). Generally, lower doses will be administered when parenteral routes are used. Thus, for example, for intravenous or intraperitoneal administration, a dose ranging, for example, from 0.1 mg / kg to 30 mg / kg of body weight will generally be used. Similarly, for administration by inhalation, a dose ranging, for example, from 0.05 mg / kg to 25 mg / kg of body weight will be used. Oral administration, particularly in tablet form, may also be suitable. Typically, a unit dosage form will contain about 0.5 mg to 0.5 g of a compound of the present invention.

[0126] Administration route The compounds of the invention or pharmaceutical compositions containing the active compounds may be administered to a subject by any convenient route of administration, whether systemic / peripheral or local (i.e., at the desired site of action).

[0127] Routes of administration include, but are not limited to, oral (e.g., by ingestion); buccal; sublingual; transdermal (including, e.g., by patches, patches, etc.); transmucosal (including, e.g., by patches, patches, etc.); intranasal (e.g., by nose drops); ophthalmic (e.g., by eye drops); pulmonary (e.g., through the mouth or nose, e.g., using via aerosol, e.g., by inhalation or insufflation therapy); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); parenteral, e.g., by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, and intrasternal; e.g., by implantation of a depot or reservoir, subcutaneously or intramuscularly.

[0128] In a preferred embodiment, the compounds of the invention as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, are administered orally, intravenously, subcutaneously, or intramuscularly.

[0129] Therapeutic uses and applications The compounds of the present invention are inhibitors of the α4β7 integrin. As a result, they are potentially useful therapeutic agents for the treatment of diseases or conditions mediated by α4β7 inhibition.

[0130] Thus, in one aspect, the present invention relates to a compound of the invention as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, for use in therapy.

[0131] In another aspect, the invention relates to a compound of the invention as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, for use in the treatment of a disease or disorder mediated by inhibition of α4β7.

[0132] In another aspect, the invention relates to the use of a compound of the invention as defined herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of a disease or disorder mediated by α4β7 inhibition.

[0133] In another aspect, the present invention relates to a method for treating a disease or disorder mediated by inhibition of α4β7, the method comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of the invention as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein.

[0134] Examples of inflammatory diseases which may be treated using the compounds of formula I and their pharmaceutically acceptable salts are inflammatory bowel diseases such as ulcerative colitis or Crohn's disease, eosinophilic gastrointestinal disease, and pouchitis.

[0135] In another aspect, the present invention provides a compound as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition, for use in the treatment of inflammatory bowel disease, such as ulcerative colitis or Crohn's disease.

[0136] In another aspect, the invention provides the use of a compound, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of inflammatory bowel disease, such as ulcerative colitis or Crohn's disease.

[0137] In another aspect, the present invention provides a method of treating inflammatory bowel disease, such as ulcerative colitis or Crohn's disease, the method comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition.

[0138] In another aspect, the present invention provides a method for inhibiting α4β7 in vitro, the method comprising administering an effective amount of a compound, or a pharmaceutically acceptable salt thereof.

[0139] In another aspect, the present invention provides a method of inhibiting α4β7 in vivo, the method comprising administering an effective amount of a compound, or a pharmaceutically acceptable salt thereof.

[0140] In another aspect, the present invention provides a method for inhibiting α4β7 in vitro and / or in vivo, the method comprising contacting a cell with an effective amount of a compound as defined herein, or a pharmaceutically acceptable salt thereof.

[0141] Combination therapy The compounds of the invention may be administered alone as monotherapy or in combination with one or more additional therapeutic agents, the choice of which will, of course, depend on the disease or condition being treated and its severity.

[0142] Combination therapies are often used to treat certain medical conditions.

[0143] According to a particular aspect of the present invention, there is provided a combination suitable for use in the treatment of a disease or condition in which α4β7 inhibition is implicated, comprising a compound of the invention as defined hereinabove, or a pharmaceutically acceptable salt thereof, and another therapeutic agent.

[0144] According to this aspect of the invention there is provided a combination which is suitable for use in the prevention or treatment of inflammatory bowel diseases such as ulcerative colitis or Crohn's disease, which combination comprises a compound of the invention as defined hereinabove, or a pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents.

[0145] In a further aspect of the present invention, there is provided a compound of the present invention, or a pharmaceutically acceptable salt thereof, in combination with one or more additional therapeutic agents.

[0146] When the term "combination" is used herein, it should be understood that it refers to simultaneous, separate or sequential administration. In one aspect of the present invention, "combination" refers to simultaneous administration. In another aspect of the present invention, "combination" refers to separate administration. In a further aspect of the present invention, "combination" refers to sequential administration. When administration is sequential or separate, the delay in administration of the second component should not be such that the beneficial effect of the combination is lost.

[0147] According to a further aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of the present invention, or a pharmaceutically acceptable salt thereof, in combination with one or more additional therapeutic agents, in association with a pharmaceutically acceptable diluent or carrier.

[0148] The one or more additional therapeutic agents may comprise further compounds of the invention. Thus, in one embodiment, a pharmaceutical composition is provided comprising two compounds of the invention, or pharmaceutically acceptable salts thereof, in association with a pharmaceutically acceptable diluent or carrier.

[0149] Examples of other therapeutic agents that may be used as part of a combination therapy with the compounds of the invention (e.g., as one of two or more active agents as part of a two- or three-drug combination) include, but are not limited to, the following: i) Aminosalicylates (5-ASA), including sulfasalazine, mesalazine, balsalazide, and olsalazine; ii) steroids, including prednisolone, hydrocortisone, methylprednisolone, beclomethasone propionate, budesonide and budesonide-MMX; iii) immunosuppressants, including azathioprine, 6-mercaptopurine, cyclosporine, tacrolimus, and methotrexate; iv) anti-TNF biologics, including infliximab, adalimumab, certolizumab, and golimumab; v) anti-IL-12 / IL-23 biologics, including ustekinumab, mirikizumab, and risankizumab; vi) anti-a4b7 biologics, including vedolizumab; vii) JAK kinase inhibitors, including filgotinib, upadacitinib and tofacitinib; viii) S1P receptor modulators, including ozanimod, etrasimod and fingolimod; ix) antidiarrheals, including loperamide, codeine phosphate, and diphenoxylate; x) Antispasmodics, including mebeverine, hyoscine butyl bromide and alverine citrate; xi) Antibiotics, including metronidazole, ampicillin, and ciprofloxacin.

[0150] The above-mentioned combinations may conveniently be presented for use in the form of pharmaceutical formulations; thus, pharmaceutical formulations comprising a combination as defined above, together with a pharmaceutically acceptable diluent or carrier, represent a further aspect of the present invention.

[0151] Such conjoint / combined treatment may be achieved by way of the simultaneous, sequential or separate administration of the individual components of the treatment, hi one embodiment, the individual compounds will be administered simultaneously in a combined pharmaceutical formulation.

[0152] Such combination therapy would employ the compounds of this invention within the dosage ranges described herein and the other pharmaceutically active agent within its approved dosage range and / or dosages as described, for example, in the relevant publication references. [Example]

[0153] Methods for preparing compounds of the present invention are illustrated in the following examples. Starting materials are made according to procedures known in the art or exemplified herein, or are commercially available. Commercially available reagents were used without further purification. If no reaction temperature is included, the reactions were carried out at ambient temperature, typically 17-27°C.

[0154] Those skilled in the art will recognize that reaction temperatures, reaction times, and amounts of reagents may be varied from those set forth herein.

[0155] Flash chromatography is performed using a Combiflash® Nextgen 300+ and automated reverse phase chromatography is performed on an Interchim Puriflash® 4100.

[0156] The compounds described in this invention 1 For characterization by H NMR spectroscopy, a Bruker 500 MHz spectrometer or a Bruker Ultrashield 400 MHz spectrometer was used. Unless temperature was included, spectra were recorded at ambient temperature. Chemical shift values ​​are expressed in parts per million (ppm). The following abbreviations are used for the multiplicity of NMR signals: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broadband.

[0157] When the compounds described in this invention are characterized by LCMS data, retention times and molecular weights are determined using the conditions listed below. Method 1: Waters Acquity HT equipped with a diode array (210-350 nm) and a ZQ mass detector. Column: YMC Triart C18, 5 μm, 2.0 × 50 mm (flow rate 0.8 mL / min), 50 °C. Conditions: Water with 0.05% formic acid [eluent A], MeCN [eluent B]. Gradient: 0-95% B over 4.0 min, hold at 98% B for 0.5 min. Method 2: Waters Acquity H class UPLC equipped with a diode array (210-350 nm) and a QDa mass detector. Column: Acquity UPLC CSH C18, 1.7 μm, 2.1 × 50 mm (flow rate 1.0 mL / min), 50 °C. Conditions: 0.05% formic acid in water (eluent A), MeCN (eluent B). 2% B in 0.2 min. Gradient: 2-98% B over 2.3 min., hold at 98% B for 0.7 min. Method 3: Waters Acquity H class UPLC equipped with a diode array (210-350 nm) and a QDa mass detector. Column: Acquity UPLC BEH C18, 1.7 μm, 2.1 x 50 mm (flow rate 0.8 mL / min), 50 °C. Conditions: Water with 0.05% formic acid [eluent A], MeCN [eluent B]. Gradient: 0-95% B over 1.7 min, hold at 95% B for 0.4 min. Method 4: Waters Acquity H class UPLC equipped with a diode array (210-350 nm) and a QDa mass detector. Column: Acquity UPLC BEH C18, 1.7 μm, 2.1 x 50 mm (flow rate 0.8 mL / min), 50 °C. Conditions: 0.05% ammonia in water (eluent A), MeCN (eluent B). Gradient: 0-95% B over 1.7 min, hold at 95% B for 0.4 min. Method 5: Waters Acquity H class UPLC equipped with a diode array (210-350 nm) and a QDa mass detector. Column: Acquity UPLC BEH C18, 1.7 μm, 2.1 × 50 mm (flow rate 1.0 mL / min), 50 °C. Conditions: 0.05% ammonia in water [eluent A], MeCN [eluent B]. Gradient: 2-98% B over 2.3 min, hold at 98% B for 3.0 min. Method 6: Waters Acquity H class UPLC equipped with a diode array (210-350 nm) and a QDa mass detector. Column: Acquity UPLC BEH C18, 1.7 μm, 2.1 × 50 mm (flow rate 0.8 mL / min), 50 °C. Conditions: Water with 0.05% formic acid [eluent A], MeCN [eluent B]. Gradient: 2-98% B over 1.8 min, hold at 98% B for 0.3 min. Method 7: Waters Acquity H class UPLC equipped with a diode array (210-350 nm) and a QDa mass detector. Column: Acquity UPLC BEH C18, 1.7 μm, 2.1 × 50 mm (flow rate 0.8 mL / min), 50 °C. Conditions: Water with 0.05% formic acid [eluent A], MeCN [eluent B]. Gradient: 0-95% B over 2.50 min, hold at 95% B for 0.8 min. Method 8: Waters Acquity H class UPLC equipped with a diode array (210-350 nm) and a QDa mass detector. Column: Acquity UPLC BEH C18, 1.7 μm, 2.1 × 50 mm (flow rate 1.0 mL / min), 50 °C. Conditions: 0.1% formic acid in water (eluent A), MeCN (eluent B). 2% B in 0.2 min. Gradient: 2-98% B over 2.3 min., hold at 98% B for 0.8 min. Method 9: Waters Acquity H class UPLC equipped with a diode array (210-350 nm) and a QDa mass detector. Column: Acquity UPLC BEH C18, 1.7 μm, 2.1 × 50 mm (flow rate 1.0 mL / min), 50 °C. Conditions: 0.1% formic acid in water (eluent A), MeCN (eluent B). 50% B in 0.5 min. Gradient: 50-98% B over 6.0 min, hold at 98% B for 1.0 min. Method 10: Waters Acquity H class UPLC equipped with a diode array (210-350 nm) and a QDa mass detector. Column: Acquity UPLC BEH C18, 1.7 μm, 2.1 × 50 mm (flow rate 0.6 mL / min), 50 °C. Conditions: 0.1% ammonia in water [eluent A], MeCN [eluent B]. 2% B in 0.5 min. Gradient: 2-98% B over 6.0 min, hold at 98% B for 1.0 min. Method 11: Waters Acquity H class UPLC equipped with a diode array (210-350 nm) and a QDa mass detector. Column: Acquity UPLC BEH C18, 1.7 μm, 2.1 × 50 mm (flow rate 0.6 mL / min), 50 °C. Conditions: 0.1% ammonia in water (eluent A), MeCN (eluent B). 2% B in 0.2 min. Gradient: 2-98% B over 2.3 min., hold at 98% B for 0.8 min. Method 12: Waters Acquity H class UPLC equipped with a diode array (210-350 nm) and a QDa mass detector. Column: Acquity UPLC BEH C18, 1.7 μm, 2.1 x 50 mm (flow rate 0.8 mL / min), 50 °C. Conditions: 0.1% ammonia in water (eluent A), MeCN (eluent B). Gradient: 2-98% B over 1.8 min, hold at 98% B for 0.3 min. Method 13: Waters Acquity H class UPLC equipped with a diode array (210-350 nm) and a QDa mass detector. Column: Acquity UPLC BEH C18, 1.7 μm, 2.1 × 50 mm (flow rate 1.0 mL / min), 50 °C. Conditions: 0.1% formic acid in water (eluent A), MeCN (eluent B). 2% B in 0.2 min. Gradient: 2-98% B over 2.3 min., hold at 98% B for 0.8 min. Method 14: Waters Acquity H class UPLC equipped with a diode array (210-350 nm) and a QDa mass detector. Column: Acquity UPLC BEH C18, 1.7 μm, 2.1 × 50 mm (flow rate 1.0 mL / min), 50 °C. Conditions: 0.1% ammonia in water (eluent A), MeCN (eluent B). 5% B in 0.5 min. Gradient: 5-95% B over 6 min, hold at 95% B for 1 min. Method 15: Waters Acquity H class UPLC equipped with a diode array (210-350 nm) and a QDa mass detector. Column: Acquity UPLC BEH C18, 1.7 μm, 2.1 x 50 mm (flow rate 0.8 mL / min), 50 °C. Conditions: 0.1% ammonia in water (eluent A), MeCN (eluent B). Gradient: 0-95% B over 2.5 min, hold at 95% B for 0.8 min. Method 16: Waters Acquity H class UPLC equipped with a diode array (210-350 nm) and a QDa mass detector. Column: Acquity UPLC BEH C18, 1.7 μm, 2.1 × 50 mm (flow rate 1.0 mL / min), 50 °C. Conditions: 0.1% formic acid in water (eluent A), MeCN (eluent B). 5% B in 0.5 min. Gradient: 5-95% B over 6 min, hold at 95% B for 1 min. Method 17: Waters Acquity H class UPLC equipped with a diode array (210-350 nm) and a QDa mass detector. Column: Acquity UPLC BEH C18, 1.7 μm, 2.1 x 50 mm (flow rate 0.8 mL / min), 50 °C. Conditions: 0.05% ammonia in water (eluent A), MeCN (eluent B). Gradient: 0-95% B over 2.5 min, hold at 95% B for 0.5 min. Method 18: Waters Acquity H class UPLC equipped with a diode array (210-350 nm) and a QDa mass detector. Column: Acquity UPLC BEH C18, 1.7 μm, 2.1 x 50 mm (flow rate 0.8 mL / min), 50 °C. Conditions: Water with 0.05% formic acid [eluent A], MeCN [eluent B]. Gradient: 0-95% B over 1.70 min, hold at 95% B for 0.4 min. Method 19: Waters Acquity H class UPLC equipped with a diode array (210-350 nm) and a QDa mass detector. Column: Acquity UPLC BEH C18, 1.7 μm, 2.1 × 50 mm (flow rate 1.0 mL / min), 50 °C. Conditions: 0.1% ammonia in water (eluent A), MeCN (eluent B). 0% B for 0.5 min. Gradient: 0-98% B over 6 min, hold at 98% B for 1 min. Method 20: Waters Acquity H class UPLC equipped with a diode array (210-350 nm) and a QDa mass detector. Column: Acquity UPLC BEH C18, 1.7 μm, 2.1 × 50 mm (flow rate 1.0 mL / min), 50 °C. Conditions: 0.1% formic acid in water (eluent A), MeCN (eluent B). 2% B in 0.5 min. Gradient: 2-98% B over 6 min. Hold at 98% B for 1 min. Method 21: Waters Acquity H class UPLC equipped with a diode array (210-350 nm) and a QDa mass detector. Column: Acquity UPLC BEH C18, 1.7 μm, 2.1 x 50 mm (flow rate 1.0 mL / min), 50 °C. Conditions: 0.1% ammonia in water (eluent A), MeCN (eluent B). 0% B for 0.5 min. Gradient: 0-95% B over 6 min, hold at 95% B for 1 min. Method 22: Waters Acquity H class UPLC equipped with a diode array (210-350 nm) and a QDa mass detector. Column: Acquity UPLC BEH C18, 1.7 μm, 2.1 x 50 mm (flow rate 0.8 mL / min), 50 °C. Conditions: 0.1% ammonia in water (eluent A), MeCN (eluent B). Gradient: 0-95% B over 1.7 min, hold at 95% B for 0.4 min. Method 23: Waters Acquity H class UPLC equipped with a diode array (210-350 nm) and a QDa mass detector. Column: Acquity UPLC BEH C18, 1.7 μm, 2.1 × 50 mm (flow rate 0.6 mL / min), 50 °C. Conditions: Water with 0.1% formic acid [eluent A], MeCN [eluent B]. Gradient: 2-98% B over 2.50 min, hold at 98% B for 0.8 min. Method 24: Waters Acquity H class UPLC equipped with a diode array (210-350 nm) and a QDa mass detector. Column: Acquity UPLC BEH C18, 1.7 μm, 2.1 × 50 mm (flow rate 0.8 mL / min), 50 °C. Conditions: 0.1% formic acid in water (eluent A), MeCN (eluent B). 0% B for 0.5 min. Gradient: 0-95% B over 6 min, hold at 95% B for 1 min. Method 25: Waters Acquity H class UPLC equipped with a diode array (210-350 nm) and a QDa mass detector. Column: Acquity UPLC BEH C18, 1.7 μm, 2.1 x 50 mm (flow rate 0.8 mL / min), 50 °C. Conditions: 0.1% ammonia in water [eluent A], MeCN [eluent B]. Gradient: 10-95% B over 3.5 min, hold at 95% B for 0.9 min. Method 26: Waters Acquity H class UPLC equipped with a diode array (210-350 nm) and a QDa mass detector. Column: Acquity UPLC BEH C18, 1.7 μm, 2.1 x 50 mm (flow rate 0.6 mL / min), 50 °C. Conditions: Water with 0.1% formic acid [eluent A], MeCN [eluent B]. Gradient: 15-98% B over 4 min, hold at 98% B for 0.8 min. Method 27: Waters Acquity H class UPLC equipped with a diode array (210-350 nm) and a QDa mass detector. Column: Acquity UPLC BEH C18, 1.7 μm, 2.1 x 50 mm (flow rate 0.8 mL / min), 50 °C. Conditions: 0.1% ammonia in water (eluent A), MeCN (eluent B). Gradient: 50-95% B over 3.5 min, hold at 95% B for 0.9 min. Method 28: Waters Acquity H class UPLC equipped with a diode array (210-350 nm) and a QDa mass detector. Column: Acquity UPLC BEH C18, 1.7 μm, 2.1 x 50 mm (flow rate 0.6 mL / min), 50 °C. Conditions: 0.1% ammonia in water [eluent A], MeCN [eluent B]. Gradient: 15-98% B over 4.0 min, hold at 98% B for 0.8 min. Method 29: Waters Acquity H class UPLC equipped with a diode array (210-350 nm) and a QDa mass detector. Column: Acquity UPLC BEH C18, 1.7 μm, 2.1 x 50 mm (flow rate 0.6 mL / min), 50 °C. Conditions: 0.1% formic acid in water (eluent A), MeCN (eluent B). 2% B in 0.5 min. Gradient: 2-98% B over 6 min, hold at 98% B for 1 min.

[0158] Preparative HPLC was performed using a Waters 2545 binary gradient module equipped with a 2998 PDA and 2767 sample manager, a Waters SFO module. [Table 1-1] [Table 1-2]

[0159] Synthesis of intermediates Intermediate 1: Methyl (S)-3-(3-bromophenyl)-3-((tert-butoxycarbonyl)amino)propanoate To a stirred suspension of methyl (S)-3-amino-3-(3-bromophenyl)propanoate hydrochloride (12.1 g, 41.1 mmol, CAS 1391379-45-5) and triethylamine (6.23 g, 61.6 mmol) in DCM (28.5 mL), Boc anhydride (9.86 g, 45.2 mmol) was added and the reaction mixture was stirred at room temperature for 20 hours. The reaction mixture was diluted with water and the crude product was extracted into DCM. The combined organics were washed with water, brine, dried over MgSO4, filtered, and concentrated under reduced pressure to give the title compound (15.5 g). 1 H NMR (500 MHz;CDCl3) δ: 7.46 (s, 1H), 7.41 (d, 1H), 7.26 - 7.20 (m, 2H), 5.56 (br s, 1H), 5.08 (br s, 1H), 3.65 (s, 3H), 2.84 (br s, 2H), 1.45 (br s, 9H).

[0160] Intermediate 2: Methyl (S)-3-((tert-butoxycarbonyl)amino)-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate A solution of intermediate 1 (14.7 g, 37.0 mmol) and bis(pinacolato)diboron (10.33 g, 40.68 mmol) in 1,4-dioxane (125 mL) was degassed with nitrogen. To this solution was then added potassium acetate (9.07 g, 92.5 mmol), followed by Pd(dppf)Cl (2.71 g, 3.70 mmol), and the reaction mixture was stirred at 95 °C for 20 h. The mixture was cooled and filtered through Celite®, washing with EtOAc and water. The organic layer was dried over MgSO, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, eluting with 50% EtOAc in petroleum ether) to give the title compound (7.0 g). LCMS (Method 1): 3.55 min, 406.1 [M+H] + .

[0161] Intermediate 3: Methyl (S)-3-((tert-butoxycarbonyl)amino)-3-(2'-hydroxy-6'-methyl-[1,1'-biphenyl]-3-yl)propanoate A mixture of intermediate 2 (14.7 g, 37.0 mmol), 2-bromo-3-methylphenol (0.67 g, 3.60 mmol, CAS 22061-78-5), and NaHCO (0.80 g, 7.56 mmol) in toluene (25 mL), ethanol (5 mL), and water (5.5 mL) was degassed with nitrogen. To this was added Pd(PPh) (0.21 g, 0.18 mmol), and the reaction mixture was stirred at 85 °C for 16 h. The mixture was diluted with water and extracted into EtOAc. The organic layer was dried over MgSO, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography (24 g silica gel, eluted with 20-50% EtOAc in petroleum ether) to give the title compound (1.12 g). LCMS (Method 2): 2.07 min, 408.1 [M+Na] + .

[0162] Intermediate 4: Methyl (S)-3-amino-3-(2'-hydroxy-6'-methyl-[1,1'-biphenyl]-3-yl)propanoate hydrochloride A suspension of intermediate 3 (0.19 g, 0.48 mmol) in 4 M HCl in 1,4-dioxane (3.0 mL) was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure to give the title compound (0.15 g). LCMS (Method 2): 1.31 min, 286.2 [M+H] + .

[0163] Intermediate 5: Methyl (S)-3-((S)-2-((tert-butoxycarbonyl)amino)pent-4-enamido)-3-(2'-hydroxy-6'-methyl-[1,1'-biphenyl]-3-yl)propanoate To a solution of intermediate 4 (0.76 g, 2.37 mmol) and N-Boc-(S)-allylglycine (0.51 g, 2.37 mmol, CAS 90600-20-7) in DMF (5 mL), DIPEA (0.83 mL, 4.74 mmol), HOBt (0.44 g, 4.74 mmol), and EDCI (0.55 g, 2.85 mmol) were added, and the mixture was stirred at room temperature for 4 h. The mixture was diluted with water and extracted into EtOAc. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography (24 g silica gel, eluted with 30-50% EtOAc in petroleum ether) to give the title compound (0.78 g). LCMS (Method 3): 1.63 min, 427.1 [M-tBu+H] + .

[0164] Intermediate 6: Methyl (S)-3-(2'-(but-3-en-1-yloxy)-6'-methyl-[1,1'-biphenyl]-3-yl)-3-((S)-2-((tert-butoxycarbonyl)amino)pent-4-enamido)propanoate To a suspension of intermediate 5 (0.78 g, 1.61 mmol) and K2CO3 (0.56 g, 4.02 mmol) in MeCN (5 mL) was added 4-bromobut-1-ene (0.33 mL, 3.22 mmol) and the mixture was stirred at reflux for 16 h. Additional 4-bromobut-1-ene (0.33 mL, 3.22 mmol) was added and stirring at reflux continued for 24 h. The mixture was diluted with water and extracted into EtOAc. The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (24 g silica gel, eluted with 30-50% EtOAc in petroleum ether) to give the title compound (0.68 g). LCMS (Method 3): 1.90 min, 537.2 [M+H] + .

[0165] Intermediate 7: Methyl 2-((9S,12S)-9-((tert-butoxycarbonyl)amino)-2 6-methyl-10-oxo-3-oxa-11-aza-1(1,3),2(1,2)-dibenzeneacyclododecaphan-6-en-12-yl)acetate A solution of intermediate 6 (0.27 g, 0.51 mmol) in DCE (4 mL) was degassed with nitrogen. To this was added Grubbs II (43 mg, 0.05 mmol) as a solution in degassed DCE (4 mL), and the mixture was stirred at 40° C. for 4 h. The mixture was cooled, ethyl vinyl ether (0.05 mL, 0.51 mmol) was added, and the mixture was concentrated under reduced pressure. The crude product was purified by flash chromatography (24 g silica gel, eluted with 30-50% EtOAc in petroleum ether) to give the title compound (0.25 g). LCMS (Method 3): 1.78 min, 509.2 [M+H] + .

[0166] Intermediate 8: Methyl 2-((9S,12S)-9-((tert-butoxycarbonyl)amino)-2 6 -methyl-10-oxo-3-oxa-11-aza-1(1,3),2(1,2)-dibenzeneacyclododecaphan-12-yl)acetate To a solution of Intermediate 7 (0.25 g, 0.49 mmol) in MeOH (5 mL) was added 5% palladium on carbon (52 mg), and the reaction was stirred under a hydrogen atmosphere at room temperature for 2 hours. The mixture was filtered through Celite®, washing with MeOH, and the filtrate was concentrated under reduced pressure to give the title compound (0.22 g). LCMS (Method 3): 1.79 min, 511.1 [M+H] + .

[0167] Intermediate 9: Methyl 2-((9S,12S)-9-amino-2 6 -Methyl-10-oxo-3-oxa-11-aza-1(1,3),2(1,2)-dibenzeneacyclododecaphan-12-yl)acetate hydrochloride A suspension of intermediate 8 (0.22 g, 0.44 mmol) in 4 M HCl in 1,4-dioxane (5.0 mL) was stirred at room temperature for 1.5 hours. The mixture was concentrated under reduced pressure to give the title compound (0.22 g). LCMS (Method 2): 1.26 min, 411.2 [M+H]+ .

[0168] Intermediate 10: Methyl 2-((9S,12S)-9-acetamido-2 6 -methyl-10-oxo-3-oxa-11-aza-1(1,3),2(1,2)-dibenzeneacyclododecaphan-12-yl)acetate To a solution of intermediate 9 (0.20 g, 0.44 mmol) and triethylamine (0.13 mL, 0.96 mmol) in DCM (4 mL) was added acetyl chloride (0.03 mL, 0.48 mmol), and the mixture was stirred at room temperature for 20 minutes. The mixture was concentrated under reduced pressure. The crude product was purified by flash chromatography (12 g silica gel, eluted with 0-10% MeOH in DCM) to give the title compound (0.15 g). LCMS (Method 3): 1.53 min, 453.2 [M+H] + .

[0169] Intermediate 11: Methyl (S)-3-(2'-(allyloxy)-6'-methyl-[1,1'-biphenyl]-3-yl)-3-((S)-2-((tert-butoxycarbonyl)amino)pent-4-enamido)propanoate Prepared in a manner similar to Intermediate 6. Intermediate 5 (0.72 g, 1.48 mmol), KCO (0.51 g, 3.71 mmol), and allyl bromide (0.26 mL, 2.97 mmol) in MeCN (20 mL) were used at room temperature for 72 h. Purification by flash chromatography (24 g silica gel, eluting with 30-50% EtOAc in petroleum ether) gave the title compound (0.60 g). LCMS (Method 3): 1.84 min, 523.2 [M+H] + .

[0170] Intermediate 12: Methyl 2-((8S,11S)-8-((tert-butoxycarbonyl)amino)-2 6 -methyl-9-oxo-3-oxa-10-aza-1(1,3),2(1,2)-dibenzeneacycloundecaphan-5-en-11-yl)acetate Prepared in a manner similar to Intermediate 7. Intermediate 11 (0.24 g, 0.46 mmol) in DCE (2 mL) and Grubbs II (39 mg, 0.05 mmol) in DCE (2 mL) were used at 40° C. for 4 h. The reaction was quenched with ethyl vinyl ether (0.04 mL, 0.46 mmol). Purification by flash chromatography (24 g silica gel, eluting with 30-50% EtOAc in petroleum ether) gave the title compound (0.23 g). LCMS (Method 3): 1.70 min, 495.1 [M+H] + .

[0171] Intermediate 13: Methyl 2-((8S,11S)-8-((tert-butoxycarbonyl)amino)-2 6 -methyl-9-oxo-3-oxa-10-aza-1(1,3),2(1,2)-dibenzeneacycloundecaphan-11-yl)acetate Prepared in a manner similar to Intermediate 8. Intermediate 12 (0.23 g, 0.47 mmol) and 5% palladium on carbon (50 mg) in MeOH (5 mL) were used under a hydrogen atmosphere at room temperature for 2 hours to give the title compound (0.18 g). LCMS (Method 3): 1.71 min, 497.1 [M+H] + .

[0172] Intermediate 14: Methyl 2-((8S,11S)-8-amino-2 6 -Methyl-9-oxo-3-oxa-10-aza-1(1,3),2(1,2)-dibenzeneacycloundecaphan-11-yl)acetate hydrochloride A suspension of intermediate 13 (0.18 g, 0.37 mmol) in 4 M HCl in 1,4-dioxane (4.0 mL) was stirred at room temperature for 1.5 hours. The mixture was concentrated under reduced pressure to give the title compound (0.16 g). LCMS (Method 3): 1.19 min, 397.2 [M+H] + .

[0173] Intermediate 15: Methyl 2-((8S,11S)-8-acetamido-2 6-methyl-9-oxo-3-oxa-10-aza-1(1,3),2(1,2)-dibenzeneacycloundecaphan-11-yl)acetate Prepared in a manner similar to Intermediate 10. Intermediate 14 (0.16 g, 0.37 mmol), triethylamine (0.11 mL, 0.81 mmol), acetyl chloride (0.03 mL, 0.41 mmol) in DCM (5 mL) was used at room temperature for 30 min. Purification by flash chromatography (12 g silica gel, eluting with 0-10% MeOH in DCM) gave the title compound (0.12 g). LCMS (Method 3): 1.45 min, 439.1 [M+H] + .

[0174] Intermediate 16: Methyl (S)-3-((S)-2-((tert-butoxycarbonyl)amino)pent-4-enamido)-3-(2'-methyl-6'-(pent-4-en-1-yloxy)-[1,1'-biphenyl]-3-yl)propanoate Prepared in a manner similar to Intermediate 6. Intermediate 5 (0.72 g, 1.48 mmol), K2CO3 (0.51 g, 3.71 mmol), and 5-bromopent-1-ene (0.35 mL, 2.97 mmol) in MeCN (20 mL) were used at room temperature for 72 h. Purification by flash chromatography (24 g silica gel, eluting with 30-50% EtOAc in petroleum ether) gave the title compound (0.59 g). LCMS (Method 3): 1.96 min, 551.2 [M+H] + .

[0175] Intermediate 17: Methyl 2-((10S,13S)-10-((tert-butoxycarbonyl)amino)-2 6 -methyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-7-en-13-yl)acetate Prepared in a manner similar to Intermediate 7. Intermediate 16 (0.24 g, 0.43 mmol) in DCE (3 mL) and Grubbs II (36 mg, 0.04 mmol) in DCE (3 mL) were used at 40° C. for 4 h. The reaction was quenched with ethyl vinyl ether (2.0 mL, 20.1 mmol). Purification by flash chromatography (24 g silica gel, eluting with 30-50% EtOAc in petroleum ether) gave the title compound (0.21 g). LCMS (Method 3): 1.82 min, 523.2 [M+H] + .

[0176] Intermediate 18: Methyl 2-((10S,13S)-10-((tert-butoxycarbonyl)amino)-2 6 -methyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetate Prepared in a manner similar to Intermediate 8. Intermediate 17 (0.21 g, 0.41 mmol) and 5% palladium on carbon (43 mg) in MeOH (5 mL) were used under a hydrogen atmosphere at room temperature for 2 hours to give the title compound (0.21 g). LCMS (Method 3): 1.86 min, 525.2 [M+H] + .

[0177] Intermediate 19: Methyl 2-((10S,13S)-10-amino-2 6 -Methyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetate hydrochloride A suspension of intermediate 18 (0.21 g, 0.39 mmol) in 4 M HCl in 1,4-dioxane (6 mL) was stirred at room temperature for 1.5 hours. The mixture was concentrated under reduced pressure to give the title compound (0.18 g). LCMS (Method 3): 1.26 min, 425.2 [M+H] + .

[0178] Intermediate 20: Methyl 2-((10S,13S)-10-acetamido-2 6-methyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetate Prepared in a manner similar to Intermediate 10. Intermediate 19 (0.18 g, 0.39 mmol), triethylamine (0.12 mL, 0.87 mmol), acetyl chloride (0.03 mL, 0.43 mmol) in DCM (5 mL) was used at room temperature for 30 min. Purification by flash chromatography (12 g silica gel, eluting with 0-10% MeOH in DCM) gave the title compound (96 mg). LCMS (Method 3): 1.59 min, 467.2 [M+H] + .

[0179] Intermediate 21: Methyl (S)-3-((S)-2-((tert-butoxycarbonyl)amino)-4-methylpent-4-enamido)-3-(2'-hydroxy-6'-methyl-[1,1'-biphenyl]-3-yl)propanoate Prepared in a manner similar to Intermediate 5. Intermediate 4 (0.25 g, 0.78 mmol), (2S)-2-(tert-butoxycarbonylamino)-4-methyl-pent-4-enoic acid (0.18 g, 0.78 mmol, CAS 87325-47-1), DIPEA (0.27 mL, 1.56 mmol), HOBt (0.14 g, 0.93 mmol), and EDCI (0.18 g, 0.93 mmol) in DMF (5 mL) were used at room temperature for 4 h. Purification by flash chromatography (24 g silica gel, eluting with 30-50% EtOAc in petroleum ether) gave the title compound (0.24 g). LCMS (Method 3): 1.68 min, 497.1 [M+H] + .

[0180] Intermediate 22: Methyl (S)-3-((S)-2-((tert-butoxycarbonyl)amino)-4-methylpent-4-enamido)-3-(2'-methyl-6'-(pent-4-en-1-yloxy)-[1,1'-biphenyl]-3-yl)propanoate Prepared in a manner similar to Intermediate 6. Intermediate 21 (0.14 g, 0.28 mmol), K2CO3 (0.10 g, 0.71 mmol), and 5-bromopent-1-ene (0.07 mL, 0.57 mmol) in MeCN (20 mL) were used at reflux for 72 h. Purification by flash chromatography (24 g silica gel, eluting with 30-50% EtOAc in petroleum ether) gave the title compound (86 mg). LCMS (Method 3): 1.99 min, 565.3 [M+H] + .

[0181] Intermediate 23: Methyl 2-((10S,13S)-10-((tert-butoxycarbonyl)amino)-2 6 ,8-Dimethyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-7-en-13-yl)acetate Prepared in a manner similar to Intermediate 7. Intermediate 22 (54 mg, 0.10 mmol) and Grubbs II (8.1 mg, 0.01 mmol) in DCE (45 mL) were used at 40° C. for 4 h. The reaction was quenched with ethyl vinyl ether (0.45 mL, 4.68 mmol). Purification by flash chromatography (24 g silica gel, eluting with 30-50% EtOAc in petroleum ether) gave the title compound (21 mg). LCMS (Method 4): 1.89 min, 537.1 [M+H] + .

[0182] Intermediate 24: Methyl 2-((10S,13S)-10-((tert-butoxycarbonyl)amino)-2 6 ,8-Dimethyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetate Prepared in a manner similar to Intermediate 8. Intermediate 23 (21 mg, 0.04 mmol) and 5% palladium on carbon (4 mg) in MeOH (5 mL) were used under a hydrogen atmosphere at room temperature for 3 hours to give the title compound (0.21 g). LCMS (Method 4): 1.92 min, 539.2 [M+H] + .

[0183] Intermediate 25: Methyl 2-((10S,13S)-10-amino-2 6 ,8-Dimethyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetate hydrochloride A suspension of intermediate 24 (21 g, 0.39 mmol) in 4 M HCl in 1,4-dioxane (2 mL) was stirred at room temperature for 1.5 hours. The mixture was concentrated under reduced pressure to give the title compound (18 mg). LCMS (Method 4): 1.62 min, 439.2 [M+H] + .

[0184] Intermediate 26: Methyl 2-((10S,13S)-10-acetamido-2 6 ,8-Dimethyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetate Prepared in a manner similar to Intermediate 10. Intermediate 25 (18 mg, 0.04 mmol), triethylamine (12 μL, 0.09 mmol), acetyl chloride (3 μL, 0.04 mmol) in DCM (5 mL) was used at room temperature for 30 min. Purification by flash chromatography (12 g silica gel, eluting with 0-10% MeOH in DCM) gave the title compound (19 mg). LCMS (Method 4): 2.08 min, 481.2 [M+H] + .

[0185] Intermediate 27: Methyl (S)-3-((tert-butoxycarbonyl)amino)-3-(5'-hydroxy-2'-methyl-[1,1'-biphenyl]-3-yl)propanoate Prepared in a manner similar to Intermediate 3. Intermediate 2 (1.0 g, 1.80 mmol), 3-bromo-4-methylphenol (0.31 g, 0.91 mmol, CAS 60710-39-6), NaCO (0.80 g, 7.56 mmol), and Pd(PPh) (95 mg, 0.05 mmol) in toluene (10.2 mL), ethanol (2 mL), and water (2 mL) were used at 85 °C for 16 h. Purification by flash chromatography (40 g silica gel, eluting with 5-20% EtOAc in petroleum ether, then 100% EtOAc) gave the title compound (0.64 g). LCMS (Method 5): 1.48 min, 408.1 [M+Na] + .

[0186] Intermediate 28: Methyl (S)-3-((tert-butoxycarbonyl)amino)-3-(2'-methyl-5'-(pent-4-en-1-yloxy)-[1,1'-biphenyl]-3-yl)propanoate Prepared in a manner similar to Intermediate 6. Intermediate 27 (0.32 g, 0.83 mmol), K2CO3 (0.29 g, 2.08 mmol) and 5-bromopent-1-ene (0.20 mL, 1.66 mmol) in MeCN (20 mL) were used at reflux for 24 h to give the title compound (0.37 g). LCMS (Method 5): 1.94 min, 452.4 [MH] - .

[0187] Intermediate 29: Methyl (S)-3-amino-3-(2'-methyl-5'-(pent-4-en-1-yloxy)-[1,1'-biphenyl]-3-yl)propanoate hydrochloride A suspension of Intermediate 28 (0.27 g, 0.59 mmol) in 4 M HCl in 1,4-dioxane (5.0 mL) was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure to give the title compound (0.26 g). LCMS (Method 5): 1.71 min, 354.3 [M+H] + .

[0188] Intermediate 30: Methyl (S)-3-((S)-2-((tert-butoxycarbonyl)amino)pent-4-enamido)-3-(2'-methyl-5'-(pent-4-en-1-yloxy)-[1,1'-biphenyl]-3-yl)propanoate Prepared in a manner similar to Intermediate 5. Intermediate 29 (0.23 g, 0.59 mmol), N-Boc-(S)-allylglycine (0.13 g, 0.59 mmol, CAS90600-20-7), DIPEA (0.31 mL, 1.77 mmol), HOBt (0.10 g, 0.65 mmol), and EDCI (0.15 g, 0.77 mmol) in DMF (5 mL) were used at room temperature for 16 h. Purification by flash chromatography (24 g silica gel, eluting with 0-50% EtOAc in petroleum ether) gave the title compound (0.14 g). LCMS (Method 4): 1.88 min, 551.4 [M+H] + .

[0189] Intermediate 31: Methyl 2-((10S,13S)-10-((tert-butoxycarbonyl)amino)-2 6 -methyl-11-oxo-3-oxa-12-aza-1,2(1,3)-dibenzeneacyclotridecaphan-7-en-13-yl)acetate Prepared in a manner similar to Intermediate 7. Intermediate 30 (0.13 g, 0.24 mmol) in DCE (50 mL) and Grubbs II (20 mg, 0.02 mmol) in DCE (11 mL) were used at 40° C. for 5 h. The reaction was quenched with ethyl vinyl ether (3.0 mL, 31.3 mmol). Purification by flash chromatography (24 g silica gel, eluting with 20-40% EtOAc in petroleum ether) gave the title compound (93 mg). LCMS (Method 4): 1.69 and 1.73 min, 523.4 [M+H] + .

[0190] Intermediate 32: Methyl 2-((10S,13S)-10-((tert-butoxycarbonyl)amino)-2 6-methyl-11-oxo-3-oxa-12-aza-1,2(1,3)-dibenzeneacyclotridecaphan-13-yl)acetate Prepared in a manner similar to Intermediate 8. Intermediate 31 (93 mg, 0.13 mmol) and 5% palladium on carbon (14 mg) in MeOH (1.4 mL) were used under a hydrogen atmosphere at room temperature for 2 hours to give the title compound (47 mg). LCMS (Method 4): 1.73 min, 525.4 [M+H] + .

[0191] Intermediate 33: Methyl 2-((10S,13S)-10-amino-2 6 -Methyl-11-oxo-3-oxa-12-aza-1,2(1,3)-dibenzeneacyclotridecaphan-13-yl)acetate hydrochloride A solution of thionyl chloride (0.01 mL, 0.11 mmol) in MeOH (2 mL) was added to Intermediate 32 (47 mg, 0.09 mmol) and the mixture was stirred at 60° C. for 4 hours. The mixture was concentrated under reduced pressure to give the title compound (38 mg). LCMS (Method 4): 1.42 min, 425.3 [M+H] + .

[0192] Intermediate 34: Methyl 2-((10S,13S)-10-acetamido-2 6 -methyl-11-oxo-3-oxa-12-aza-1,2(1,3)-dibenzeneacyclotridecaphan-13-yl)acetate Prepared in a manner similar to Intermediate 10. Intermediate 33 (38 mg, 0.09 mmol), triethylamine (2.8 μL, 0.20 mmol), acetyl chloride (7 μL, 0.10 mmol) in DCM (1 mL) was used at room temperature for 1 h to give the title compound (37 mg). LCMS (Method 4): 1.44 min, 467.3 [M+H] + .

[0193] Intermediate 35: Methyl (S)-3-(2'-(allyloxy)-6'-methyl-[1,1'-biphenyl]-3-yl)-3-((S)-2-((tert-butoxycarbonyl)amino)-4-methylpent-4-enamido)propanoate Prepared in a manner similar to Intermediate 6. Intermediate 21 (0.14 g, 0.28 mmol), K2CO3 (0.10 g, 0.71 mmol), and allyl bromide (0.05 mL, 0.57 mmol) in MeCN (10 mL) were used at room temperature for 72 h. Purification by flash chromatography (24 g silica gel, eluting with 30-50% EtOAc in petroleum ether) gave the title compound (0.11 g). LCMS (Method 4): 1.90 min, 537.2 [M+H] + .

[0194] Intermediate 36: Methyl 2-((8S,11S)-8-((tert-butoxycarbonyl)amino)-2 6 ,6-Dimethyl-9-oxo-3-oxa-10-aza-1(1,3),2(1,2)-dibenzeneacycloundecaphan-5-en-11-yl)acetate Prepared in a manner similar to Intermediate 7. Intermediate 35 (0.11 g, 0.20 mmol) and Grubbs II (17 mg, 0.02 mmol) in DCE (98 mL) were used at 40° C. for 4 h. Purification by flash chromatography (24 g silica gel, eluting with 30-50% EtOAc in petroleum ether) gave the title compound (50 mg). LCMS (Method 4): 1.77 min, 509.0 [M+H] + .

[0195] Intermediate 37: Methyl 2-((8S,11S)-8-((tert-butoxycarbonyl)amino)-2 6 ,6-Dimethyl-9-oxo-3-oxa-10-aza-1(1,3),2(1,2)-dibenzeneacycloundecaphan-11-yl)acetate Prepared in a manner similar to Intermediate 8. Intermediate 36 (50 mg, 0.10 mmol) and 5% palladium on carbon (11 mg) in MeOH (5 mL) were used under a hydrogen atmosphere at room temperature for 4 hours to give the title compound (46 mg). LCMS (Method 4): 1.77 min, 511.3 [M+H] + .

[0196] Intermediate 38: Methyl 2-((8S,11S)-8-amino-2 6 ,6-Dimethyl-9-oxo-3-oxa-10-aza-1(1,3),2(1,2)-dibenzeneacycloundecaphan-11-yl)acetate hydrochloride A suspension of intermediate 37 (46 mg, 0.09 mmol) in 4 M HCl in 1,4-dioxane (2.0 mL) was stirred at room temperature for 1.5 hours. The mixture was concentrated under reduced pressure to give the title compound (40 mg). LCMS (Method 4): 1.50 min, 411.2 [M+H] + .

[0197] Intermediate 39: Methyl 2-((8S,11S)-8-acetamido-2 6 ,6-Dimethyl-9-oxo-3-oxa-10-aza-1(1,3),2(1,2)-dibenzeneacycloundecaphan-11-yl)acetate Prepared in a manner similar to Intermediate 10. Intermediate 38 (40 mg, 0.09 mmol), triethylamine (2.7 μL, 0.20 mmol), acetyl chloride (7 μL, 0.10 mmol) in DCM (10 mL) was used at room temperature for 30 min. Purification by flash chromatography (12 g silica gel, eluting with 0-10% MeOH in DCM) gave the title compound (30 mg). LCMS (Method 4): 1.84 min, 453.2 [M+H] + .

[0198] Intermediate 40: Methyl (S)-3-((S)-2-((tert-butoxycarbonyl)(methyl)amino)penta-4-enamido)-3-(2'-hydroxy-6'-methyl-[1,1'-biphenyl]-3-yl)propanoate Prepared in a manner similar to Intermediate 5. Intermediate 4 (0.17 g, 0.52 mmol), N-Boc-N-methyl-(S)-allylglycine (0.12 g, 0.52 mmol, CAS 136092-76-7), DIPEA (0.18 mL, 1.04 mmol), HOBt (95 mg, 0.62 mmol) and EDCI (0.12 g, 0.62 mmol) in DMF (2 mL) were used at room temperature for 4 h to give the title compound (0.18 g). LCMS (Method 3): 1.73 min, 497.2 [M+H] + .

[0199] Intermediate 41: Methyl (S)-3-((S)-2-((tert-butoxycarbonyl)(methyl)amino)pent-4-enamido)-3-(2'-methyl-6'-(pent-4-en-1-yloxy)-[1,1'-biphenyl]-3-yl)propanoate Prepared in a manner similar to Intermediate 6. Intermediate 40 (0.18 g, 0.37 mmol), K2CO3 (0.13 g, 0.91 mmol), and 5-bromopent-1-ene (0.09 mL, 0.73 mmol) in MeCN (20 mL) were used at reflux for 16 h. Purification by flash chromatography (24 g silica gel, eluting with 30-50% EtOAc in petroleum ether) gave the title compound (0.12 g). LCMS (Method 4): 2.04 min, 565.3 [M+H] + .

[0200] Intermediate 42: Methyl 2-((10S,13S)-10-((tert-butoxycarbonyl)(methyl)amino)-2 6 -methyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-7-en-13-yl)acetate Prepared in a manner similar to Intermediate 7. Intermediate 41 (0.10 g, 0.17 mmol) and Grubbs II (14 mg, 0.17 mmol) in DCE (85 mL) were used at 40 °C for 4 h. Purification by flash chromatography (12 g XTYPE cartridge, eluting with 10-40% EtOAc in petroleum ether) gave the title compound (91 mg). LCMS (Method 4): 1.90 min, 537.3 [M+H] + .

[0201] Intermediate 43: Methyl 2-((10S,13S)-10-((tert-butoxycarbonyl)(methyl)amino)-2 6 -methyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetate Prepared in a manner similar to Intermediate 8. Intermediate 42 (91 mg, 0.17 mmol) and 5% palladium on carbon (18 mg) in MeOH (10 mL) were used under a hydrogen atmosphere at room temperature for 3 hours to give the title compound (90 mg). LCMS (Method 4): 1.94 min, 539.3 [M+H] + .

[0202] Intermediate 44: Methyl 2-((10S,13S)-2 6 -Methyl-10-(methylamino)-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetate hydrochloride A suspension of intermediate 43 (90 mg, 0.17 mmol) in 4 M HCl in 1,4-dioxane (3.0 mL) was stirred at room temperature for 1.5 hours. The mixture was concentrated under reduced pressure to give the title compound (79 mg). LCMS (Method 4): 1.48 min, 439.4 [M+H] + .

[0203] Intermediate 45: Methyl 2-((10S,13S)-2 6 -Methyl-10-(N-methylacetamido)-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetate Prepared in a manner similar to Intermediate 10. Intermediate 44 (79 mg, 0.17 mmol), triethylamine (0.05 mL, 0.37 mmol), acetyl chloride (13 μL, 0.18 mmol) in DCM (5 mL) was used at room temperature for 30 min to give the title compound (80 mg). LCMS (Method 4): 1.56 min, 481.4 [M+H] + .

[0204] Intermediate 46: Methyl (S)-3-((tert-butoxycarbonyl)amino)-3-(2'-methyl-6'-vinyl-[1,1'-biphenyl]-3-yl)propanoate Prepared in a manner similar to Intermediate 3. Intermediate 2 (1.1 g, 2.58 mmol), 2-bromo-1-methyl-3-vinylbenzene (0.59 g, 2.83 mmol, CAS 1835-81-0), KCO (0.71 g, 5.16 mmol), and Pd(dppf)Cl (0.11 g, 0.15 mmol) in 1,4-dioxane (19 mL) and water (6.4 mL) were used at 90 °C for 3 h. Purification by flash chromatography (40 g silica gel, eluted with 100% DCM) gave the title compound (0.76 g). LCMS (Method 4): 1.83 min, 418.3 [M+Na] + .

[0205] Intermediate 47: Methyl (S)-3-amino-3-(2'-methyl-6'-vinyl-[1,1'-biphenyl]-3-yl)propanoate hydrochloride A suspension of intermediate 46 (0.76 g, 1.69 mmol) in 4 M HCl in 1,4-dioxane (10 mL) was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure to give the title compound (0.56 g). LCMS (Method 4): 1.65 min, 296.0 [M+H] + .

[0206] Intermediate 48: Methyl (S)-3-((S)-2-((tert-butoxycarbonyl)(methyl)amino)non-8-enamido)-3-(2'-methyl-6'-vinyl-[1,1'-biphenyl]-3-yl)propanoate Prepared in a manner similar to Intermediate 5. Intermediate 47 (0.21 g, 0.62 mmol), methyl (S)-2-((tert-butoxycarbonyl)amino)non-8-enoate (0.18 g, 0.62 mmol, CAS 2375587-63-4), DIPEA (0.32 mL, 1.86 mmol), HOBt (92 mg, 0.68 mmol), and EDCI (0.15 g, 0.81 mmol) in DMF (18 mL) were used at room temperature for 4 h. Purification by flash chromatography (40 g silica gel, eluting with 0-10% EtOAc in DCM) gave the title compound (0.10 g). LCMS (Method 5): 2.14 min, 463.2 [M-Boc+H] + .

[0207] Intermediate 49: Methyl 2-((3S,6S)-6-((tert-butoxycarbonyl)(methyl)amino)-1 6 -Methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-12-en-3-yl)acetate Prepared in a manner similar to Intermediate 7. Intermediate 48 (0.20 g, 0.32 mmol) and Grubbs II (27 mg, 0.04 mmol) in DCE (15 mL) were used at 60 °C for 16 h and quenched with ethyl vinyl ether (3.04 mL, 31.7 mmol). Purification by flash chromatography (silica gel, eluting with 5% EtOAc in DCM) gave the title compound (0.11 g). LCMS (Method 4): 1.98 min, 535.5 [M+H] + .

[0208] Intermediate 50: Methyl 2-((3S,6S)-6-((tert-butoxycarbonyl)(methyl)amino)-1 6 -Methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetate Prepared in a manner similar to Intermediate 8. Intermediate 49 (91 mg, 0.17 mmol) and 5% palladium on carbon (18 mg) in MeOH (10 mL) were used under a hydrogen atmosphere at room temperature for 3 hours to give the title compound (90 mg). LCMS (Method 4): 1.94 min, 537.2 [M+H] + .

[0209] Intermediate 51: Methyl 2-((3S,6S)-1 6 -Methyl-6-(methylamino)-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetate hydrochloride A suspension of intermediate 50 (91 mg, 0.17 mmol) in 4 M HCl in 1,4-dioxane (1.5 mL) was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure to give the title compound (79 mg). LCMS (Method 4): 1.66 min, 437.5 [M+H] + .

[0210] Intermediate 52: Methyl 2-((3S,6S)-1 6 -Methyl-6-(N-methylacetamido)-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetate Prepared in a manner similar to Intermediate 10. Intermediate 51 (79 mg, 0.17 mmol), triethylamine (0.05 mL, 0.37 mmol), acetyl chloride (13 μL, 0.18 mmol) in DCM (1.7 mL) was used at room temperature for 2 h to give the title compound (77 mg). LCMS (Method 4): 1.83 min, 479.3 [M+H] + .

[0211] Intermediate 53: methyl (S)-3-(2'-(but-3-en-1-yloxy)-6'-methyl-[1,1'-biphenyl]-3-yl)-3-((tert-butoxycarbonyl)amino)propanoate Prepared in a manner similar to Intermediate 6. Intermediate 3 (1.80 g, 4.67 mmol), K2CO3 (1.63 g, 11.7 mmol), and 4-bromobut-1-ene (0.96 mL, 9.34 mmol) in MeCN (41 mL) were used at reflux for 16 h. Purification by flash chromatography (25 g XTYPE cartridge, eluting with 0-50% EtOAc in petroleum ether) gave the title compound (1.0 g). LCMS (Method 3): 1.93 min, 462.2 [M+Na] + .

[0212] Intermediate 54: Methyl (S)-3-amino-3-(2'-(but-3-en-1-yloxy)-6'-methyl-[1,1'-biphenyl]-3-yl)propanoate hydrochloride A suspension of intermediate 53 (1.0 g, 2.28 mmol) in 4 M HCl in 1,4-dioxane (53 mL) was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure to give the title compound (0.85 g). LCMS (Method 3): 1.19 min, 340.3 [M+H] + .

[0213] Intermediate 55: Methyl (S)-3-(2'-(but-3-en-1-yloxy)-6'-methyl-[1,1'-biphenyl]-3-yl)-3-((R)-2-hydroxyhex-5-enamido)propanoate Prepared in a manner similar to Intermediate 5. Intermediate 54 (1.0 g, 2.66 mmol), (2R)-2-hydroxyhex-5-enoic acid (0.41 g, 2.66 mmol, CAS 612825-60-2), DIPEA (1.39 mL, 7.98 mmol), HOBt (0.36 g, 2.66 mmol), and EDCI (0.51 g, 2.66 mmol) in MeCN (27 mL) were used at room temperature for 5 h. Purification by flash chromatography (25 g silica gel, eluting with 30-100% EtOAc in petroleum ether) gave the title compound (0.80 g). LCMS (Method 3): 1.68 min, 452.4 [M+H] + .

[0214] Intermediate 56: Methyl (S)-3-(2'-(but-3-en-1-yloxy)-6'-methyl-[1,1'-biphenyl]-3-yl)-3-((R)-2-((methylsulfonyl)oxy)hex-5-enamido)propanoate To a solution of intermediate 55 (0.80 g, 1.77 mmol) and triethylamine (0.49 mL, 3.54 mmol) in DCM (125 mL) was added methanesulfonyl chloride (0.21 mL, 2.66 mmol), and the mixture was stirred at room temperature for 1 hour. The mixture was washed with 2 M aqueous HCl, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (0.94 g). LCMS (Method 3): 1.82 min, 530.1 [M+H] + .

[0215] Intermediate 57: Methyl (S)-3-(2'-(but-3-en-1-yloxy)-6'-methyl-[1,1'-biphenyl]-3-yl)-3-((S)-2-(2-oxopyridin-1(2H)-yl)hex-5-enamido)propanoate To a solution of intermediate 56 (0.47 g, 0.89 mmol) and pyridin-2-ol (0.19 g, 1.95 mmol) in MeCN (1 mL) was added K2CO3 (0.37 g, 2.66 mmol) and the mixture was stirred at 95 °C for 1 h. Additional K2CO3 (0.37 g, 2.66 mmol) was added and the mixture was stirred at 95 °C for 2 h. The mixture was cooled, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by flash chromatography (24 g silica gel, eluted with 0-100% EtOAc in petroleum ether) to give the title compound (0.33 g). LCMS (Method 2): 2.28 min, 551.3 [M+Na] + .

[0216] Intermediate 58: Methyl 2-((10S,13S)-2 6 -Methyl-11-oxo-10-(2-oxopiperidin-1(2H)-yl)-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-6-en-13-yl)acetate Prepared in a manner similar to Intermediate 7. Intermediate 57 (0.33 g, 0.62 mmol) and Grubbs II (53 mg, 0.06 mmol) in DCE (31 mL) were used at 40 °C for 1 h and quenched with ethyl vinyl ether (0.06 mL, 0.62 mmol). Purification by flash chromatography (25 g silica gel, eluting with 0-100% EtOAc in petroleum ether) gave the title compound (0.10 g). LCMS (Method 4): 1.66 min, 501.2 [M+H] + .

[0217] Intermediate 59: Methyl 2-((10S,13S)-2 6 -Methyl-11-oxo-10-(2-oxopyridin-1(2H)-yl)-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetate Prepared in a manner similar to Intermediate 8. Intermediate 58 (0.10 g, 0.20 mmol) and 5% palladium on carbon (21 mg) in MeOH (5 mL) were used under a hydrogen atmosphere at room temperature for 2 hours to give the title compound (75 mg). LCMS (Method 3): 1.70 min, 503.2 [M+H] + .

[0218] Intermediate 60: Methyl (S)-3-(2'-(but-3-en-1-yloxy)-6'-methyl-[1,1'-biphenyl]-3-yl)-3-((S)-2-(2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)hex-5-enamido)propanoate Prepared in a manner similar to Intermediate 57. Intermediate 56 (0.20 g, 0.38 mmol), 4-(trifluoromethyl)pyridin-2-ol (0.14 g, 0.83 mmol), and K2CO3 (0.16 g, 1.13 mmol) in MeCN (1 mL) were used at 95 °C for 2 h. Purification by flash chromatography (24 g silica gel, eluting with 0-100% EtOAc in petroleum ether) gave the title compound (0.20 g). LCMS (Method 3): 1.94 min, 597.3 [M+H] + .

[0219] Intermediate 61: Methyl 2-((10S,13S)-2 6 -Methyl-11-oxo-10-(2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-6-en-13-yl)acetate Prepared in a manner similar to Intermediate 7. Intermediate 60 (0.20 g, 0.34 mmol) and Grubbs II (28 mg, 0.03 mmol) in DCE (17 mL) were used at 40° C. for 1 h. Purification by flash chromatography (24 g silica gel, eluting with 0-100% EtOAc in petroleum ether) gave the title compound (0.10 g). LCMS (Method 3): 1.84 min, 569.2 [M+H] + .

[0220] Intermediate 62: Methyl 2-((10S,13S)-2 6 -Methyl-11-oxo-10-(2-oxo-4-(trifluoromethyl)-pyridin-1(2H)-yl)-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetate Prepared in a manner similar to Intermediate 8. Intermediate 61 (0.10 g, 0.20 mmol) and 5% palladium on carbon (10 mg) in MeOH (5 mL) were used under a hydrogen atmosphere at room temperature for 1 h to give the title compound (0.10 g). LCMS (Method 3): 1.87 min, 571.2 [M+H] + .

[0221] Intermediate 63: Methyl (S)-3-(2'-(but-3-en-1-yloxy)-6'-methyl-[1,1'-biphenyl]-3-yl)-3-((R)-2-hydroxypent-4-enamido)propanoate Prepared in a manner similar to Intermediate 5. Intermediate 54 (0.10 g, 0.27 mmol), (2R)-2-hydroxypent-4-enoic acid (31 mg, 0.27 mmol, CAS 413622-10-3), DIPEA (0.14 mL, 0.80 mmol), HOBt (36 mg, 0.27 mmol) and EDCI (56 mg, 0.27 mmol) in MeCN (10 mL) were used at room temperature for 5 hours to give the title compound (0.11 g). LCMS (Method 3): 1.72 min, 438.2 [M+H] + .

[0222] Intermediate 64: Methyl (S)-3-(2'-(but-3-en-1-yloxy)-6'-methyl-[1,1'-biphenyl]-3-yl)-3-((R)-2-((methylsulfonyl)oxy)pent-4-enamido)propanoate Prepared in a manner similar to Intermediate 56. Intermediate 63 (0.11 g, 0.25 mmol), triethylamine (35 μL, 0.50 mmol), and methanesulfonyl chloride (29 μL, 0.38 mmol) in DCM (5 mL) were used at room temperature for 10 min. Purification by flash chromatography (12 g silica gel, eluting with 0-50% EtOAc in petroleum ether) gave the title compound (75 mg). LCMS (Method 3): 1.78 min, 516.2 [M+H] + .

[0223] Intermediate 65: Methyl (S)-3-(2'-(but-3-en-1-yloxy)-6'-methyl-[1,1'-biphenyl]-3-yl)-3-((S)-2-(2-oxopyridin-1(2H)-yl)pent-4-enamido)propanoate To a solution of pyridin-2-ol (17 mg, 0.18 mmol) in THF (3 mL) was added sodium hydride (60% dispersion in mineral oil, 7 mg, 0.18 mmol) at room temperature. After 5 min, Intermediate 64 (75 mg, 0.15 mmol) was added as a solution in THF (3 mL), and the mixture was stirred at reflux for 18 h. The mixture was cooled, diluted with EtOAc, washed with water, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by flash chromatography (12 g silica gel, eluted with 50-100% EtOAc in petroleum ether) to give the title compound (30 mg). LCMS (Method 3): 2.23 min, 515.2 [M+H] + .

[0224] Intermediate 66: Methyl 2-((9S,12S)-2 6 -Methyl-10-oxo-9-(2-oxopyridin-1(2H)-yl)-3-oxa-11-aza-1(1,3),2(1,2)-dibenzeneacyclododecaphan-6-en-12-yl)acetate Prepared in a manner similar to Intermediate 7. Intermediate 65 (45 mg, 0.09 mmol) and Grubbs II (7.4 mg, 8.7 μmol) in DCE (4.4 mL) were used at 40° C. for 2 h. Purification by flash chromatography (14 g XTYPE cartridge, eluted with 100% EtOAc) gave the title compound (5 mg). LCMS (Method 3): 1.50 min, 487.4 [M+H] + .

[0225] Intermediate 67: Methyl 2-((9S,12S)-2 6 -Methyl-10-oxo-9-(2-oxopiperidin-1-yl)-3-oxa-11-aza-1(1,3),2(1,2)-dibenzeneacyclododecaphan-12-yl)acetate Prepared in a manner similar to Intermediate 8. Intermediate 66 (5 mg, 0.01 mmol) and platinum oxide (1 mg, 4.4 μmol) in MeOH (5 mL) were used under a hydrogen atmosphere at room temperature for 2 hours to give the title compound (5 mg). LCMS (Method 3): 1.66 min, 493.3 [M+H]+ .

[0226] Intermediate 68: Methyl 2-((10R,13S)-10-hydroxy-2 6 -methyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-6-en-13-yl)acetate Prepared in a manner similar to Intermediate 7. Intermediate 55 (550 mg, 1.22 mmol) and Grubbs II (0.10 g, 0.12 mmol) in DCE (58 mL) were used at 40° C. for 4 h. Purification by flash chromatography (40 g silica gel, eluting with 50-100% EtOAc in petroleum ether) gave the title compound (0.32 g). LCMS (Method 3): 1.58 min, 424.3 [M+H] + .

[0227] Intermediate 69: Methyl 2-((10R,13S)-2 6 -Methyl-10-((methylsulfonyl)oxy)-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-6-en-13-yl)acetate To a solution of intermediate 68 (0.32 g, 0.55 mmol) and triethylamine (0.09 mL, 0.64 mmol) in DCM (5 mL) was added methanesulfonyl chloride (0.04 mL, 0.48 mmol), and the mixture was stirred at room temperature for 1 h. The mixture was concentrated under reduced pressure, and the crude product was purified by flash chromatography (40 g silica gel, eluted with 20-100% EtOAc in petroleum ether) to give the title compound (0.33 g). LCMS (Method 3): 1.68 min, 502.1 [M+H] + .

[0228] Intermediate 70: Methyl 2-((10S,13S)-10-azido-2 6 -methyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-6-en-13-yl)acetate To a solution of intermediate 69 (0.32 g, 0.47 mmol) in DMF (6.4 mL) was added sodium azide (34 mg, 0.52 mmol), and the mixture was stirred at 90° C. for 72 h. The mixture was diluted with EtOAc and water. The aqueous layer was extracted with EtOAc, and then the organics were washed with brine and concentrated under reduced pressure. The crude product was purified by flash chromatography (12 g silica gel, eluted with 20-50% EtOAc in petroleum ether) to give the title compound (0.12 g). LCMS (Method 4): 1.69 and 1.77 min, 449.1 [M+H] + .

[0229] Intermediate 71: Methyl 2-((10S,13S)-10-amino-2 6 -methyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetate Prepared in a manner similar to Intermediate 8. Intermediate 70 (0.12 g, 0.24 mmol) and 10% palladium on carbon (11 mg) in MeOH (8 mL) were used under a hydrogen atmosphere at room temperature for 2 hours to give the title compound (52 mg). LCMS (Method 4): 1.27 min, 425.2 [M+H] + .

[0230] Intermediate 72: 4-(((10S,13S)-13-(2-methoxy-2-oxoethyl)-2 6 -Methyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-10-yl)amino)butanoic acid To a solution of intermediate 71 (47 mg, 0.11 mmol) and succinic semialdehyde (83 mg, 0.12 mmol, CAS 629-29-5) in DCE (2 mL) and AcOH (7 μL, 0.12 mmol), STAB (26 mg, 0.12 mmol) was added, and the mixture was stirred at room temperature for 15 h. The mixture was diluted with water (2 mL) and extracted with 10% MeOH in DCM. The organic layer was dried over NaSO, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography (12 g silica gel, eluting with 50-100% EtOAc in petroleum ether, then 20% MeOH in DCM) to give the title compound (12 mg). LCMS (Method 4): 1.63 min, 511.2 [M+H] + .

[0231] Intermediate 73: Methyl (S)-3-(2'-(allyloxy)-6'-methyl-[1,1'-biphenyl]-3-yl)-3-((tert-butoxycarbonyl)amino)propanoate Prepared in a manner similar to Intermediate 6. Intermediate 3 (1.0 g, 2.59 mmol), KCO (0.39 g, 2.85 mmol) and allyl bromide (0.25 mL, 2.85 mmol) in MeCN (50 mL) was used at 50 °C for 16 h to give the title compound (1.1 g). LCMS (Method 4): 1.86 min, 448.1 [M+Na] + .

[0232] Intermediate 74: Methyl (S)-3-(2'-(allyloxy)-6'-methyl-[1,1'-biphenyl]-3-yl)-3-aminopropanoate hydrochloride A suspension of intermediate 73 (1.1 g, 2.58 mmol) in 4 M HCl in 1,4-dioxane (50 mL) was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure to give the title compound (0.93 g). LCMS (Method 3): 1.22 min, 326.1 [M+H] + .

[0233] Intermediate 75: Methyl (S)-3-(2'-(allyloxy)-6'-methyl-[1,1'-biphenyl]-3-yl)-3-((R)-2-hydroxypent-4-enamido)propanoate Prepared in a manner similar to Intermediate 5. Intermediate 74 (0.94 g, 2.87 mmol), (2R)-2-hydroxypent-4-enoic acid (0.33 g, 2.87 mmol, CAS 413622-10-3), DIPEA (1.50 mL, 8.62 mmol), HOBt (0.43 g, 3.16 mmol), and EDCI (0.61 g, 3.16 mmol) in MeCN (20 mL) were used at room temperature for 16 h. Purification by flash chromatography (24 g silica gel, eluting with 50-100% EtOAc in petroleum ether) gave the title compound (0.13 g). LCMS (Method 3): 1.63 min, 424.2 [M+H] + .

[0234] Intermediate 76: Methyl (S)-3-(2'-(allyloxy)-6'-methyl-[1,1'-biphenyl]-3-yl)-3-((R)-2-((methylsulfonyl)oxy)pent-4-enamido)propanoate Prepared in a manner similar to Intermediate 56. Intermediate 75 (0.50 g, 1.18 mmol), triethylamine (0.17 mL, 1.18 mmol), and methanesulfonyl chloride (0.09 mL, 1.18 mmol) in DCM (10 mL) were used at room temperature for 10 min. Purification by flash chromatography (24 g silica gel, eluting with 0-60% EtOAc in petroleum ether) gave the title compound (0.45 g). LCMS (Method 3): 1.62 min, 524.3 [M+Na] + .

[0235] Intermediate 77: Methyl (S)-3-(2'-(allyloxy)-6'-methyl-[1,1'-biphenyl]-3-yl)-3-((S)-2-(2-oxopyridin-1(2H)-yl)pent-4-enamido)propanoate Prepared in a manner similar to Intermediate 65. Intermediate 76 (0.45 g, 0.90 mmol), pyridin-2-ol (0.10 g, 1.08 mmol), and sodium hydride (60% dispersion in mineral oil, 43 mg, 1.08 mmol) in THF (10 mL) were used at 80 °C for 16 h. Purification by flash chromatography (12 g silica gel, eluting with 50-100% EtOAc in petroleum ether) gave the title compound (0.25 g). LCMS (Method 3): 1.71 min, 501.2 [M+H] + .

[0236] Intermediate 78: Methyl 2-((8S,11S)-2 6 -Methyl-9-oxo-8-(2-oxopyridin-1(2H)-yl)-3-oxa-10-aza-1(1,3),2(1,2)-dibenzeneacycloundecaphan-5-en-11-yl)acetate Prepared in a manner similar to Intermediate 7. Intermediate 77 (0.23 g, 0.45 mmol) and Grubbs II (38 mg, 0.05 mmol) in DCE (23 mL) were used at 40° C. for 2 h. Purification by flash chromatography (12 g silica gel, eluting with 50-100% EtOAc in petroleum ether) gave the title compound (0.20 g). LCMS (Method 3): 1.56 min, 473.2 [M+H] + .

[0237] Intermediate 79: Methyl 2-((8S,11S)-2 6 -Methyl-9-oxo-8-(2-oxopyridin-1(2H)-yl)-3-oxa-10-aza-1(1,3),2(1,2)-dibenzeneacycloundecaphan-11-yl)acetate Prepared in a manner similar to Intermediate 8. Intermediate 78 (0.20 g, 0.42 mmol) and 10% palladium on carbon (12 mg) in MeOH (5 mL) and THF (5 mL) were used under a hydrogen atmosphere at room temperature for 2 hours. Purification by flash chromatography (40 g silica gel, eluting with 50-100% EtOAc in petroleum ether) gave the title compound (0.10 g). LCMS (Method 3): 1.57 min, 475.2 [M+H] + .

[0238] Intermediate 80: Methyl (S)-3-((tert-butoxycarbonyl)amino)-3-(4'-fluoro-2'-hydroxy-6'-methyl-[1,1'-biphenyl]-3-yl)propanoate Prepared in a manner similar to Intermediate 3. Intermediate 2 (0.80 g, 1.68 mmol), 2-bromo-5-fluoro-3-methylphenol (0.41 g, 1.68 mmol, CAS 1807192-21-7), NaCO (0.53 g, 5.03 mmol), and Pd(PPh) (0.09 g, 0.08 mmol) in toluene (14.8 mL), ethanol (3.1 mL), and water (3.1 mL) were used at 85 °C for 8 h. Purification by flash chromatography (40 g silica gel, eluting with 0-20% EtOAc in petroleum ether) gave the title compound (0.42 g). LCMS (Method 3): 1.66 min, 426.1 [M+Na] + .

[0239] Intermediate 81: Methyl (S)-3-((tert-butoxycarbonyl)amino)-3-(4'-fluoro-2'-methyl-6'-(pent-4-en-1-yloxy)-[1,1'-biphenyl]-3-yl)propanoate Prepared in a manner similar to Intermediate 6. Intermediate 80 (0.42 g, 1.04 mmol), K2CO3 (0.22 g, 1.56 mmol), and 5-bromopent-1-ene (0.19 mL, 1.56 mmol) in MeCN (20 mL) were used at reflux for 16 h. Purification by flash chromatography (12 g silica gel, eluting with 0-60% EtOAc in petroleum ether) gave the title compound (0.35 g). LCMS (Method 6): 1.93 min, 494.4 [M+Na] + .

[0240] Intermediate 82: Methyl (S)-3-amino-3-(4'-fluoro-2'-methyl-6'-(pent-4-en-1-yloxy)-[1,1'-biphenyl]-3-yl)propanoate hydrochloride A suspension of intermediate 81 (0.35 g, 0.74 mmol) in 4 M HCl in 1,4-dioxane (5 mL) was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure to give the title compound (0.30 g). LCMS (Method 3): 1.54 min, 372.2 [M+H] + .

[0241] Intermediate 83: Methyl (S)-3-(4'-fluoro-2'-methyl-6'-(pent-4-en-1-yloxy)-[1,1'-biphenyl]-3-yl)-3-((R)-2-hydroxypent-4-enamido)propanoate Prepared in a manner similar to Intermediate 5. Intermediate 82 (0.32 g, 0.80 mmol), (2R)-2-hydroxypent-4-enoic acid (0.14 g, 1.19 mmol, CAS 413622-10-3), DIPEA (0.42 mL, 2.38 mmol), HOBt (0.12 g, 0.88 mmol) and EDCI (0.12 g, 1.03 mmol) in MeCN (20 mL) were used at room temperature for 16 hours to give the title compound (0.13 g). LCMS (Method 7): 2.29 min, 470.2 [M+H] + .

[0242] Intermediate 84: Methyl (S)-3-(4'-fluoro-2'-methyl-6'-(pent-4-en-1-yloxy)-[1,1'-biphenyl]-3-yl)-3-((R)-2-((methylsulfonyl)oxy)pent-4-enamido)propanoate Prepared in a manner similar to Intermediate 56. Intermediate 83 (0.35 g, 0.75 mmol), triethylamine (0.16 mL, 1.12 mmol), and methanesulfonyl chloride (0.09 mL, 1.12 mmol) in DCM (10 mL) were used at room temperature for 10 min. Purification by flash chromatography (24 g silica gel, eluting with 0-60% EtOAc in petroleum ether) gave the title compound (0.20 g). LCMS (Method 3): 1.86 min, 548.3 [M+H] + .

[0243] Intermediate 85: Methyl (S)-3-(4'-fluoro-2'-methyl-6'-(pent-4-en-1-yloxy)-[1,1'-biphenyl]-3-yl)-3-((S)-2-(2-oxopyridin-1(2H)-yl)pent-4-enamido)propanoate Prepared in a manner similar to Intermediate 65. Intermediate 84 (0.20 g, 0.37 mmol), pyridin-2-ol (42 mg, 0.44 mmol), and sodium hydride (60% dispersion in mineral oil, 17.5 mg, 0.44 mmol) in THF (10 mL) were used at 80 °C for 16 h. Purification by flash chromatography (12 g silica gel, eluting with 50-100% EtOAc in petroleum ether) gave the title compound (35 mg). LCMS (Method 3): 1.84 min, 547.2 [M+H] + .

[0244] Intermediate 86: Methyl 2-((10S,13S)-2 4 -Fluoro-2 6 -Methyl-11-oxo-10-(2-oxopyridin-1(2H)-yl)-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-7-en-13-yl)acetate Prepared in a manner similar to Intermediate 7. Intermediate 85 (35 mg, 0.06 mmol) and Grubbs II (5.4 mg, 6.4 μmol) in DCE (3.2 mL) were used at 40° C. for 0.5 h. Purification by flash chromatography (4 g silica gel, eluting with 50-100% EtOAc in petroleum ether) gave the title compound (20 mg). LCMS (Method 3): 1.71 min, 519.2 [M+H] + .

[0245] Intermediate 87: Methyl 2-((10S,13S)-2 4 -Fluoro-2 6 -Methyl-11-oxo-10-(2-oxopyridin-1(2H)-yl)-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetate Prepared in a manner similar to Intermediate 8. Intermediate 86 (20 mg, 0.04 mmol) and 10% palladium on carbon (0.4 mg) in MeOH (1 mL) and THF (1 mL) were used under a hydrogen atmosphere at room temperature for 8 hours to give the title compound (20 mg). LCMS (Method 3): 1.75 min, 521.3 [M+H] + .

[0246] Intermediate 88: methyl (S)-3-(2'-(but-3-en-1-yloxy)-6'-methyl-[1,1'-biphenyl]-3-yl)-3-((S)-2-(5-fluoro-2-oxopyridin-1(2H)-yl)hex-5-enamido)propanoate Prepared in a manner similar to Intermediate 65. Intermediate 56 (0.25 g, 0.47 mmol), 5-fluoropyridin-2-ol (64 mg, 0.57 mmol, CAS 51173-05-8), and sodium hydride (60% dispersion in mineral oil, 23 mg, 0.57 mmol) in THF (10 mL) were used at 80 °C for 16 h. Purification by flash chromatography (40 g silica gel, eluting with 50-100% EtOAc in petroleum ether) gave the title compound (25 mg). LCMS (Method 7): 2.51 min, 547.2 [M+H] + .

[0247] Intermediate 89: Methyl 2-((10S,13S)-10-(5-fluoro-2-oxopyridin-1(2H)-yl)-2 6 -methyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-6-en-13-yl)acetate Prepared in a manner similar to Intermediate 7. Intermediate 88 (25 mg, 0.05 mmol) and Grubbs II (7.8 mg, 9.1 μmol) in DCE (5 mL) were used at 40° C. for 2 h. Purification by flash chromatography (12 g silica gel, eluting with 30-100% EtOAc in petroleum ether) gave the title compound (14 mg). LCMS (Method 6): 1.61 min, 519.2 [M+H] + .

[0248] Intermediate 90: Methyl 2-((10S,13S)-10-(5-fluoro-2-oxopyridin-1(2H)-yl)-2 6 -methyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetate Prepared in a manner similar to Intermediate 8. Intermediate 89 (14 mg, 0.02 mmol) and 10% palladium on carbon (0.2 mg) in MeOH (1.5 mL) were used under a hydrogen atmosphere at room temperature for 24 hours to give the title compound (10 mg). LCMS (Method 3): 1.77 min, 521.3 [M+H] + .

[0249] Intermediate 91: Methyl 3-(5-bromopyridin-3-yl)-3-((tert-butoxycarbonyl)amino)-propanoate To a solution of 5-bromopyridine-3-carbaldehyde (20 g, 0.11 mol, CAS 113118-81-3) and malonic acid (11.2 g, 108 mmol) in ethanol (100 mL), ammonium acetate (8.29 g, 108 mmol) was added, and the mixture was stirred at 75 °C for 24 h. The mixture was cooled to room temperature and filtered, washing the solid with ice-cold ethanol, IPA, and petroleum ether. The solid was dissolved in 1 M HCl in methanol (400 mL) and stirred at 65 °C for 24 h. The mixture was concentrated under reduced pressure and then suspended in DCM (200 mL), followed by the addition of triethylamine (45 mL, 323 mmol) and Boc anhydride (23.5 g, 0.11 mol) and stirring at room temperature for 6 h. The mixture was washed with water (2 mL) and brine, dried over Na SO , filtered, and concentrated under reduced pressure. The crude product was purified by dry flash chromatography (silica gel, eluting with 5-35% EtOAc in petroleum ether) to give the title compound (14.7 g). LCMS (Method 4): 1.42 min, 359.1 [M+H] + .

[0250] Intermediate 92: Methyl 3-((tert-butoxycarbonyl)amino)-3-(5-(2-hydroxy-6-methylphenyl)pyridin-3-yl)propanoate A solution of intermediate 91 (4.0 g, 11.1 mmol) and bis(pinacolato)diboron (4.24 g, 16.7 mmol) in 1,4-dioxane (60 mL) was degassed with nitrogen. To this solution was then added potassium acetate (2.73 g, 27.8 mmol), followed by Pd(dppf)Cl (0.41 g, 0.56 mmol), and the reaction mixture was stirred at 100 °C for 1 hour. The mixture was cooled, and then a degassed solution of NaCO (2.36 g, 22.3 mmol) in water (40 mL) was added, followed by 2-bromo-3-methylphenol (3.12 g, 16.7 mmol), and the mixture was stirred at 95 °C for 2 hours. The mixture was cooled and filtered through Celite®, washing with EtOAc and water. The organic layer was washed with brine, dried over MgSO, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography (120 g silica gel, eluting with 0-100% EtOAc in petroleum ether) to give the title compound (2.6 g). LCMS (Method 6): 1.16 min, 387.4 [M+H] + .

[0251] Intermediate 93: methyl 3-((tert-butoxycarbonyl)amino)-3-(5-(2-methyl-6-(pent-4-en-1-yloxy)phenyl)pyridin-3-yl)propanoate Prepared in a manner similar to Intermediate 6. Intermediate 92 (2.60 g, 6.32 mmol), K2CO3 (1.75 g, 12.7 mmol), and 5-bromopent-1-ene (0.90 mL, 7.59 mmol) in MeCN (35 mL) were used at reflux for 6 h. Purification by flash chromatography (80 g silica gel, eluting with 0-60% EtOAc in petroleum ether) gave the title compound (2.00 g). LCMS (Method 3): 1.77 min, 455.2 [M+H] + .

[0252] Intermediate 94: Methyl 3-amino-3-(5-(2-methyl-6-(pent-4-en-1-yloxy)phenyl)pyridin-3-yl)propanoate hydrochloride A suspension of intermediate 93 (2.00 g, 4.40 mmol) in 4 M HCl in 1,4-dioxane (62 mL) was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure to give the title compound (1.90 g). LCMS (Method 6): 1.42 min, 355.4 [M+H] + .

[0253] Intermediate 95: Methyl (S)-3-((R)-2-hydroxypent-4-enamido)-3-(5-(2-methyl-6-(pent-4-en-1-yloxy)phenyl)pyridin-3-yl)propanoate Prepared in a manner similar to Intermediate 5. Intermediate 94 (2.0 g, 5.12 mmol), (2R)-2-hydroxypent-4-enoic acid (0.59 g, 5.12 mmol, CAS 413622-10-3), DIPEA (0.89 mL, 5.12 mmol), HOBt (0.69 g, 5.12 mmol), and EDCI (1.08 g, 5.63 mmol) in MeCN (20 mL) were used at room temperature for 2 h. Purification by flash chromatography (80 g silica gel, eluting with 50-100% EtOAc in petroleum ether) afforded the title compound (0.48 g) as the second diastereomer eluted. LCMS (Method 4): 1.55 min, 453.2 [M+H] + .

[0254] Intermediate 96: Methyl (S)-3-(5-(2-methyl-6-(pent-4-en-1-yloxy)phenyl)pyridin-3-yl)-3-((R)-2-((methylsulfonyl)oxy)penta-4-enamido)propanoate Prepared in a manner similar to Intermediate 56. Intermediate 95 (0.48 g, 1.06 mmol), triethylamine (0.30 mL, 2.12 mmol), and methanesulfonyl chloride (0.12 mL, 1.59 mmol) in DCM (20 mL) were used at room temperature for 10 min. Purification by flash chromatography (40 g silica gel, eluting with 0-50% EtOAc in petroleum ether) gave the title compound (0.38 g). LCMS (Method 3): 1.59 min, 531.2 [M+H] + .

[0255] Intermediate 97: Methyl (S)-3-(5-(2-methyl-6-(pent-4-en-1-yloxy)phenyl)pyridin-3-yl)-3-((S)-2-(2-oxopyridin-1(2H)-yl)pent-4-enamido)propanoate Prepared in a manner similar to Intermediate 65. Intermediate 96 (0.38 g, 0.71 mmol), pyridin-2-ol (81 mg, 0.85 mmol), and sodium hydride (60% dispersion in mineral oil, 34 mg, 0.85 mmol) in THF (20 mL) were used at 80° C. for 16 h. Purification by flash chromatography (12 g silica gel, eluting with 50-100% EtOAc in petroleum ether) gave the title compound (0.12 g). LCMS (Method 3): 1.54 min, 530.3 [M+H] + .

[0256] Intermediate 98: Methyl 2-((10S,13S)-2 6 -Methyl-11-oxo-10-(2-oxopyridin-1(2H)-yl)-3-oxa-12-aza-1(3,5)-pyridin-2(1,2)-benzeneacyclotridecaphan-7-en-13-yl)acetate Prepared in a manner similar to Intermediate 7. Intermediate 97 (0.12 g, 0.23 mmol) and Grubbs II (38 mg, 0.05 mmol) in DCE (9 mL) were used at 40° C. for 24 h. Additional Grubbs II (19 mg, 0.02 mmol) was added and heated at 40° C. for 15 h. Purification by flash chromatography (40 g silica gel, eluting with 30-100% EtOAc in petroleum ether) gave the title compound (60 mg). LCMS (Method 3): 1.35 min, 502.2 [M+H] + .

[0257] Intermediate 99: Methyl 2-((10S,13S)-2 6 -Methyl-11-oxo-10-(2-oxopyridin-1(2H)-yl)-3-oxa-12-aza-1(3,5)-pyridin-2(1,2)-benzeneacyclotridecaphan-13-yl)acetate Prepared in a manner similar to Intermediate 8. Intermediate 98 (43 mg, 0.09 mmol) and platinum oxide (1.9 mg) in MeOH (1.5 mL) were used under a hydrogen atmosphere at room temperature for 3.5 hours to give the title compound (35 mg). LCMS (Method 3): 1.40 min, 504.2 [M+H] + Note that the -lactam (508.3 by LCMS) was also contaminated.

[0258] Intermediate 100:2-((10S,13S)-2 6 -Methyl-11-oxo-10-(2-oxopyridin-1(2H)-yl)-3-oxa-12-aza-1(3,5)-pyridin-2(1,2)-benzeneacyclotridecaphan-13-yl)acetic acid A mixture of intermediate 99 (53 mg, 0.10 mmol) was dissolved in MeOH (2 mL), THF (1 mL), and water (1 mL). Lithium hydroxide (2.5 mg, 0.10 mmol) was then added, and the solution was stirred at room temperature for 4 hours. The solution was adjusted to pH 4 with 2 M aqueous HCl, and the mixture was then concentrated under reduced pressure. The crude product was purified by flash chromatography (32 g C18, eluted with 0-60% MeCN in 1% aqueous formic acid) to give the title compound (12 mg) contaminated with the lactam. LCMS (Method 3): 1.21 min, 490.1 [M+H] + ;1.23 minutes, 494.2 [M+H] + Lactam.

[0259] Intermediate 101: 5-(4-fluoro-2-hydroxy-6-methylphenyl)nicotinaldehyde Prepared in a manner similar to Intermediate 3 using 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-3-carbaldehyde (1.70 g, 7.29 mmol, CAS 848093-29-8), 2-bromo-5-fluoro-3-methylphenol (1.76 g, 7.29 mmol, CAS 1807192-21-7), NaCO (2.32 g, 21.9 mmol), and Pd(PPh) (0.38 g, 0.33 mmol) in toluene (52 mL), ethanol (13 mL), and water (13 mL) at 85 °C for 8 h. Purification by dry flash chromatography (silica gel, eluting with 50% EtOAc in petroleum ether) gave the title compound (1.37 g). LCMS (Method 3): 1.25 min, 232.0 [M+H] + .

[0260] Intermediate 102: (R,E)-N-((5-(4-fluoro-2-hydroxy-6-methylphenyl)pyridin-3-yl)methylene)-2-methylpropane-2-sulfinamide To a solution of intermediate 101 (1.37 g, 5.93 mmol) in THF (0.11 L) was added (R)-2-methylpropane-2-sulfinimide (0.79 g, 6.51 mmol, CAS 196929-78-9) and titanium ethoxide (1.38 g, 8.89 mmol), and the mixture was then stirred at 60 °C for 2 h. The mixture was diluted with water and extracted into EtOAc. The organic layer was dried over Na SO , filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography (12 g silica gel, eluted with 50-100% EtOAc in petroleum ether) to give the title compound (0.75 g). LCMS (Method 3): 1.48 min, 335.1 [M+H] + .

[0261] Intermediate 103: (R,E)-N-((5-(4-fluoro-2-methyl-6-(pent-4-en-1-yloxy)phenyl)pyridin-3-yl)methylene)-2-methylpropane-2-sulfinamide Prepared in a manner similar to Intermediate 6. Intermediate 102 (0.75 g, 2.24 mmol), K2CO3 (0.62 g, 4.49 mmol), and 5-bromopent-1-ene (0.53 mL, 4.49 mmol) in MeCN (22 mL) were used at reflux for 18 h. Additional K2CO3 (0.62 g, 4.49 mmol) and 5-bromopent-1-ene (0.53 mL, 4.49 mmol) were added and heating was continued for 5 h. Purification by flash chromatography (24 g silica gel, eluting with 0-50% EtOAc in petroleum ether) gave the title compound (0.85 g). LCMS (Method 3): 1.90 min, 403.1 [M+H] + .

[0262] Intermediate 104: Ethyl (S)-3-(((R)-tert-butylsulfinyl)amino)-3-(5-(4-fluoro-2-methyl-6-(pent-4-en-1-yloxy)phenyl)pyridin-3-yl)propanoate To a suspension of zinc (0.69 g, 10.6 mmol) in THF (15 mL) was added chlorotrimethylsilane (0.05 mL, 0.42 mmol) and stirred at 60° C. for 1 hour. The mixture was cooled to room temperature, then ethyl bromoacetate (0.59 mL, 5.30 mmol) was added, and the mixture was placed in a sonic bath at 40° C. for 15 minutes. The mixture was cooled at 0° C., then a solution of intermediate 103 (0.85 g, 2.11 mmol) in THF (15 mL) was added, and the mixture was stirred at room temperature for 1 hour. The mixture was diluted with water and extracted into EtOAc. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (0.80 g). LCMS (Method 3): 1.69 min, 491.1 [M+H] + .

[0263] Intermediate 105: Ethyl (S)-3-amino-3-(5-(4-fluoro-2-methyl-6-(pent-4-en-1-yloxy)phenyl)pyridin-3-yl)propanoate hydrochloride To a suspension of intermediate 104 (0.80 g, 1.63 mmol) in DCM (1.1 mL), 4 M HCl in 1,4-dioxane (2.45 mL) was added and stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure to give the title compound (0.63 g). LCMS (Method 3): 1.31 min, 387.1 [M+H] + .

[0264] Intermediate 106: Ethyl (S)-3-(5-(4-fluoro-2-methyl-6-(pent-4-en-1-yloxy)phenyl)pyridin-3-yl)-3-((R)-2-hydroxypent-4-enamido)propanoate Prepared in a manner similar to Intermediate 5. Intermediate 105 (0.69 g, 1.63 mmol), (2R)-2-hydroxypent-4-enoic acid (0.28 g, 2.45 mmol, CAS 413622-10-3), DIPEA (0.85 mL, 4.89 mmol), HOBt (0.29 g, 2.12 mmol) and EDCI (0.34 g, 1.79 mmol) in MeCN (20 mL) at room temperature for 4 h to give the title compound (0.55 g) as the second diastereomer eluting. LCMS (Method 3): 1.57 min, 485.2 [M+H] + .

[0265] Intermediate 107: Ethyl (S)-3-(5-(4-fluoro-2-methyl-6-(pent-4-en-1-yloxy)phenyl)pyridin-3-yl)-3-((R)-2-((methylsulfonyl)oxy)penta-4-enamido)propanoate Prepared in a manner similar to Intermediate 56. Intermediate 106 (0.55 g, 1.14 mmol), triethylamine (0.32 mL, 2.27 mmol), and methanesulfonyl chloride (0.13 mL, 1.48 mmol) in DCM (10 mL) were used at room temperature for 30 min. Purification by flash chromatography (24 g silica gel, eluting with 0-10% MeOH in DCM) gave the title compound (0.52 g). LCMS (Method 6): 1.57 min, 563.5 [M+H] + .

[0266] Intermediate 108: ethyl (S)-3-(5-(4-fluoro-2-methyl-6-(pent-4-en-1-yloxy)phenyl)pyridin-3-yl)-3-((S)-2-(2-oxopyridin-1(2H)-yl)pent-4-enamido)propanoate Prepared in a manner similar to Intermediate 65. Intermediate 107 (0.55 g, 0.98 mmol), pyridin-2-ol (0.11 g, 0.85 mmol), and sodium hydride (60% dispersion in mineral oil, 47 mg, 1.17 mmol) in THF (20 mL) were used at 80° C. for 10 h. Purification by flash chromatography (24 g silica gel, eluting with 50-100% EtOAc in petroleum ether) gave the title compound (0.14 g). LCMS (Method 3): 1.62 min, 562.3 [M+H] + .

[0267] Intermediate 109: Ethyl 2-((10S,13S)-2 4 -Fluoro-2 6 -Methyl-11-oxo-10-(2-oxopyridin-1(2H)-yl)-3-oxa-12-aza-1(3,5)-pyridin-2(1,2)-benzeneacyclotridecaphan-7-en-13-yl)acetate Prepared in a manner similar to Intermediate 7. Intermediate 108 (0.13 g, 0.22 mmol) and Grubbs II (19 mg, 0.02 mmol) in DCE (9 mL) were used at 40° C. for 18 h. Additional Grubbs II (19 mg, 0.02 mmol) was added and heated at 40° C. for 24 h. Additional Grubbs II (19 mg, 0.02 mmol) was added and heated at 40° C. for 24 h. Additional Grubbs II (19 mg, 0.02 mmol) was added and heated at 40° C. for 24 h. Purification by flash chromatography (24 g silica gel, eluting with 50-100% EtOAc in petroleum ether) gave the title compound (80 mg). LCMS (Method 3): 1.43 min, 534.2 [M+H] + .

[0268] Intermediate 110: Ethyl 2-((10S,13S)-24 -Fluoro-2 6 -Methyl-11-oxo-10-(2-oxopyridin-1(2H)-yl)-3-oxa-12-aza-1(3,5)-pyridin-2(1,2)-benzeneacyclotridecaphan-13-yl)acetate Prepared in a manner similar to Intermediate 8. Intermediate 109 (80 mg, 0.15 mmol) and 10% palladium on carbon (10 mg) in MeOH (2 mL) were used under a hydrogen atmosphere at room temperature for 4 hours to give the title compound (10 mg). LCMS (Method 6): 1.40 min, 536.5 [M+H] + .

[0269] Intermediate 111: Methyl (S)-3-((tert-butoxycarbonyl)amino)-3-(2'-methyl-6'-(pent-4-en-1-yloxy)-[1,1'-biphenyl]-3-yl)propanoate Prepared in a manner similar to Intermediate 6. Intermediate 3 (3.06 g, 6.91 mmol), K2CO3 (1.91 g, 13.8 mmol), and 5-bromopent-1-ene (0.92 mL, 13.8 mmol) in MeCN (38 mL) were refluxed for 8 h. Additional K2CO3 (0.95 g, 6.91 mmol) and 5-bromopent-1-ene (0.82 mL, 6.91 mmol) were added, and heating was continued for 4 h. Additional K2CO3 (0.48 g, 3.45 mmol) and 5-bromopent-1-ene (0.41 mL, 3.45 mmol) were added, and heating was continued for 4 h. Purification by flash chromatography (120 g silica gel, eluting with 0-30% EtOAc in petroleum ether) gave the title compound (2.63 g). LCMS (Method 6): 1.92 min, 454.5 [M+H] + .

[0270] Intermediate 112: Methyl (S)-3-amino-3-(2'-methyl-6'-(pent-4-en-1-yloxy)-[1,1'-biphenyl]-3-yl)propanoate hydrochloride A suspension of intermediate 111 (2.79 g, 5.79 mmol) in 4 M HCl in 1,4-dioxane (60 mL) was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure to give the title compound (3.06 g). LCMS (Method 6): 1.20 min, 354.4 [M+H] + .

[0271] Intermediate 113: Methyl (S)-3-((R)-2-hydroxypent-4-enamido)-3-(2'-methyl-6'-(pent-4-en-1-yloxy)-[1,1'-biphenyl]-3-yl)propanoate Prepared in a manner similar to Intermediate 5. Intermediate 112 (2.15 g, 5.18 mmol), (2R)-2-hydroxypent-4-enoic acid (0.90 g, 7.77 mmol, CAS 413622-10-3), DIPEA (2.71 mL, 15.5 mmol), HOBt (0.77 g, 5.70 mmol) and EDCI (1.29 g, 6.74 mmol) in MeCN (0.10 L) was used at room temperature for 18 hours to give the title compound (3.98 g). LCMS (Method 6): 1.68 min, 452.4 [M+H] + .

[0272] Intermediate 114: Methyl (S)-3-(2'-methyl-6'-(pent-4-en-1-yloxy)-[1,1'-biphenyl]-3-yl)-3-((R)-2-((methylsulfonyl)oxy)pent-4-enamido)propanoate Prepared in a manner similar to Intermediate 56. Intermediate 113 (2.80 g, 6.20 mmol), triethylamine (1.72 mL, 12.4 mmol), and methanesulfonyl chloride (0.72 mL, 9.30 mmol) in DCM (20 mL) were stirred at room temperature for 2 h. Additional triethylamine (0.86 mL, 6.20 mmol) and methanesulfonyl chloride (0.48 mL, 6.20 mmol) were added and stirred at room temperature for 2 h. Additional triethylamine (0.86 mL, 6.20 mmol) and methanesulfonyl chloride (0.48 mL, 6.20 mmol) were added and stirred at room temperature for 18 h. Purification by flash chromatography (24 g silica gel, eluting with 0-10% MeOH in DCM) gave the title compound (1.76 g). LCMS (Method 3): 1.83 min, 530.2 [M+H] + .

[0273] Intermediate 115: Methyl (S)-3-((S)-2-(4-fluoro-2-oxopyridin-1(2H)-yl)pent-4-enamido)-3-(2'-methyl-6'-(pent-4-en-1-yloxy)-[1,1'-biphenyl]-3-yl)propanoate Prepared in a manner similar to Intermediate 65. Intermediate 114 (0.35 g, 0.66 mmol), 4-fluoro-1H-pyridin-2-one (92 mg, 0.79 mmol, CAS 96530-75-5), and sodium hydride (60% dispersion in mineral oil, 32 mg, 0.79 mmol) in THF (14 mL) were used at 80 °C for 18 h. Purification by flash chromatography (40 g silica gel, eluting with 30-100% EtOAc in petroleum ether) and reverse-phase chromatography (32 g C18, eluting with 30-90% MeCN in 1% aqueous formic acid) gave the title compound (16 mg). LCMS (Method 3): 1.76 min, 547.2 [M+H] + .

[0274] Intermediate 116: Methyl 2-((10S,13S)-10-(4-fluoro-2-oxopyridin-1(2H)-yl)-2 6-methyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-7-en-13-yl)acetate Prepared in a manner similar to Intermediate 7. Intermediate 115 (16 mg, 0.03 mmol) and Grubbs II (2.5 mg, 3 μmol) in DCE (3.3 mL) were used at room temperature for 5 h. Purification by flash chromatography (4 g silica gel, eluting with 0-100% EtOAc in petroleum ether) gave the title compound (10 mg). LCMS (Method 3): 1.59 min, 519.2 [M+H] + .

[0275] Intermediate 117: Methyl 2-((10S,13S)-10-(4-fluoro-2-oxopyridin-1(2H)-yl)-2 6 -methyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetate Prepared in a manner similar to Intermediate 8. Intermediate 116 (10 mg, 0.02 mmol) and 10% palladium on carbon (0.2 mg) in MeOH (1.5 mL) were used under a hydrogen atmosphere at room temperature for 5 hours to give the title compound (10 mg). LCMS (Method 3): 1.63 min, 521.3 [M+H] + .

[0276] Intermediate 118: Methyl (S)-3-(2'-methyl-6'-(pent-4-en-1-yloxy)-[1,1'-biphenyl]-3-yl)-3-((S)-2-(2-oxo-5-(trifluoromethyl)pyridin-1(2H)-yl)pent-4-enamido)propanoate Prepared in a manner similar to Intermediate 65. Intermediate 114 (0.20 g, 0.38 mmol), 5-(trifluoromethyl)-1H-pyridin-2-one (74 mg, 0.45 mmol, CAS 33252-63-0), and K2CO3 (52 mg, 0.38 mmol) in THF (20 mL) were used at 80 °C for 2 h. Additional K2CO3 (52 mg, 0.38 mmol) was added and stirred at 80 °C for 2 h, followed by additional K2CO3 (52 mg, 0.38 mmol) and stirring at 80 °C for 12 h. Purification by flash chromatography (40 g silica gel, eluting with 15-100% EtOAc in petroleum ether) gave the title compound (0.15 g). LCMS (Method 3): 1.84 min, 597.3 [M+H] + .

[0277] Intermediate 119: Methyl 2-((10S,13S)-2 6 -Methyl-11-oxo-10-(2-oxo-5-(trifluoromethyl)-pyridin-1(2H)-yl)-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-7-en-13-yl)acetate Prepared in a manner similar to Intermediate 7. Intermediate 118 (0.15 g, 0.23 mmol) and Grubbs II (19 mg, 0.03 mmol) in DCE (26 mL) were used at room temperature for 4 h. Purification by flash chromatography (25 g silica gel, eluting with 0-100% EtOAc in petroleum ether) gave the title compound (90 mg). LCMS (Method 3): 1.73 min, 569.3 [M+H] + .

[0278] Intermediate 120: Methyl 2-((10S,13S)-2 6 -Methyl-11-oxo-10-(2-oxo-5-(trifluoromethyl)-pyridin-1(2H)-yl)-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetate Prepared in a manner similar to Intermediate 8. Intermediate 119 (90 mg, 0.15 mmol) and 10% palladium on carbon (1.6 mg) in MeOH (12 mL) were used under a hydrogen atmosphere at room temperature for 5 hours to give the title compound (82 mg). LCMS (Method 3): 1.78 min, 571.2 [M+H] + .

[0279] Intermediate 121: (2-(benzyloxy)-6-methylphenyl)boronic acid A mixture of magnesium (0.53 g, 21.7 mmol) and iodine (0.11 g, 0.45 mmol) was heated at 30°C under nitrogen. To this was added a few drops of 1-(benzyloxy)-2-bromo-3-methylbenzene (5.0 g, 18.0 mmol, CAS 1381944-69-9) in THF (10 mL), and the mixture was heated to 47°C. The remainder of the solution was then added over 5 minutes. Additional THF (4 mL) was added, and the mixture was stirred at 47°C for 2 hours until most of the magnesium was consumed. The mixture was cooled to room temperature. This solution was added dropwise to a solution of trimethyl borate (3.75 g, 4.02 mmol) in THF (20 mL) at -30°C over 5 minutes. The mixture was stirred at -30°C for 2 hours. The pH of the mixture was adjusted to 4 with 2 M aqueous HCl, and the mixture was stirred at room temperature for 30 minutes. The mixture was extracted with DCM, and the organics were then washed with water, brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was recrystallized from diethyl ether / petroleum ether, filtered, and dried under vacuum to give the title compound (0.88 g). LCMS (Method 7): 1.64 min, 243.0 [M+H] + Additional product (0.45 g) was isolated from the filtrate and then purified by flash chromatography (80 g silica gel, eluting with 20% EtOAc in petroleum ether).

[0280] Intermediate 122: (R,E)-N-(5-bromo-2-fluoro-3-methylbenzylidene)-2-methylpropane-2-sulfinamide Prepared in a manner similar to Intermediate 102. 5-Bromo-2-fluoro-3-methylbenzaldehyde (1.50 g, 6.91 mmol, CAS 903875-64-9), (R)-2-methylpropane-2-sulfinimide (0.92 g, 7.60 mmol, CAS 196929-78-9) and titanium ethoxide (2.36 g, 10.4 mmol) in THF (25 mL) at 40 °C for 2.5 h gave the title compound (90 mg). LCMS (Method 7): 2.29 min, 322.0 [M+H] + .

[0281] Intermediate 123: Ethyl (S)-3-(5-bromo-2-fluoro-3-methylphenyl)-3-(((R)-tert-butylsulfinyl)amino)propanoate Prepared in a manner similar to Intermediate 104 using zinc (0.69 g, 10.6 mmol), chlorotrimethylsilane (0.15 mL, 1.22 mmol), and ethyl bromoacetate (1.69 mL, 15.2 mmol) in THF (25 mL) at 60 °C for 1 h, followed by Intermediate 122 (1.95 g, 6.09 mmol) in THF (25 mL) at room temperature for 16 h. Purification by flash chromatography (80 g silica gel, eluting with 1-10% MeOH in DCM) gave the title compound (1.55 g). LCMS (Method 8): 2.07 min, 410.3 [M+H] + .

[0282] Intermediate 124: Ethyl (S)-3-(2'-(benzyloxy)-4-fluoro-5,6'-dimethyl-[1,1'-biphenyl]-3-yl)-3-(((R)-tert-butylsulfinyl)amino)propanoate Prepared in a manner similar to Intermediate 3. Intermediate 121 (0.80 g, 3.14 mmol), Intermediate 123 (1.39 g, 3.14 mmol), K2CO3 (1.08 g, 7.85 mmol), and Pd(dppf)Cl2 (0.11 g, 0.15 mmol) in 1,4-dioxane (30 mL) and water (3 mL) were used at 85 °C for 2.5 h. Purification by flash chromatography (40 g silica gel, eluted with 50% EtOAc in petroleum ether) gave the title compound (1.41 g). LCMS (Method 7): 2.49 min, 526.2 [M+H] + .

[0283] Intermediate 125: Ethyl (S)-3-amino-3-(2'-(benzyloxy)-4-fluoro-5,6'-dimethyl-[1,1'-biphenyl]-3-yl)propanoate hydrochloride A suspension of intermediate 124 (1.13 g, 2.15 mmol) in ethanol (10 mL) and 4 M HCl in 1,4-dioxane (10.75 mL) was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure to give the title compound (0.98 g). LCMS (Method 8): 1.70 min, 422.4 [M+H] + .

[0284] Intermediate 126: Ethyl (S)-3-(2'-(benzyloxy)-4-fluoro-5,6'-dimethyl-[1,1'-biphenyl]-3-yl)-3-((tert-butoxycarbonyl)amino)propanoate To a stirred suspension of intermediate 125 (0.98 g, 1.17 mmol) and Boc anhydride (0.46 g, 2.09 mmol) in DCM (25 mL) was added DIPEA (0.3 mL, 3.48 mmol), and the mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with DCM, washed with 1 M aqueous HCl, water, brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography (40 g silica gel, eluted with 20-40% EtOAc in petroleum ether) to give the title compound (0.75 g). LCMS (Method 8): 2.56 min, 520.5 [MH] - .

[0285] Intermediate 127: Ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(4-fluoro-2'-hydroxy-5,6'-dimethyl-[1,1'-biphenyl]-3-yl)propanoate To a stirred solution of intermediate 126 (0.68 g, 1.29 mmol) in ethanol (25 mL) were added ammonium formate (1.63 g, 25.9 mmol) and 10% palladium on carbon (0.28 g, 0.26 mmol), and the mixture was stirred at reflux for 2 hours. Additional ammonium formate (1.63 g, 25.9 mmol) was added, and heating was continued for 1.5 hours. Additional 10% palladium on carbon (0.28 g, 0.26 mmol) was added, and heating was continued for 2 hours. The mixture was cooled to room temperature, diluted with EtOAc and water, and filtered through Celite®. The organic layer was separated, and the aqueous layer was extracted with EtOAc. The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (0.52 g). LCMS (Method 8): 2.19 min, 430.5 [MH] - .

[0286] Intermediate 128: Ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(4-fluoro-2',5-dimethyl-6'-(pent-4-en-1-yloxy)-[1,1'-biphenyl]-3-yl)propanoate Prepared in a manner similar to Intermediate 6. Intermediate 127 (0.56 g, 1.12 mmol), K2CO3 (0.19 g, 1.35 mmol), and 5-bromopent-1-ene (0.13 mL, 1.12 mmol) in MeCN (15 mL) were used at reflux for 8 h. Additional K2CO3 (0.19 g, 1.35 mmol) and 5-bromopent-1-ene (0.13 mL, 1.12 mmol) were added and heating was continued for 4 h. Additional K2CO3 (0.16 g, 1.12 mmol) was added and heating was continued for 5 h to give the title compound (0.53 g). LCMS (Method 8): 2.63 min, 522.5 [M+Na] + .

[0287] Intermediate 129: Ethyl (S)-3-amino-3-(4-fluoro-2',5-dimethyl-6'-(pent-4-en-1-yloxy)-[1,1'-biphenyl]-3-yl)propanoate hydrochloride To a suspension of intermediate 128 (0.53 g, 0.98 mmol) in 1,4-dioxane (5 mL), 4 M HCl in 1,4-dioxane (4.9 mL) was added and stirred at room temperature for 3 hours. The mixture was concentrated under reduced pressure to give the title compound (0.43 g). LCMS (Method 8): 1.71 min, 400.4 [M+H] + .

[0288] Intermediate 130: Ethyl (S)-3-(4-fluoro-2',5-dimethyl-6'-(pent-4-en-1-yloxy)-[1,1'-biphenyl]-3-yl)-3-((R)-2-hydroxypent-4-enamido)propanoate Prepared in a manner similar to Intermediate 5. Intermediate 129 (0.43 g, 0.98 mmol), (2R)-2-hydroxypent-4-enoic acid (0.13 g, 0.98 mmol, CAS 413622-10-3), DIPEA (0.51 mL, 2.93 mmol), HOBt (0.13 g, 0.98 mmol), and EDCI (0.21 g, 1.08 mmol) in MeCN (20 mL) was used at room temperature for 4 h, followed by additional (2R)-2-hydroxypent-4-enoic acid (0.13 g, 0.98 mmol, CAS 413622-10-3) and EDCI (0.19 g, 0.98 mmol) and stirred at room temperature for 3 h. Purification by flash chromatography (24 g silica gel, eluting with 25-50% EtOAc in petroleum ether) gave the title compound (0.27 g). LCMS (Method 6): 1.83 min, 498.5 [M+H] + .

[0289] Intermediate 131: Ethyl (S)-3-(4-fluoro-2',5-dimethyl-6'-(pent-4-en-1-yloxy)-[1,1'-biphenyl]-3-yl)-3-((R)-2-((methylsulfonyl)oxy)pent-4-enamido)propanoate Prepared in a manner similar to Intermediate 56. Intermediate 130 (0.27 g, 0.54 mmol), triethylamine (0.15 mL, 1.08 mmol) and methanesulfonyl chloride (0.06 mL, 0.81 mmol) in DCM (5.4 mL) were used at room temperature for 0.5 h to give the title compound (0.31 g). LCMS (Method 3): 1.84 min, 576.3 [M+H] + .

[0290] Intermediate 132: Ethyl (S)-3-(4-fluoro-2',5-dimethyl-6'-(pent-4-en-1-yloxy)-[1,1'-biphenyl]-3-yl)-3-((S)-2-(2-oxopyridin-1(2H)-yl)pent-4-enamido)propanoate Prepared in a manner similar to Intermediate 65. Intermediate 131 (0.31 g, 0.54 mmol), pyridin-2-ol (0.11 g, 1.18 mmol, CAS 142-08-5), and K2CO3 (0.17 g, 1.19 mmol) in MeCN (5.4 mL) were used at 85 °C for 1 h. Additional K2CO3 (0.17 g, 1.19 mmol) was added and stirred at 95 °C for 9 h. Purification by flash chromatography (12 g silica gel, eluting with 0-100% EtOAc in petroleum ether) gave the title compound (0.14 g). LCMS (Method 3): 1.82 min, 575.3 [M+H] + .

[0291] Intermediate 133: Ethyl 2-((10S,13S)-1 4 -Fluoro-1 5 ,2 6 -Dimethyl-11-oxo-10-(2-oxopyridin-1(2H)-yl)-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-7-en-13-yl)acetate Prepared in a manner similar to Intermediate 7. Intermediate 132 (0.14 g, 0.24 mmol) and Grubbs II (20.7 mg, 0.02 mmol) in DCE (0.11 L) were used at 40° C. for 4 h. Purification by flash chromatography (24 g silica gel, eluting with 50-80% EtOAc in petroleum ether) gave the title compound (0.10 g). LCMS (Method 8): 2.22 min, 547.5 [M+H] + .

[0292] Intermediate 134: Ethyl 2-((10S,13S)-1 4 -Fluoro-1 5 ,2 6 -Dimethyl-11-oxo-10-(2-oxopyridin-1(2H)-yl)-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetate Prepared in a manner similar to Intermediate 8. Intermediate 133 (0.10 g, 0.18 mmol) and 10% palladium on carbon (19.5 mg) in MeOH (4 mL) were used under a hydrogen atmosphere at room temperature for 0.5 h to give the title compound (97 mg). LCMS (Method 9): 4.65 min, 549.6 [M+H] + .

[0293] Intermediate 135: 5-(2-methoxyvinyl)pyridin-2(1H)-one To a stirred solution of (methoxymethyl)triphenylphosphonium chloride (10.4 g, 30.5 mmol, CAS 4009-98-7) in 1,4-dioxane (49.5 mL), potassium tert-butoxide (1 M in THF, 50.8 mL, 50.8 mmol) was added dropwise, and the mixture was stirred at room temperature for 15 minutes. 6-Oxo-1H-pyridine-3-carbaldehyde (2.50 g, 20.3 mmol) was added as a solution in THF (16.5 mL), and the mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with water, and the crude product was extracted into EtOAc and then 10% MeOH in DCM. The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by reverse phase chromatography (32g C18, eluting with 0-50% MeCN in water (0.1% ammonia)) to give the title compound (0.93g). LCMS (Method 4): 0.81 and 0.86 min, 152.0 [M+H] + .

[0294] Intermediate 136: 5-(2,2-dihydroxyethyl)pyridin-2(1H)-one A suspension of Intermediate 135 (0.30 g, 1.97 mmol) in formic acid (5.22 mL, 138 mmol) was stirred for 2 hours at 70° C. The mixture was concentrated under reduced pressure to give the title compound (0.27 g). 1 H NMR (400 MHz;CD3OD) δ: 7.57 (dd, 1H), 7.28 (d, 1H), 6.49 (d, 1H), 4.59 (t, 1H), 2.71 - 2.59 (m, 2H).

[0295] Intermediate 137: 5-(2-(dimethylamino)ethyl)pyridin-2(1H)-one To a stirred solution of Intermediate 136 (0.27 g, 1.97 mmol), dimethylamine (2 M solution in MeOH, 1.48 mL, 2.96 mmol) in MeOH (4.5 mL), DCM (1.0 mL), and AcOH (0.14 mL) was added 4 Å molecular sieves, and the mixture was stirred at room temperature for 30 min. STAB (1.25 g, 5.91 mmol) was added, and the mixture was stirred at room temperature for 16 h. Additional dimethylamine (2 M solution in MeOH, 1.48 mL, 2.96 mmol) and STAB (1.25 g, 5.91 mmol) were added, and the mixture was stirred at room temperature for 6 h. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by catch-and-release chromatography (eluting with 5 g SCX, MeOH, followed by 1 M ammonia in MeOH) to give the title compound (0.24 g). LCMS (Method 4): 0.86 min, 167.0 [M+H] + .

[0296] Intermediate 138: methyl (S)-3-((S)-2-(5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)pent-4-enamido)-3-(2'-methyl-6'-(pent-4-en-1-yloxy)-[1,1'-biphenyl]-3-yl)propanoate Prepared in a manner similar to Intermediate 65. Intermediate 114 (0.25 g, 0.47 mmol), Intermediate 137 (0.09 g, 0.57 mmol), and K2CO3 (0.13 g, 0.94 mmol) in MeCN (12 mL) were used at 90 °C for 10 h. Additional K2CO3 (0.13 g, 0.94 mmol) was added and stirred at 90 °C for 40 h. Purification by flash chromatography (24 g silica gel, eluting with 5-10% MeOH in DCM with 0.5% ammonia in MeOH) gave the title compound (0.09 g). LCMS (Method 5): 2.10 min, 600.1 [M+H] + .

[0297] Intermediate 139: Methyl 2-((10S,13S)-10-(5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-2 6-methyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-7-en-13-yl)acetate Prepared in a manner similar to Intermediate 7. Intermediate 138 (89 mg, 0.15 mmol) and Grubbs II (12.6 mg, 14.8 μmol) in DCE (64 mL) were used at 40° C. for 4 h. Additional Grubbs II (12.6 mg, 14.8 μmol) was added and stirred at 40° C. for 2 h. Purification by flash chromatography (12 g silica gel, eluting with 5-10% MeOH in DCM with 0.1% ammonia in MeOH) gave the title compound (66 mg). LCMS (Method 5): 2.07 min, 570.5 [M H ] - .

[0298] Intermediate 140: Methyl 2-((10S,13S)-10-(5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-2 6 -methyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetate Prepared in a manner similar to Intermediate 8. Intermediate 139 (48 mg, 0.08 mmol) and 10% palladium on carbon (9 mg) in MeOH (8 mL) were used under a hydrogen atmosphere at room temperature for 15 minutes. Additional 10% palladium on carbon (9 mg) was added and stirred under hydrogen at room temperature for 20 minutes to give the title compound (67 mg). LCMS (Method 10): 4.33 min, 572.5 [MH] - .

[0299] Intermediate 141: Methyl (S)-3-(2'-(allyloxy)-6'-methyl-[1,1'-biphenyl]-3-yl)-3-((S)-2-(5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)penta-4-enamido)propanoate Prepared in a manner similar to Intermediate 65. Intermediate 76 (0.43 g, 0.86 mmol), Intermediate 137 (0.17 g, 1.03 mmol), and K2CO3 (0.24 g, 1.72 mmol) in MeCN (5 mL) were used at 90 °C for 16 h. Purification by flash chromatography (40 g silica gel, eluting with 0-20% MeOH in DCM) gave the title compound (0.14 g). LCMS (Method 11): 2.10 min, 572.1 [M+H] + .

[0300] Intermediate 142: Methyl 2-((8S,11S)-8-(5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-2 6 -methyl-9-oxo-3-oxa-10-aza-1(1,3),2(1,2)-dibenzeneacycloundecaphan-5-en-11-yl)acetate Prepared in a manner similar to Intermediate 7. Intermediate 141 (0.14 g, 0.24 mmol) and Grubbs II (20 mg, 24.5 μmol) in DCE (50 mL) were used at 40° C. for 96 h. Purification by flash chromatography (25 g silica gel, eluting with 0-10% MeOH in DCM) gave the title compound (0.14 g). LCMS (Method 5): 2.07 min, 544.3 [M+H] + .

[0301] Intermediate 143: Methyl 2-((8S,11S)-8-(5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-2 6 -methyl-9-oxo-3-oxa-10-aza-1(1,3),2(1,2)-dibenzeneacycloundecaphan-11-yl)acetate Prepared in a manner similar to Intermediate 8. Intermediate 142 (0.14 g, 0.18 mmol) and 10% palladium on carbon (19 mg) in MeOH (5 mL) were used under a hydrogen atmosphere at room temperature for 5 hours. Purification was performed by flash chromatography (12 g silica gel, eluting with 0-10% MeOH in DCM). This material was then treated with 10% palladium on carbon (12 mg) in MeOH (4 mL) under a hydrogen atmosphere at room temperature for 15 minutes to give the title compound (12 mg). LCMS (Method 5): 1.95 min, 546.3 [M+H] + .

[0302] Intermediate 144: Methyl (S)-3-(4'-bromo-2'-hydroxy-6'-methyl-[1,1'-biphenyl]-3-yl)-3-((tert-butoxycarbonyl)amino)propanoate Prepared in a manner similar to Intermediate 3. Intermediate 2 (0.40 g, 0.99 mmol), 5-bromo-2-iodo-3-methylphenol (0.31 g, 0.99 mmol, CAS 2091225-92-0), NaCO (0.26 g, 2.48 mmol), and Pd(dppf)Cl (81 mg, 0.10 mmol) in 1,4-dioxane (9.3 mL) and water (3.1 mL) were used at 55 °C for 2.5 h. Purification by flash chromatography (12 g silica gel, eluting with 0-35% EtOAc in petroleum ether) gave the title compound (0.38 g). LCMS (Method 6): 1.66 min, 486.2 [M+Na] + .

[0303] Intermediate 145: methyl (S)-3-(4'-bromo-2'-methyl-6'-(pent-4-en-1-yloxy)-[1,1'-biphenyl]-3-yl)-3-((tert-butoxycarbonyl)amino)propanoate Prepared in a manner similar to Intermediate 6. Intermediate 144 (0.32 g, 0.69 mmol), K2CO3 (0.12 g, 0.90 mmol) and 5-bromopent-1-ene (0.10 mL, 0.83 mmol) in MeCN (36 mL) were used at reflux for 18 h to give the title compound (0.34 g). LCMS (Method 6): 2.03 min, 556.2 [M+Na] + .

[0304] Intermediate 146: Methyl (S)-3-amino-3-(4'-bromo-2'-methyl-6'-(pent-4-en-1-yloxy)-[1,1'-biphenyl]-3-yl)propanoate hydrochloride A suspension of intermediate 145 (0.29 g, 0.54 mmol) in 4 M HCl in 1,4-dioxane (4.1 mL) was stirred at room temperature for 3 hours. The mixture was concentrated under reduced pressure to give the title compound (0.43 g). LCMS (Method 12): 1.86 min, 456.1 [M+Na] + .

[0305] Intermediate 147: Methyl (S)-3-(4'-bromo-2'-methyl-6'-(pent-4-en-1-yloxy)-[1,1'-biphenyl]-3-yl)-3-((R)-2-hydroxypent-4-enamido)propanoate Prepared in a manner similar to Intermediate 5. Intermediate 146 (0.66 g, 1.40 mmol), (2R)-2-hydroxypent-4-enoic acid (0.16 g, 1.40 mmol, CAS 413622-10-3), DIPEA (0.73 mL, 4.20 mmol), HOBt (0.21 g, 1.40 mmol), and EDCI (0.32 g, 1.68 mmol) in DMF (12 mL) were used at room temperature for 18 h. Purification by flash chromatography (12 g silica gel, eluting with 15-55% EtOAc in petroleum ether) gave the title compound (0.33 g). 1H NMR (400 MHz, CDCl3) δ 7.46 (d, 1H), 7.29 (t, 1H), 7.18 (d, 1H), 7.05 - 6.98 (m, 2H), 6.97 (d, 1H), 6.85 (d, 1H), 5.76 - 5.51 (m, 2H), 5.40 (dt, 1H), 5.14 - 5.02 (m, 2H), 4.75 - 4.60 (m, 2H), 4.11 (dt, 1H), 3.76 (t, 2H), 3.53 (s, 3H), 2.88 (dd, 1H), 2.78 (dd, 1H), 2.63 - 2.52 (m, 2H), 2.34 (dt, 1H), 1.94 (s, 3H), 1.87 (q, 2H), 1.66 - 1.48 (m, 2H).

[0306] Intermediate 148: Methyl (S)-3-(4'-bromo-2'-methyl-6'-(pent-4-en-1-yloxy)-[1,1'-biphenyl]-3-yl)-3-((R)-2-((methylsulfonyl)oxy)pent-4-enamido)propanoate Prepared in a manner similar to Intermediate 56. Intermediate 147 (0.39 g, 0.74 mmol), triethylamine (0.21 mL, 1.47 mmol), and methanesulfonyl chloride (0.09 mL, 1.10 mmol) in DCM (6 mL) were used at room temperature for 18 h. Purification by flash chromatography (12 g silica gel, eluting with 15-55% EtOAc in petroleum ether) gave the title compound (0.45 g). LCMS (Method 4): 1.99 min, 606.1 [MH] - .

[0307] Intermediate 149: methyl (S)-3-(4'-bromo-2'-methyl-6'-(pent-4-en-1-yloxy)-[1,1'-biphenyl]-3-yl)-3-((S)-2-(2-oxopyridin-1(2H)-yl)pent-4-enamido)propanoate Prepared in a manner similar to Intermediate 65 using Intermediate 148 (0.45 g, 0.67 mmol), pyridin-2-ol (0.14 g, 1.48 mmol), and KCO (0.28 g, 2.02 mmol) in MeCN (10 mL) at 90° C. for 16 h. Purification by flash chromatography (12 g silica gel, eluting with 10-100% EtOAc in petroleum ether) gave the title compound (0.15 g). 1 H NMR (400 MHz, CDCl3) δ 7.69 (d, 1H), 7.47 (dd, 1H), 7.33 - 7.14 (m, 3H), 7.09 - 6.99 (m, 2H), 6.96 (d, 1H), 6.84 (d, 1H), 6.45 (d, 1H), 6.18 (td, 1H), 5.67 - 5.45 (m, 3H), 5.32 (q, 1H), 4.97 (dd, 1H), 4.92 - 4.77 (m, 3H), 3.76 (t, 2H), 3.41 (s, 3H), 2.75 - 2.62 (m, 3H), 2.52 (dt, 1H), 1.94 (s, 3H), 1.87 (q, 2H), 1.59 - 1.56 (m, 2H).

[0308] Intermediate 150: Methyl 2-((10S,13S)-2 4 -Bromo-2 6 -Methyl-11-oxo-10-(2-oxopyridin-1(2H)-yl)-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-7-en-13-yl)acetate Prepared in a manner similar to Intermediate 7. Intermediate 149 (0.17 g, 0.28 mmol) and Grubbs II (24 mg, 28.4 μmol) in DCE (30 mL) were used at 40° C. for 4 h. Purification by flash chromatography (25 g silica gel, eluting with 50-100% EtOAc in petroleum ether) afforded the title compound (90 mg). LCMS (Method 4): 1.84 min, 581.0 [M+H] + .

[0309] Intermediate 151: Methyl 2-((10S,13S)-2 4 -(3,6-dihydro-2H-pyran-4-yl)-2 6 -Methyl-11-oxo-10-(2-oxopyridin-1(2H)-yl)-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-7-en-13-yl)acetate A mixture of intermediate 150 (85 mg, 0.15 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (34 mg, 0.16 mmol, CAS 287944-16-5), and Na2CO3 (39 mg, 0.37 mmol) in 1,4-dioxane (4 mL) and water (2 mL) was degassed with nitrogen. To this was added Pd(dppf)Cl2 (5.4 mg, 0.05 mmol), and the reaction mixture was stirred at 80 °C for 16 hours. The mixture was concentrated under reduced pressure, then diluted with water and extracted into DCM. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (0.13 g). LCMS (Method 4): 1.68 min, 583.2 [M+H] + .

[0310] Intermediate 152:2-((10S,13S)-2 4 -(3,6-dihydro-2H-pyran-4-yl)-2 6 -Methyl-11-oxo-10-(2-oxopyridin-1(2H)-yl)-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-7-en-13-yl)acetic acid Intermediate 151 (0.13 g, 0.15 mmol) was dissolved in MeOH (6 mL), THF (10 mL) and water (6 mL), then lithium hydroxide (7.9 mg, 0.33 mmol) was added and the solution was stirred at room temperature for 2 h. Additional lithium hydroxide (7.9 mg, 0.33 mmol) was added and stirring was continued at room temperature for 3 h. The mixture was concentrated under reduced pressure, and the residue was acidified with 2 M aqueous HCl and extracted with DCM. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (70 mg). LCMS (Method 4): 1.12 min, 569.1 [M+H]+ .

[0311] Intermediate 153: Methyl 2-((10S,13S)-2 6 -methyl-11-oxo-10-(2-oxopyridin-1(2H)-yl)-2 4 -(Tetrahydro-2H-pyran-4-yl)-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetate Prepared in a manner similar to Intermediate 8. Intermediate 152 (70 mg, 0.12 mmol) and 10% palladium on carbon (13 mg) in MeOH (5 mL) were used under a hydrogen atmosphere at room temperature for 24 hours to give the title compound (63 mg). LCMS (Method 12): 1.60 min, 587.4 [M+H] + .

[0312] Intermediate 154: Benzyl (S)-3'-(1-((tert-butoxycarbonyl)amino)-3-methoxy-3-oxopropyl)-6-methyl-[1,1'-biphenyl]-2-carboxylate Prepared in a manner similar to Intermediate 3. Intermediate 2 (0.38 g, 0.94 mmol), benzyl 2-bromo-3-methylbenzoate (0.26 g, 0.86 mmol, CAS 291289-66-2), NaCO (0.18 g, 1.71 mmol), and Pd(dppf)Cl (63 mg, 0.09 mmol) in 1,4-dioxane (3 mL) and water (1.8 mL) were used at 85 °C for 16 h. Purification by flash chromatography (24 g silica gel, eluting with 5-35% EtOAc in petroleum ether) gave the title compound (0.25 g). LCMS (Method 4): 1.91 min, 404.1 [M-Boc+H] + .

[0313] Intermediate 155: (S)-3'-(1-((tert-butoxycarbonyl)amino)-3-methoxy-3-oxopropyl)-6-methyl-[1,1'-biphenyl]-2-carboxylic acid Prepared in a manner similar to Intermediate 8. Intermediate 154 (0.25 g, 0.49 mmol) and 10% palladium on carbon (52 mg) in THF (15 mL) were used under a hydrogen atmosphere at room temperature for 16 hours to give the title compound (0.19 g). LCMS (Method 3): 1.56 min, 314.0 [M-Boc+H] + .

[0314] Intermediate 156: Methyl (S)-3-(2'-(allylcarbamoyl)-6'-methyl-[1,1'-biphenyl]-3-yl)-3-((tert-butoxycarbonyl)amino)propanoate Prepared in a manner similar to Intermediate 5. Intermediate 155 (96 mg, 0.23 mmol), allylamine (17.5 μL, 0.23 mmol), DIPEA (81 μL, 0.47 mmol), HOBt (36 mg, 0.23 mmol) and EDCI (54 mg, 0.28 mmol) in DMF (2 mL) were used at room temperature for 16 h to give the title compound (0.33 g). LCMS (Method 3): 1.59 min, 353.1 [M-Boc+H] + .

[0315] Intermediate 157: Methyl (S)-3-(2'-(allylcarbamoyl)-6'-methyl-[1,1'-biphenyl]-3-yl)-3-aminopropanoate hydrochloride A suspension of intermediate 156 (83 mg, 0.18 mmol) in 4 M HCl in 1,4-dioxane (2 mL) was stirred at room temperature for 1.5 hours. The mixture was concentrated under reduced pressure to give the title compound (71 mg). LCMS (Method 3): 1.07 min, 353.1 [M+H] + .

[0316] Intermediate 158: Methyl (S)-3-(2'-(allylcarbamoyl)-6'-methyl-[1,1'-biphenyl]-3-yl)-3-((S)-2-((tert-butoxycarbonyl)amino)pent-4-enamido)propanoate Prepared in a manner similar to Intermediate 5. Intermediate 157 (71 mg, 0.18 mmol), N-Boc-L-allylglycine (39 mg, 0.18 mmol, CAS90600-20-7), DIPEA (64 μL, 0.37 mmol), HOBt (28 mg, 0.18 mmol) and EDCI (42 mg, 0.22 mmol) in DMF (2 mL) were used at room temperature for 18 h to give the title compound (77 mg). LCMS (Method 3): 1.58 min, 550.2 [M+H] + .

[0317] Intermediate 159: Methyl 2-((3S,6S)-6-((tert-butoxycarbonyl)amino)-1 6 -Methyl-5,12-dioxo-4,11-diaza-1(1,2),2(1,3)-dibenzeneacyclododecaphan-8-en-3-yl)acetate Prepared in a manner similar to Intermediate 7. Intermediate 158 (77 mg, 0.14 mmol) and Grubbs II (12 mg, 14 μmol) in DCE (5 mL) were used at 40° C. for 4 h. Purification by flash chromatography (12 g silica gel, eluting with 50-100% EtOAc in petroleum ether) gave the title compound (51 mg). LCMS (Method 3): 1.42 min, 522.1 [M+H] + .

[0318] Intermediate 160: Methyl 2-((3S,6S)-6-((tert-butoxycarbonyl)amino)-1 6 -Methyl-5,12-dioxo-4,11-diaza-1(1,2),2(1,3)-dibenzeneacyclododecaphan-3-yl)acetate Prepared in a manner similar to Intermediate 8. Intermediate 159 (55 mg, 0.11 mmol) and 10% palladium on carbon (11 mg) in MeOH (10 mL) were used under a hydrogen atmosphere at room temperature for 3 hours to give the title compound (47 mg). LCMS (Method 3): 1.40 min, 524.2 [M+H] + .

[0319] Intermediate 161: Methyl 2-((3S,6S)-6-amino-16 -Methyl-5,12-dioxo-4,11-diaza-1(1,2),2(1,3)-dibenzeneacyclododecaphan-3-yl)acetate hydrochloride A suspension of intermediate 160 (47 mg, 0.09 mmol) in 4 M HCl in 1,4-dioxane (2 mL) was stirred at room temperature for 1.5 hours. The mixture was concentrated under reduced pressure to give the title compound (41 mg). LCMS (Method 3): 1.05 min, 424.2 [M+H] + .

[0320] Intermediate 162: Methyl 2-((3S,6S)-6-acetamido-1 6 -Methyl-5,12-dioxo-4,11-diaza-1(1,2),2(1,3)-dibenzeneacyclododecaphan-3-yl)acetate Prepared in a manner similar to Intermediate 10. Intermediate 161 (41 mg, 0.09 mmol), triethylamine (27 μL, 0.20 mmol), acetyl chloride (7 μL, 0.10 mmol) in DCM (2 mL) was used at room temperature for 1 h. Purification by flash chromatography (12 g silica gel, eluting with 0-10% MeOH in DCM) gave the title compound (20 mg). LCMS (Method 3): 1.15 min, 466.2 [M+H] + .

[0321] Intermediate 163: Methyl (S)-3-(2'-(but-3-en-1-ylcarbamoyl)-6'-methyl-[1,1'-biphenyl]-3-yl)-3-((tert-butoxycarbonyl)amino)propanoate Prepared in a manner similar to Intermediate 5. Intermediate 155 (97 mg, 0.23 mmol), but-3-en-1-amine (21 μL, 0.23 mmol), DIPEA (81 μL, 0.47 mmol), HOBt (36 mg, 0.23 mmol), and EDCI (54 mg, 0.28 mmol) in DMF (2 mL) were used at room temperature for 16 h. Purification by flash chromatography (12 g silica gel, eluting with 50-100% EtOAc in petroleum ether) gave the title compound (83 mg). LCMS (Method 3): 1.63 min, 367.1 [M-Boc+H] + .

[0322] Intermediate 164: Methyl (S)-3-amino-3-(2'-(but-3-en-1-ylcarbamoyl)-6'-methyl-[1,1'-biphenyl]-3-yl)propanoate hydrochloride A suspension of intermediate 163 (83 mg, 0.18 mmol) in 4 M HCl in 1,4-dioxane (2 mL) was stirred at room temperature for 1.5 hours. The mixture was concentrated under reduced pressure to give the title compound (72 mg). LCMS (Method 3): 1.11 min, 367.1 [M+H] + .

[0323] Intermediate 165: methyl (S)-3-(2'-(but-3-en-1-ylcarbamoyl)-6'-methyl-[1,1'-biphenyl]-3-yl)-3-((S)-2-((tert-butoxycarbonyl)amino)pent-4-enamido)propanoate Prepared in a manner similar to Intermediate 5. Intermediate 164 (72 mg, 0.18 mmol), N-Boc-L-allylglycine (39 mg, 0.18 mmol, CAS90600-20-7), DIPEA (62 μL, 0.36 mmol), HOBt (27 mg, 0.18 mmol) and EDCI (41 mg, 0.21 mmol) in DMF (2 mL) were used at room temperature for 4 h to give the title compound (67 mg). LCMS (Method 3): 1.57 min, 564.2 [M+H] + .

[0324] Intermediate 166: Methyl 2-((3S,6S)-6-((tert-butoxycarbonyl)amino)-1 6 -Methyl-5,13-dioxo-4,12-diaza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-8-en-3-yl)acetate Prepared in a manner similar to Intermediate 7. Intermediate 165 (67 mg, 0.12 mmol) and Grubbs II (10 mg, 12 μmol) in DCE (4 mL) were used at 40° C. for 4 h. Additional Grubbs II (10 mg, 12 μmol) was added in DCE (2 mL) at 40° C. for 3 h. Purification by flash chromatography (12 g silica gel, eluting with 50-100% EtOAc in petroleum ether) gave the title compound (44 mg). LCMS (Method 4): 1.47 min, 536.2 [M+H] + .

[0325] Intermediate 167: Methyl 2-((3S,6S)-6-((tert-butoxycarbonyl)amino)-1 6 -Methyl-5,13-dioxo-4,12-diaza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetate Prepared in a manner similar to Intermediate 8. Intermediate 166 (44 mg, 0.08 mmol) and 10% palladium on carbon (8.7 mg) in MeOH (10 mL) were used under a hydrogen atmosphere at room temperature for 2 hours to give the title compound (36 mg). LCMS (Method 4): 1.53 min, 538.2 [M+H] +

[0326] Intermediate 168: Methyl 2-((3S,6S)-6-amino-1 6 -Methyl-5,13-dioxo-4,12-diaza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetate hydrochloride A suspension of intermediate 167 (36 mg, 0.07 mmol) in 4 M HCl in 1,4-dioxane (2 mL) was stirred at room temperature for 1.5 hours. The mixture was concentrated under reduced pressure to give the title compound (32 mg). LCMS (Method 4): 1.17 min, 438.2 [M+H]+ .

[0327] Intermediate 169: Methyl 2-((3S,6S)-6-acetamido-1 6 -Methyl-5,13-dioxo-4,12-diaza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetate Prepared in a manner similar to Intermediate 10. Intermediate 168 (32 mg, 0.07 mmol), triethylamine (21 μL, 0.15 mmol), acetyl chloride (5 μL, 0.07 mmol) in DCM (5 mL) was used at room temperature for 0.5 h. Purification by flash chromatography (12 g silica gel, eluting with 0-10% MeOH in DCM) gave the title compound (39 mg). LCMS (Method 4): 1.11 min, 480.2 [M+H] + .

[0328] Intermediate 170: methyl (S)-3-((tert-butoxycarbonyl)amino)-3-(2'-(hex-5-en-1-yloxy)-6'-methyl-[1,1'-biphenyl]-3-yl)propanoate Prepared in a manner similar to Intermediate 6. Intermediate 3 (0.20 g, 0.52 mmol), K2CO3 (0.18 g, 1.30 mmol), and 6-bromohex-1-ene (0.14 mL, 1.04 mmol) in MeCN (5 mL) were used at reflux for 18 h. Purification by flash chromatography (12 g silica gel, eluting with 0-50% EtOAc in petroleum ether) gave the title compound (0.14 g). LCMS (Method 4): 2.05 min, 368.2 [M-Boc+H] + .

[0329] Intermediate 171: Methyl (S)-3-amino-3-(2'-(hex-5-en-1-yloxy)-6'-methyl-[1,1'-biphenyl]-3-yl)propanoate hydrochloride A suspension of intermediate 170 (0.14 g, 0.31 mmol) in 4 M HCl in 1,4-dioxane (3 mL) was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure to give the title compound (0.13 g). LCMS (Method 4): 1.85 min, 368.2 [M+H] + .

[0330] Intermediate 172: Methyl (S)-3-((S)-2-((tert-butoxycarbonyl)amino)pent-4-enamido)-3-(2'-(hex-5-en-1-yloxy)-6'-methyl-[1,1'-biphenyl]-3-yl)propanoate Prepared in a manner similar to Intermediate 5. Intermediate 171 (0.13 g, 0.33 mmol), N-Boc-L-allylglycine (71 mg, 0.33 mmol, CAS90600-20-7), DIPEA (0.17 mL, 1.00 mmol), HOBt (51 mg, 0.33 mmol) and EDCI (76 mg, 0.40 mmol) in DMF (2 mL) were used at room temperature for 4 h to give the title compound (0.18 g). LCMS (Method 4): 2.02 min, 565.3 [M+H] + .

[0331] Intermediate 173: Methyl 2-((11S,14S,E)-11-((tert-butoxycarbonyl)amino)-2 6 -Methyl-12-oxo-3-oxa-13-aza-1(1,3),2(1,2)-dibenzeneacyclotetradecaphan-8-en-14-yl)acetate Prepared in a manner similar to Intermediate 7. Intermediate 172 (0.17 g, 0.30 mmol) and Grubbs II (30 mg, 0.12 mmol) in DCE (0.15 L) were used at 40° C. for 2.5 h. Purification by flash chromatography (12 g silica gel, eluting with 0-50% EtOAc in petroleum ether) gave the title compound (0.11 g). LCMS (Method 4): 1.91 min, 537.1 [M+H] + .

[0332] Intermediate 174: Methyl 2-((11S,14S,E)-11-amino-26 -Methyl-12-oxo-3-oxa-13-aza-1(1,3),2(1,2)-dibenzeneacyclotetradecaphan-8-en-14-yl)acetate hydrochloride A suspension of intermediate 173 (30 mg, 0.06 mmol) in 4 M HCl in 1,4-dioxane (3 mL) was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure to give the title compound (26 mg). LCMS (Method 4): 1.62 min, 437.1 [M+H] + .

[0333] Intermediate 175: Methyl 2-((11S,14S,E)-11-acetamido-2 6 -Methyl-12-oxo-3-oxa-13-aza-1(1,3),2(1,2)-dibenzeneacyclotetradecaphan-8-en-14-yl)acetate Prepared in a manner similar to Intermediate 10. Intermediate 174 (28 mg, 0.06 mmol), triethylamine (18 μL, 0.13 mmol), acetyl chloride (5 μL, 0.07 mmol) in DCM (3 mL) was used at room temperature for 1 h to give the title compound (28 mg). LCMS (Method 4): 1.65 min, 479.3 [M+H] + .

[0334] Intermediate 176: Methyl 2-((11S,14S)-11-((tert-butoxycarbonyl)amino)-2 6 -methyl-12-oxo-3-oxa-13-aza-1(1,3),2(1,2)-dibenzeneacyclotetradecaphan-14-yl)acetate Prepared in a manner similar to Intermediate 8. Intermediate 173 (80 mg, 0.15 mmol) and 10% palladium on carbon (16 mg) in MeOH (19 mL) were used under a hydrogen atmosphere at room temperature for 3 hours to give the title compound (77 mg). LCMS (Method 12): 1.82 min, 539.4 [M+H] + .

[0335] Intermediate 177: Methyl 2-((11S,14S)-11-amino-2 6-Methyl-12-oxo-3-oxa-13-aza-1(1,3),2(1,2)-dibenzeneacyclotetradecaphan-14-yl)acetate hydrochloride A suspension of intermediate 176 (77 mg, 0.14 mmol) in 4 M HCl in 1,4-dioxane (7.7 mL) was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure to give the title compound (77 mg). LCMS (Method 4): 1.66 min, 439.2 [M+H] + .

[0336] Intermediate 178: Methyl 2-((11S,14S)-11-acetamido-2 6 -methyl-12-oxo-3-oxa-13-aza-1(1,3),2(1,2)-dibenzeneacyclotetradecaphan-14-yl)acetate Prepared in a manner similar to Intermediate 10. Intermediate 177 (68 mg, 0.14 mmol), triethylamine (44 μL, 0.32 mmol), acetyl chloride (11 μL, 0.16 mmol) in DCM (5 mL) was used at room temperature for 1 h to give the title compound (69 mg). LCMS (Method 4): 1.69 min, 481.2 [M+H] + .

[0337] Intermediate 179: methyl 3-((tert-butoxycarbonyl)amino)-3-(5-(4-fluoro-2-hydroxy-6-methylphenyl)pyridin-3-yl)propanoate Prepared in a manner similar to Intermediate 92. Intermediate 91 (0.50 g, 1.39 mmol), bis(pinacolato)diboron (0.53 g, 2.09 mmol), potassium acetate (0.34 g, 3.48 mmol), and Pd(dppf)Cl (51 mg, 0.07 mmol) in 1,4-dioxane (6.5 mL) were used at 100 °C for 1 h, followed by the addition of NaCO (0.30 g, 2.78 mmol) and 2-bromo-5-fluoro-3-methylphenol (0.34 g, 1.67 mmol, CAS 1807192-21-7) in water (6.6 mL), followed by heating at 100 °C for 2 h. Purification by flash chromatography (12 g silica gel, eluting with 40-100% EtOAc in petroleum ether) gave the title compound (0.34 g). LCMS (Method 12): 1.26 min, 405.4 [M+H] + .

[0338] Intermediate 180: methyl 3-((tert-butoxycarbonyl)amino)-3-(5-(4-fluoro-2-methyl-6-(pent-4-en-1-yloxy)phenyl)pyridin-3-yl)propanoate Prepared in a manner similar to Intermediate 6. Intermediate 179 (0.34 g, 0.84 mmol), K2CO3 (0.29 g, 2.10 mmol), and 5-bromopent-1-ene (0.11 mL, 0.92 mmol) in MeCN (7 mL) were used at reflux for 3 h. Purification by flash chromatography (12 g silica gel, eluting with 0-50% EtOAc in petroleum ether) gave the title compound (0.14 g). LCMS (Method 4): 1.83 min, 473.3 [M+H] + .

[0339] Intermediate 181: Methyl 3-amino-3-(5-(4-fluoro-2-methyl-6-(pent-4-en-1-yloxy)phenyl)pyridin-3-yl)propanoate hydrochloride A suspension of intermediate 180 (0.18 g, 0.38 mmol) in 4 M HCl in 1,4-dioxane (1.7 mL) was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure to give the title compound (0.16 g). LCMS (Method 4): 1.57 min, 373.2 [M+H] + .

[0340] Intermediate 182: methyl 3-((S)-2-((tert-butoxycarbonyl)(methyl)amino)pent-4-enamido)-3-(5-(4-fluoro-2-methyl-6-(pent-4-en-1-yloxy)phenyl)pyridin-3-yl)propanoate Prepared in a manner similar to Intermediate 5. Intermediate 181 (0.16 g, 0.40 mmol), N-methyl-N-Boc-L-allylglycine (96 mg, 0.42 mmol, CAS 136092-76-7), DIPEA (0.20 mL, 1.14 mmol), HOBt (58 mg, 0.38 mmol), and EDCI (87 mg, 0.46 mmol) in DMF (3 mL) were used at room temperature for 3 h. Purification by flash chromatography (12 g silica gel, eluting with 0-70% EtOAc in petroleum ether) gave the title compound (0.14 g). LCMS (Method 4): 1.88 min, 584.3 [M+H] + .

[0341] Intermediate 183: Methyl 2-((10S)-10-((tert-butoxycarbonyl)(methyl)amino)-2 4 -Fluoro-2 6 -methyl-11-oxo-3-oxa-12-aza-1(3,5)-pyridin-2(1,2)-benzeneacyclotridecaphan-7-en-13-yl)acetate Prepared in a manner similar to Intermediate 7. Intermediate 182 (0.14 g, 0.25 mmol) and Grubbs II (25 mg, 0.03 mmol) in DCE (141 mL) were used at 40 °C for 48 h. Purification by flash chromatography (12 g silica gel, eluting with 0-7% MeOH in DCM) gave the title compound (64 mg). LCMS (Method 4): 1.78 min, 556.3 [M+H]+ .

[0342] Intermediate 184: Methyl 2-((10S)-10-((tert-butoxycarbonyl)(methyl)amino)-2 4 -Fluoro-2 6 -methyl-11-oxo-3-oxa-12-aza-1(3,5)-pyridin-2(1,2)-benzeneacyclotridecaphan-13-yl)acetate Prepared in a manner similar to Intermediate 8. Intermediate 183 (64 mg, 0.12 mmol) and 10% palladium on carbon (12 mg) in MeOH (12 mL) were used under a hydrogen atmosphere at room temperature for 1 h to give the title compound (54 mg). LCMS (Method 4): 1.83 and 1.85 min, 558.3 ​​[M+H] + .

[0343] Intermediate 185: Methyl 2-((10S)-2 4 -Fluoro-2 6 -Methyl-10-(methylamino)-11-oxo-3-oxa-12-aza-1(3,5)-pyridina-2(1,2)-benzeneacyclotridecaphan-13-yl)acetate hydrochloride A suspension of intermediate 184 (54 mg, 0.10 mmol) in 4 M HCl in 1,4-dioxane (2 mL) was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure to give the title compound (0.16 g). LCMS (Method 4): 1.48 and 1.56 min, 458.3 [M+H] + .

[0344] Intermediate 186: Methyl 2-((10S)-2 4 -Fluoro-2 6 -Methyl-10-(N-methylacetamido)-11-oxo-3-oxa-12-aza-1(3,5)-pyridina-2(1,2)-benzeneacyclotridecaphan-13-yl)acetate Prepared in a manner similar to Intermediate 10. Intermediate 185 (49 mg, 0.10 mmol), triethylamine (30 μL, 0.22 mmol), acetyl chloride (8 μL, 0.11 mmol) in DCM (1 mL) was used at room temperature for 2 h to give the title compound (49 mg). LCMS (Method 7): 1.77 min, 500.3 [M+H] + .

[0345] Intermediate 187: methyl (S)-3-((S)-2-(5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)pent-4-enamido)-3-(4'-fluoro-2'-methyl-6'-(pent-4-en-1-yloxy)-[1,1'-biphenyl]-3-yl)propanoate Prepared in a manner similar to Intermediate 65. Intermediate 84 (0.10 g, 0.18 mmol), Intermediate 137 (39 mg, 0.24 mmol), and K2CO3 (76 mg, 0.55 mmol) in MeCN (5 mL) were used at 90 °C for 2 h. Additional K2CO3 (76 mg, 0.55 mmol) was added and stirred at 90 °C for 16 h. Purification by flash chromatography (4 g silica gel, eluting with 5-10% MeOH in DCM with 0.5% ammonia in MeOH) gave the title compound (50 mg). LCMS (Method 14): 5.01 min, 618.3 [M+H] + .

[0346] Intermediate 188: Methyl 2-((10S,13S)-10-(5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-2 4 -Fluoro-2 6 -methyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-7-en-13-yl)acetate Prepared in a manner similar to Intermediate 7. Intermediate 187 (50 mg, 0.06 mmol) and Grubbs II (5.3 mg, 6.2 μmol) in DCE (30 mL) were used at 40° C. for 4 h. Additional Grubbs II (2.6 mg, 3.1 μmol) was added and heating was continued at 40° C. for 45 min. Purification by flash chromatography (4 g silica gel, eluting with 5-10% MeOH in DCM with 0.5% ammonia) gave the title compound (20 mg). LCMS (Method 15): 2.29 min, 590.2 [M+H] + .

[0347] Intermediate 189: Methyl 2-((10S,13S)-10-(5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-2 4 -Fluoro-2 6 -methyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetate Prepared in a manner similar to Intermediate 8. Intermediate 188 (17 mg, 0.03 mmol) and 10% palladium on carbon (3 mg) in MeOH (2.4 mL) were used under a hydrogen atmosphere at room temperature for 15 minutes to give the title compound (15 mg). LCMS (Method 15): 2.36 min, 592.2 [M+H] + .

[0348] Intermediate 190: 5-(2-(pyrrolidin-1-yl)ethyl)pyridin-2(1H)-one Prepared in a manner similar to Intermediate 137. Intermediate 136 (0.71 g, 4.59 mmol), pyrrolidine (1.13 mL, 13.8 mmol), and 4 Å molecular sieves in MeOH (7 mL), DCM (56 mL) were used at room temperature for 30 min, followed by STAB (2.92 g, 13.8 mmol) at room temperature for 18 h. Purification by flash chromatography (40 g silica gel, eluting with 0-20% 1M ammonia in MeOH in DCM) followed by reverse-phase chromatography (38 g C18, 0-50% MeCN in 0.1% ammonia water) gave the title compound (0.34 g). LCMS (Method 12): 0.82 min, 193.1 [M+H] + .

[0349] Intermediate 191: methyl (S)-3-(2'-methyl-6'-(pent-4-en-1-yloxy)-[1,1'-biphenyl]-3-yl)-3-((S)-2-(2-oxo-5-(2-(pyrrolidin-1-yl)ethyl)pyridin-1(2H)-yl)penta-4-enamido)propanoate Prepared in a manner similar to Intermediate 65. Intermediate 114 (0.18 g, 0.30 mmol), Intermediate 190 (58 mg, 0.30 mmol), and K2CO3 (0.12 g, 0.91 mmol) in MeCN (1 mL) were used at 80 °C for 22 h. Purification by flash chromatography (25 g silica gel, eluting with 0-10% MeOH in DCM) gave the title compound (49 mg). LCMS (Method 8): 1.70 min, 624.7 [MH] - .

[0350] Intermediate 192: Methyl 2-((10S,13S)-2 6 -methyl-11-oxo-10-(2-oxo-5-(2-(pyrrolidin-1-yl)ethyl)pyridin-1(2H)-yl)-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-7-en-13-yl)acetate Prepared in a manner similar to Intermediate 7. Intermediate 191 (49 mg, 0.08 mmol) and Grubbs II (6.7 mg, 7.8 μmol) in DCE (39 mL) were used at 40° C. for 3 h. Additional Grubbs II (6.7 mg, 7.8 μmol) was added and heating was continued at 40° C. for 6 h. Purification by flash chromatography (12 g silica gel, eluting with 8% MeOH in DCM with 0.5% ammonia) gave the title compound (23 mg). LCMS (Method 8): 1.56 min, 596.6 [M H ] - .

[0351] Intermediate 193: Methyl 2-((10S,13S)-2 6 -methyl-11-oxo-10-(2-oxo-5-(2-(pyrrolidin-1-yl)ethyl)pyridin-1(2H)-yl)-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetate Prepared in a manner similar to Intermediate 8. Intermediate 192 (47 mg, 0.06 mmol) and 10% palladium on carbon (6.4 mg) in MeOH (4 mL) were used under a hydrogen atmosphere at room temperature for 40 minutes. Additional 10% palladium on carbon (6.4 mg) was added and stirring was continued under a hydrogen atmosphere at room temperature for 40 minutes to give the title compound (35 mg). LCMS (Method 11): 2.52 min, 598.6 [MH] - .

[0352] Intermediate 194: Methyl (S)-3-(2'-(but-3-en-1-yloxy)-6'-methyl-[1,1'-biphenyl]-3-yl)-3-((S)-2-(4-oxoquinazolin-3(4H)-yl)hex-5-enamido)propanoate Prepared in a manner similar to Intermediate 57. Intermediate 56 (0.47 g, 0.89 mmol), quinazolin-4-ol (0.29 g, 1.95 mmol, CAS 491-36-1), and K2CO3 (0.37 g, 2.66 mmol) in MeCN (20 mL) were used at 95 °C for 1 h. Additional K2CO3 (0.37 g, 2.66 mmol) was added and heating was continued for 2 h. Purification by flash chromatography (24 g silica gel, eluting with 0-100% EtOAc in petroleum ether) gave the title compound (0.32 g). LCMS (Method 17): 2.40 min, 580.3 [M+H] + .

[0353] Intermediate 195: Methyl 2-((10S,13S)-2 6 -Methyl-11-oxo-10-(4-oxoquinazolin-3(4H)-yl)-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-6-en-13-yl)acetate Prepared in a manner similar to Intermediate 7. Intermediate 194 (0.35 g, 0.61 mmol) and Grubbs II (51 mg, 0.06 mmol) in DCE (31 mL) were used at 40 °C for 1 h. The reaction was quenched with ethyl vinyl ether (0.06 mL, 0.61 mmol). Purification by flash chromatography (25 g silica gel, eluting with 0-100% EtOAc in petroleum ether) gave the title compound (0.17 g). LCMS (Method 3): 1.75 min, 552.2 [M+H] + .

[0354] Intermediate 196: Methyl 2-((10S,13S)-2 6 -Methyl-11-oxo-10-(4-oxoquinazolin-3(4H)-yl)-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetate Prepared in a manner similar to Intermediate 8. Intermediate 195 (0.17 g, 0.31 mmol) and 10% palladium on carbon (32 mg) in MeOH (5 mL) were used under a hydrogen atmosphere at room temperature for 2 hours to give the title compound (0.12 g). LCMS (Method 15): 2.24 min, 554.2 [M+H] + .

[0355] Intermediate 197: (E)-5-(2-ethoxyvinyl)-3-fluoro-2-methoxypyridine A solution of 5-bromo-3-fluoro-2-methoxypyridine (1.07 g, 5.18 mmol, CAS 124432-70-8) and 2-[(E)-2-ethoxyvinyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.54 g, 7.70 mmol, CAS 1201905-61-4) in 1,4-dioxane (18 mL) and water (6 mL) was degassed with nitrogen. To this solution was then added KCO (2.15 g, 15.5 mmol), followed by Pd(PPh) (0.30 g, 0.26 mmol), and the reaction mixture was stirred at 100 °C for 3 h. The mixture was cooled and filtered through Celite®, washing with EtOAc and water. The organic layer was dried over MgSO, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography (40 g silica gel, eluted with 0-80% EtOAc in petroleum ether) to give the title compound (0.94 g). LCMS (Method 4): 1.48 min, 198.0 [M+H] + .

[0356] Intermediate 198: 2-(5-fluoro-6-methoxypyridin-3-yl)acetaldehyde A solution of intermediate 197 (0.15 g, 0.77 mmol) in DCE (3.1 mL) and TFA (0.59 mL) was stirred at 35° C. for 3 h. The mixture was cooled and concentrated under reduced pressure to give the title compound (0.12 g). LCMS (Method 4): 1.04 min, 169.9 [M+H] + .

[0357] Intermediate 199: 2-(5-fluoro-6-methoxypyridin-3-yl)-N,N-dimethylethan-1-amine Prepared in a manner similar to Intermediate 137. Intermediate 198 (0.25 g, 1.49 mmol), dimethylamine (2 M in THF, 0.89 mL, 1.78 mmol), triethylamine (0.41 mL, 2.97 mmol), and 4 Å molecular sieves in DCM (9.2 mL) were used at room temperature for 3 h, followed by STAB (0.63 g, 2.97 mmol) at room temperature for 18 h. Purification by flash chromatography (4 g silica gel, eluting with 0-10% 1 M ammonia in MeOH in DCM) followed by reverse-phase chromatography (32 g C18, 5-60% MeCN in 0.1% ammonia in water) gave the title compound (63 mg). 1 H NMR (400 MHz; CDCl3) δ: 7.76 (s, 1H), 7.22 (d, 1H), 3.99 (s, 3H), 2.71 (dd, 2H), 2.51 (dd, 2H), 2.29 (s, 6H).

[0358] Intermediate 200: 5-(2-(dimethylamino)ethyl)-3-fluoropyridin-2(1H)-one A solution of intermediate 199 (60 mg, 0.30 mmol) in 33% HBr in AcOH (1.05 mL, 6.06 mmol) was stirred at 85° C. for 2 hours. The mixture was cooled and concentrated under reduced pressure. The crude product was purified by catch-and-release chromatography (eluting with 1 g SCX, MeOH, followed by 1 M ammonia in MeOH) to give the title compound (40 mg). 1 H NMR (400 MHz;CD3OD) δ: 7.29 (dd, 1H), 7.03 (d, 1H), 2.53 - 2.48 (m, 2H), 2.46 - 2.42 (m, 2H), 2.20 (s, 6H).

[0359] Intermediate 201: methyl (S)-3-((S)-2-(5-(2-(dimethylamino)ethyl)-3-fluoro-2-oxopyridin-1(2H)-yl)pent-4-enamido)-3-(2'-methyl-6'-(pent-4-en-1-yloxy)-[1,1'-biphenyl]-3-yl)propanoate Prepared in a manner similar to Intermediate 65. Intermediate 114 (0.17 g, 0.33 mmol), Intermediate 200 (50 g, 0.27 mmol), and KCO (75 mg, 0.54 mmol) in MeCN (3.5 mL) were used at 85° C. for 18 h. Purification by flash chromatography (25 g silica gel, eluting with 0-8% MeOH in DCM with 0.5% ammonia in MeOH) gave the title compound (58 mg). 1 H NMR (400 MHz;CDCl3) δ: 7.52 (d, 1H), 7.31 - 7.03 (m, 6H), 7.00 (dd, 1H), 6.80 (d, 1H), 5.65 - 5.42 (m, 3H), 5.38 - 5.27 (m, 1H), 4.97 (dd, 1H), 4.89 (dd, 1H), 4.86 - 4.82 (m, 1H), 4.81 (t, 1H), 3.78 (t, 2H), 3.44 (s, 3H), 2.82 - 2.60 (m, 3H), 2.55 - 2.35 (m, 5H), 2.24 (s, 6H), 1.98 (s, 3H), 1.88 (q, 2H), 1.61 - 1.54 (m, 2H) - NH not observed.

[0360] Intermediate 202: Methyl 2-((10S,13S)-10-(5-(2-(dimethylamino)ethyl)-3-fluoro-2-oxopyridin-1(2H)-yl)-2 6 -methyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-7-en-13-yl)acetate Prepared in a manner similar to Intermediate 7. Intermediate 201 (58 mg, 0.10 mmol) and Grubbs II (8 mg, 0.10 mmol) in DCE (45 mL) were used at 40° C. for 18 h. Additional Grubbs II (8 mg, 0.10 mmol) was added at 40° C. for 24 h. Purification by flash chromatography (25 g silica gel, eluting with 5-8% MeOH in DCM containing 0.5% ammonia) gave the title compound (18 mg). LCMS (Method 18): 1.23 min, 590.2 [M+H] + .

[0361] Intermediate 203: Methyl 2-((10S,13S)-10-(5-(2-(dimethylamino)ethyl)-3-fluoro-2-oxopyridin-1(2H)-yl)-2 6 -methyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetate Prepared in a manner similar to Intermediate 8. Intermediate 202 (18 mg, 0.03 mmol) and 10% palladium on carbon (3.2 mg) in MeOH (2.5 mL) were used under a hydrogen atmosphere at room temperature for 2 hours to give the title compound (17 mg). LCMS (Method 18): 1.25 min, 592.2 [M+H] + .

[0362] Intermediate 204: Ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(4-fluoro-2',5-dimethyl-6'-(but-3-en-1-yloxy)-[1,1'-biphenyl]-3-yl)propanoate Prepared in a manner similar to Intermediate 6. Intermediate 127 (0.60 g, 1.39 mmol), K2CO3 (0.29 g, 2.09 mmol), and 4-bromobut-1-ene (0.16 mL, 1.53 mmol) in MeCN (14 mL) were refluxed for 16 h. Additional K2CO3 (0.38 g, 2.78 mmol) and 4-bromobut-1-ene (0.28 mL, 2.78 mmol) were added, and heating was continued for 7 h. Additional K2CO3 (0.38 g, 2.78 mmol) and 4-bromobut-1-ene (0.28 mL, 2.78 mmol) were added, and heating was continued for 18 h. Purification by flash chromatography (25 g silica gel, eluting with 0-50% EtOAc in petroleum ether) gave the title compound (0.49 g). 1 H NMR (400 MHz;CDCl3) δ: 7.05 (t, 1H), 6.89 (dd, 1H), 6.84 (dd, 1H), 6.74 (d, 1H), 6.66 (d, 1H), 5.60 - 5.49 (m, 2H), 5.27 (br s, 1H), 4.91 - 4.84 (m, 2H), 4.04 - 3.91 (m, 2H), 3.78 (t, 2H), 2.80 - 2.60 (m, 2H), 2.17 (d, 2H), 2.13 (s, 3H), 1.94 (s, 3H), 1.30 (s, 9H), 1.06 (t, 3H).

[0363] Intermediate 205: Ethyl (S)-3-amino-3-(2'-(but-3-en-1-yloxy)-4-fluoro-5,6'-dimethyl-[1,1'-biphenyl]-3-yl)propanoate hydrochloride A suspension of intermediate 204 (0.49 g, 1.01 mmol) in 4 M HCl in 1,4-dioxane (0.25 mL) was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure to give the title compound (0.43 g). LCMS (Method 18): 1.25 min, 386.1 [M+H] + .

[0364] Intermediate 206: Ethyl (S)-3-(2'-(but-3-en-1-yloxy)-4-fluoro-5,6'-dimethyl-[1,1'-biphenyl]-3-yl)-3-((R)-2-hydroxyhex-5-enamido)propanoate Prepared in a manner similar to Intermediate 5. Intermediate 205 (0.33 g, 0.77 mmol), (2R-)2-hydroxyhex-5-enoic acid (0.15 g, 0.85 mmol, CAS 612825-60-2), DIPEA (0.40 mL, 2.31 mmol), HOBt (0.10 g, 0.77 mmol), and EDCI (0.15 g, 0.77 mmol) in MeCN (10 mL) were used at room temperature for 4 h. Purification by flash chromatography (25 g silica gel, eluting with 30-100% EtOAc in petroleum ether) gave the title compound (0.25 g). 1 H NMR (400 MHz;CDCl3) δ: 7.68 (d, 1H), 7.08 (t, 1H), 6.88 (d, 2H), 6.86 (d, 1H), 6.78 (d, 1H), 5.87 - 5.50 (m, 3H), 4.95 - 4.79 (m, 4H), 4.04 (dd, 1H), 3.98 - 3.91 (m, 2H), 3.89 (t, 2H), 3.48 (br s, 1H), 2.85 - 2.68 (m, 2H), 2.22 - 2.18 (m, 2H), 2.15 (s, 3H), 2.06 - 2.03 (m, 2H), 1.95 (s, 3H), 1.89 - 1.75 (m, 1H), 1.60 - 1.49 (m, 1H), 1.06 (t, 3H).

[0365] Intermediate 207: Ethyl (S)-3-(2'-(but-3-en-1-yloxy)-4-fluoro-5,6'-dimethyl-[1,1'-biphenyl]-3-yl)-3-((R)-2-((methylsulfonyl)oxy)hex-5-enamido)propanoate Prepared in a similar manner to Intermediate 56. Intermediate 206 (0.11 g, 0.21 mmol), triethylamine (0.06 mL, 0.43 mmol) and methanesulfonyl chloride (25 μL, 0.32 mmol) in DCM (1 mL) were used at room temperature for 1 h to give the title compound (0.12 g). 1 H NMR (400 MHz;CDCl3) δ: 7.49 (br s, 1H), 7.11 (t, 1H), 6.89 (dd, 2H), 6.79 (d, 1H), 6.70 (d, 1H), 5.68 - 5.50 (m, 3H), 4.98 - 4.92 (m, 5H), 4.01 - 3.95 (m, 2H), 3.81 (t, 2H), 3.60 (s, 2H), 3.04 (s, 3H), 2.91 - 2.80 (m, 2H), 2.22 (s, 3H), 2.06 - 2.03 (m, 2H), 1.99 (s, 3H), 1.98 - 1.81 (m, 2H), 1.09 (t, 3H).

[0366] Intermediate 208: Ethyl (S)-3-(2'-(but-3-en-1-yloxy)-4-fluoro-5,6'-dimethyl-[1,1'-biphenyl]-3-yl)-3-((S)-2-(5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)hexa-5-enamido)propanoate Prepared in a manner similar to Intermediate 65. Intermediate 137 (40 mg, 0.24 mmol), Intermediate 207 (0.11 g, 0.18 mmol), and KCO (76 mg, 0.55 mmol) in MeCN (2.4 mL) were used at 85° C. for 18 h. Purification by flash chromatography (25 g silica gel, eluting with 2-8% MeOH in DCM containing 0.5% ammonia in MeOH) gave the title compound (25 mg). 1H NMR (400 MHz; CDCl3) δ: 7.47 (br s, 1H), 7.34 (d, 1H), 7.26 (d, 1H), 7.18 (t, 1H), 6.96 (d, 2H), 6.87 (d, 1H), 6.78 (d, 1H), 6.50 (d, 1H), 5.63 - 5.52 (m, 2H), 5.51 - 5.47 (m, 1H), 5.45 (t, 1H), 4.96 - 4.86 (m, 4H), 3.96 - 3.88 (m, 4H), 2.71 - 2.60 (m, 2H), 2.54 - 2.40 (m, 5H), 2.28 (s, 6H), 2.27 - 2.05 (m, 5H), 1.99 (s, 3H), 1.98 - 1.72 (m, 2H), 1.03 (t, 3H) - NH not observed.

[0367] Intermediate 209: Ethyl 2-((10S,13S)-10-(5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-1 4 -Fluoro-1 5 ,2 6 -Dimethyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-6-en-13-yl)acetate Prepared in a manner similar to Intermediate 7. Intermediate 208 (41 mg, 0.06 mmol) and Grubbs II (5.4 mg, 6.4 μmol) in DCE (30 mL) were used at 40° C. for 18 h. Purification by flash chromatography (12 g silica gel, eluting with 5-8% MeOH in DCM containing 0.5% ammonia) gave the title compound (18 mg). LCMS (Method 18): 2.00 min, 618.3 [M+H] + .

[0368] Intermediate 210: Ethyl 2-((10S,13S)-10-(5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-1 4 -Fluoro-1 5 ,2 6-Dimethyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetate Prepared in a manner similar to Intermediate 8. Intermediate 209 (18 mg, 0.03 mmol) and 10% palladium on carbon (3.2 mg) in MeOH (3.1 mL) were used under a hydrogen atmosphere at room temperature for 2 hours to give the title compound (14 mg). LCMS (Method 18): 2.02 min, 620.3 [M+H] + .

[0369] Intermediate 211: Methyl (S)-3-((tert-butoxycarbonyl)amino)-3-(2'-hydroxy-4'-6'-dimethyl-[1,1'-biphenyl]-3-yl)propanoate Prepared in a manner similar to Intermediate 3. Intermediate 2 (1.51 g, 3.73 mmol), 2-bromo-3,5-dimethylphenol (0.75 g, 3.73 mmol, CAS 125237-08-3), NaCO (1.19 g, 11.2 mmol), and Pd(dppf)Cl (0.14 g, 0.19 mmol) in 1,4-dioxane (30 mL) and water (15 mL) were used at 80 °C for 16 h. Purification by flash chromatography (40 g silica gel, eluting with 10-80% EtOAc in petroleum ether) gave the title compound (0.45 g). LCMS (Method 4): 1.65 min, 422.1 [M+Na] + .

[0370] Intermediate 212: methyl (S)-3-((tert-butoxycarbonyl)amino)-3-(2',4'-dimethyl-6'-(pent-4-en-1-yloxy)-[1,1'-biphenyl]-3-yl)propanoate Prepared in a manner similar to Intermediate 6. Intermediate 211 (0.45 g, 1.13 mmol), K2CO3 (0.20 g, 1.46 mmol), and 5-bromopent-1-ene (0.16 mL, 1.35 mmol) in MeCN (10 mL) were used at reflux for 24 hours to give the title compound (0.47 g). LCMS (Method 4): 2.03 min, 490.0 [M+Na] + .

[0371] Intermediate 213: Methyl (S)-3-amino-3-(2',4'-dimethyl-6'-(pent-4-en-1-yloxy)-[1,1'-biphenyl]-3-yl)propanoate hydrochloride A suspension of intermediate 212 (0.47 g, 1.00 mmol) in 4 M HCl in 1,4-dioxane (3.75 mL) was stirred at room temperature for 3 hours. The mixture was concentrated under reduced pressure to give the title compound (0.39 g). LCMS (Method 4): 1.83 min, 368.1 [M+H] + .

[0372] Intermediate 214: Methyl (S)-3-(2',4'-dimethyl-6'-(pent-4-en-1-yloxy)-[1,1'-biphenyl]-3-yl)-3-((R)-2-hydroxypent-4-enamido)propanoate Prepared in a manner similar to Intermediate 5. Intermediate 213 (0.68 g, 1.68 mmol), (2R)-2-hydroxypent-4-enoic acid (0.29 g, 2.52 mmol, CAS 413622-10-3), DIPEA (1.17 mL, 6.73 mmol), HOBt (0.25 g, 1.85 mmol), and EDCI (0.48 g, 2.52 mmol) in DMF (2 mL) and MeCN (8 mL) were used at room temperature for 18 h. Purification by flash chromatography (40 g silica gel, eluting with 5-80% EtOAc in petroleum ether) gave the title compound (0.33 g). LCMS (Method 11): 2.27 min, 466.0 [M+H] + .

[0373] Intermediate 215: Methyl (S)-3-(2',4'-dimethyl-6'-(pent-4-en-1-yloxy)-[1,1'-biphenyl]-3-yl)-3-((R)-2-((methylsulfonyl)oxy)pent-4-enamido)propanoate Prepared in a manner similar to Intermediate 56. Intermediate 214 (0.30 g, 0.61 mmol), triethylamine (0.17 mL, 1.22 mmol) and methanesulfonyl chloride (0.07 mL, 0.92 mmol) in DCM (3.9 mL) were used at room temperature for 2 hours to give the title compound (0.33 g). LCMS (Method 4): 1.97 min, 544.1 [M+H] + .

[0374] Intermediate 216: methyl (S)-3-(2',4'-dimethyl-6'-(pent-4-en-1-yloxy)-[1,1'-biphenyl]-3-yl)-3-((S)-2-(5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)pent-4-enamido)propanoate Prepared in a manner similar to Intermediate 65. Intermediate 137 (0.15 g, 0.90 mmol), Intermediate 215 (0.33 g, 0.60 mmol), and K2CO3 (0.17 g, 1.20 mmol) in MeCN (6 mL) were used at 90 °C for 18 h. Purification by flash chromatography (12 g silica gel, eluting with 0-50% EtOAc in petroleum ether) gave the title compound (94 mg). LCMS (Method 11): 2.45 min, 612.7 [MH] - .

[0375] Intermediate 217: Methyl 2-((10S,13S)-10-(5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-2 4 ,2 6 -Dimethyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-7-en-13-yl)acetate Prepared in a manner similar to Intermediate 7. Intermediate 216 (0.18 g, 0.29 mmol) and Grubbs II (25 mg, 0.03 mmol) in DCE (40 mL) were used at 40 °C for 4 h. Purification by flash chromatography (25 g silica gel, eluting with 5-65% 9:1 MeOH / DCM containing 0.5% ammonia in DCM) gave the title compound (0.11 g). LCMS (Method 11): 2.24 min, 584.6 [MH] - .

[0376] Intermediate 218: Methyl 2-((10S,13S)-10-(5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-2 4 ,2 6 -Dimethyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetate Prepared in a manner similar to Intermediate 8. Intermediate 217 (95 mg, 0.16 mmol) and 10% palladium on carbon (17 mg) in MeOH (2 mL) were used under a hydrogen atmosphere at room temperature for 18 hours to give the title compound (80 mg). LCMS (Method 4): 1.93 min, 588.2 [M+H] + .

[0377] Intermediate 219: (R,E)-N-(5-bromo-2-fluorobenzylidene)-2-methylpropane-2-sulfinamide Prepared in a manner similar to Intermediate 102. 5-Bromo-2-fluoro-benzaldehyde (2.50 g, 12.3 mmol, CAS 196929-78-9), (R)-2-methylpropane-2-sulfinimide (1.64 g, 13.6 mmol, CAS 196929-78-9) and titanium ethoxide (4.21 g, 18.5 mmol) in THF (20 mL) was used at 40° C. for 2.5 h to give the title compound (3.75 g). LCMS (Method 11): 2.10 min, 306.0 [M+H] + .

[0378] Intermediate 220: Ethyl (S)-3-(5-bromo-2-fluorophenyl)-3-(((R)-tert-butylsulfinyl)amino)propanoate Prepared in a manner similar to Intermediate 104. Zinc (4.0 g, 61.2 mmol), chlorotrimethylsilane (0.31 mL, 2.45 mmol), and ethyl bromoacetate (3.40 mL, 30.6 mmol) in THF (50 mL) were used at 60° C. for 1 h, followed by Intermediate 219 (3.75 g, 12.2 mmol) in THF (15 mL) at room temperature for 1.5 h. Purification by flash chromatography (80 g silica gel, eluting with 5-80% EtOAc in petroleum ether) gave the title compound (4.45 g). LCMS (Method 11): 1.94 min, 392.2 [MH] - .

[0379] Intermediate 221: Ethyl (S)-3-amino-3-(5-bromo-2-fluorophenyl)propanoate hydrochloride A suspension of intermediate 220 (4.45 g, 10.7 mmol) in 4 M HCl in 1,4-dioxane (13.4 mL) was stirred at room temperature for 3 hours. The mixture was concentrated under reduced pressure to give the title compound (3.21 g). LCMS (Method 11): 1.68 min, 290.4 [M+H] + .

[0380] Intermediate 222: Ethyl (S)-3-(5-bromo-2-fluorophenyl)-3-((tert-butoxycarbonyl)amino)propanoate To a stirred suspension of intermediate 221 (3.0 g, 9.19 mmol) and Boc anhydride (2.21 g, 10.1 mmol) in DCM (50 mL) was added triethylamine (1.92 mL, 13.8 mmol), and the mixture was stirred at room temperature for 20 h. The reaction mixture was diluted with DCM, washed with water, brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography (80 g silica gel, eluted with 5-35% EtOAc in petroleum ether) to give the title compound (2.08 g). LCMS (Method 11): 2.12 min, 412.1 [M+Na] +.

[0381] Intermediate 223: Ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate Prepared in a manner similar to Intermediate 2 using Intermediate 222 (1.98 g, 5.07 mmol), bis(pinacolato)diboron (1.55 g, 6.09 mmol), potassium acetate (1.24 g, 12.7 mmol), and Pd(dppf)Cl (0.37 g, 0.51 mmol) in 1,4-dioxane (20 mL) at 90 °C for 2 h. Purification by flash chromatography (silica gel, eluting with 6:1 EtOAc / petroleum ether) gave the title compound (2.12 g). 1 H NMR (400 MHz;CDCl3) δ: 7.69 - 7.67 (m, 1H), 7.65 - 7.60 (m, 1H), 6.95 (dd, 1H), 5.47 - 5.43 (m, 1H), 5.34 - 5.28 (m, 1H), 4.03 - 3.96 (m, 2H), 2.84 - 2.66 (m, 2H), 1.35 (s, 9H), 1.25 (s, 12H), 1.10 (t, 3H).

[0382] Intermediate 224: Ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(4-fluoro-2'-hydroxy-6'-methyl-[1,1'-biphenyl]-3-yl)propanoate Prepared in a manner similar to Intermediate 3. Intermediate 223 (1.05 g, 2.40 mmol), 2-bromo-3-methylphenol (0.45 g, 2.40 mmol, CAS 22061-78-5), NaCO (0.64 g, 6.00 mmol), and Pd(dppf)Cl (98 mg, 0.12 mmol) in 1,4-dioxane (18 mL) and water (9 mL) were used at 90 °C for 16 h. Purification by flash chromatography (40 g silica gel, eluted with 6:1 EtOAc / petroleum ether) gave the title compound (0.69 g). LCMS (Method 4): 1.78 min, 440.0 [M+Na] + .

[0383] Intermediate 225: ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(4-fluoro-2'-methyl-6'-(pent-4-en-1-yloxy)-[1,1'-biphenyl]-3-yl)propanoate Prepared in a manner similar to Intermediate 6. Intermediate 224 (0.69 g, 1.65 mmol), K2CO3 (0.70 g, 2.15 mmol) and 5-bromopent-1-ene (0.24 mL, 1.98 mmol) in MeCN (15 mL) were used at reflux for 24 hours to give the title compound (0.70 g). LCMS (Method 4): 2.10 min, 508.1 [M+Na] + .

[0384] Intermediate 226: Ethyl (S)-3-amino-3-(4-fluoro-2'-methyl-6'-(pent-4-en-1-yloxy)-[1,1'-biphenyl]-3-yl)propanoate hydrochloride A suspension of intermediate 225 (0.70 g, 1.45 mmol) in 4 M HCl in 1,4-dioxane (5.44 mL) was stirred at room temperature for 3 hours. The mixture was concentrated under reduced pressure to give the title compound (0.61 g). LCMS (Method 12): 1.74 min, 386.3 [M+H] + .

[0385] Intermediate 227: Ethyl (S)-3-(4-fluoro-2'-methyl-6'-(pent-4-en-1-yloxy)-[1,1'-biphenyl]-3-yl)-3-((R)-2-hydroxypent-4-enamido)propanoate Prepared in a manner similar to Intermediate 5. Intermediate 226 (0.61 g, 1.45 mmol), (2R)-2-hydroxypent-4-enoic acid (0.25 g, 2.18 mmol, CAS 413622-10-3), DIPEA (1.03 mL, 5.81 mmol), HOBt (0.25 g, 1.74 mmol), and EDCI (0.42 g, 2.18 mmol) in DMF (1.5 mL) and MeCN (7 mL) were used at room temperature for 18 hours. Purification by flash chromatography (12 g silica gel, eluting with 15-55% EtOAc in petroleum ether) gave the title compound (0.47 g). 1 H NMR (400 MHz;CDCl3) δ: 7.52 (br d, 1H), 7.13 (t, 1H), 7.11 - 6.96 (m, 3H), 6.80 (d, 1H), 6.71 (d, 1H), 5.73 - 5.55 (m, 3H), 5.12 - 4.99 (m, 2H), 4.85 (dd, 1H), 4.82 (s, 1H), 4.09 (dd, 1H), 4.01 - 3.95 (m, 2H), 3.78 (t, 2H), 2.89 (dd, 1H), 2.79 (dd, 1H), 2.60 - 2.49 (m, 1H), 2.39 - 2.27 (m, 1H), 1.97 (s, 3H), 1.92 - 1.85 (m, 2H), 1.60 - 1.52 (m, 3H), 1.10 (t, 3H).

[0386] Intermediate 228: Ethyl (S)-3-(4-fluoro-2'-methyl-6'-(pent-4-en-1-yloxy)-[1,1'-biphenyl]-3-yl)-3-((R)-2-((methylsulfonyl)oxy)pent-4-enamido)propanoate Prepared in a manner similar to Intermediate 56. Intermediate 227 (0.47 g, 0.98 mmol), triethylamine (0.27 mL, 1.96 mmol) and methanesulfonyl chloride (0.11 mL, 1.47 mmol) in DCM (10 mL) were used at room temperature for 1 h to give the title compound (0.48 g). LCMS (Method 12): 1.78 min, 562.6 [M+H] + .

[0387] Intermediate 229: Ethyl (S)-3-((S)-2-(5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)pent-4-enamido)-3-(4-fluoro-2'-methyl-6'-(pent-4-en-1-yloxy)-[1,1'-biphenyl]-3-yl)propanoate Prepared in a manner similar to Intermediate 65. Intermediate 137 (0.24 g, 0.86 mmol), Intermediate 228 (0.37 g, 0.66 mmol), and K2CO3 (0.27 g, 1.98 mmol) in MeCN (37 mL) were used at 90 °C for 16 h. Purification by flash chromatography (4 g silica gel, eluting with 0-20% 0.1% ammonia in MeOH in DCM) gave the title compound (0.15 g). LCMS (Method 6): 1.35 min, 632.4 [M+H] + .

[0388] Intermediate 230: Ethyl 2-((10S,13S)-10-(5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-1 4 -Fluoro-2 6 -methyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-7-en-13-yl)acetate Prepared in a manner similar to Intermediate 7. Intermediate 229 (0.16 g, 0.25 mmol) and Grubbs II (21 mg, 0.03 mmol) in DCE (33 mL) were used at 40° C. for 18 h. Additional Grubbs II (21 mg, 0.03 mmol) was added and stirred at 40° C. for 24 h. Purification by flash chromatography (12 g silica gel, eluting with 0-10% MeOH in DCM) gave the title compound (0.10 g). LCMS (Method 15): 2.39 min, 604.3 [M+H] + .

[0389] Intermediate 231: Ethyl 2-((10S,13S)-10-(5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-1 4 -Fluoro-2 6 -methyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetate Prepared in a manner similar to Intermediate 8. Intermediate 230 (0.10 g, 0.10 mmol) and 10% palladium on carbon (11 mg) in ethanol (5 mL) were used under a hydrogen atmosphere at room temperature for 5 hours to give the title compound (17 mg). LCMS (Method 11): 2.26 min, 606.5 [M+H] + .

[0390] Intermediate 232: Ethyl (S)-3-amino-3-(5-bromo-3-methyl-2-fluorophenyl)propanoate hydrochloride A suspension of intermediate 123 (3.92 g, 9.60 mmol) in 4 M HCl in 1,4-dioxane (14.4 mL) was stirred at room temperature for 3 hours. The mixture was concentrated under reduced pressure and triturated with petroleum ether to give the title compound (3.26 g). LCMS (Method 12): 1.41 min, 304.1 [M+H] + .

[0391] Intermediate 233: Ethyl (S)-3-(5-bromo-2-fluoro-3-methylphenyl)-3-((tert-butoxycarbonyl)amino)propanoate To a stirred suspension of intermediate 232 (3.22 g, 9.45 mmol) and Boc anhydride (2.48 g, 11.3 mmol) in DCM (100 mL) was added DIPEA (2.5 mL, 14.2 mmol), and the mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with DCM, washed with 1 M aqueous HCl, water, brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography (12 g silica gel, eluted with 0-30% EtOAc in petroleum ether) to give the title compound (3.11 g). LCMS (Method 4): 1.78 min, 305.8 [M-Boc+H] + .

[0392] Intermediate 234: Ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(2-fluoro-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate Prepared in a manner similar to Intermediate 2. Intermediate 233 (2.67 g, 6.60 mmol), bis(pinacolato)diboron (2.01 g, 7.93 mmol), potassium acetate (1.62 g, 16.5 mmol), and Pd(dppf)Cl (0.48 g, 0.66 mmol) in 1,4-dioxane (43 mL) were used at 90° C. for 16 h. Purification by flash chromatography (40 g silica gel, eluting with 0-50% EtOAc in petroleum ether) gave the title compound (2.98 g). 1 H NMR (400 MHz;CDCl3) δ: 7.59 - 7.52 (m, 2H), 5.47 - 5.43 (m, 1H), 5.34 - 5.28 (m, 1H), 4.10 - 3.99 (m, 2H), 2.90 - 2.66 (m, 2H), 2.25 (s, 3H), 1.42 (s, 9H), 1.32 (s, 12H), 1.18 (t, 3H).

[0393] Intermediate 235: Ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(4,4'-difluoro-2'-hydroxy-5,6'-dimethyl-[1,1'-biphenyl]-3-yl)propanoate Prepared in a manner similar to Intermediate 3 using Intermediate 234 (3.00 g, 6.65 mmol), 2-bromo-5-fluoro-3-methylphenol (1.50 g, 7.31 mmol, CAS 1807192-21-7), NaCO (2.11 g, 19.9 mmol), and Pd(dppf)Cl (0.36 g, 0.50 mmol) in 1,4-dioxane (180 mL) and water (45 mL) at 85 °C for 20 h. Purification by dry flash chromatography (silica gel, eluting with 0-30% EtOAc in petroleum ether) gave the title compound (1.15 g). 1 H NMR (400 MHz; CDCl3) δ: 7.08–6.92 (m, 2H), 6.54 (d, 2H), 5.81–5.64 (m, 1H), 5.42–5.21 (m, 1H), 4.09–3.96 (m, 2H), 2.86 (d, 2H), 2.30 (s, 3H), 2.02 (s, 3H), 1.41 (s, 9H), 1.18 (t, 3H). No OH was observed.

[0394] Intermediate 236: Ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(4,4'-difluoro-2',5-dimethyl-6'-(pent-4-en-1-yloxy)-[1,1'-biphenyl]-3-yl)propanoate Prepared in a manner similar to Intermediate 6. Intermediate 235 (1.15 g, 2.56 mmol), K2CO3 (0.53 g, 3.84 mmol), and 5-bromopent-1-ene (0.33 mL, 2.81 mmol) in MeCN (32 mL) were used at reflux for 16 h to give the title compound (0.86 g). LCMS (Method 4): 2.16 min, 418.1 [M-Boc+H] + .

[0395] Intermediate 237: Ethyl (S)-3-amino-3-(4,4'-difluoro-2',5-dimethyl-6'-(pent-4-en-1-yloxy)-[1,1'-biphenyl]-3-yl)propanoate hydrochloride A suspension of Intermediate 236 (0.86 g, 1.67 mmol) in 4 M HCl in 1,4-dioxane (5 mL) was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure to give the title compound (0.64 g). 1 H NMR (400 MHz;CDCl3) δ: 8.97 (br s, 3H), 7.15 (br s, 1H), 7.01 (d, 1H), 6.56 - 6.40 (m, 2H), 5.76 - 5.55 (m, 1H), 5.06 - 4.89 (m, 3H), 4.06 - 3.93 (m, 2H), 3.82 - 3.78 (m, 2H), 3.26 (br d, 1H), 3.07 (br s, 1H), 2.27 (s, 3H), 2.01 (s, 3H), 1.99 - 1.90 (m, 2H), 1.67 - 1.61 (m, 2H), 1.12 (t, 3H).

[0396] Intermediate 238: Ethyl (S)-3-(4,4'-difluoro-2',5-dimethyl-6'-(pent-4-en-1-yloxy)-[1,1'-biphenyl]-3-yl)-3-((R)-2-hydroxypent-4-enamido)propanoate Prepared in a manner similar to Intermediate 5. Intermediate 237 (0.64 g, 1.41 mmol), (2R)-2-hydroxypent-4-enoic acid (0.25 g, 2.12 mmol, CAS 413622-10-3), DIPEA (0.98 mL, 5.64 mmol), HOBt (0.21 g, 1.55 mmol), and EDCI (0.41 g, 2.12 mmol) in MeCN (10 mL) were used at room temperature for 16 h. Purification by flash chromatography (12 g silica gel, eluting with 5-80% EtOAc in petroleum ether) gave the title compound (0.57 g). 1H NMR (400 MHz;CDCl3) δ: 7.58 (br s, 1H), 6.95 - 6.90 (m, 2H), 6.58 - 6.47 (m, 2H), 5.76 - 5.55 (m, 3H), 5.20 - 5.02 (m, 2H), 4.97 - 4.88 (m, 2H), 4.19 - 4.12 (m, 1H), 4.10 - 3.98 (m, 2H), 3.82 (t, 2H), 2.99 - 2.75 (m, 2H), 2.69 - 2.53 (m, 1H), 2.47 - 2.34 (m, 1H), 2.29 (d, 3H), 2.02 (s, 3H), 2.01 - 1.95 (m, 2H), 1.71 - 1.59 (m, 2H), 1.17 (t, 3H) - OH not observed.

[0397] Intermediate 239: Ethyl (S)-3-(4,4'-difluoro-2',5-dimethyl-6'-(pent-4-en-1-yloxy)-[1,1'-biphenyl]-3-yl)-3-((R)-2-((methylsulfonyl)oxy)pent-4-enamido)propanoate Prepared in a manner similar to Intermediate 56. Intermediate 238 (0.57 g, 1.10 mmol), triethylamine (0.31 mL, 2.20 mmol) and methanesulfonyl chloride (0.13 mL, 1.65 mmol) in DCM (7.3 mL) were used at room temperature for 1 h to give the title compound (0.64 g). LCMS (Method 12): 1.84 min, 592.5 [MH] - .

[0398] Intermediate 240: ethyl (S)-3-(4,4'-difluoro-2',5-dimethyl-6'-(pent-4-en-1-yloxy)-[1,1'-biphenyl]-3-yl)-3-((S)-2-(5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)pent-4-enamido)propanoate Prepared in a manner similar to Intermediate 65 using Intermediate 239 (0.50 g, 0.80 mmol), Intermediate 137 (0.17 g, 1.04 mmol), and KCO (0.33 g, 2.40 mmol) in MeCN (23 mL) at 90 °C for 16 h. Purification by flash chromatography (40 g silica gel, eluting with 0-10% 0.1% ammonia in MeOH in DCM) gave the title compound (0.11 g). 1 H NMR (400 MHz;CDCl3) δ: 7.54 - 7.37 (m, 1H), 7.31 (d, 1H), 7.27 - 7.23 (m, 1H), 6.95 - 6.89 (m, 2H), 6.63 - 6.46 (m, 3H), 5.75 - 5.52 (m, 4H), 5.03 (d, 1H), 4.98 - 4.89 (m, 3H), 3.97 - 3.87 (m, 2H), 3.83 (t, 2H), 2.85 - 2.65 (m, 3H), 2.63 - 2.44 (m, 5H), 2.42 - 2.23 (m, 9H), 2.00 (s, 3H), 1.99 - 1.90 (m, 2H), 1.65 - 1.53 (m, 2H), 1.11 (t, 3H).

[0399] Intermediate 241: Ethyl 2-((10S,13S)-10-(5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-1 4 ,2 4 -difluoro-1 5 ,2 6 -Dimethyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-7-en-13-yl)acetate Prepared in a manner similar to Intermediate 7. Intermediate 240 (0.11 g, 0.12 mmol) and Grubbs II (10.6 mg, 0.01 mmol) in DCE (79 mL) were used at 40° C. for 18 h. Additional Grubbs II (10.6 mg, 0.01 mmol) was added and stirred at 40° C. for 24 h. Purification by flash chromatography (12 g silica gel, eluting with 0-10% 2M ammonia in MeOH in DCM) and again (12 g silica gel, 8% (0.5% ammonia in MeOH) in DCM) gave the title compound (48 mg). LCMS (Method 13): 2.33 min, 634.6 [M H ] - .

[0400] Intermediate 242: Ethyl 2-((10S,13S)-10-(5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-1 4 ,2 4 -difluoro-1 5 ,2 6 -Dimethyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetate Prepared in a manner similar to Intermediate 8. Intermediate 241 (48 mg, 0.06 mmol) and 10% palladium on carbon (6.1 mg) in MeOH (6.3 mL) were used under a hydrogen atmosphere at room temperature for 36 hours to give the title compound (30 mg). LCMS (Method 16): 3.50 min, 638.1 [M+H] + .

[0401] Intermediate 243: 5-(2-(3-fluoroazetidin-1-yl)ethyl)pyridin-2(1H)-one Prepared in a manner similar to Intermediate 137. Intermediate 136 (0.71 g, 4.59 mmol), 3-fluoroazetidine hydrochloride (0.62 g, 5.51 mmol), and triethylamine (1.28 mL, 9.19 mmol) in MeOH (7 mL), DCM (56 mL), and 4 Å molecular sieves were used at room temperature for 2 h, followed by STAB (2.92 g, 13.8 mmol) at room temperature for 2 h. Purification by flash chromatography (12 g silica gel, eluting with 0-20% 1 M ammonia in DCM with MeOH) followed by reverse-phase chromatography (38 g C18, 0-50% MeCN in 0.1% ammonia water) gave the title compound (0.28 g). 1 H NMR (400 MHz;CD3OD) δ: 7.55 (dd, 1H), 7.27 (d, 1H), 6.52 (d, 1H), 5.21 - 5.02 (m, 1H), 3.69 - 3.56 (m, 2H), 3.29 - 3.17 (m, 2H), 2.71 (t, 2H), 2.47 (t, 2H).

[0402] Intermediate 244: methyl (S)-3-((S)-2-(5-(2-(3-fluoroazetidin-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)pent-4-enamido)-3-(2'-methyl-6'-(pent-4-en-1-yloxy)-[1,1'-biphenyl]-3-yl)propanoate Prepared in a manner similar to Intermediate 65. Intermediate 114 (0.20 g, 0.38 mmol), Intermediate 243 (74 mg, 0.38 mmol), and K2CO3 (0.16 g, 1.13 mmol) in MeCN (4 mL) were used at 85 °C for 18 h. Additional K2CO3 (0.16 g, 1.13 mmol) was added and heated at 85 °C for 24 h. Purification by flash chromatography (24 g silica gel, eluting with 2-10% (0.1% ammonia in MeOH) in DCM) gave the title compound (69 mg). LCMS (Method 13): 1.66 min, 628.6 [M H] - .

[0403] Intermediate 245: Methyl 2-((10S,13S)-10-(5-(2-(3-fluoroazetidin-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-2 6 -methyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-7-en-13-yl)acetate Prepared in a manner similar to Intermediate 7. Intermediate 244 (69 mg, 0.11 mmol) and Grubbs II (9.3 mg, 0.01 mmol) in DCE (55 mL) were used at 40 °C for 24 h. Purification by flash chromatography (12 g silica gel, eluting with 2-10% 2M ammonia MeOH in DCM) gave the title compound (54 mg). LCMS (Method 13): 1.54 min, 600.6 [MH] - .

[0404] Intermediate 246: Methyl 2-((10S,13S)-10-(5-(2-(3-fluoroazetidin-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-2 6 -methyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetate Prepared in a manner similar to Intermediate 8. Intermediate 245 (54 mg, 0.08 mmol) and 10% palladium on carbon (8 mg) in MeOH (5 mL) were used under a hydrogen atmosphere at room temperature for 40 minutes. Additional 10% palladium on carbon (8 mg) was added and stirred under a hydrogen atmosphere at room temperature for 40 minutes to give the title compound (48 mg). LCMS (Method 16): 3.17 min, 602.6 [MH] - .

[0405] Intermediate 247: (R)-5-(2-(3-fluoropyrrolidin-1-yl)ethyl)pyridin-2(1H)-one Prepared in a manner similar to Intermediate 137. Intermediate 136 (0.82 g, 5.29 mmol), 3-(R)-fluoropyrrolidine hydrochloride (0.73 g, 5.82 mmol), and triethylamine (0.88 mL, 6.34 mmol) in MeOH (7 mL), DCM (56 mL), and 4 Å molecular sieves were used at room temperature for 3 h, followed by STAB (3.36 g, 15.0 mmol) at room temperature for 18 h. Purification by flash chromatography (12 g silica gel, eluting with 0-20% 1 M ammonia in DCM with MeOH) followed by reverse-phase chromatography (38 g C18, 0-50% MeCN in 0.1% ammonia water) gave the title compound (0.28 g). 1 H NMR (400 MHz;CD3OD) δ: 7.57 (dd, 1H), 7.31 (dd, 1H), 6.52 (dd, 1H), 5.29 - 5.06 (m, 1H), 3.06 - 2.89 (m, 2H), 2.77 - 2.58 (m, 5H), 2.51 - 2.40 (m, 1H), 2.30 - 2.10 (m, 1H), 2.10 - 1.92 (m, 1H).

[0406] Intermediate 248: methyl (S)-3-((S)-2-(5-(2-((R)-3-fluoropyrrolidin-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)pent-4-enamido)-3-(2'-methyl-6'-(pent-4-en-1-yloxy)-[1,1'-biphenyl]-3-yl)propanoate Prepared in a manner similar to Intermediate 65. Intermediate 114 (0.20 g, 0.38 mmol), Intermediate 247 (79 mg, 0.38 mmol), and K2CO3 (0.16 g, 1.13 mmol) in MeCN (4 mL) were used at 85 °C for 18 h. Purification by flash chromatography (24 g silica gel, eluting with 2-10% (0.1% ammonia MeOH) in DCM) gave the title compound (0.15 g). LCMS (Method 13): 1.71 min, 644.6 [M+H] + .

[0407] Intermediate 249: Methyl 2-((10S,13S)-10-(5-(2-((R)-3-fluoropyrrolidin-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-2 6 -methyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-7-en-13-yl)acetate Prepared in a manner similar to Intermediate 7. Intermediate 248 (0.15 g, 0.11 mmol) and Grubbs II (19.1 mg, 0.02 mmol) in DCE (0.11 L) were used at 40° C. for 18 h. Additional Grubbs II (9.6 mg, 0.01 mmol) was added and heated at 40° C. for 6 h. Purification by flash chromatography (24 g silica gel, eluting with 2-8% 2M ammonia MeOH in DCM) gave the title compound (91 mg). LCMS (Method 16): 3.12 min, 614.7 [M H ] - .

[0408] Intermediate 250: Methyl 2-((10S,13S)-10-(5-(2-((R)-3-fluoropyrrolidin-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-2 6 -methyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetate Prepared in a manner similar to Intermediate 8. Intermediate 249 (91 mg, 0.14 mmol) and 10% palladium on carbon (14.8 mg) in MeOH (8 mL) were used under a hydrogen atmosphere at room temperature for 40 minutes. Additional 10% palladium on carbon (14.8 mg) was added and stirred under a hydrogen atmosphere at room temperature for 40 minutes to give the title compound (72 mg). LCMS (Method 16): 4.33 min, 616.6 [MH] - .

[0409] Intermediate 251: 5-(2-(3-methoxyazetidin-1-yl)ethyl)pyridin-2(1H)-one Prepared in a manner similar to Intermediate 137. Intermediate 136 (0.78 g, 5.05 mmol), 3-methoxyazetidine hydrochloride (0.69 g, 5.55 mmol), and triethylamine (1.41 mL, 10.1 mmol) in MeOH (7.7 mL), DCM (62 mL), and 4 Å molecular sieves were used at room temperature for 2 h, followed by STAB (3.21 g, 15.2 mmol) at room temperature for 18 h. Purification by flash chromatography (40 g silica gel, eluting with 0-20% 1 M ammonia in MeOH in DCM) followed by reverse-phase chromatography (38 g C18, 0-50% MeCN in 0.1% ammonia in water) gave the title compound (0.35 g). 1 H NMR (400 MHz;CD3OD) δ: 7.54 (dd, 1H), 7.26 (d, 1H), 6.51 (d, 1H), 4.10 - 3.99 (m, 1H), 3.58 (dd, 2H), 3.24 (s, 3H), 3.02 - 2.94 (m, 2H), 2.67 (t, 2H), 2.46 (t, 2H).

[0410] Intermediate 252: methyl (S)-3-((S)-2-(5-(2-(3-methoxyazetidin-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)pent-4-enamido)-3-(2'-methyl-6'-(pent-4-en-1-yloxy)-[1,1'-biphenyl]-3-yl)propanoate Prepared in a manner similar to Intermediate 65. Intermediate 114 (0.20 g, 0.38 mmol), Intermediate 251 (79 mg, 0.38 mmol), and K2CO3 (0.16 g, 1.13 mmol) in MeCN (4 mL) were used at 85 °C for 18 h. Purification by flash chromatography (24 g silica gel, eluting with 4-10% (0.1% ammonia MeOH) in DCM) gave the title compound (97 mg). LCMS (Method 13): 1.70 min, 640.6 [MH] - .

[0411] Intermediate 253: Methyl 2-((10S,13S)-10-(5-(2-(3-methoxyazetidin-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-2 6 -methyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-7-en-13-yl)acetate Prepared in a manner similar to Intermediate 7. Intermediate 252 (97 mg, 0.14 mmol) and Grubbs II (12.1 mg, 0.02 mmol) in DCE (75 mL) were used at 40° C. for 18 h. Additional Grubbs II (6 mg, 0.01 mmol) was added and heated at 40° C. for 6 h. Purification by flash chromatography (24 g silica gel, eluting with 2-8% 2M ammonia MeOH in DCM) gave the title compound (42 mg). LCMS (Method 16): 3.12 min, 612.6 [M H] - .

[0412] Intermediate 254: Methyl 2-((10S,13S)-10-(5-(2-(3-methoxyazetidin-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-2 6 -methyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetate Prepared in a manner similar to Intermediate 8. Intermediate 253 (42 mg, 0.06 mmol) and 10% palladium on carbon (6.4 mg) in MeOH (5 mL) were used under a hydrogen atmosphere at room temperature for 40 minutes. Additional 10% palladium on carbon (6.4 mg) was added and stirred under a hydrogen atmosphere at room temperature for 40 minutes to give the title compound (40 mg). LCMS (Method 16): 3.18 min, 616.2 [M+H] + .

[0413] Intermediate 255: (E)-5-(2-ethoxyvinyl)-2-methoxy-4-(trifluoromethyl)pyridine Prepared in a manner similar to Intermediate 197. 5-Bromo-4-trifluoromethyl-2-methoxypyridine (2.25 g, 8.79 mmol, CAS 688047-09-8), 2-[(E)-2-ethoxyvinyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.09 g, 10.6 mmol), KCO (3.64 g, 26.4 mmol), and Pd(PPh) (0.51 g, 0.44 mmol) in 1,4-dioxane (27 mL) and water (6 mL) were used at 100 °C for 3 h. Purification by flash chromatography (40 g silica gel, eluting with 0-20% 1 M ammonia in MeOH in DCM) followed by reverse-phase chromatography (40 g silica gel, 0-60% MeCN in petroleum ether) gave the title compound (1.81 g). LCMS (Method 4): 1.72 min, 247.9 [M+H] + .

[0414] Intermediate 256: 2-(6-methoxy-4-(trifluoromethyl)pyridin-3-yl)ethane-1,1-diol A solution of intermediate 255 (0.50 g, 1.82 mmol) in TFA (2.2 mL) was stirred for 2 h at 20° C. The mixture was cooled and concentrated under reduced pressure to give the title compound (0.43 g). 1 H NMR (400 MHz;CD3OD) δ: 8.26 (s, 1H), 7.02 (s, 1H), 4.62 (t, 1H), 3.95 (s, 3H), 2.96 (dq, 2H).

[0415] Intermediate 257: 2-(6-methoxy-4-(trifluoromethyl)pyridin-3-yl)-N,N-dimethylethan-1-amine Prepared in a manner similar to Intermediate 137. Intermediate 256 (0.43 g, 1.82 mmol), dimethylamine (2 M in THF, 1.82 mL, 3.63 mmol), triethylamine (0.425 mL, 1.82 mmol), and 4 Å molecular sieves in DCM (15 mL) were used at room temperature for 16 h, followed by STAB (0.77 g, 3.63 mmol) at room temperature for 6 h. Purification by flash chromatography (12 g silica gel, eluting with 0-6% MeOH in DCM) followed by flash chromatography (20 g C18, 0-100% MeCN in 0.1 M ammonia water) gave the title compound (0.29 g). LCMS (Method 4): 1.48 min, 249.0 [M+H] + .

[0416] Intermediate 258: 5-(2-(dimethylamino)ethyl)-4-(trifluoromethyl)pyridin-2(1H)-one A solution of intermediate 257 (0.29 g, 1.17 mmol) in 33% HBr in AcOH (4.03 mL, 23.4 mmol) was stirred at 85° C. for 1 h. The mixture was cooled and concentrated under reduced pressure. The crude product was purified by catch-and-release chromatography (eluting with 1 g SCX, MeOH, followed by 1 M ammonia in MeOH) to give the title compound (0.15 g). LCMS (Method 4): 1.00 min, 234.9 [M+H] + .

[0417] Intermediate 259: methyl (S)-3-((S)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)pent-4-enamido)-3-(2'-methyl-6'-(pent-4-en-1-yloxy)-[1,1'-biphenyl]-3-yl)propanoate Prepared in a manner similar to Intermediate 65. Intermediate 114 (0.23 g, 0.39 mmol), Intermediate 258 (92 mg, 0.39 mmol), and K2CO3 (0.16 g, 1.18 mmol) in MeCN (3 mL) were used at 85 °C for 18 h. Purification by flash chromatography (24 g silica gel, eluting with 2-8% (0.1% ammonia MeOH) in DCM) and again (24 g silica gel, eluting with 2.5% (0.1% ammonia MeOH) in DCM) gave the title compound (0.10 g). LCMS (Method 13): 1.70 min, 666.7 [M H] - .

[0418] Intermediate 260: Methyl 2-((10S,13S)-10-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-2 6 -methyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-7-en-13-yl)acetate Prepared in a manner similar to Intermediate 7. Intermediate 259 (0.10 g, 0.15 mmol) and Grubbs II (12.7 mg, 0.02 mmol) in DCE (75 mL) were used at 40° C. for 18 h. Additional Grubbs II (12.7 mg, 0.02 mmol) was added and heated at 40° C. for 6 h. Purification by flash chromatography (24 g silica gel, eluting with 0-10% 2M ammonia MeOH in DCM) gave the title compound (44 mg). LCMS (Method 16): 3.18 min, 638.5 [M H] - .

[0419] Intermediate 261: Methyl 2-((10S,13S)-10-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-2 6 -methyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetate Prepared in a manner similar to Intermediate 8. Intermediate 260 (44 mg, 0.06 mmol) and 10% palladium on carbon (6.5 mg) in MeOH (3 mL) were used under a hydrogen atmosphere at room temperature for 1 h. Purification by flash chromatography (24 g silica gel, eluting with 0-10% 2M ammonia in DCM MeOH) gave the title compound (35 mg). LCMS (Method 7): 1.59 min, 642.2 [M+H] + .

[0420] Intermediate 262: 5-(2-(azetidin-1-yl)ethyl)pyridin-2(1H)-one Prepared in a manner similar to Intermediate 137. Intermediate 136 (0.78 g, 5.05 mmol), azetidine (0.68 mL, 10.1 mmol), triethylamine (1.41 mL, 10.1 mmol), and 4 Å molecular sieves in DCM (15 mL) were used at room temperature for 2 h, followed by STAB (3.21 g, 15.2 mmol) at room temperature for 2 h. Purification by flash chromatography (40 g silica gel, eluting with 0-20% MeOH in DCM) followed by flash c...

Claims

1. A compound of formula I, or a pharmaceutically acceptable salt thereof, 【Chemistry 1】 During the ceremony, A is an aromatic ring, and Z １ , Z ２ , Z ３ and Z ４ are independently N or CR ２ and B is aryl, 5- to 10-membered heteroaryl, C ３－１０ cycloalkyl, or 4- to 10-membered heterocyclyl, where B is C １－５ Alkyl, halo, cyano, hydroxyl, NR ３ R ４ , C １－５ Alkoxy, C １－５ Haloalkyl, C １－５ Haloalkoxy, C １－４ Alkylene -O-C １－４ Alkyl, C ３－１０ optionally substituted with 1 to 5 substituents independently selected from cycloalkyl, and 4- to 10-membered heterocyclyl; L is C ３－８ Alkylene, C ３－８ Alkenylene, or C ３－８ Alkynylene, where one, two or three methylene groups in L are —O—, —S—, —C(O)—, or —N(R ５ )-, and L is C １－５ Alkyl, halo, hydroxyl, C １－５ Alkoxy, C １－５ Haloalkyl, C １－５ Haloalkoxy and NR ６ R ７ optionally substituted with 1 to 5 substituents independently selected from R １ is 4- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, aryl, C ３－１０ cycloalkyl, or NR ８ C(O)R ９ where: i) the 4- to 10-membered heterocyclyl, the 5- to 10-membered heteroaryl, the aryl, and the C ３－１０ Each cycloalkyl is C １－５ Alkyl, halo, oxo, cyano, C １－５ Alkoxy, C １－５ Haloalkyl, C １－５ Haloalkoxy, C １－４ Alkylene -O-C １－４ Alkyl, C １－４ Alkylene-OH, C ３－６ Cycloalkyl, 4- to 6-membered heterocyclyl, and C １－４ Alkylene -NR １０ R １１ optionally substituted with 1 to 5 substituents independently selected from ii) the 4- to 10-membered heterocyclyl group optionally contains one or two carbon-carbon double bonds and is optionally fused to a 5- or 6-membered heteroaryl ring, or a phenyl ring; R ２ is independently at each occurrence H, halo, cyano, hydroxyl, C １－５ Alkyl, C １－５ Alkoxy, C １－５ Haloalkyl, C １－５ Haloalkoxy, C １－４ Alkylene -O-C １－４ Alkyl, C ３－６ selected from cycloalkyl and 4- to 6-membered heterocyclyl; R ３ and R ４ are independent, H, C １－５ Alkyl, C １－５ Haloalkyl, and C ３－１０ cycloalkyl; R ５ , R ６ and R ７ are independently H or C １－５ is alkyl, R ８ But H, C １－６ Alkyl, C ２－６ Haloalkyl, C ２－４ Alkylene -O-C １－４ Alkyl; C ３－６ cycloalkyl, 4- to 6-membered heterocyclyl, or C ２－５ Alkylene -NR １２ R １３ and R ９ But C １－６ Alkyl, C １－６ Alkoxy, C １－６ Haloalkyl, C １－６ Haloalkoxy, C ２－４ Alkylene -O-C １－４ Alkyl, C ３－６ Cycloalkyl, 4- to 6-membered heterocyclyl, NR １４ R １５ or C １－５ Alkylene -NR １６ R １７ and R １０ and R １１ are independent, H, C １－５ Alkyl, C １－５ haloalkyl or -C １－４ Alkylene -O-C １－４ alkyl, or R １０ and R １１ together with the nitrogen attached to them, form halo, C １－５ Alkyl, C １－５ Alkoxy, C １－５ Haloalkyl, and C １－５ forming a 4- to 6-membered heterocyclyl ring optionally substituted with 1 to 4 groups independently selected from haloalkoxy; R １２ , R １３ , R １４ , R １５ , R １６ , and R １７ are independent, H, C １－５ Alkyl, or C １－５ haloalkyl, or R １２ and R １３ , R １４ and R １５ , or R １６ and R １７ independently, together with the nitrogen atom to which they are attached, represent halo and C １－５ The compound or a pharmaceutically acceptable salt thereof, wherein the compound forms a 4- to 6-membered heterocyclyl ring, optionally substituted with 1 to 4 groups independently selected from alkyl.

2. The compound has formula IA or formula IB: 【Chemistry 2】 10. The compound of claim 1, having a structure according to any one of:

3. Z １ , Z ２ , Z ３ and Z ４ All of this is CR ２ 3. The compound of claim 1 or claim 2, wherein:

4. Z １ , Z ２ , Z ３ and Z ４ One of them is N and the other three are CR ２ 3. The compound of claim 1 or claim 2, wherein:

5. R ２ is independently at each occurrence H, halo, cyano, hydroxyl, C １－５ Alkyl, C １－５ Alkoxy, C １－５ Haloalkyl, and C ３－６ The compound according to any one of claims 1 to 4, wherein the compound is selected from cycloalkyl.

6. R ２ 6. The compound of claim 5, wherein each occurrence is independently selected from H, fluoro, chloro, methyl, ethyl, trifluoromethyl, and cyclopropyl.

7. A is, 【Transformation 3】 3. The compound of claim 1 or claim 2, wherein "b" is the point of attachment to the B ring.

8. B is aryl or 5- to 6-membered heteroaryl, where B is C １－３ Alkyl, halo, cyano, hydroxyl, NR ３ R ４ , C １－５ Alkoxy, C １－５ Haloalkyl, C １－５ Haloalkoxy, C １－４ Alkylene -O-C １－４ Alkyl, C ３－７ The compound of any one of claims 1 to 7, optionally substituted with 1 to 4 substituents independently selected from cycloalkyl and 4- to 10-membered heterocyclyl.

9. B is C １－３ Alkyl, halo, cyano, C １－５ Alkoxy, C １－５ Haloalkyl, C ３－７ The compound of any one of claims 1 to 7, which is phenyl optionally substituted with 1 to 4 substituents independently selected from cycloalkyl and 4- to 10-membered heterocyclyl.

10. 8. The compound of any one of claims 1 to 7, wherein B is phenyl optionally substituted with 1 to 3 substituents independently selected from methyl, fluoro, cyclopropyl, and 5- to 6-membered heterocyclyl.

11. B, 【Chemistry 4】 wherein "a" is the point of attachment to the A ring and "l" is the point of attachment to the linker L.

12. L is C ３－８ Alkylene, or C ３－８ alkenylene, where one, two or three methylene groups in L are —O—, —S—, —C(O)—, or —N(R ５ )-, and L is C １－５ Alkyl, halo, hydroxyl, C １－５ Alkoxy, C １－５ Haloalkyl, C １－５ Haloalkoxy and NR ６ R ７ 12. The compound of any one of claims 1 to 11, optionally substituted with 1 to 5 substituents independently selected from:

13. L is C ５－８ Alkylene, or C ５－８ alkenylene, where one, two or three methylene groups in L are —O—, —C(O)—, or —N(R ５ )-, and L is C １－５ Alkyl, halo, hydroxyl, C １－５ Alkoxy, and C １－５ The compound of any one of claims 1 to 11, optionally substituted with 1 to 5 substituents independently selected from haloalkyl.

14. L is C ５－８ alkylene, where one or two methylene groups in L are —O—, —C(O)—, or —N(R ５ )-, and L is selected from 1 to 3 independently selected C １－５ The compound of any one of claims 1 to 11, optionally substituted with alkyl substituents.

15. L, 【Transformation 5】 12. The compound of any one of claims 1 to 11, wherein "b" is the point of attachment to the B ring.

16. R １ is 4- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, aryl, C ３－１０ cycloalkyl, or NR ８ C(O)R ９ where: i) the 4- to 10-membered heterocyclyl, the 5- to 10-membered heteroaryl, the aryl, and the C ３－１０ Each cycloalkyl is C １－５ Alkyl, halo, oxo, cyano, C １－５ Alkoxy, C １－５ Haloalkyl, C １－５ Haloalkoxy, C １－４ Alkylene -O-C １－４ Alkyl, C ３－６ Cycloalkyl, 4- to 6-membered heterocyclyl, and C １－４ Alkylene -NR １０ R １１ optionally substituted with 1 to 5 substituents independently selected from ii) The compound of any one of claims 1 to 15, wherein the 4- to 10-membered heterocyclyl group optionally contains one or two carbon-carbon double bonds and is optionally fused to a 5- or 6-membered heteroaryl ring, or a phenyl ring.

17. R １ is a 4- to 10-membered heterocyclyl, a 5- to 10-membered heteroaryl, or —NR ８ C(O)R ９ where: i) each of said 4- to 10-membered heterocyclyl and said 5- to 10-membered heteroaryl is C １－５ Alkyl, halo, oxo, cyano, C １－５ Alkoxy, C １－５ Haloalkyl, C １－５ Haloalkoxy, C １－４ Alkylene -O-C １－４ Alkyl, C ３－６ Cycloalkyl, 4- to 6-membered heterocyclyl, and C １－４ Alkylene -NR １０ R １１ optionally substituted with 1 to 5 substituents independently selected from ii) The compound of any one of claims 1 to 15, wherein the 4- to 10-membered heterocyclyl group optionally contains one or two carbon-carbon double bonds and is optionally fused to a 5- or 6-membered heteroaryl ring, or a phenyl ring.

18. R １ is a 5- to 6-membered heterocyclyl, and C １－５ Alkyl, halo, oxo, cyano, C １－５ Alkoxy, C １－５ Haloalkyl, C １－５ Haloalkoxy, C １－４ Alkylene -O-C １－４ Alkyl, C ３－６ Cycloalkyl, 4- to 6-membered heterocyclyl, and C １－４ Alkylene -NR １０ R １１ 16. The compound of any one of claims 1 to 15, wherein said 5- to 6-membered heterocyclyl is optionally substituted with 1 to 5 substituents independently selected from:

19. R １ but, 【Transformation 6】 is selected from C １－５ Alkyl, halo, oxo, cyano, C １－５ Alkoxy, C １－５ Haloalkyl, C １－５ Haloalkoxy, C １－４ Alkylene -O-C １－４ Alkyl, C １－４ Alkylene-OH, C ３－６ Cycloalkyl, 4- to 6-membered heterocyclyl, and C １－４ Alkylene -NR １０ R １１ 16. The compound of any one of claims 1 to 15, optionally substituted with 1 to 3 substituents independently selected from:

20. R １ but, 【Transformation 7】 wherein R １８ But hydrogen, C １－５ Alkyl, halo, C １－５ Alkoxy, C １－５ Haloalkyl, and C ３－６ cycloalkyl, R １９ But hydrogen, halo, C １－４ Alkylene -O-C １－４ Alkyl, C １－４ Alkylene-OH, and C １－４ Alkylene -NR １０ R １１ The compound according to any one of claims 1 to 15, selected from:

21. R １ But NR ８ C(O)R ９ and R ８ is H or C １－６ The compound of any one of claims 1 to 15, which is alkyl.

22. R １ But NR ８ C(O)R ９ and R ９ But C １－６ The compound of any one of claims 1 to 15 or claim 21, which is alkyl.

23. R １０ and R １１ are independently H or C １－５ The compound of any one of claims 1 to 22, which is alkyl.

24. R １０ and R １１ together with the nitrogen attached to them, form halo, C １－５ Alkyl, C １－５ Alkoxy, and C １－５ 23. The compound of any one of claims 1 to 22, forming a 4- to 6-membered heterocyclyl ring, optionally substituted with 1 to 4 groups independently selected from haloalkyl.

25. The following compounds: 2-((9S,12S)-9-acetamide-2 ６ -methyl-10-oxo-3-oxa-11-aza-1(1,3),2(1,2)-dibenzeneacyclododecaphan-12-yl)acetic acid, 2-((8S,11S)-8-acetamide-2 ６ -methyl-9-oxo-3-oxa-10-aza-1(1,3),2(1,2)-dibenzeneacycloundecaphan-11-yl)acetic acid, 2-((10S,13S)-10-acetamide-2 ６ -methyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetic acid, 2-((10S,13S)-10-acetamide-2 ６ ,8-dimethyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetic acid, 2-((10S,13S)-10-acetamide-2 ６ -methyl-11-oxo-3-oxa-12-aza-1,2(1,3)-dibenzeneacyclotridecaphan-13-yl)acetic acid, 2-((8S,11S)-8-acetamide-2 ６ ,6-dimethyl-9-oxo-3-oxa-10-aza-1(1,3),2(1,2)-dibenzeneacycloundecaphan-11-yl)acetic acid, 2-((10S,13S)-2 ６ -methyl-10-(N-methylacetamido)-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetic acid, 2-((3S,6S)-1 ６ -methyl-6-(N-methylacetamido)-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((10S,13S)-2 ６ -methyl-11-oxo-10-(2-oxopyridin-1(2H)-yl)-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetic acid, 2-((10S,13S)-2 ６ -methyl-11-oxo-10-(2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetic acid, 2-((10S,13S)-2 ６ -methyl-11-oxo-10-(2-oxopiperidin-1-yl)-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetic acid, 2-((9S,12S)-2 ６ -methyl-10-oxo-9-(2-oxopiperidin-1-yl)-3-oxa-11-aza-1(1,3),2(1,2)-dibenzeneacyclododecaphan-12-yl)acetic acid, 2-((10S,13S)-2 ６ -methyl-11-oxo-10-(2-oxopyrrolidin-1-yl)-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetic acid, 2-((8S,11S)-2 ６ -methyl-9-oxo-8-(2-oxopyridin-1(2H)-yl)-3-oxa-10-aza-1(1,3),2(1,2)-dibenzeneacycloundecaphan-11-yl)acetic acid, 2-((10S,13S)-2 ４ -Fluoro-2 ６ -methyl-11-oxo-10-(2-oxopyridin-1(2H)-yl)-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetic acid, 2-((10S,13S)-10-(5-fluoro-2-oxopyridin-1(2H)-yl)-2 ６ -methyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetic acid, 2-((10S,13S)-2 ６ -methyl-11-oxo-10-(2-oxopiperidin-1-yl)-3-oxa-12-aza-1(3,5)-pyridin-2(1,2)-benzeneacyclotridecaphan-13-yl)acetic acid, 2-((10S,13S)-2 ４ -Fluoro-2 ６ -methyl-11-oxo-10-(2-oxopyridin-1(2H)-yl)-3-oxa-12-aza-1(3,5)-pyridin-2(1,2)-benzeneacyclotridecaphan-13-yl)acetic acid, 2-((10S,13S)-10-(4-fluoro-2-oxopyridin-1(2H)-yl)-2 ６ -methyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetic acid, 2-((10S,13S)-2 ６ -methyl-11-oxo-10-(2-oxo-5-(trifluoromethyl)pyridin-1(2H)-yl)-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetic acid, 2-((10S,13S)-1 ４ -Fluoro-1 ５ , 2 ６ -dimethyl-11-oxo-10-(2-oxopyridin-1(2H)-yl)-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetic acid, 2-((10S,13S)-10-(5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-2 ６ -methyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetic acid, 2-((8S,11S)-8-(5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-2 ６ -methyl-9-oxo-3-oxa-10-aza-1(1,3),2(1,2)-dibenzeneacycloundecaphan-11-yl)acetic acid, 2-((10S,13S)-2 ６ -methyl-11-oxo-10-(2-oxopyridin-1(2H)-yl)-2 ４ -(tetrahydro-2H-pyran-4-yl)-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetic acid, 2-((3S,6S)-6-acetamide-1 ６ -methyl-5,12-dioxo-4,11-diaza-1(1,2),2(1,3)-dibenzeneacyclododecaphan-3-yl)acetic acid, 2-((3S,6S)-6-acetamide-1 ６ -methyl-5,13-dioxo-4,12-diaza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((11S,14S,E)-11-acetamide-2 ６ -methyl-12-oxo-3-oxa-13-aza-1(1,3),2(1,2)-dibenzeneacyclotetradecaphan-8-en-14-yl)acetic acid, 2-((11S,14S)-11-acetamide-2 ６ -methyl-12-oxo-3-oxa-13-aza-1(1,3),2(1,2)-dibenzeneacyclotetradecaphan-14-yl)acetic acid, 2-((10S,13S)-2 ４ -Fluoro-2 ６ -methyl-10-(N-methylacetamido)-11-oxo-3-oxa-12-aza-1(3,5)-pyridin-2(1,2)-benzeneacyclotridecaphan-13-yl)acetic acid, 2-((10S,13S)-10-(5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-2 ４ -Fluoro-2 ６ -methyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetic acid, 2-((10S,13S)-2 ６ -methyl-11-oxo-10-(2-oxo-5-(2-(pyrrolidin-1-yl)ethyl)pyridin-1(2H)-yl)-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetic acid, 2-((10S,13S)-2 ４ -Fluoro-2 ６ -methyl-10-(N-methylacetamido)-11-oxo-3-oxa-12-aza-1(3,5)-pyridin-2(1,2)-benzeneacyclotridecaphan-13-yl)acetic acid, 2-((10S,13S)-2 ６ -methyl-11-oxo-10-(4-oxoquinazolin-3(4H)-yl)-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetic acid, 2-((10S,13S)-10-(5-(2-(dimethylamino)ethyl)-3-fluoro-2-oxopyridin-1(2H)-yl)-2 ６ -methyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetic acid, 2-((10S,13S)-10-(5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-1 ４ -Fluoro-1 ５ , 2 ６ -dimethyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetic acid, 2-((10S,13S)-10-(5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-2 ４ , 2 ６ -dimethyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetic acid, 2-((10S,13S)-10-(5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-1 ４ -Fluoro-2 ６ -methyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetic acid, 2-((10S,13S)-10-(5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-1 ４ , 2 ４ -difluoro-1 ５ , 2 ６ -dimethyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetic acid, 2-((10S,13S)-10-(5-(2-(3-fluoroazetidin-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-2 ６ -methyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetic acid, 2-((10S,13S)-10-(5-(2-((R)-3-fluoropyrrolidin-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-2 ６ -methyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetic acid, 2-((10S,13S)-10-(5-(2-(3-methoxyazetidin-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-2 ６ -methyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetic acid, 2-((10S,13S)-10-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-2 ６ -methyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetic acid, 2-((10S,13S)-10-(5-(2-(azetidin-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-1 ５ , 2 ６ -dimethyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetic acid, 2-((10S,13S)-1 ４ , 2 ４ -difluoro-10-(3-fluoro-5-(2-((R)-3-fluoropyrrolidin-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-1 ５ , 2 ６ -dimethyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetic acid, 2-((10S,13S)-1 ４ -fluoro-10-(3-fluoro-5-(2-(3-fluoroazetidin-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-1 ５ , 2 ４ , 2 ６ -trimethyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetic acid, 2-((10S,13S)-1 ４ , 2 ４ -difluoro-10-(3-fluoro-5-(2-(3-fluoroazetidin-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-1 ５ , 2 ６ -dimethyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetic acid, 2-((10S,13S)-10-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 ４ -Fluoro-1 ５ , 2 ４ , 2 ６ -trimethyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetic acid, 2-((10S,13S)-1 ４ , 2 ４ -difluoro-10-(5-(2-(3-methoxyazetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 ５ , 2 ６ -dimethyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetic acid, 2-((10S,13S)-10-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 ４ , 2 ４ -difluoro-1 ５ , 2 ６ -dimethyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetic acid 2-((10S,13S)-1 ５ -cyclopropyl-10-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 ２ , 1 ４ -difluoro-2 ４ , 2 ６ -dimethyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetic acid, 2-((10S,13S)-1 ４ -Fluoro-1 ５ , 2 ４ , 2 ６ -trimethyl-11-oxo-10-(2-oxo-5-(2-(pyrrolidin-1-yl)ethyl)-4-(trifluoromethyl)pyridin-1(2H)-yl)-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetic acid, 2-((10S,13S)-1 ４ , 2 ４ -difluoro-1 ５ , 2 ６ -dimethyl-11-oxo-10-(2-oxo-5-(2-(pyrrolidin-1-yl)ethyl)-4-(trifluoromethyl)pyridin-1(2H)-yl)-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetic acid, 2-((10S,13S)-10-(5-(2-(dimethylamino)ethyl)-4-methyl-2-oxopyridin-1(2H)-yl)-1 ４ -Fluoro-1 ５ , 2 ４ , 2 ６ -trimethyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetic acid, 2-((10S,13S)-24-cyclopropyl-10-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 ４ -Fluoro-1 ５ , 2 ６ -dimethyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetic acid, 2-((10S,13S)-10-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 ４ -Fluoro-2 ４ , 2 ６ -dimethyl-11-oxo-1 ５ -(trifluoromethyl)-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetic acid, 2-((8S,11S)-8-(5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-2 ４ -Fluoro-2 ６ -methyl-9-oxo-3-oxa-10-aza-1(1,3),2(1,2)-dibenzeneacycloundecaphan-11-yl)acetic acid, 2-((10S,13S)-10-(5-(2-(azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 ５ -cyclopropyl-1 ２ , 1 ４ -difluoro-2 ４ , 2 ６ -dimethyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetic acid, 2-((10S,13S)-10-(5-(3-(dimethylamino)propyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 ４ -Fluoro-1 ５ , 2 ４ , 2 ６ -trimethyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetic acid, 2-((10S,13S)-1 ５ -cyclopropyl-10-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 ４ -Fluoro-2 ４ , 2 ６ -dimethyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetic acid, 2-((10S,13S)-1 ４ -Fluoro-1 ５ , 2 ４ , 2 ６ -trimethyl-11-oxo-10-(2-oxo-5-(3-(pyrrolidin-1-yl)propyl)-4-(trifluoromethyl)pyridin-1(2H)-yl)-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetic acid, 2-((10S,13S)-1 ５ -cyclopropyl-10-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 ４ , 2 ５ -difluoro-2 ４ , 2 ６ -dimethyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetic acid, 2-((10S,13S)-10-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 ２ , 1 ４ -difluoro-1 ５ , 2 ４ , 2 ６ -trimethyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetic acid, 2-((10S,13S)-1 ５ -cyclopropyl-10-(5-(3-(dimethylamino)propyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 ２ , 1 ４ -difluoro-2 ４ , 2 ６ -dimethyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetic acid, 2-((3S,6S)-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-2 ４ -Fluoro-1 ４ , 1 ６ -dimethyl-5-oxo-2 ５ -(trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzeneacyclotetradecaphan-3-yl)acetic acid, 2-((3S,6S)-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-2 ４ -Fluoro-1 ４ , 1 ６ -dimethyl-5-oxo-2 ５ -(trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-2 ４ -Fluoro-1 ４ , 1 ６ -dimethyl-5-oxo-2 ５ -(trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzeneacyclododecaphan-3-yl)acetic acid, 2-((10S,13S)-1 ５ -cyclopropyl-1 ４ -Fluoro-2 ４ , 2 ６ -dimethyl-11-oxo-10-(2-oxo-5-(2-(pyrrolidin-1-yl)ethyl)-4-(trifluoromethyl)pyridin-1(2H)-yl)-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetic acid, 2-((10S,13S)-1 ５ -cyclopropyl-10-(5-(3-(dimethylamino)propyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 ４ -Fluoro-2 ４ , 2 ６ -dimethyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetic acid, 2-((10S,13S)-1 ５ -cyclopropyl-10-(5-(2-(diethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 ４ -Fluoro-2 ４ , 2 ６ -dimethyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetic acid, 2-((3S,6S)-2 ５ -cyclopropyl-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-2 ４ -Fluoro-1 ４ , 1 ６ -dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-2 ５ -cyclopropyl-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-2 ４ -Fluoro-1 ４ , 1 ６ -dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclododecaphan-3-yl)acetic acid, 2-((10S,13S)-1 ４ , 2 ４ -difluoro-2 ６ -methyl-11-oxo-10-(2-oxo-5-(2-(pyrrolidin-1-yl)ethyl)-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 ５ -(trifluoromethyl)-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetic acid, 2-((10S,13S)-2 ４ -cyclopentyl-1 ５ -cyclopropyl-10-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 ４ -Fluoro-2 ６ -methyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetic acid, 2-((10S,13S)-1 ５ -cyclopropyl-10-(5-(3-(diethylamino)propyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 ４ -Fluoro-2 ４ , 2 ６ -dimethyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetic acid, 2-((3S,6S)-2 ５ -cyclopropyl-6-(5-(3-(dimethylamino)propyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-2 ４ -Fluoro-1 ４ , 1 ６ -dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-1 ４ -cyclopropyl-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-2 ４ -Fluoro-1 ６ , 2 ５ -dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-1 ４ -cyclopropyl-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-2 ４ -Fluoro-1 ６ , 2 ５ -dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclododecaphan-3-yl)acetic acid, 2-((3S,6S)-2 ５ -cyclopropyl-6-(5-(2-(dimethylamino)ethyl)-3-fluoro-2-oxopyridin-1(2H)-yl)-2 ４ -Fluoro-1 ４ , 1 ６ -dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((10S,13S)-1 ５ , 2 ４ -dicyclopropyl-10-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 ４ -Fluoro-2 ６ -methyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetic acid, 2-((9S,12S)-1 ５ , 2 ４ -dicyclopropyl-9-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 ４ -Fluoro-2 ６ -methyl-10-oxo-3-oxa-11-aza-1(1,3),2(1,2)-dibenzeneacyclododecaphan-12-yl)acetic acid, 2-((10S,13S)-1 ５ -cyclopropyl-10-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 ４ -Fluoro-2 ４ , 2 ５ , 2 ６ -trimethyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetic acid, 2-((9S,12S)-1 ５ -cyclopropyl-9-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 ４ -Fluoro-2 ４ , 2 ５ , 2 ６ -trimethyl-10-oxo-3-oxa-11-aza-1(1,3),2(1,2)-dibenzeneacyclododecaphan-12-yl)acetic acid, 2-((3S,6S)-2 ５ -cyclopropyl-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 ４ -Fluoro-1 ６ , 2 ４ -dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-2 ５ -cyclopropyl-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 ４ , 2 ４ -difluoro-1 ６ -methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclododecaphan-3-yl)acetic acid, 2-((10S,13S)-1 ５ -cyclopropyl-10-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 ４ -Fluoro-2 ６ -methyl-11-oxo-2 ４ -(trifluoromethyl)-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetic acid, 2-((9S,12S)-1 ５ -cyclopropyl-9-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 ４ -Fluoro-2 ６ -methyl-10-oxo-2 ４ -(trifluoromethyl)-3-oxa-11-aza-1(1,3),2(1,2)-dibenzeneacyclododecaphan-12-yl)acetic acid, 2-((3S,6S)-6-(5-(2-(azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-2 ４ -Fluoro-1 ４ , 1 ６ -dimethyl-5-oxo-2 ５ -(trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-2 ５ -cyclopropyl-1 ４ , 2 ４ -difluoro-6-(5-(2-(3-fluoroazetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 ６ -methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-2 ５ -cyclopropyl-1 ４ , 2 ４ -difluoro-6-(5-(2-(3-fluoroazetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 ６ -methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclododecaphan-3-yl)acetic acid, 2-((3S,6S)-1 ４ -cyclopropyl-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-2 ４ -Fluoro-1 ６ -methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-1 ４ -cyclopropyl-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-2 ４ -Fluoro-1 ６ -methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclododecaphan-3-yl)acetic acid, 2-((3S,6S)-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-2 ４ -Fluoro-1 ４ , 1 ６ -dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-2 ４ -Fluoro-1 ４ , 1 ６ -dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclododecaphan-3-yl)acetic acid, 2-((3S,6S)-2 ５ -cyclopropyl-6-(5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-2 ４ -Fluoro-1 ４ , 1 ６ -dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-2 ５ -cyclopropyl-6-(5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-2 ４ -Fluoro-1 ４ , 1 ６ -dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclododecaphan-3-yl)acetic acid, 2-((3S,6S)-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-2 ４ -Fluoro-1 ４ , 1 ６ , 2 ５ -trimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-2 ４ -Fluoro-1 ４ , 1 ６ , 2 ５ -trimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclododecaphan-3-yl)acetic acid, 2-((10S,13S)-10-(5-(3-(dimethylamino)propyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 ４ -Fluoro-2 ４ , 2 ６ -dimethyl-11-oxo-1 ５ -(trifluoromethyl)-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetic acid, 2-((3S,6S)-2 ５ -cyclopropyl-2 ４ -fluoro-6-(5-(2-(3-fluoroazetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 ４ , 1 ６ -dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((10S,13S)-10-(5-(2-(azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 ４ -Fluoro-2 ４ , 2 ６ -dimethyl-11-oxo-1 ５ -(trifluoromethyl)-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetic acid, 2-((3S,6S)-6-(5-(3-(dimethylamino)propyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-2 ４ -Fluoro-1 ４ , 1 ６ -dimethyl-5-oxo-2 ５ -(trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((10S,13S)-10-(5-(2-(azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 ５ -cyclopropyl-1 ４ -Fluoro-2 ４ , 2 ６ -dimethyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetic acid, 2-((3S,6S)-6-(5-(2-(azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-2 ５ -cyclopropyl-2 ４ -Fluoro-1 ４ , 1 ６ -dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-6-(5-(2-(azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-2 ５ -cyclopropyl-1 ４ , 2 ４ -difluoro-1 ６ -methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-6-(5-(2-(azetidin-1-yl)ethyl)-3-fluoro-2-oxopyridin-1(2H)-yl)-2 ５ -cyclopropyl-2 ４ -Fluoro-1 ４ , 1 ６ -dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-2 ５ -cyclopropyl-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-2 ４ -Fluoro-1 ４ -methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-2 ５ -cyclopropyl-6-(5-(3-(dimethylamino)propyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 ４ , 2 ４ -difluoro-1 ６ -methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-2 ５ -cyclopropyl-6-(5-(2-(dimethylamino)ethyl)-3-fluoro-2-oxopyridin-1(2H)-yl)-1 ４ , 2 ４ -difluoro-1 ６ -methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-2 ５ -cyclopropyl-6-(5-(2-(dimethylamino)ethyl)-4-methyl-2-oxopyridin-1(2H)-yl)-1 ４ , 2 ４ -difluoro-1 ６ -methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-2 ５ -cyclopropyl-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-2 ４ -Fluoro-1 ６ -methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-2 ５ -cyclopropyl-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-2 ４ -Fluoro-1 ６ -methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclododecaphan-3-yl)acetic acid, 2-((3S,6S)-2 ５ -cyclopropyl-2 ４ -fluoro-6-(3-fluoro-5-(2-(3-fluoroazetidin-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-1 ４ , 1 ６ -dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((10S,13S)-1 ５ -cyclopropyl-1 ４ -fluoro-10-(4-methoxy-2-oxopyridin-1(2H)-yl)-2 ４ , 2 ６ -dimethyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetic acid, 2-((3S,6S)-6-(5-(2-(azetidin-1-yl)ethyl)-4-methyl-2-oxopyridin-1(2H)-yl)-2 ５ -cyclopropyl-2 ４ -Fluoro-1 ４ , 1 ６ -dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 ４ , 2 ４ -difluoro-1 ６ -methyl-5-oxo-2 ５ -(trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 ４ , 2 ４ -difluoro-1 ６ -methyl-5-oxo-2 ５ -(trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzeneacyclododecaphan-3-yl)acetic acid, 2-((3S,6S)-2 ５ -cyclopropyl-1 ４ , 2 ４ -difluoro-6-(5-(3-(3-fluoroazetidin-1-yl)propyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 ６ -methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-6-(5-(2-(azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-2 ４ -Fluoro-1 ４ , 1 ６ , 2 ５ -trimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-6-(5-(3-(dimethylamino)propyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-2 ４ -Fluoro-1 ４ , 1 ６ , 2 ５ -trimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-2 ５ -cyclopropyl-1 ４ , 2 ４ -difluoro-6-(5-(2-(3-methoxyazetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 ６ -methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-2 ５ -cyclopropyl-1 ４ , 2 ４ -difluoro-6-(5-(2-(3-methoxyazetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 ６ -methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclododecaphan-3-yl)acetic acid, 2-((3S,6S)-6-(5-(2-(azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-2 ５ -cyclopropyl-2 ４ -Fluoro-1 ６ -methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-2 ５ -cyclopropyl-6-(5-(2-(dimethylamino)ethyl)-4-methyl-2-oxopyridin-1(2H)-yl)-2 ４ -Fluoro-1 ４ , 1 ６ -dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-2 ５ -cyclopropyl-6-(5-(2-(dimethylamino)ethyl)-4-methyl-2-oxopyridin-1(2H)-yl)-2 ４ -Fluoro-1 ４ , 1 ６ -dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclododecaphan-3-yl)acetic acid, 2-((10S,13S)-1 ５ -cyclopropyl-1 ４ -fluoro-10-(4-fluoro-2-oxopyridin-1(2H)-yl)-2 ４ , 2 ６ -dimethyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetic acid, 2-((3S,6S)-2 ５ -cyclopropyl-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 ４ , 1 ６ -dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-6-(5-(2-(azetidin-1-yl)ethyl)-4-methyl-2-oxopyridin-1(2H)-yl)-2 ５ -cyclopropyl-1 ４ , 2 ４ -difluoro-1 ６ -methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-2 ５ -cyclopropyl-1 ４ , 2 ４ -difluoro-1 ６ -methyl-6-(4-methyl-2-oxopyridin-1(2H)-yl)-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-2 ４ -chloro-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 ４ , 1 ６ -dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-2 ５ -cyclopropyl-6-(5-(3-(dimethylamino)propyl)-4-methyl-2-oxopyridin-1(2H)-yl)-1 ４ , 2 ４ -difluoro-1 ６ -methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-6-(5-(2-(azetidin-1-yl)ethyl)-3-fluoro-2-oxopyridin-1(2H)-yl)-2 ５ -cyclopropyl-1 ４ , 2 ４ -difluoro-1 ６ -methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-2 ５ -cyclopropyl-6-(4-cyclopropyl-5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-2 ４ -Fluoro-1 ４ , 1 ６ -dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-1 ４ , 2 ４ -difluoro-6-(3-(2-(3-fluoroazetidin-1-yl)ethyl)-6-oxo-4-(trifluoromethyl)pyridazin-1(6H)-yl)-1 ６ , 2 ５ -dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-2 ５ -cyclopropyl-6-(5-(3-(dimethylamino)propyl)-4-methyl-2-oxopyridin-1(2H)-yl)-2 ４ -Fluoro-1 ４ , 1 ６ -dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-2 ５ -cyclopropyl-6-(5-(3-(dimethylamino)propyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-2 ４ -Fluoro-1 ６ -methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-2 ５ -cyclopropyl-6-(5-(3-(dimethylamino)propyl)-3-fluoro-2-oxopyridin-1(2H)-yl)-2 ４ -Fluoro-1 ４ , 1 ６ -dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-2 ５ -cyclopropyl-6-(4-cyclopropyl-5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-1 ４ , 2 ４ -difluoro-1 ６ -methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-2 ５ -cyclopropyl-6-(5-(3-(dimethylamino)propyl)-3-fluoro-2-oxopyridin-1(2H)-yl)-1 ４ , 2 ４ -difluoro-1 ６ -methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-2 ５ -cyclopropyl-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 ４ , 1 ６ , 2 ４ -trifluoro-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-2 ５ -cyclopropyl-2 ４ -fluoro-6-(5-(3-(3-fluoroazetidin-1-yl)propyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 ４ , 1 ６ -dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-6-(5-(2-(azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 ４ , 2 ４ -difluoro-1 ６ -methyl-5-oxo-2 ５ -(trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-6-(5-(2-(diethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 ４ , 2 ４ -difluoro-1 ６ -methyl-5-oxo-2 ５ -(trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-6-(5-(3-(dimethylamino)propyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 ４ , 2 ４ -difluoro-1 ６ -methyl-5-oxo-2 ５ -(trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-6-(5-(3-(azetidin-1-yl)propyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-2 ５ -cyclopropyl-1 ４ , 2 ４ -difluoro-1 ６ -methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-2 ５ -cyclopropyl-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 ４ , 2 ２ , 2 ４ -trifluoro-1 ６ -methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 ４ , 2 ４ -difluoro-1 ６ , 2 ５ -dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-6-(5-(2-(diethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 ４ , 2 ４ -difluoro-1 ６ , 2 ５ -dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-6-(5-(2-(azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 ４ , 2 ４ -difluoro-1 ６ , 2 ５ -dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-1 ６ -chloro-2 ５ -cyclopropyl-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-2 ４ -fluoro-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-2 ５ -cyclopropyl-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 ４ -Fluoro-1 ６ -methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-6-(5-(3-(azetidin-1-yl)propyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 ４ , 2 ４ -difluoro-1 ６ -methyl-5-oxo-2 ５ -(trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-2 ４ -Fluoro-1 ４ , 1 ６ , 2 ５ -trimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-8-en-3-yl)acetic acid, 2-((3S,6S)-6-(4-(difluoromethyl)-5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-1 ４ , 2 ４ -difluoro-1 ６ -methyl-5-oxo-2 ５ -(trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 ４ , 2 ４ , 2 ５ -trifluoro-1 ６ -methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-2 ５ -chloro-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 ４ , 2 ４ -difluoro-1 ６ -methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-6-(5-(2-(azetidin-1-yl)ethyl)-3-methyl-2-oxopyridin-1(2H)-yl)-2 ５ -cyclopropyl-1 ４ , 2 ４ -difluoro-1 ６ -methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((10S,13S)-1 ４ , 2 ４ -difluoro-1 ５ , 2 ６ -dimethyl-11-oxo-10-(3-oxo-2-azaspiro[4.5]decan-2-yl)-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetic acid, 2-((10S,13S)-1 ５ -cyclopropyl-10-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 ４ -Fluoro-2 ３ , 2 ４ , 2 ６ -trimethyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetic acid, 2-((3S,6S)-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 ４ -Fluoro-1 ６ -methyl-5-oxo-2 ５ -(trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 ４ , 1 ６ , 2 ４ -trifluoro-2 ６ -methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 ４ -Fluoro-1 ６ , 2 ５ -dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 ４ , 2 ２ -difluoro-1 ６ -methyl-5-oxo-2 ５ -(trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((10S,13S)-1 ５ -cyclopropyl-10-(5-(3-(dimethylamino)propyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 ４ , 2 ３ , 2 ４ -trifluoro-2 ６ -methyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetic acid, 2-((3S,6S)-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 ４ , 2 ４ -difluoro-1 ６ ,8-dimethyl-5-oxo-2 ５ -(trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 ４ , 2 ４ -difluoro-1 ６ ,8-dimethyl-5-oxo-2 ５ -(trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzeneacyclododecaphan-3-yl)acetic acid, 2-((3S,6S)-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 ４ , 2 ４ -difluoro-1 ６ , 2 ６ -dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((10S,13S)-1 ４ , 2 ４ -difluoro-1 ５ , 2 ６ -dimethyl-10-(3-methyl-2-oxotetrahydropyrimidin-1(2H)-yl)-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetic acid, 2-((3S,6S)-1 ４ , 2 ４ -difluoro-6-(5-(2-(3-methoxyazetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 ６ -methyl-5-oxo-2 ５ -(trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-6-(5-(2-(ethyl(methyl)amino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 ４ , 2 ４ -difluoro-1 ６ -methyl-5-oxo-2 ５ -(trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-6-(5-(3-(dimethylamino)propyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 ４ , 2 ４ -difluoro-1 ６ , 2 ５ -dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-1 ４ , 2 ４ -difluoro-6-(5-(2-(3-fluoroazetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 ６ -methyl-5-oxo-2 ５ -(trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-6-(5-(3-(azetidin-1-yl)propyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 ４ , 2 ４ -difluoro-1 ６ , 2 ５ -dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 ４ , 1 ６ , 2 ４ , 2 ５ -tetrafluoro-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 ４ , 1 ６ , 2 ４ , 2 ５ -tetrafluoro-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclododecaphan-3-yl)acetic acid, 2-((3S,6S)-1 ４ , 2 ４ -difluoro-1 ６ -methyl-5-oxo-6-(2-oxo-5-(2-(pyrrolidin-1-yl)ethyl)-4-(trifluoromethyl)pyridin-1(2H)-yl)-2 ５ -(trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-1 ４ , 2 ４ -difluoro-1 ６ -methyl-5-oxo-6-(3-oxo-3,4-dihydroisoquinolin-2(1H)-yl)-2 ５ -(trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-1 ４ , 2 ４ -difluoro-1 ６ , 2 ５ -dimethyl-5-oxo-6-(3-oxo-2-azaspiro[4.5]decan-2-yl)-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 ４ , 2 ４ -difluoro-1 ６ ,9-dimethyl-5-oxo-2 ５ -(trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 ４ , 1 ６ , 2 ４ -trifluoro-5-oxo-2 ５ -(trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-1 ４ , 2 ４ , 2 ５ -trifluoro-1 ６ -methyl-5-oxo-6-(3-oxo-2-azaspiro[4.5]decan-2-yl)-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((10S,13S)-10-(4,4-dimethyl-2-oxopyrrolidin-1-yl)-1 ４ , 2 ４ -difluoro-1 ５ , 2 ６ -dimethyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetic acid, 2-((3S,6S)-1 ４ , 2 ４ -difluoro-1 ６ -methyl-5-oxo-6-(3-oxo-2-azaspiro[4.4]nonan-2-yl)-2 ５ -(trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-2 ５ -cyclopropyl-1 ４ , 2 ４ -difluoro-1 ６ -methyl-5-oxo-6-(3-oxo-2,8-diazaspiro[4.5]decan-2-yl)-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-2 ５ -cyclopropyl-1 ４ , 2 ４ -difluoro-1 ６ -methyl-5-oxo-6-(8-methyl-3-oxo-2,8-diazaspiro[4.5]decan-2-yl)-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-1 ４ , 2 ４ -difluoro-6-(3-fluoro-5-(2-(3-fluoroazetidin-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-1 ６ -methyl-5-oxo-2 ５ -(trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-1 ４ , 2 ４ -difluoro-6-(5-(2-(3-methoxyazetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 ６ , 2 ５ -dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-6-(5-bromo-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 ４ , 2 ４ -difluoro-1 ６ -methyl-5-oxo-2 ５ -(trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-6-(5-(3-(dimethylamino)propyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 ４ , 2 ４ , 2 ５ -trifluoro-1 ６ -methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-6-(5-(3-(dimethylamino)propyl)-2-oxopyridin-1(2H)-yl)-1 ４ , 2 ４ -difluoro-1 ６ -methyl-5-oxo-2 ５ -(trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-6-(5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-1 ６ -methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-1 ４ , 2 ４ -difluoro-1 ６ -methyl-5-oxo-6-(3-oxo-8-oxa-2-azaspiro[4.5]decan-2-yl)-2 ５ -(trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 ６ -ethyl-1 ４ , 2 ４ -difluoro-5-oxo-2 ５ -(trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-6-(5-(3-(dimethylamino)propyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 ４ , 1 ６ , 2 ４ -trifluoro-5-oxo-2 ５ -(trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-1 ４ , 2 ４ , 2 ５ -trifluoro-1 ６ -methyl-6-(1-methyl-2-oxo-1,3-diazaspiro[4.5]decan-3-yl)-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-2 ５ -cyclopropyl-2 ４ -Fluoro-1 ４ , 1 ６ -dimethyl-5-oxo-6-(2-oxo-5-(2-(pyrrolidin-1-yl)ethyl)-4-(trifluoromethyl)pyridin-1(2H)-yl)-12-oxa-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((10S,13S)-10-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 ４ , 2 ４ -difluoro-2 ６ ,7-dimethyl-11-oxo-1 ５ -(trifluoromethyl)-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetic acid, 2-((10S,13S)-10-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 ４ , 2 ４ -difluoro-2 ６ ,4-dimethyl-11-oxo-1 ５ -(trifluoromethyl)-3-oxa-12-aza-1(1,3),2(1,2)-dibenzeneacyclotridecaphan-13-yl)acetic acid, 2-((3S,6S)-1 ４ , 2 ４ -difluoro-1 ６ -methyl-6-(5-(2-morpholinoethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-5-oxo-2 ５ -(trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-6-(3-(2-(azetidin-1-yl)ethyl)-6-oxo-5-(trifluoromethyl)pyridazin-1(6H)-yl)-2 ５ -cyclopropyl-1 ４ , 2 ４ -difluoro-1 ６ -methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-2 ５ -cyclopropyl-1 ４ , 2 ４ -difluoro-6-(3-(2-(3-fluoroazetidin-1-yl)ethyl)-6-oxo-5-(trifluoromethyl)pyridazin-1(6H)-yl)-1 ６ -methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-6-(3-(2-(azetidin-1-yl)ethyl)-6-oxo-5-(trifluoromethyl)pyridazin-1(6H)-yl)-1 ４ , 2 ４ -difluoro-1 ６ -methyl-5-oxo-2 ５ -(trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-6-(3-(2-(azetidin-1-yl)ethyl)-5-methyl-6-oxopyridazin-1(6H)-yl)-2 ５ -cyclopropyl-1 ４ , 2 ４ -difluoro-1 ６ -methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-6-(3-(3-(dimethylamino)propyl)-6-oxo-5-(trifluoromethyl)pyridazin-1(6H)-yl)-1 ４ , 2 ４ -difluoro-1 ６ -methyl-5-oxo-2 ５ -(trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-1 ４ , 2 ４ -difluoro-6-(3-(2-(3-fluoroazetidin-1-yl)ethyl)-5-methyl-6-oxopyridazin-1(6H)-yl)-1 ６ -methyl-5-oxo-2 ５ -(trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-1 ４ , 2 ４ -difluoro-6-(3-(2-(3-methoxyazetidin-1-yl)ethyl)-5-methyl-6-oxopyridazin-1(6H)-yl)-1 ６ -methyl-5-oxo-2 ５ -(trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-6-(3-(2-(azetidin-1-yl)ethyl)-5-methyl-6-oxopyridazin-1(6H)-yl)-1 ４ , 2 ４ -difluoro-1 ６ -methyl-5-oxo-2 ５ -(trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-6-(3-(3-(dimethylamino)propyl)-5-methyl-6-oxopyridazin-1(6H)-yl)-1 ４ , 2 ４ -difluoro-1 ６ -methyl-5-oxo-2 ５ -(trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-6-(3-(3-(dimethylamino)propyl)-6-oxo-4-(trifluoromethyl)pyridazin-1(6H)-yl)-1 ４ , 2 ４ -difluoro-1 ６ -methyl-5-oxo-2 ５ -(trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-1 ４ , 2 ４ -difluoro-6-(3-(2-(3-fluoroazetidin-1-yl)ethyl)-6-oxo-4-(trifluoromethyl)pyridazin-1(6H)-yl)-1 ６ -methyl-5-oxo-2 ５ -(trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-6-(3-(3-(dimethylamino)propyl)-6-oxo-4-(trifluoromethyl)pyridazin-1(6H)-yl)-1 ４ , 2 ４ -difluoro-1 ６ , 2 ５ -dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-2 ５ -cyclopropyl-6-(3-(3-(dimethylamino)propyl)-6-oxo-4-(trifluoromethyl)pyridazin-1(6H)-yl)-1 ４ , 2 ４ -difluoro-1 ６ -methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-6-(3-(3-(azetidin-1-yl)propyl)-6-oxo-4-(trifluoromethyl)pyridazin-1(6H)-yl)-1 ４ , 2 ４ -difluoro-1 ６ -methyl-5-oxo-2 ５ -(trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-2 ５ -cyclopropyl-1 ４ , 2 ４ -difluoro-6-(3-(2-(3-methoxyazetidin-1-yl)ethyl)-6-oxo-4-(trifluoromethyl)pyridazin-1(6H)-yl)-1 ６ -methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-2 ５ -cyclopropyl-1 ４ , 2 ４ -difluoro-6-(3-(2-(3-fluoroazetidin-1-yl)ethyl)-6-oxo-4-(trifluoromethyl)pyridazin-1(6H)-yl)-1 ６ -methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-2 ５ -cyclopropyl-1 ４ , 2 ４ -difluoro-6-(5-(3-hydroxypropyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 ６ -methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-1 ４ , 2 ４ -difluoro-6-(3-(2-(3-methoxyazetidin-1-yl)ethyl)-6-oxo-4-(trifluoromethyl)pyridazin-1(6H)-yl)-1 ６ -methyl-5-oxo-2 ５ -(trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-1 ４ , 1 ６ , 2 ４ -trifluoro-6-(5-(2-morpholinoethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-5-oxo-2 ５ -(trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-6-(5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-1 ４ , 2 ４ -difluoro-1 ６ -methyl-5-oxo-2 ５ -(trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-6-(3-(2-(dimethylamino)ethyl)-6-oxo-4-(trifluoromethyl)pyridazin-1(6H)-yl)-1 ４ , 2 ４ -difluoro-1 ６ -methyl-5-oxo-2 ５ -(trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-2 ５ -cyclopropyl-1 ４ , 2 ４ -difluoro-6-(3-(2-(3-fluoroazetidin-1-yl)ethyl)-5-methyl-6-oxopyridazin-1(6H)-yl)-1 ６ -methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-1 ４ , 2 ４ -difluoro-6-(3-(2-(3-methoxyazetidin-1-yl)ethyl)-6-oxo-4-(trifluoromethyl)pyridazin-1(6H)-yl)-1 ６ , 2 ５ -dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-2 ５ -cyclopropyl-1 ４ , 1 ６ , 2 ４ -trifluoro-6-(5-(2-(3-methoxyazetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-6-(3-(3-(dimethylamino)propyl)-6-oxo-4-(trifluoromethyl)pyridazin-1(6H)-yl)-1 ４ , 2 ４ , 2 ５ -trifluoro-1 ６ -methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-2 ５ -cyclopropyl-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-1 ３ , 1 ４ , 2 ４ -trifluoro-1 ６ -methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-6-(3-(2-(azetidin-1-yl)ethyl)-6-oxo-4-(trifluoromethyl)pyridazin-1(6H)-yl)-1 ４ , 2 ４ -difluoro-1 ６ -methyl-5-oxo-2 ５ -(trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-2 ５ -cyclopropyl-6-(3-(2-(dimethylamino)ethyl)-6-oxo-4-(trifluoromethyl)pyridazin-1(6H)-yl)-1 ４ , 1 ６ , 2 ４ -trifluoro-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-6-(3-(2-(azetidin-1-yl)ethyl)-6-oxo-4-(trifluoromethyl)pyridazin-1(6H)-yl)-1 ４ , 2 ４ -difluoro-1 ６ , 2 ５ -dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-2 ５ -cyclopropyl-6-(5-(2-(dimethylamino)ethyl)-4-methyl-2-oxopyrimidin-1(2H)-yl)-1 ４ , 2 ４ -difluoro-1 ６ -methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, 2-((3S,6S)-6-(5-(2-(3-methoxyazetidin-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-1 ６ -methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, and 2-((3S,6S)-6-(5-(2-(3-fluoroazetidin-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-1 ６ -methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzeneacyclotridecaphan-3-yl)acetic acid, or a pharmaceutically acceptable salt thereof.

26. A pharmaceutical composition comprising a compound according to any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

27. A compound according to any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 26, for use in therapy.

28. A compound according to any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 26, for use in the treatment of a disease or disorder mediated by α4β7.

29. A compound according to any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 26, for use in the treatment of inflammatory bowel diseases such as ulcerative colitis or Crohn's disease.

30. 27. A method for treating a disease or disorder mediated by α4β7, comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound according to any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 26.

31. A method for treating inflammatory bowel disease, such as ulcerative colitis or Crohn's disease, comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound according to any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 26.

Images