Macrocyclic alpha4beta7 integrin inhibitors

Abstract

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

Description

THERAPEUTIC COMPOUNDS INTRODUCTION

[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 show selectivity over the closely related integrin receptor α4β1. The present invention also relates to processes for the preparation of these compounds, to pharmaceutical compositions comprising them, and to their use in the treatment of diseases or disorders associated with α4β7, such as inflammatory bowel disease, including ulcerative colitis and Crohn’s disease. BACKGROUND OF THE INVENTION

[0002] Integrins are a family of transmembrane adhesion receptors, that facilitate the adhesive connection between cells and their surrounding extracellular matrix or neighbouring cells (DOI: 10.1007 / s00441-009-0834-6; DOI: 10.1016 / j.bbamem.2020.183206). They comprise of heterodimeric Type I transmembrane proteins consisting of two non-covalently 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 a binding site for extracellular ligands while the short cytoplasmic tails interact with a cluster of associated proteins that ultimately connects to the cytoskeleton. In mammals, there are 18 known alpha subunits and eight known beta subunits, which combine to form 24 distinct integrin receptors that play an important role 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, by the differential expression of integrins, and second, by chemokines that induce changes in integrin adhesive state (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, which is highly expressed on lymphocytes, including B and T lymphocytes, directs the homing of lymphocytes to the intestine via binding to its primary ligand, MAdCAM-1, which is expressed predominantly 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 from binding to MAdCAM-1 may be a useful method for treating inflammatory conditions of the intestine. Indeed, monoclonal antibodies displaying high binding affinity for α4β7, for exampleNatalizumab (Tysabri®) and Vedolizumab (Entyvio®), have displayed therapeutic benefits for 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, immunogenicity, which leads to a decrease in the effectiveness of drugs and an increase in the 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 ^4 ^1 integrin-ligand interactions, which carries an increased risk of development of progressive multifocal leukoencephalopathy (PML), an opportunistic brain infection caused by reactivated John Cunningham virus, which usually leads to death or severe disability (DOI: 10.1111 / j.1527- 3458.2007.00003.x).

[0004] Therefore, the development of an effective and safe small molecule α4β7 integrin inhibitor that can be administered orally, potentially increasing patient drug adherence, would be an important addition to the therapeutic armamentarium for α4β7 mediated conditions, such as the inflammatory bowel diseases ulcerative colitis, and Crohn’s disease. Indeed, clinical studies are ongoing with two selective small molecule α4β7 integrin inhibitors (NCT05291689; ACTRN12621000612819).

[0005] Therefore, there is an ongoing need for development of an effective and safe small molecule α4β7 integrin inhibitor, given the role of α4β7 in inflammatory bowel diseases. SUMMARY OF THE INVENTION

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

[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 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 the treatment of diseases or disorders mediated by α4β7.

[0010] In another aspect, the present invention relates to a method of treating a disease or disorder mediated by α4β7, said 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 disease, including ulcerative colitis and Crohn’s disease.

[0012] In another aspect, the present invention provides a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, 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, said method comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein.

[0014] The present invention further provides a method of synthesising a compound, or a pharmaceutically acceptable salt thereof, as defined herein.

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

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

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

[0018] Unless otherwise stated, the following terms used in the specification and claims have the following meanings set out below.

[0019] It is to be appreciated that references to “treating” or “treatment” include prophylaxis as well as the alleviation of established symptoms of a condition. “Treating” or “treatment” of a state, disorder or condition therefore includes: (1) preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a human that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience ordisplay clinical or subclinical symptoms of the state, disorder or condition, (2) inhibiting the state, disorder or condition, i.e., arresting, reducing or delaying the development of the disease or a relapse thereof (in case of maintenance treatment) or at least one clinical or subclinical symptom thereof, or (3) relieving or attenuating the disease, i.e., causing regression of the state, 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 to be treated.

[0021] In this specification the term “alkyl” includes both straight 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] In this specification the term “alkylene” includes both straight and branched chain divalent alkyl groups. For example, “C1-4alkylene” includes methylene (-CH2-), ethylene (-CH2CH2-), propylene and butylene.

[0023] In this specification the term “alkoxy” includes both straight and branched chain alkyl groups singularly bonded to oxygen. For example, “C1-4alkoxy” 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, cycloheptyl. Bicyclic rings may be fused or spiro attached; 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 an alkyl group respectively in which one or more hydrogen atoms have been replaced by halogen (e.g. fluorine) atoms. Examples of haloalkyl groups include fluoroalkyl groups such as –CHF2, –CH2CF3, or perfluoroalkyl / alkoxy groups such as –CF3, or –CF2CF3.

[0028] The term “heterocyclyl”, “heterocyclic” or “heterocycle” means a non-aromatic saturated or partially saturated monocyclic, fused, bridged, or spiro bicyclic heterocyclic ring system(s). Monocyclic heterocyclic rings contain from about 3 to 12 (suitably from 3 to 7) ring atoms, with from 1 to 5 (suitably 1, 2 or 3) heteroatoms selected from nitrogen, oxygen or sulfur in the ring. Bicyclic heterocycles contain from 7 to 17 member atoms, suitably 7 to 12 member atoms, in the ring. Bicyclic heterocyclic(s) rings may be fused, spiro, or bridged ring systems. Conveniently, the heterocyclic group is a 4- to 10-membered heterocyclyl. Suitable 4- to 10-membered heterocyclyl groups comprise monocyclic and bicyclic heterocycles. Conveniently, the monocyclic heterocycles contain 4 to 6 ring atoms with 1 to 3 heteroatoms selected from nitrogen, oxygen or sulfur in the ring. Conveniently, the bicyclic heterocycles contain 8 to 10 ring atoms with 1 to 3 heteroatoms selected from nitrogen, oxygen or sulfur in the ring. Suitable bicyclic heterocyclyl groups comprise 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 cyclic ethers such as oxiranyl, oxetanyl, tetrahydrofuranyl, dioxanyl, and substituted cyclic ethers. Heterocycles containing nitrogen include, for example, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrotriazinyl, tetrahydropyrazolyl, 1,2-diazacyclohexanyl, and the like. Typical sulfur containing heterocycles include tetrahydrothienyl, dihydro-1,3-dithiol, tetrahydro-2H-thiopyran, and hexahydrothiepine. Other heterocycles include dihydro-oxathiolyl, dihydroisoxazolyl (such as 4,5-dihydroisoxazolyl), dihydropyridinyl (such as 1,2-dihydropyridinyl or 1,6-dihydropyridinyl), tetrahydro-oxazolyl, tetrahydro-oxadiazolyl, tetrahydro-dioxazolyl, tetrahydro-oxathiazolyl, hexahydrotriazinyl, tetrahydro-oxazinyl, morpholinyl, thiomorpholinyl, tetrahydropyrimidinyl, dioxolinyl, octahydrobenzofuranyl, octahydrobenzimidazolyl, and octahydrobenzothiazolyl. For heterocycles containing sulfur, the oxidized sulfur heterocycles containing SO or SO2 groups are also included. Examples include the sulfoxide and sulfone forms of tetrahydrothienyl and thiomorpholinyl such as tetrahydrothiene 1,1-dioxide and thiomorpholinyl 1,1-dioxide. A suitable value for a heterocyclyl group which bears 1 or 2 oxo (=O) or thioxo (=S) substituents is, for example, 2-oxopyrrolidinyl, 2-thioxopyrrolidinyl, 2- oxoimidazolidinyl, 2-thioxoimidazolidinyl, 2-oxopiperidinyl, 2,5-dioxopyrrolidinyl, 2,5- dioxoimidazolidinyl or 2,6-dioxopiperidinyl. Particular heterocyclyl groups are saturated monocyclic 3 to 7 membered heterocyclyls containing 1, 2 or 3 heteroatoms selected from nitrogen, oxygen or sulfur, for example azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, morpholinyl, tetrahydrothienyl, tetrahydrothienyl 1,1-dioxide, thiomorpholinyl, thiomorpholinyl 1,1-dioxide, piperidinyl, homopiperidinyl, piperazinyl or homopiperazinyl. As the skilled person would appreciate, any heterocycle may be linked to another group via any suitable atom, such as via a carbon or nitrogen atom. Suitably, the term “heterocyclyl”,“heterocyclic” or “heterocycle” will refer to 4, 5, 6 or 7 membered monocyclic rings as defined above, unless specified otherwise.

[0029] The term “heteroaryl” or “heteroaromatic” means an aromatic mono-, bi-, or polycyclic ring incorporating one or more (for example 1-4, particularly 1, 2 or 3) heteroatoms selected from nitrogen, oxygen or sulfur. Examples of heteroaryl groups are monocyclic and bicyclic groups containing from five to twelve ring members, and more usually from five to ten ring members. The heteroaryl group can be, for example, a 5- or 6-membered monocyclic ring or a 9- or 10-membered bicyclic ring, for example a bicyclic structure formed from fused five and six membered rings or two fused six membered rings. Each ring may contain up to about four heteroatoms typically selected from nitrogen, sulfur and oxygen. Typically, the heteroaryl ring will contain up to 3 heteroatoms, more usually up to 2, for example a single heteroatom. In one embodiment, the heteroaryl ring contains at least one ring nitrogen atom. The nitrogen atoms in the heteroaryl rings 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. In general, the number of basic nitrogen atoms present in the heteroaryl group, including any amino group substituents of the ring, will be less than five. Suitably, the term “heteroaryl” or “heteroaromatic” will refer to 5 or 6 membered monocyclic heteroaryl rings 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, 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, imidazo[1,2- b][1,2,4]triazinyl. “Heteroaryl” also covers partially aromatic bi- or polycyclic ring systems wherein at least one ring is an aromatic ring and one or more of the other ring(s) is a non- aromatic, saturated or partially saturated ring, provided 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, dihydrobenzthienyl, dihydrobenzfuranyl, 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- tetrahydrobenzo[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 five 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 six membered heteroaryl groups include but are not limited to pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl and triazinyl.

[0033] Particular non-limiting examples of bicyclic heteroaryl groups containing a six membered ring fused to a five 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] Particular 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, quinolizinyl, benzoxazinyl, benzodiazinyl, pyridopyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl and pteridinyl groups.

[0035] Particular non-limiting examples of bicyclic heteroaryl groups containing a five membered ring fused to a five 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” means a cyclic or polycyclic aromatic ring having from 6 to 12 carbon atoms. The term aryl includes both monovalent species and divalent species. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl and the like. In this particular embodiment, an aryl is phenyl or naphthyl, especially phenyl.

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

[0038] Where optional substituents are chosen from “one or more” groups it is to be understood that this definition includes all substituents being chosen from one of the specified groups or the substituents being chosen from two or more of the specified groups.

[0039] The phrase “compound of the invention” means those compounds which are disclosed herein, both generically and specifically.Compounds of the Invention

[0040] In a first aspect, the present invention provides a compound of Formula I, or a pharmaceutically acceptable salt thereof: (I)wherein: A is an aromatic ring and Z1, Z2, Z3and Z4are independently N or CR2; B is aryl, 5- to 10-membered heteroaryl, C3-10cycloalkyl, or 4- to 10-membered heterocyclyl; wherein B is optionally substituted with one to five substituents independently selected from C1-5alkyl, halo, cyano, hydroxyl, NR3R4, C1-5alkoxy, C1-5haloalkyl, C1-5haloalkoxy, C1-4alkylene-O-C1-4alkyl, C3-10cycloalkyl, and 4- to 10-membered heterocyclyl; L is C3-8alkylene, C3-8alkenylene, or C3-8alkynylene, wherein one, two or three methylene groups in L are optionally substituted with -O-, -S-, -C(O)-, or -N(R5)-; and wherein L is optionally substituted with one to five substituents independently selected from C1-5alkyl, halo, hydroxyl, C1-5alkoxy, C1-5haloalkyl, C1-5haloalkoxy, and NR6R7; R1is 4- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, aryl, C3-10cycloalkyl, or -NR8C(O)R9; wherein: i) each of 4- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, aryl, and C3-10cycloalkyl is optionally substituted with one to five substituents independently selected from C1-5alkyl, halo, oxo, cyano, C1-5alkoxy, C1-5haloalkyl, C1-5haloalkoxy, C1-4alkylene-O-C1-4alkyl, C1-4alkylene-OH, C3-6cycloalkyl, 4- to 6-membered heterocyclyl, and C1-4alkylene-NR10R11; and 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; R2at each occurrence is independently selected from H, halo, cyano, hydroxyl, C1-5alkyl, C1-5alkoxy, C1-5haloalkyl, C1-5haloalkoxy, C1-4alkylene-O-C1-4alkyl, C3-6cycloalkyl and 4-6 membered heterocyclyl; R3and R4are independently selected from H, C1-5alkyl, C1-5haloalkyl, and C3-10cycloalkyl;R5, R6and R7are independently H or C1-5alkyl; R8is H, C1-6alkyl, C2-6haloalkyl, C2-4alkylene-O-C1-4alkyl; C3-6cycloalkyl, 4- to 6-membered heterocyclyl, or C2-5alkylene-NR12R13; R9is C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, C1-6haloalkoxy, C2-4alkylene-O-C1-4alkyl, C3-6cycloalkyl, 4- to 6-membered heterocyclyl, NR14R15or C1-5alkylene-NR16R17; R10and R11are independently H, C1-5alkyl, C1-5haloalkyl or -C1-4alkylene-O-C1-4alkyl; or R10and R11, taken together with the nitrogen to which they are attached, form a 4- to 6- membered heterocyclyl ring optionally substituted with one to four groups independently selected from halo, C1-5alkyl, C1-5alkoxy, C1-5haloalkyl, and C1-5haloalkoxy; and R12, R13, R14, R15, R16, and R17are independently H, C1-5alkyl, or C1-5haloalkyl; or R12and R13, R14and R15, or R16and R17, taken together with the nitrogen atoms to which they are attached, independently form a 4- to 6-membered heterocyclyl ring optionally substituted with one to four groups independently selected from halo and C1-5alkyl.

[0041] Particular compounds of the invention include, for example, compounds of the formula I, or pharmaceutically acceptable salts thereof, wherein, unless otherwise stated, each of Z1, Z2, Z3, Z4, A, B, L, R1, R2, R10, and R11has any of the meanings defined hereinbefore or in any of paragraphs (1) to (60) hereinafter. For the avoidance of doubt, the scope of the present invention encompasses compounds of formula I, or pharmaceutically acceptable salts thereof, wherein any of the substituent definitions defined herein may be combined with any of the other substituent definitions also defined herein: (1) Z1, Z2, Z3and Z4are all CR2; (2) Two of Z1, Z2, Z3and Z4are N and the other two are CR2; (3) One of Z1, Z2, Z3and Z4is N and the other three are CR2; (4) Z2is N and Z1, Z3and Z4are CR2; (5) R2at each occurrence is independently selected from H, halo, cyano, hydroxyl, C1-5alkyl, C1-5alkoxy, C1-5haloalkyl, and C3-6cycloalkyl; (6) R2at each occurrence is independently selected from H, halo, C1-5alkyl, C1-5haloalkyl, and C3-6cycloalkyl; (7) R2at each occurrence is independently selected from H, fluoro, chloro, methyl, ethyl, trifluoromethyl, and cyclopropyl; (8) R2at each occurrence is independently selected from H, fluoro, methyl, trifluoromethyl, and cyclopropyl;(9) R2at each occurrence is H; (10) A is selected from:wherein ‘b’ is the point of attachment to the B ring; (11) A is selected from:, wherein ‘b’ is the point of attachment to the B ring; (12) A is selected from:wherein ‘b’ is the point of attachment to the B ring; (13) B is aryl, 5- to 6-membered heteroaryl, C3-8cycloalkyl, or 4- to 8-membered heterocyclyl; wherein B is optionally substituted with one to five substituents independently selectedfrom C1-5alkyl, halo, cyano, hydroxyl, NR3R4, C1-5alkoxy, C1-5haloalkyl, C1-5haloalkoxy, C1-4alkylene-O-C1-4alkyl, C3-10cycloalkyl, and 4- to 10-membered heterocyclyl; (14) B is aryl, or 5- to 6-membered heteroaryl; wherein B is optionally substituted with one to four substituents independently selected from C1-3alkyl, halo, cyano, hydroxyl, NR3R4, C1-5alkoxy, C1-5haloalkyl, C1-5haloalkoxy, C1-4alkylene-O-C1-4alkyl, C3-7cycloalkyl, and 4- to 10-membered heterocyclyl; (15) B is aryl, optionally substituted with one to four substituents independently selected from C1-3alkyl, halo, cyano, hydroxyl, NR3R4, C1-5alkoxy, C1-5haloalkyl, C1-5haloalkoxy, C1-4alkylene-O-C1-4alkyl, C3-7cycloalkyl, and 4- to 10-membered heterocyclyl; (16) B is phenyl, optionally substituted with one to four substituents independently selected from C1-3alkyl, halo, cyano, C1-5alkoxy, C1-5haloalkyl, C3-7cycloalkyl, and 4- to 10- membered heterocyclyl; (17) B is phenyl, optionally substituted with one to three substituents independently selected from C1-3alkyl, halo, C3-7cycloalkyl, and 4- to 10-membered heterocyclyl; (18) B is phenyl, optionally substituted with one to three substituents independently selected from methyl, fluoro, cyclopropyl, and 5- to 6-membered heterocyclyl; (19) B is selected from: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 selected from:, 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 selected from: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 C3-8alkylene, or C3-8alkenylene, wherein one, two or three methylene groups in L are optionally substituted with -O-, -S-, -C(O)-, or -N(R5)-; and wherein L is optionally substituted with one to five substituents independently selected from C1-5alkyl, halo, hydroxyl, C1-5alkoxy, C1-5haloalkyl, C1-5haloalkoxy, and NR6R7; (23) L is C5-8alkylene, or C5-8alkenylene, wherein one, two or three methylene groups in L are optionally substituted with -O-, -S-, -C(O)-, or -N(R5)-; and wherein L is optionally substituted with one to five substituents independently selected from C1-5alkyl, halo, hydroxyl, C1-5alkoxy, C1-5haloalkyl, C1-5haloalkoxy, and NR6R7; (24) L is C5-8alkylene, or C5-8alkenylene, wherein one, two or three methylene groups in L are optionally substituted with -O-, -C(O)-, or -N(R5)-; and wherein L is optionally substituted with one to five substituents independently selected from C1-5alkyl, halo, hydroxyl, C1-5alkoxy, and C1-5haloalkyl; (25) L is C5-8alkylene, or C5-8alkenylene, wherein one or two methylene groups in L are optionally substituted with -O-, -C(O)-, or -N(R5)-; and wherein L is optionally substituted with one to three substituents independently selected from C1-5alkyl, halo, hydroxyl, C1-5alkoxy, and C1-5haloalkyl; (26) L is C5-8alkylene, wherein one or two methylene groups in L are optionally substituted with -O-, -C(O)-, or -N(R5)-; and wherein L is optionally substituted with one to three independently selected C1-5alkyl substituents; (27) L is C5-8alkylene, wherein one or two methylene groups in L are optionally substituted with -O-, -C(O)-, or -N(R5)-; and wherein L is optionally substituted with one to three methyl substituents; (28) L is selected from:wherein ‘b’ is the point of attachment to the B ring; (29) L is selected from:wherein ‘b’ is the point of attachment to the B ring; (30) L is selected from:wherein ‘b’ is the point of attachment to the B ring; (31) R1is 4- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, aryl, C3-10cycloalkyl, or -NR8C(O)R9; wherein: i) each of 4- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, aryl, and C3-10cycloalkyl is optionally substituted with one to five substituents independently selected from C1-5alkyl, halo, oxo, cyano, C1-5alkoxy, C1-5haloalkyl, C1-5haloalkoxy, C1-4alkylene-O-C1-4alkyl, C3-6cycloalkyl, 4- to 6-membered heterocyclyl, and C1-4alkylene- NR10R11; and 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) R1is 4- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, or -NR8C(O)R9; wherein:i) each of 4- to 10-membered heterocyclyl, and 5- to 10-membered heteroaryl is optionally substituted with one to five substituents independently selected from C1-5alkyl, halo, oxo, cyano, C1-5alkoxy, C1-5haloalkyl, C1-5haloalkoxy, C1-4alkylene-O- C1-4alkyl, C3-6cycloalkyl, 4- to 6-membered heterocyclyl, and C1-4alkylene-NR10R11; and 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) R1is 4- to 10-membered heterocyclyl, or -NR8C(O)R9; wherein the 4- to 10-membered heterocyclyl: i) is optionally substituted with one to five substituents independently selected from C1-5alkyl, halo, oxo, cyano, C1-5alkoxy, C1-5haloalkyl, C1-5haloalkoxy, C1-4alkylene-O- C1-4alkyl, C3-6cycloalkyl, 4- to 6-membered heterocyclyl, and C1-4alkylene-NR10R11; and ii) 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; (34) R1is 5- to 6-membered heterocyclyl; optionally substituted with one to five substituents independently selected from C1-5alkyl, halo, oxo, cyano, C1-5alkoxy, C1-5haloalkyl, C1-5haloalkoxy, C1-4alkylene-O-C1-4alkyl, C3-6cycloalkyl, 4- to 6-membered heterocyclyl, and C1-4alkylene-NR10R11; optionally containing one or two carbon-carbon double bonds; and optionally fused to a phenyl ring; (35) R1is 5- to 6-membered heterocyclyl; optionally substituted with one to four substituents independently selected from C1-5alkyl, halo, oxo, cyano, C1-5haloalkyl, and C1-4alkylene- NR10R11; optionally containing one or two carbon-carbon double bonds; and optionally fused to a phenyl ring; (36) R1is -NR8C(O)R9; (37) R1is -NR8C(O)R9, and R8is H or C1-6alkyl; (38) R1is -NR8C(O)R9, and R9is C1-6alkyl; (39) R1is -NR8C(O)R9, R8is H or C1-6alkyl, and R9is C1-6alkyl; (40) R1is selected from:, optionally substituted with one to three substituents independently selected from C1-5alkyl, halo, oxo, cyano, C1-5alkoxy, C1-5haloalkyl, C1-5haloalkoxy, C1-4alkylene-O-C1-4alkyl, C1-4alkylene-OH, C3-6cycloalkyl, 4- to 6-membered heterocyclyl, and C1-4alkylene- NR10R11; (41) R1is selected from:, optionally substituted with one to three substituents independently selected from C1-5alkyl, halo, oxo, cyano, C1-5alkoxy, C1-5haloalkyl, C1-5haloalkoxy, C1-4alkylene-O-C1-4alkyl, C3-6cycloalkyl, 4- to 6-membered heterocyclyl, and C1-4alkylene-NR10R11; (42) R1is selected from:optionally substituted with one to three substituents independently selected from C1-5alkyl, halo, C1-5haloalkyl, and C1-4alkylene-NR10R11; (43) R1is selected from:optionally substituted with one to three substituents independently selected from methyl, fluoro, trifluoromethyl, and C2-3alkylene-NR10R11; (44) R1is selected from: O Noptionally substituted with one to three substituents independently selected from C1-5alkyl, halo, oxo, cyano, C1-5alkoxy, C1-5haloalkyl, C1-5haloalkoxy, C1-4alkylene-O-C1-4alkyl, C1-4alkylene-OH, C3-6cycloalkyl, 4- to 6-membered heterocyclyl, and C1-4alkylene- NR10R11; (45) R1is selected from:optionally substituted with one to three substituents independently selected from C1-5alkyl, halo, C1-5alkoxy, C1-5haloalkyl, C1-4alkylene-OH, C3-6cycloalkyl, and C1-4alkylene- NR10R11; (46) R1is selected from:, optionally substituted with one to three substituents independently selected from C1-3alkyl, fluoro, chloro, methoxy, C1-2haloalkyl, C1-4alkylene-OH, C3-4cycloalkyl, and C1-4alkylene-NR10R11; (47) R1is selected from:wherein R18is selected from hydrogen, C1-5alkyl, halo, C1-5alkoxy, C1-5haloalkyl, and C3-6cycloalkyl; and R19is selected from hydrogen, halo, C1-4alkylene-O-C1-4alkyl, C1-4alkylene-OH, and C1-4alkylene-NR10R11; (48) R1is selected from: , wherein R18is selected from hydrogen, methyl, halo, methoxy, C1-2haloalkyl, and C3-4cycloalkyl; and R19is selected from hydrogen, C1-4alkylene-O-C1-4alkyl, C1-4alkylene-H, and C1-4alkylene-NR10R11; (49) R1is selected from: , wherein R18is selected from hydrogen, methyl, fluoro, trifluoromethyl, methoxy, and cyclopropyl; and R19is selected from hydrogen, and C2-3alkylene-NR10R11; (50) R1is selected from:(51) R10and R11are independently H or C1-5alkyl; (52) R10and R11are independently H or methyl; (53) R10and R11are both C1-5alkyl; (54) R10and R11are both methyl; (55) R10and R11, taken together with the nitrogen to which they are attached, form a 4- to 6- membered heterocyclyl ring optionally substituted with one to four groups independently selected from halo, C1-5alkyl, C1-5alkoxy, and C1-5haloalkyl; (56) R10and R11, taken together with the nitrogen to which they are attached, form a 4- to 6- membered heterocyclyl ring optionally substituted with one to four groups independently selected from halo and C1-5alkoxy; (57) R10and R11, taken together with the nitrogen to which they are attached, form a 4- to 5- membered heterocyclyl ring optionally substituted with one to three groups independently selected from halo and C1-5alkoxy; (58) R10and R11, taken 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) R10and R11, taken together with the nitrogen to which they are attached, form an azetidinyl, pyrrolidinyl, or morpholinyl ring, each being optionally substituted with one or two groups independently selected from fluoro and methoxy;(60) R10and R11, 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] Suitably, Z1, Z2, Z3and Z4are as defined in any one of paragraphs (1) to (4) above. Preferably, Z1, Z2, Z3and Z4are as defined in paragraph (1) or paragraph (4) above.

[0043] Suitably, R2is as defined in any one of paragraphs (5) to (9) above.

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

[0045] Suitably, B is as defined in any one of paragraphs (13) to (21) above. Preferably, B is as defined in paragraph (20) or paragraph (21) above.

[0046] Suitably, L is as defined in any one of paragraphs (22) to (30) above. In an embodiment, L is as defined in in any one of paragraphs (27) to (30) above. In an embodiment, L is as defined in paragraph (30) above.

[0047] Suitably, R1is as defined in any one of paragraphs (31) to (50) above. In an embodiment, R1is as defined in in any one of paragraphs (44) to (49) above. In an embodiment, R1is as defined in paragraph (49) above.

[0048] Suitably, R10and R11are as defined in any one of paragraphs (51) to (60) above. Preferably, R10and R11are as defined in paragraph (59) or paragraph (60) above.

[0049] Conveniently, the compound of Formula (I) has one of the sub-structural formulae (IA) to (IF) described hereinafter.

[0050] In an embodiment there is provided a compound of formula IA or IB, or a pharmaceutically acceptable salt thereof, wherein Z1, Z2, Z3, Z4, B, L and R1are as defined herein:

[0051] In an embodiment there is provided a compound according to any one of formulae IC to IL, or a pharmaceutically acceptable salt thereof, wherein Z1, Z2, Z3, Z4, L and R1are as defined herein:, wherein the A ring in formulae ID, IE, IG, IH, IK, and IL is optionally substituted with one to three groups independently selected from halo, cyano, hydroxyl, C1-5alkyl, C1-5alkoxy, C1-5haloalkyl, C1-5haloalkoxy, C1-4alkylene-O-C1-4alkyl, C3-6cycloalkyl and 4-6 membered heterocyclyl; the B ring in formulae IC to IL is optionally substituted with one to four groups independently selected from C1-5alkyl, halo, cyano, hydroxyl, NR3R4, C1-5alkoxy, C1-5haloalkyl, C1-5haloalkoxy, C1-4alkylene-O-C1-4alkyl, C3-10cycloalkyl, and 4- to 10-membered heterocyclyl; and the C ring in formulae IF, IG, IH, IJ, IK, and IL is optionally substituted with one to three groups independently selected from C1-5alkyl, halo, cyano, C1-5alkoxy, C1-5haloalkyl, C1-5haloalkoxy, C1-4alkylene-O-C1-4alkyl, C3-6cycloalkyl, 4- to 6-membered heterocyclyl, and C1-4alkylene-NR10R11.

[0052] In a further group of compounds, the compounds have the structural formulae IC to IL above, wherein L is as defined in any one of paragraphs (27) to (30) above; R1in formulae IC, ID and IE is as defined in any one of paragraphs (44) to (46); the A ring in formulae ID, IE, IG, IH, IK, and IL is optionally substituted with one to three groups independently selected from halo, C1-5alkyl, C1-5haloalkyl, and C3-6cycloalkyl; the B ring in formulae IC to IL is optionallysubstituted with one to three groups independently selected from C1-3alkyl, halo, C3-7cycloalkyl, and 4- to 10-membered heterocyclyl; and the C ring in formulae IF, IG, IH, IJ, IK, and IL is optionally substituted with one to three groups independently selected from C1-5alkyl, halo, C1-5haloalkyl, and C1-4alkylene-NR10R11.

[0053] In a further group of compounds, the compounds have the structural formulae IC to IL above, wherein L is as defined in paragraph (30) above; R1in formulae IC, ID and IE is as defined in paragraph (46) above; the A ring in formulae ID, IE, IG, IH, IK, and IL is optionally substituted with one to three groups independently selected from fluoro, methyl, trifluoromethyl, and cyclopropyl; the B ring in formulae IC to IL is optionally substituted with one to three 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 one to three groups independently selected from methyl, fluoro, trifluoromethyl, and C2-3alkylene-NR10R11.

[0054] In an embodiment, the compound according to formula I is selected from one of the following compounds, or a pharmaceutically acceptable salt thereof: 2-((9S,12S)-9-Acetamido-26-methyl-10-oxo-3-oxa-11-aza-1(1,3),2(1,2)- dibenzenacyclododecaphane-12-yl)acetic acid; 2-((8S,11S)-8-Acetamido-26-methyl-9-oxo-3-oxa-10-aza-1(1,3),2(1,2)- dibenzenacycloundecaphane-11-yl)acetic acid; 2-((10S,13S)-10-Acetamido-26-methyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)- dibenzenacyclotridecaphane-13-yl)acetic acid; 2-((10S,13S)-10-Acetamido-26,8-dimethyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)- dibenzenacyclotridecaphane-13-yl)acetic acid; 2-((10S,13S)-10-acetamido-26-methyl-11-oxo-3-oxa-12-aza-1,2(1,3)- dibenzenacyclotridecaphane-13-yl)acetic acid; 2-((8S,11S)-8-Acetamido-26,6-dimethyl-9-oxo-3-oxa-10-aza-1(1,3),2(1,2)- dibenzenacycloundecaphane-11-yl)acetic acid; 2-((10S,13S)-26-Methyl-10-(N-methylacetamido)-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)- dibenzenacyclotridecaphane-13-yl)acetic acid; 2-((3S,6S)-16-Methyl-6-(N-methylacetamido)-5-oxo-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((10S,13S)-26-methyl-11-oxo-10-(2-oxopyridin-1(2H)-yl)-3-oxa-12-aza-1(1,3),2(1,2)- dibenzenacyclotridecaphane-13-yl)acetic acid; 2-((10S,13S)-26-Methyl-11-oxo-10-(2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-3-oxa-12-aza- 1(1,3),2(1,2)-dibenzenacyclotridecaphane-13-yl)acetic acid; 2-((10S,13S)-26-Methyl-11-oxo-10-(2-oxopiperidin-1-yl)-3-oxa-12-aza-1(1,3),2(1,2)- dibenzenacyclotridecaphane-13-yl)acetic acid; 2-((9S,12S)-26-Methyl-10-oxo-9-(2-oxopiperidin-1-yl)-3-oxa-11-aza-1(1,3),2(1,2)- dibenzenacyclododecaphane-12-yl)acetic acid; 2-((10S,13S)-26-Methyl-11-oxo-10-(2-oxopyrrolidin-1-yl)-3-oxa-12-aza-1(1,3),2(1,2)- dibenzenacyclotridecaphane-13-yl)acetic acid;2-((8S,11S)-26-Methyl-9-oxo-8-(2-oxopyridin-1(2H)-yl)-3-oxa-10-aza-1(1,3),2(1,2)- dibenzenacycloundecaphane-11-yl)acetic acid; 2-((10S,13S)-24-fluoro-26-methyl-11-oxo-10-(2-oxopyridin-1(2H)-yl)-3-oxa-12-aza- 1(1,3),2(1,2)-dibenzenacyclotridecaphane-13-yl)acetic acid; 2-((10S,13S)-10-(5-Fluoro-2-oxopyridin-1(2H)-yl)-26-methyl-11-oxo-3-oxa-12-aza- 1(1,3),2(1,2)-dibenzenacyclotridecaphane-13-yl)acetic acid; 2-((10S,13S)-26-Methyl-11-oxo-10-(2-oxopiperidin-1-yl)-3-oxa-12-aza-1(3,5)-pyridina-2(1,2)- benzenacyclotridecaphane-13-yl)acetic acid; 2-((10S,13S)-24-Fluoro-26-methyl-11-oxo-10-(2-oxopyridin-1(2H)-yl)-3-oxa-12-aza-1(3,5)- pyridina-2(1,2)-benzenacyclotridecaphane-13-yl)acetic acid; 2-((10S,13S)-10-(4-Fluoro-2-oxopyridin-1(2H)-yl)-26-methyl-11-oxo-3-oxa-12-aza- 1(1,3),2(1,2)-dibenzenacyclotridecaphane-13-yl)acetic acid; 2-((10S,13S)-26-Methyl-11-oxo-10-(2-oxo-5-(trifluoromethyl)pyridin-1(2H)-yl)-3-oxa-12-aza- 1(1,3),2(1,2)-dibenzenacyclotridecaphane-13-yl)acetic acid; 2-((10S,13S)-14-Fluoro-15,26-dimethyl-11-oxo-10-(2-oxopyridin-1(2H)-yl)-3-oxa-12-aza- 1(1,3),2(1,2)-dibenzenacyclotridecaphane-13-yl)acetic acid; 2-((10S,13S)-10-(5-(2-(Dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-26-methyl-11-oxo-3-oxa- 12-aza-1(1,3),2(1,2)-dibenzenacyclotridecaphane-13-yl)acetic acid; 2-((8S,11S)-8-(5-(2-(Dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-26-methyl-9-oxo-3-oxa-10- aza-1(1,3),2(1,2)-dibenzenacycloundecaphane-11-yl)acetic acid; 2-((10S,13S)-26-Methyl-11-oxo-10-(2-oxopyridin-1(2H)-yl)-24-(tetrahydro-2H-pyran-4-yl)-3- oxa-12-aza-1(1,3),2(1,2)-dibenzenacyclotridecaphane-13-yl)acetic acid; 2-((3S,6S)-6-Acetamido-16-methyl-5,12-dioxo-4,11-diaza-1(1,2),2(1,3)- dibenzenacyclododecaphane-3-yl)acetic acid; 2-((3S,6S)-6-Acetamido-16-methyl-5,13-dioxo-4,12-diaza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((11S,14S,E)-11-acetamido-26-methyl-12-oxo-3-oxa-13-aza-1(1,3),2(1,2)- dibenzenacyclotetradecaphan-8-en-14-yl)acetic acid; 2-((11S,14S)-11-Acetamido-26-methyl-12-oxo-3-oxa-13-aza-1(1,3),2(1,2)- dibenzenacyclotetradecaphane-14-yl)acetic acid; 2-((10S,13S)-24-Fluoro-26-methyl-10-(N-methylacetamido)-11-oxo-3-oxa-12-aza-1(3,5)- pyridina-2(1,2)-benzenacyclotridecaphane-13-yl)acetic acid; 2-((10S,13S)-10-(5-(2-(Dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-24-fluoro-26-methyl-11- oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzenacyclotridecaphane-13-yl)acetic acid; 2-((10S,13S)-26-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)-dibenzenacyclotridecaphane-13-yl)acetic acid; 2-((10S,13S)-24-Fluoro-26-methyl-10-(N-methylacetamido)-11-oxo-3-oxa-12-aza-1(3,5)- pyridina-2(1,2)-benzenacyclotridecaphane-13-yl)acetic acid; 2-((10S,13S)-26-Methyl-11-oxo-10-(4-oxoquinazolin-3(4H)-yl)-3-oxa-12-aza-1(1,3),2(1,2)- dibenzenacyclotridecaphane-13-yl)acetic acid; 2-((10S,13S)-10-(5-(2-(Dimethylamino)ethyl)-3-fluoro-2-oxopyridin-1(2H)-yl)-26-methyl-11- oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzenacyclotridecaphane-13-yl)acetic acid; 2-((10S,13S)-10-(5-(2-(Dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-14-fluoro-15,26-dimethyl- 11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzenacyclotridecaphane-13-yl)acetic acid; 2-((10S,13S)-10-(5-(2-(Dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-24,26-dimethyl-11-oxo-3- oxa-12-aza-1(1,3),2(1,2)-dibenzenacyclotridecaphane-13-yl)acetic acid; 2-((10S,13S)-10-(5-(2-(Dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-14-fluoro-26-methyl-11- oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzenacyclotridecaphane-13-yl)acetic acid;2-((10S,13S)-10-(5-(2-(Dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-14,24-difluoro-15,26- dimethyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzenacyclotridecaphane-13-yl)acetic acid; 2-((10S,13S)-10-(5-(2-(3-Fluoroazetidin-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-26-methyl-11-oxo- 3-oxa-12-aza-1(1,3),2(1,2)-dibenzenacyclotridecaphane-13-yl)acetic acid; 2-((10S,13S)-10-(5-(2-((R)-3-Fluoropyrrolidin-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-26-methyl-11- oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzenacyclotridecaphane-13-yl)acetic acid; 2-((10S,13S)-10-(5-(2-(3-Methoxyazetidin-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-26-methyl-11- oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzenacyclotridecaphane-13-yl)acetic acid; 2-((10S,13S)-10-(5-(2-(Dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-26- methyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzenacyclotridecaphane-13-yl)acetic acid; 2-((10S,13S)-10-(5-(2-(Azetidin-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-15,26-dimethyl-11-oxo-3- oxa-12-aza-1(1,3),2(1,2)-dibenzenacyclotridecaphane-13-yl)acetic acid; 2-((10S,13S)-14,24-Difluoro-10-(3-fluoro-5-(2-((R)-3-fluoropyrrolidin-1-yl)ethyl)-2-oxopyridin- 1(2H)-yl)-15,26-dimethyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzenacyclotridecaphane-13- yl)acetic acid; 2-((10S,13S)-14-Fluoro-10-(3-fluoro-5-(2-(3-fluoroazetidin-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)- 15,24,26-trimethyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzenacyclotridecaphane-13- yl)acetic acid; 2-((10S,13S)-14,24-Difluoro-10-(3-fluoro-5-(2-(3-fluoroazetidin-1-yl)ethyl)-2-oxopyridin-1(2H)- yl)-15,26-dimethyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzenacyclotridecaphane-13- yl)acetic acid; 2-((10S,13S)-10-(5-(2-(Dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-14- fluoro-15,24,26-trimethyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzenacyclotridecaphane-13- yl)acetic acid; 2-((10S,13S)-14,24-Difluoro-10-(5-(2-(3-methoxyazetidin-1-yl)ethyl)-2-oxo-4- (trifluoromethyl)pyridin-1(2H)-yl)-15,26-dimethyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)- dibenzenacyclotridecaphane-13-yl)acetic acid; 2-((10S,13S)-10-(5-(2-(Dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-14,24- difluoro-15,26-dimethyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzenacyclotridecaphane-13- yl)acetic acid 2-((10S,13S)-15-cyclopropyl-10-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin- 1(2H)-yl)-12,14-difluoro-24,26-dimethyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)- dibenzenacyclotridecaphane-13-yl)acetic acid; 2-((10S,13S)-14-fluoro-15,24,26-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)-dibenzenacyclotridecaphane-13- yl)acetic acid; 2-((10S,13S)-14,24-difluoro-15,26-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)-dibenzenacyclotridecaphane-13- yl)acetic acid; 2-((10S,13S)-10-(5-(2-(dimethylamino)ethyl)-4-methyl-2-oxopyridin-1(2H)-yl)-14-fluoro- 15,24,26-trimethyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzenacyclotridecaphane-13- yl)acetic acid; 2-((10S,13S)-24-cyclopropyl-10-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin- 1(2H)-yl)-14-fluoro-15,26-dimethyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)- dibenzenacyclotridecaphane-13-yl)acetic acid; 2-((10S,13S)-10-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-14- fluoro-24,26-dimethyl-11-oxo-15-(trifluoromethyl)-3-oxa-12-aza-1(1,3),2(1,2)- dibenzenacyclotridecaphane-13-yl)acetic acid;2-((8S,11S)-8-(5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-24-fluoro-26-methyl-9-oxo- 3-oxa-10-aza-1(1,3),2(1,2)-dibenzenacycloundecaphane-11-yl)acetic acid; 2-((10S,13S)-10-(5-(2-(azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-15- cyclopropyl-12,14-difluoro-24,26-dimethyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)- dibenzenacyclotridecaphane-13-yl)acetic acid; 2-((10S,13S)-10-(5-(3-(dimethylamino)propyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-14- fluoro-15,24,26-trimethyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzenacyclotridecaphane-13- yl)acetic acid; 2-((10S,13S)-15-cyclopropyl-10-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin- 1(2H)-yl)-14-fluoro-24,26-dimethyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)- dibenzenacyclotridecaphane-13-yl)acetic acid; 2-((10S,13S)-14-fluoro-15,24,26-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)-dibenzenacyclotridecaphane-13- yl)acetic acid; 2-((10S,13S)-15-cyclopropyl-10-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin- 1(2H)-yl)-14,25-difluoro-24,26-dimethyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)- dibenzenacyclotridecaphane-13-yl)acetic acid; 2-((10S,13S)-10-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-12,14- difluoro-15,24,26-trimethyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzenacyclotridecaphane- 13-yl)acetic acid; 2-((10S,13S)-15-cyclopropyl-10-(5-(3-(dimethylamino)propyl)-2-oxo-4-(trifluoromethyl)pyridin- 1(2H)-yl)-12,14-difluoro-24,26-dimethyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)- dibenzenacyclotridecaphane-13-yl)acetic acid; 2-((3S,6S)-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-24-fluoro- 14,16-dimethyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzenacyclotetradecaphane- 3-yl)acetic acid; 2-((3S,6S)-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-24-fluoro- 14,16-dimethyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3- yl)acetic acid; 2-((3S,6S)-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-24-fluoro- 14,16-dimethyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzenacyclododecaphane-3- yl)acetic acid; 2-((10S,13S)-15-Cyclopropyl-14-fluoro-24,26-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)- dibenzenacyclotridecaphane-13-yl)acetic acid; 2-((10S,13S)-15-Cyclopropyl-10-(5-(3-(dimethylamino)propyl)-2-oxo-4- (trifluoromethyl)pyridin-1(2H)-yl)-14-fluoro-24,26-dimethyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)- dibenzenacyclotridecaphane-13-yl)acetic acid; 2-((10S,13S)-15-Cyclopropyl-10-(5-(2-(diethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin- 1(2H)-yl)-14-fluoro-24,26-dimethyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)- dibenzenacyclotridecaphane-13-yl)acetic acid; 2-((3S,6S)-25-Cyclopropyl-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin- 1(2H)-yl)-24-fluoro-14,16-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3- yl)acetic acid; 2-((3S,6S)-25-Cyclopropyl-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin- 1(2H)-yl)-24-fluoro-14,16-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclododecaphane-3- yl)acetic acid;2-((10S,13S)-14,24-Difluoro-26-methyl-11-oxo-10-(2-oxo-5-(2-(pyrrolidin-1-yl)ethyl)-4- (trifluoromethyl)pyridin-1(2H)-yl)-15-(trifluoromethyl)-3-oxa-12-aza-1(1,3),2(1,2)- dibenzenacyclotridecaphane-13-yl)acetic acid; 2-((10S,13S)-24-Cyclopentyl-15-cyclopropyl-10-(5-(2-(dimethylamino)ethyl)-2-oxo-4- (trifluoromethyl)pyridin-1(2H)-yl)-14-fluoro-26-methyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)- dibenzenacyclotridecaphane-13-yl)acetic acid; 2-((10S,13S)-15-Cyclopropyl-10-(5-(3-(diethylamino)propyl)-2-oxo-4-(trifluoromethyl)pyridin- 1(2H)-yl)-14-fluoro-24,26-dimethyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)- dibenzenacyclotridecaphane-13-yl)acetic acid; 2-((3S,6S)-25-Cyclopropyl-6-(5-(3-(dimethylamino)propyl)-2-oxo-4-(trifluoromethyl)pyridin- 1(2H)-yl)-24-fluoro-14,16-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3- yl)acetic acid; 2-((3S,6S)-14-Cyclopropyl-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin- 1(2H)-yl)-24-fluoro-16,25-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3- yl)acetic acid; 2-((3S,6S)-14-Cyclopropyl-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin- 1(2H)-yl)-24-fluoro-16,25-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclododecaphane-3- yl)acetic acid; 2-((3S,6S)-25-Cyclopropyl-6-(5-(2-(dimethylamino)ethyl)-3-fluoro-2-oxopyridin-1(2H)-yl)-24- fluoro-14,16-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((10S,13S)-15,24-Dicyclopropyl-10-(5-(2-(dimethylamino)ethyl)-2-oxo-4- (trifluoromethyl)pyridin-1(2H)-yl)-14-fluoro-26-methyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)- dibenzenacyclotridecaphane-13-yl)acetic acid; 2-((9S,12S)-15,24-Dicyclopropyl-9-(5-(2-(dimethylamino)ethyl)-2-oxo-4- (trifluoromethyl)pyridin-1(2H)-yl)-14-fluoro-26-methyl-10-oxo-3-oxa-11-aza-1(1,3),2(1,2)- dibenzenacyclododecaphane-12-yl)acetic acid; 2-((10S,13S)-15-Cyclopropyl-10-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin- 1(2H)-yl)-14-fluoro-24,25,26-trimethyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)- dibenzenacyclotridecaphane-13-yl)acetic acid; 2-((9S,12S)-15-Cyclopropyl-9-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin- 1(2H)-yl)-14-fluoro-24,25,26-trimethyl-10-oxo-3-oxa-11-aza-1(1,3),2(1,2)- dibenzenacyclododecaphane-12-yl)acetic acid; 2-((3S,6S)-25-Cyclopropyl-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin- 1(2H)-yl)-14-fluoro-16,24-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3- yl)acetic acid; 2-((3S,6S)-25-Cyclopropyl-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin- 1(2H)-yl)-14,24-difluoro-16-methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclododecaphane-3- yl)acetic acid; 2-((10S,13S)-15-Cyclopropyl-10-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin- 1(2H)-yl)-14-fluoro-26-methyl-11-oxo-24-(trifluoromethyl)-3-oxa-12-aza-1(1,3),2(1,2)- dibenzenacyclotridecaphane-13-yl)acetic acid; 2-((9S,12S)-15-Cyclopropyl-9-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin- 1(2H)-yl)-14-fluoro-26-methyl-10-oxo-24-(trifluoromethyl)-3-oxa-11-aza-1(1,3),2(1,2)- dibenzenacyclododecaphane-12-yl)acetic acid; 2-((3S,6S)-6-(5-(2-(Azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-24-fluoro- 14,16-dimethyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3- yl)acetic acid;2-((3S,6S)-25-Cyclopropyl-14,24-difluoro-6-(5-(2-(3-fluoroazetidin-1-yl)ethyl)-2-oxo-4- (trifluoromethyl)pyridin-1(2H)-yl)-16-methyl-5-oxo-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-25-Cyclopropyl-14,24-difluoro-6-(5-(2-(3-fluoroazetidin-1-yl)ethyl)-2-oxo-4- (trifluoromethyl)pyridin-1(2H)-yl)-16-methyl-5-oxo-4-aza-1(1,2),2(1,3)- dibenzenacyclododecaphane-3-yl)acetic acid; 2-((3S,6S)-14-Cyclopropyl-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin- 1(2H)-yl)-24-fluoro-16-methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3- yl)acetic acid; 2-((3S,6S)-14-Cyclopropyl-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin- 1(2H)-yl)-24-fluoro-16-methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclododecaphane-3- yl)acetic acid; 2-((3S,6S)-6-(5-(2-(Dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-24-fluoro- 14,16-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-6-(5-(2-(Dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-24-fluoro- 14,16-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclododecaphane-3-yl)acetic acid; 2-((3S,6S)-25-Cyclopropyl-6-(5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-24-fluoro- 14,16-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-25-Cyclopropyl-6-(5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-24-fluoro- 14,16-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclododecaphane-3-yl)acetic acid; 2-((3S,6S)-6-(5-(2-(Dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-24-fluoro- 14,16,25-trimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-6-(5-(2-(Dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-24-fluoro- 14,16,25-trimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclododecaphane-3-yl)acetic acid; 2-((10S,13S)-10-(5-(3-(Dimethylamino)propyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-14- fluoro-24,26-dimethyl-11-oxo-15-(trifluoromethyl)-3-oxa-12-aza-1(1,3),2(1,2)- dibenzenacyclotridecaphane-13-yl)acetic acid; 2-((3S,6S)-25-Cyclopropyl-24-fluoro-6-(5-(2-(3-fluoroazetidin-1-yl)ethyl)-2-oxo-4- (trifluoromethyl)pyridin-1(2H)-yl)-14,16-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((10S,13S)-10-(5-(2-(Azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-14- fluoro-24,26-dimethyl-11-oxo-15-(trifluoromethyl)-3-oxa-12-aza-1(1,3),2(1,2)- dibenzenacyclotridecaphane-13-yl)acetic acid; 2-((3S,6S)-6-(5-(3-(Dimethylamino)propyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-24- fluoro-14,16-dimethyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((10S,13S)-10-(5-(2-(Azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-15- cyclopropyl-14-fluoro-24,26-dimethyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)- dibenzenacyclotridecaphane-13-yl)acetic acid; 2-((3S,6S)-6-(5-(2-(Azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-25- cyclopropyl-24-fluoro-14,16-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane- 3-yl)acetic acid; 2-((3S,6S)-6-(5-(2-(Azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-25- cyclopropyl-14,24-difluoro-16-methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane- 3-yl)acetic acid; 2-((3S,6S)-6-(5-(2-(Azetidin-1-yl)ethyl)-3-fluoro-2-oxopyridin-1(2H)-yl)-25-cyclopropyl-24- fluoro-14,16-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3-yl)acetic acid;2-((3S,6S)-25-Cyclopropyl-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin- 1(2H)-yl)-24-fluoro-14-methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3- yl)acetic acid; 2-((3S,6S)-25-Cyclopropyl-6-(5-(3-(dimethylamino)propyl)-2-oxo-4-(trifluoromethyl)pyridin- 1(2H)-yl)-14,24-difluoro-16-methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3- yl)acetic acid; 2-((3S,6S)-25-Cyclopropyl-6-(5-(2-(dimethylamino)ethyl)-3-fluoro-2-oxopyridin-1(2H)-yl)- 14,24-difluoro-16-methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-25-Cyclopropyl-6-(5-(2-(dimethylamino)ethyl)-4-methyl-2-oxopyridin-1(2H)-yl)- 14,24-difluoro-16-methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-25-Cyclopropyl-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin- 1(2H)-yl)-24-fluoro-16-methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3- yl)acetic acid; 2-((3S,6S)-25-Cyclopropyl-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin- 1(2H)-yl)-24-fluoro-16-methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclododecaphane-3- yl)acetic acid; 2-((3S,6S)-25-Cyclopropyl-24-fluoro-6-(3-fluoro-5-(2-(3-fluoroazetidin-1-yl)ethyl)-2-oxopyridin- 1(2H)-yl)-14,16-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((10S,13S)-15-Cyclopropyl-14-fluoro-10-(4-methoxy-2-oxopyridin-1(2H)-yl)-24,26-dimethyl- 11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzenacyclotridecaphane-13-yl)acetic acid; 2-((3S,6S)-6-(5-(2-(Azetidin-1-yl)ethyl)-4-methyl-2-oxopyridin-1(2H)-yl)-25-cyclopropyl-24- fluoro-14,16-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-6-(5-(2-(Dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-14,24- difluoro-16-methyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-6-(5-(2-(Dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-14,24- difluoro-16-methyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclododecaphane-3-yl)acetic acid; 2-((3S,6S)-25-Cyclopropyl-14,24-difluoro-6-(5-(3-(3-fluoroazetidin-1-yl)propyl)-2-oxo-4- (trifluoromethyl)pyridin-1(2H)-yl)-16-methyl-5-oxo-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-6-(5-(2-(Azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-24-fluoro- 14,16,25-trimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-6-(5-(3-(Dimethylamino)propyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-24- fluoro-14,16,25-trimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-25-Cyclopropyl-14,24-difluoro-6-(5-(2-(3-methoxyazetidin-1-yl)ethyl)-2-oxo-4- (trifluoromethyl)pyridin-1(2H)-yl)-16-methyl-5-oxo-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-25-Cyclopropyl-14,24-difluoro-6-(5-(2-(3-methoxyazetidin-1-yl)ethyl)-2-oxo-4- (trifluoromethyl)pyridin-1(2H)-yl)-16-methyl-5-oxo-4-aza-1(1,2),2(1,3)- dibenzenacyclododecaphane-3-yl)acetic acid; 2-((3S,6S)-6-(5-(2-(Azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-25- cyclopropyl-24-fluoro-16-methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3- yl)acetic acid;2-((3S,6S)-25-Cyclopropyl-6-(5-(2-(dimethylamino)ethyl)-4-methyl-2-oxopyridin-1(2H)-yl)-24- fluoro-14,16-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-25-Cyclopropyl-6-(5-(2-(dimethylamino)ethyl)-4-methyl-2-oxopyridin-1(2H)-yl)-24- fluoro-14,16-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclododecaphane-3-yl)acetic acid; 2-((10S,13S)-15-cyclopropyl-14-fluoro-10-(4-fluoro-2-oxopyridin-1(2H)-yl)-24,26-dimethyl-11- oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzenacyclotridecaphane-13-yl)acetic acid; 2-((3S,6S)-25-Cyclopropyl-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin- 1(2H)-yl)-14,16-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-6-(5-(2-(Azetidin-1-yl)ethyl)-4-methyl-2-oxopyridin-1(2H)-yl)-25-cyclopropyl-14,24- difluoro-16-methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-25-Cyclopropyl-14,24-difluoro-16-methyl-6-(4-methyl-2-oxopyridin-1(2H)-yl)-5-oxo- 4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-24-Chloro-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)- 14,16-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-25-Cyclopropyl-6-(5-(3-(dimethylamino)propyl)-4-methyl-2-oxopyridin-1(2H)-yl)- 14,24-difluoro-16-methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-6-(5-(2-(Azetidin-1-yl)ethyl)-3-fluoro-2-oxopyridin-1(2H)-yl)-25-cyclopropyl-14,24- difluoro-16-methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-25-Cyclopropyl-6-(4-cyclopropyl-5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)- yl)-24-fluoro-14,16-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-14,24-Difluoro-6-(3-(2-(3-fluoroazetidin-1-yl)ethyl)-6-oxo-4- (trifluoromethyl)pyridazin-1(6H)-yl)-16,25-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-25-Cyclopropyl-6-(5-(3-(dimethylamino)propyl)-4-methyl-2-oxopyridin-1(2H)-yl)-24- fluoro-14,16-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-25-Cyclopropyl-6-(5-(3-(dimethylamino)propyl)-2-oxo-4-(trifluoromethyl)pyridin- 1(2H)-yl)-24-fluoro-16-methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3- yl)acetic acid; 2-((3S,6S)-25-Cyclopropyl-6-(5-(3-(dimethylamino)propyl)-3-fluoro-2-oxopyridin-1(2H)-yl)-24- fluoro-14,16-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-25-Cyclopropyl-6-(4-cyclopropyl-5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)- yl)-14,24-difluoro-16-methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-25-Cyclopropyl-6-(5-(3-(dimethylamino)propyl)-3-fluoro-2-oxopyridin-1(2H)-yl)- 14,24-difluoro-16-methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-25-Cyclopropyl-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin- 1(2H)-yl)-14,16,24-trifluoro-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-25-Cyclopropyl-24-fluoro-6-(5-(3-(3-fluoroazetidin-1-yl)propyl)-2-oxo-4- (trifluoromethyl)pyridin-1(2H)-yl)-14,16-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid;2-((3S,6S)-6-(5-(2-(Azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-14,24- difluoro-16-methyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-6-(5-(2-(Diethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-14,24- difluoro-16-methyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-6-(5-(3-(Dimethylamino)propyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-14,24- difluoro-16-methyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-6-(5-(3-(Azetidin-1-yl)propyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-25- cyclopropyl-14,24-difluoro-16-methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane- 3-yl)acetic acid; 2-((3S,6S)-25-Cyclopropyl-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin- 1(2H)-yl)-14,22,24-trifluoro-16-methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane- 3-yl)acetic acid; 2-((3S,6S)-6-(5-(2-(Dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-14,24- difluoro-16,25-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-6-(5-(2-(Diethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-14,24- difluoro-16,25-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-6-(5-(2-(Azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-14,24- difluoro-16,25-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-16-Chloro-25-cyclopropyl-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4- (trifluoromethyl)pyridin-1(2H)-yl)-24-fluoro-5-oxo-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-25-Cyclopropyl-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin- 1(2H)-yl)-14-fluoro-16-methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3- yl)acetic acid; 2-((3S,6S)-6-(5-(3-(Azetidin-1-yl)propyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-14,24- difluoro-16-methyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-6-(5-(2-(Dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-24-fluoro- 14,16,25-trimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphan-8-en-3-yl)acetic acid; 2-((3S,6S)-6-(4-(Difluoromethyl)-5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-14,24- difluoro-16-methyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-6-(5-(2-(Dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-14,24,25- trifluoro-16-methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-25-Chloro-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)- 14,24-difluoro-16-methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-6-(5-(2-(Azetidin-1-yl)ethyl)-3-methyl-2-oxopyridin-1(2H)-yl)-25-cyclopropyl-14,24- difluoro-16-methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((10S,13S)-14,24-Difluoro-15,26-dimethyl-11-oxo-10-(3-oxo-2-azaspiro[4.5]decan-2-yl)-3- oxa-12-aza-1(1,3),2(1,2)-dibenzenacyclotridecaphane-13-yl)acetic acid;2-((10S,13S)-15-Cyclopropyl-10-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin- 1(2H)-yl)-14-fluoro-23,24,26-trimethyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)- dibenzenacyclotridecaphane-13-yl)acetic acid; 2-((3S,6S)-6-(5-(2-(Dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-14-fluoro- 16-methyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3- yl)acetic acid; 2-((3S,6S)-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-14,16,24- trifluoro-26-methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-6-(5-(2-(Dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-14-fluoro- 16,25-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-6-(5-(2-(Dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-14,22- difluoro-16-methyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((10S,13S)-15-Cyclopropyl-10-(5-(3-(dimethylamino)propyl)-2-oxo-4- (trifluoromethyl)pyridin-1(2H)-yl)-14,23,24-trifluoro-26-methyl-11-oxo-3-oxa-12-aza- 1(1,3),2(1,2)-dibenzenacyclotridecaphane-13-yl)acetic acid; 2-((3S,6S)-6-(5-(2-(Dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-14,24- difluoro-16,8-dimethyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-6-(5-(2-(Dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-14,24- difluoro-16,8-dimethyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclododecaphane-3-yl)acetic acid; 2-((3S,6S)-6-(5-(2-(Dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-14,24- difluoro-16,26-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((10S,13S)-14,24-Difluoro-15,26-dimethyl-10-(3-methyl-2-oxotetrahydropyrimidin-1(2H)-yl)- 11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzenacyclotridecaphane-13-yl)acetic acid; 2-((3S,6S)-14,24-Difluoro-6-(5-(2-(3-methoxyazetidin-1-yl)ethyl)-2-oxo-4- (trifluoromethyl)pyridin-1(2H)-yl)-16-methyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-6-(5-(2-(Ethyl(methyl)amino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-14,24- difluoro-16-methyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-6-(5-(3-(Dimethylamino)propyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-14,24- difluoro-16,25-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-14,24-Difluoro-6-(5-(2-(3-fluoroazetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin- 1(2H)-yl)-16-methyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-6-(5-(3-(Azetidin-1-yl)propyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-14,24- difluoro-16,25-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-6-(5-(2-(Dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)- 14,16,24,25-tetrafluoro-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-6-(5-(2-(Dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)- 14,16,24,25-tetrafluoro-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclododecaphane-3-yl)acetic acid;2-((3S,6S)-14,24-Difluoro-16-methyl-5-oxo-6-(2-oxo-5-(2-(pyrrolidin-1-yl)ethyl)-4- (trifluoromethyl)pyridin-1(2H)-yl)-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-14,24-Difluoro-16-methyl-5-oxo-6-(3-oxo-3,4-dihydroisoquinolin-2(1H)-yl)-25- (trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-14,24-Difluoro-16,25-dimethyl-5-oxo-6-(3-oxo-2-azaspiro[4.5]decan-2-yl)-4-aza- 1(1,2),2(1,3)-dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-6-(5-(2-(Dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-14,24- difluoro-16,9-dimethyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-6-(5-(2-(Dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-14,16,24- trifluoro-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3- yl)acetic acid; 2-((3S,6S)-14,24,25-Trifluoro-16-methyl-5-oxo-6-(3-oxo-2-azaspiro[4.5]decan-2-yl)-4-aza- 1(1,2),2(1,3)-dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((10S,13S)-10-(4,4-Dimethyl-2-oxopyrrolidin-1-yl)-14,24-difluoro-15,26-dimethyl-11-oxo-3- oxa-12-aza-1(1,3),2(1,2)-dibenzenacyclotridecaphane-13-yl)acetic acid; 2-((3S,6S)-14,24-Difluoro-16-methyl-5-oxo-6-(3-oxo-2-azaspiro[4.4]nonan-2-yl)-25- (trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-25-Cyclopropyl-14,24-difluoro-16-methyl-5-oxo-6-(3-oxo-2,8-diazaspiro[4.5]decan- 2-yl)-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-25-Cyclopropyl-14,24-difluoro-16-methyl-5-oxo-6-(8-methyl-3-oxo-2,8- diazaspiro[4.5]decan-2-yl)-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-14,24-Difluoro-6-(3-fluoro-5-(2-(3-fluoroazetidin-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)- 16-methyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3- yl)acetic acid; 2-((3S,6S)-14,24-Difluoro-6-(5-(2-(3-methoxyazetidin-1-yl)ethyl)-2-oxo-4- (trifluoromethyl)pyridin-1(2H)-yl)-16,25-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-6-(5-Bromo-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-14,24-difluoro-16-methyl-5- oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-6-(5-(3-(Dimethylamino)propyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-14,24,25- trifluoro-16-methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-6-(5-(3-(Dimethylamino)propyl)-2-oxopyridin-1(2H)-yl)-14,24-difluoro-16-methyl-5- oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-6-(5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-16-methyl-5-oxo-4-aza- 1(1,2),2(1,3)-dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-14,24-Difluoro-16-methyl-5-oxo-6-(3-oxo-8-oxa-2-azaspiro[4.5]decan-2-yl)-25- (trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-6-(5-(2-(Dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-16-ethyl- 14,24-difluoro-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3- yl)acetic acid; 2-((3S,6S)-6-(5-(3-(Dimethylamino)propyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-14,16,24- trifluoro-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3- yl)acetic acid; 2-((3S,6S)-14,24,25-Trifluoro-16-methyl-6-(1-methyl-2-oxo-1,3-diazaspiro[4.5]decan-3-yl)-5- oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3-yl)acetic acid;2-((3S,6S)-25-Cyclopropyl-24-fluoro-14,16-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)-dibenzenacyclotridecaphane- 3-yl)acetic acid; 2-((10S,13S)-10-(5-(2-(Dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-14,24- difluoro-26,7-dimethyl-11-oxo-15-(trifluoromethyl)-3-oxa-12-aza-1(1,3),2(1,2)- dibenzenacyclotridecaphane-13-yl)acetic acid; 2-((10S,13S)-10-(5-(2-(Dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-14,24- difluoro-26,4-dimethyl-11-oxo-15-(trifluoromethyl)-3-oxa-12-aza-1(1,3),2(1,2)- dibenzenacyclotridecaphane-13-yl)acetic acid; 2-((3S,6S)-14,24-Difluoro-16-methyl-6-(5-(2-morpholinoethyl)-2-oxo-4-(trifluoromethyl)pyridin- 1(2H)-yl)-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3- yl)acetic acid; 2-((3S,6S)-6-(3-(2-(Azetidin-1-yl)ethyl)-6-oxo-5-(trifluoromethyl)pyridazin-1(6H)-yl)-25- cyclopropyl-14,24-difluoro-16-methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane- 3-yl)acetic acid; 2-((3S,6S)-25-Cyclopropyl-14,24-difluoro-6-(3-(2-(3-fluoroazetidin-1-yl)ethyl)-6-oxo-5- (trifluoromethyl)pyridazin-1(6H)-yl)-16-methyl-5-oxo-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-6-(3-(2-(Azetidin-1-yl)ethyl)-6-oxo-5-(trifluoromethyl)pyridazin-1(6H)-yl)-14,24- difluoro-16-methyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-6-(3-(2-(Azetidin-1-yl)ethyl)-5-methyl-6-oxopyridazin-1(6H)-yl)-25-cyclopropyl- 14,24-difluoro-16-methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-6-(3-(3-(Dimethylamino)propyl)-6-oxo-5-(trifluoromethyl)pyridazin-1(6H)-yl)-14,24- difluoro-16-methyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-14,24-Difluoro-6-(3-(2-(3-fluoroazetidin-1-yl)ethyl)-5-methyl-6-oxopyridazin-1(6H)- yl)-16-methyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3- yl)acetic acid; 2-((3S,6S)-14,24-Difluoro-6-(3-(2-(3-methoxyazetidin-1-yl)ethyl)-5-methyl-6-oxopyridazin- 1(6H)-yl)-16-methyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-6-(3-(2-(Azetidin-1-yl)ethyl)-5-methyl-6-oxopyridazin-1(6H)-yl)-14,24-difluoro-16- methyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-6-(3-(3-(Dimethylamino)propyl)-5-methyl-6-oxopyridazin-1(6H)-yl)-14,24-difluoro- 16-methyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3- yl)acetic acid; 2-((3S,6S)-6-(3-(3-(Dimethylamino)propyl)-6-oxo-4-(trifluoromethyl)pyridazin-1(6H)-yl)-14,24- difluoro-16-methyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-14,24-Difluoro-6-(3-(2-(3-fluoroazetidin-1-yl)ethyl)-6-oxo-4- (trifluoromethyl)pyridazin-1(6H)-yl)-16-methyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-6-(3-(3-(Dimethylamino)propyl)-6-oxo-4-(trifluoromethyl)pyridazin-1(6H)-yl)-14,24- difluoro-16,25-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3-yl)acetic acid;2-((3S,6S)-25-Cyclopropyl-6-(3-(3-(dimethylamino)propyl)-6-oxo-4-(trifluoromethyl)pyridazin- 1(6H)-yl)-14,24-difluoro-16-methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3- yl)acetic acid; 2-((3S,6S)-6-(3-(3-(Azetidin-1-yl)propyl)-6-oxo-4-(trifluoromethyl)pyridazin-1(6H)-yl)-14,24- difluoro-16-methyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-25-Cyclopropyl-14,24-difluoro-6-(3-(2-(3-methoxyazetidin-1-yl)ethyl)-6-oxo-4- (trifluoromethyl)pyridazin-1(6H)-yl)-16-methyl-5-oxo-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-25-Cyclopropyl-14,24-difluoro-6-(3-(2-(3-fluoroazetidin-1-yl)ethyl)-6-oxo-4- (trifluoromethyl)pyridazin-1(6H)-yl)-16-methyl-5-oxo-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-25-Cyclopropyl-14,24-difluoro-6-(5-(3-hydroxypropyl)-2-oxo-4- (trifluoromethyl)pyridin-1(2H)-yl)-16-methyl-5-oxo-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-14,24-Difluoro-6-(3-(2-(3-methoxyazetidin-1-yl)ethyl)-6-oxo-4- (trifluoromethyl)pyridazin-1(6H)-yl)-16-methyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-14,16,24-Trifluoro-6-(5-(2-morpholinoethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)- yl)-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-6-(5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-14,24-difluoro-16-methyl-5- oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-6-(3-(2-(Dimethylamino)ethyl)-6-oxo-4-(trifluoromethyl)pyridazin-1(6H)-yl)-14,24- difluoro-16-methyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-25-Cyclopropyl-14,24-difluoro-6-(3-(2-(3-fluoroazetidin-1-yl)ethyl)-5-methyl-6- oxopyridazin-1(6H)-yl)-16-methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3- yl)acetic acid; 2-((3S,6S)-14,24-Difluoro-6-(3-(2-(3-methoxyazetidin-1-yl)ethyl)-6-oxo-4- (trifluoromethyl)pyridazin-1(6H)-yl)-16,25-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-25-Cyclopropyl-14,16,24-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)-dibenzenacyclotridecaphane-3- yl)acetic acid; 2-((3S,6S)-6-(3-(3-(Dimethylamino)propyl)-6-oxo-4-(trifluoromethyl)pyridazin-1(6H)-yl)- 14,24,25-trifluoro-16-methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-25-Cyclopropyl-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin- 1(2H)-yl)-13,14,24-trifluoro-16-methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane- 3-yl)acetic acid; 2-((3S,6S)-6-(3-(2-(Azetidin-1-yl)ethyl)-6-oxo-4-(trifluoromethyl)pyridazin-1(6H)-yl)-14,24- difluoro-16-methyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-25-Cyclopropyl-6-(3-(2-(dimethylamino)ethyl)-6-oxo-4-(trifluoromethyl)pyridazin- 1(6H)-yl)-14,16,24-trifluoro-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3-yl)acetic acid;2-((3S,6S)-6-(3-(2-(Azetidin-1-yl)ethyl)-6-oxo-4-(trifluoromethyl)pyridazin-1(6H)-yl)-14,24- difluoro-16,25-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-25-Cyclopropyl-6-(5-(2-(dimethylamino)ethyl)-4-methyl-2-oxopyrimidin-1(2H)-yl)- 14,24-difluoro-16-methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-6-(5-(2-(3-Methoxyazetidin-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-16-methyl-5-oxo-4- aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3-yl)acetic acid; and 2-((3S,6S)-6-(5-(2-(3-Fluoroazetidin-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-16-methyl-5-oxo-4- aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3-yl)acetic acid.

[0055] The various functional groups and substituents making up the compounds of the present invention are typically chosen such 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 compounds of the present invention may also be suitable features of any other aspect.

[0057] A suitable pharmaceutically acceptable salt of a compound of the invention is, for example, an acid-addition salt of a compound of the invention which is sufficiently basic, for example, an acid-addition salt with, for example, an inorganic or organic acid, for example hydrochloric, hydrobromic, sulfuric, phosphoric, trifluoroacetic, formic, citric or maleic acid. In addition a suitable pharmaceutically acceptable salt of a compound of the invention which is sufficiently acidic is an alkali metal salt, for example a sodium or potassium salt, an alkaline earth metal salt, for example a calcium or magnesium salt, an ammonium salt or a salt with an organic base which affords a physiologically-acceptable cation, for example a salt 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 sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers”. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers”. Stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers”. When a compound has an asymmetric centre, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric centre and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively). A chiral compound can exist as either individual enantiomer or as amixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture”.

[0059] The compounds of this invention typically possess one or more asymmetric centres; such compounds can therefore be produced as individual (R)- or (S)-stereoisomers or as mixtures thereof. Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers, diastereoisomers and mixtures, racemic or otherwise, thereof. The methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art (see discussion in Chapter 4 of “Advanced Organic Chemistry”, 4th edition J. March, John Wiley and Sons, New York, 2001), for example by synthesis from optically active starting materials or by resolution of a racemic form. Some of the compounds of the invention may have geometric isomeric centres (E- and Z- isomers). It is to be understood that the present invention encompasses all optical, diastereoisomers and geometric isomers and mixtures thereof that possess ^4 ^7 inhibition activity.

[0060] The present invention also encompasses compounds of the invention as defined herein which comprise one or more isotopic substitutions. For example, H may be in any isotopic form, including1H,2H (D) and3H (T); C may be in any isotopic form including12C,13C, and14C; and O may be in any isotopic form, including16O and18O; and the like. In an embodiment, present invention also encompasses deuterated analogues of the compounds of the invention defined by formula I.

[0061] It is also to be understood that certain compounds of the invention may exist in solvated as well as unsolvated forms such as, for example, hydrated forms. It is to be understood that the invention encompasses all such solvated forms that possess ^4 ^7 inhibition activity.

[0062] It is also to be understood that certain compounds of the invention may exhibit polymorphism, and that the invention encompasses all such forms that possess ^4 ^7 inhibition activity.

[0063] Compounds of the invention may exist in a number of different tautomeric forms and references to compounds of the invention include 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 nevertheless embraced by compounds of the invention. Examples of tautomeric forms include keto-, enol-, and enolate-forms, as in, for example, the following tautomeric pairs: keto / enol (illustrated below), imine / enamine, amide / imino alcohol, amidine / amidine, nitroso / oxime, thioketone / enethiol and nitro / aci-nitro.H C C keto

[0064] Compounds of the invention containing an amine function may also form N-oxides. A reference herein to a compound of the formula I that contains an amine function also includes the N-oxide. Where a compound contains several amine functions, one or more than one nitrogen atom may be oxidised to form an N-oxide. Particular examples of N-oxides are the N-oxides of a tertiary amine or a nitrogen atom of a nitrogen-containing heterocycle. N- Oxides can be formed by treatment of the corresponding amine with an oxidizing agent such as hydrogen peroxide or a per-acid (e.g. a peroxycarboxylic acid), see for example Advanced Organic Chemistry, by Jerry March, 4thEdition, Wiley Interscience, pages. More particularly, N-oxides can be made by the procedure of L. W. Deady (Syn. Comm.1977, 7, 509-514) in which the amine compound is reacted with m-chloroperoxybenzoic acid (MCPBA), for example, in an inert solvent such as dichloromethane.

[0065] The compounds of the invention may be administered in the form of a pro-drug which is broken down in the human or animal body to release a compound of the invention. A pro- drug may be used to alter the physical properties and / or the pharmacokinetic properties of a compound of the invention. A pro-drug can be formed when the compound of the invention contains a suitable group or substituent to which a property-modifying group can be attached. Examples of pro-drugs include in vivo cleavable ester derivatives that may be formed at a carboxy group or a hydroxy group in a compound of the invention and in-vivo cleavable amide derivatives that may be formed at a carboxy group or an amino group in a compound of the invention.

[0066] Accordingly, the present invention includes those compounds of the formula I as defined hereinbefore when made available by organic synthesis and when made available within the human or animal body by way of cleavage of a pro-drug thereof. Accordingly, the present invention includes those compounds of the formula I that are produced by organic synthetic means and also such compounds that are produced in the human or animal body by way of metabolism of a precursor compound, that is a compound of the formula I may be a synthetically-produced compound or a metabolically-produced compound.

[0067] A suitable pharmaceutically acceptable pro-drug of a compound of the formula I is one that is based on reasonable medical judgement as being suitable for administration to the human or animal body without undesirable pharmacological activities and without undue toxicity.

[0068] Various forms of pro-drug have been 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”, A.C.S. Symposium Series, Volume 14; and h) E. Roche (editor), “Bioreversible Carriers in Drug Design”, Pergamon Press, 1987.

[0069] A suitable pharmaceutically acceptable pro-drug of a compound of the formula I that possesses a carboxy group is, for example, an in vivo cleavable ester thereof. An in vivo cleavable ester of a compound of the formula I containing a carboxy group is, for example, a pharmaceutically acceptable ester which is cleaved in the human or animal body to produce the parent acid. Suitable pharmaceutically acceptable esters for carboxy include C1-6alkyl esters such as methyl, ethyl and tert-butyl, C1-6alkoxymethyl esters such as methoxymethyl esters, C1-6alkanoyloxymethyl esters such as pivaloyloxymethyl esters, 3-phthalidyl esters, C3-8cycloalkylcarbonyloxy- C1-6alkyl esters such as cyclopentylcarbonyloxymethyl and 1- cyclohexylcarbonyloxyethyl esters, 2-oxo-1,3-dioxolenylmethyl esters such as 5-methyl-2- oxo-1,3-dioxolen-4-ylmethyl esters and C1-6alkoxycarbonyloxy-C1-6alkyl esters such as methoxycarbonyloxymethyl and 1-methoxycarbonyloxyethyl esters.

[0070] A suitable pharmaceutically acceptable pro-drug of a compound of the formula I that possesses a hydroxy group is, for example, an in vivo cleavable ester or ether thereof. An in vivo cleavable ester or ether of a compound of the formula I containing a hydroxy group is, for example, a pharmaceutically acceptable ester or ether which is cleaved in the human or animal body to produce the parent hydroxy compound. Suitable pharmaceutically acceptable ester forming groups for a hydroxy group include inorganic esters such as phosphate esters (including phosphoramidic cyclic esters). Further suitable pharmaceutically acceptable ester forming groups for a hydroxy group include C1-10alkanoyl groups such as acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups, C1-10alkoxycarbonyl groups such as ethoxycarbonyl, N,N-(C1-6)2carbamoyl, 2-dialkylaminoacetyl and 2-carboxyacetyl groups. Examples of ring substituents on the phenylacetyl and benzoyl groups includeaminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1- ylmethyl and 4-(C1-4alkyl)piperazin-1-ylmethyl. Suitable pharmaceutically acceptable ether forming groups for a hydroxy group include α-acyloxyalkyl groups such as acetoxymethyl and pivaloyloxymethyl groups.

[0071] A suitable pharmaceutically acceptable pro-drug of a compound of the formula I that possesses a carboxy group is, for example, an in vivo cleavable amide thereof, for example an amide formed with an amine such as ammonia, a C1-4alkylamine such as methylamine, a (C1-4alkyl)2 amine such as dimethylamine, N-ethyl-N-methylamine or diethylamine, a C1-4alkoxy- C2-4alkylamine such as 2-methoxyethylamine, a phenyl-C1-4alkylamine such as benzylamine and amino acids such as glycine or an ester thereof.

[0072] A suitable pharmaceutically acceptable pro-drug of a compound of the formula I that possesses an amino group is, for example, an in vivo cleavable amide derivative thereof. Suitable pharmaceutically acceptable amides from an amino group include, for example an amide formed with C1-10alkanoyl groups such as an acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups. Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N- dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl and 4-(C1-4alkyl)piperazin-1- ylmethyl.

[0073] The in vivo effects of a compound of the formula I may be exerted in part by one or more metabolites that are formed within the human or animal body after administration of a compound of the formula I. As stated hereinbefore, the in vivo effects of a compound of the formula I may also be exerted by way of metabolism of a precursor compound (a pro-drug).

[0074] It shall also be appreciated that compounds of the formula I may also be covalently linked (at any suitable position) to other groups such as, for example, solubilising moieties (for example, PEG polymers), moieties that enable them to be bound to a solid support (such as, for example, biotin-containing moieties), and targeting ligands (such as antibodies or antibody fragments). Synthesis

[0075] The compounds of the disclosure may be prepared using methods disclosed herein and routine modifications thereof which will be apparent given the disclosure herein and methods well known in the art. Conventional and well-known synthetic methods may be used in addition to the teachings herein. The synthesis of typical compounds of Formula (I), e.g., compounds having structures described by Formula (I), or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, or deuterated analogue thereof, may be accomplished as described in the following examples.

[0076] In the description of the synthetic methods described below and in the referenced synthetic methods that are used to prepare the starting materials, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, can be selected by a person 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 utilised.

[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 are obtainable by analogous procedures to those illustrated which are within the ordinary skill of an organic chemist.

[0079] It will be appreciated that during the synthesis of the compounds of the invention in the processes defined below, or during the synthesis of certain starting materials, it may be desirable to protect certain substituent groups to prevent their undesired reaction. The skilled chemist will appreciate when such protection is required, and how such protecting groups may be put in place, and later removed.

[0080] For examples of protecting groups see one of the many general texts on the subject, for example, “Protecting groups in Organic Synthesis (3rdEd), John Wiley & Sons, NY (1999)”, T. Greene & P. Wuts. 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 in question, such methods being chosen so as to effect removal of the protecting group with the minimum disturbance of groups elsewhere in the molecule.

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

[0082] By way of example, a suitable protecting group for an amino or alkylamino group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl or tert-butoxycarbonyl group, an arylmethoxycarbonyl group, for example benzyloxycarbonyl, or an aroyl group, for example benzoyl. The deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group may be removed by, for example, hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively, an acyl group such as a tert-butoxycarbonyl group may be removed, forexample, by treatment with a suitable acid as hydrochloric, sulfuric or phosphoric acid or trifluoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon, or by treatment with a Lewis acid for example 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] The person skilled in the art will recognise that the compounds of the invention may be prepared, in known manner, in a variety of ways. Compounds of formula I can be prepared by the methods given below, by the methods given in the experimental or by analogous methods. The routes described are merely illustrative of some of the methods that can be employed for the synthesis of compounds of formula I and the person skilled in the art will appreciate that the order of the reaction steps is not limited to those described. It will also be appreciated that the assignment of nucleophile and electrophile is not limited to that described herein and in some cases it may be appropriate for the assignment to be reversed. Different approaches to synthetic chemistry strategy are described in “Organic Synthesis: The Disconnection Approach”, 2ndedition, S. Warren and P. Wyatt (2008). General Methods

[0084] Compounds of Formula (I) may be prepared by a process involving first deprotection, i.e. cleavage of an ester group, followed optionally by conversion to a salt, of a compound of formula (A1) where E is defined as C1-6alkyl, for example tert-butyl or methyl, and all other variables are defined according to the scope of the present invention.

[0085] The deprotection of compounds of formula (A1), where E is tert-butyl, may be accomplished by acid hydrolysis using for example hydrochloric, sulfuric or trifluoroacetic acid, in a suitable solvent, such as dichloromethane, tetrahydrofuran or 1,4-dioxane. Where 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 the cleavage of the ester group, the resulting product may be converted to the required salt by methods well known to those skilled in the art.

[0087] Compounds of formula (A1), in which L is a -C3-8alkenylene- group, where n and m are zero to six (provided n and m combined are one to six) and one, two or three methylene groups in the -C3-8alkenylene- group are optionally substituted with -O-, -S-, -C(O)- or -N(R5)-, which are compounds of formula (A2), may be prepared from intermediates of formula (A3), via an olefin metathesis reaction 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 conducted in a suitable solvent, such as tetrahydrofuran, 1,4-dioxane, dichloromethane, 1,2-dichloroethane or toluene, at an elevated temperature under nitrogen atmosphere.

[0088] Compounds of formula (A1) in which L is -C3-8alkylene-, which are compounds of formula (A4), may be prepared from compounds of formula (A2), by reduction of the double bond. The reduction may be accomplished by catalytic hydrogenation with hydrogen in the presence of a noble metal catalyst such as Pt, Pd, Rh, Ru or Raney nickel. The hydrogenation reaction is conducted in a solvent such as methanol, ethanol, tetrahydrofuran or mixtures thereof.

[0089] Compounds of formula (A1) in which L is -C3-8alkylene-, where two adjacent methylene groups are substituted with -C(O)- and -N(R5)-, and n and m are zero to six (provided n and m combined is between one and six), which are compounds of formula (A5), may be prepared from intermediates of formula (A6), by an amide coupling. The amide coupling may be accomplished following the procedures for the formation of an amide bond described hereinafter. In particular, intermediates of formula (A6) may be treated with a coupling agent, for example 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 conducted in the presence of a base such as triethylamine, diisopropylethylamine or 1,8-diazabicyclo[5.4.0]undec- 7-ene (DBU).

[0090] Intermediates of formula (A6) can also be converted into an activated form (A9), wherein Y represents halo or the rest of an active ester, for example Y is an aryloxy group such as phenoxy, p-nitrophenoxy, pentafluorophenoxy and the like, or Y can be the rest of a mixed anhydride. The activation of the carboxylic acid in (A6) may lead to an internal cyclisation reaction to give compounds of formula (A5).

[0091] Activated intermediates of formula (A9) can be prepared from intermediates of formula (A6) as outlined in the above scheme. The amine functionality in (A6) is protected with PG1, where PG1represents a suitable amine protecting group (as defined above), to give intermediates of formula (A7). The carboxylic acid functionality in (A7) can then be activated, as described above, to give intermediates of formula (A8). Removal of the amine protecting group (PG1), which can be done following known procedures in the art, gives intermediates of formula (A9) which undergo an internal cyclisation reaction to give compounds of formula (A5).

[0092] Intermediates of formula (A3) in which R1represents an N-linked group, such as NR8C(O)R9, or N-linked heterocyclyl group (such as pyrrolidin-2-onyl, piperidin-2-onyl, or 2- oxopyridin-1(2H)-yl) and where n, m and E are defined above, which are intermediates of formula (A10), may be prepared from intermediates of formula (A14), where LG1represents a suitable leaving group, for example mesylate, triflate, tosylate, bromide, chloride and the like. The reaction between intermediates of formula (A14) and N-linked heterocyclyl group may beconducted in the presence of a base, for example sodium hydride, sodium methoxide, potassium tert-butoxide or potassium carbonate, and an inert solvent like dimethylacetamide, dimethylformamide, acetonitrile and the like.

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

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

[0095] Intermediates of formula (A11), in which the methylene group attached to B has been replaced with -O-, and where n and E are defined above, which are intermediates of formula (A15), may be prepared from intermediates of formula (A16) and (A17), followed by deprotection of the amine protecting group (PG2) in intermediates of formula (A18).

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

[0097] Intermediates of formula (A16) are commercially available, or can be prepared from intermediates of formula (A19) using the condition described above for the preparation of intermediates of formula (A14) from intermediates of formula (A13). Intermediates of formula (A19) are commercially available, or readily available through synthesis procedures known in the art.

[0098] Intermediates of formula (A17), where E and PG2are defined above, can be prepared by a transition metal catalysed cross-coupling reaction between intermediates of formula (A20) and intermediates of formula (A21), in which X1and X2represent a pair of reactive moietiescapable of undergoing a transition metal catalysed cross-coupling reaction. Exemplary reactive moieties include, but are not limited to, halide, triflate and boron-containing functional groups. When one of X1or X2is halide or triflate the other X1or X2is a boron-containing functional group of the 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 boron atom form a ring (e.g., a pinacol boronic ester).

[0099] The cross-coupling reaction can be conducted in the presence of a suitable catalyst, such as Pd(PPh3)4, Pd2(dba)3or Pd(dppf)Cl2and a mild base, such as K2CO3and Na2CO3, in a suitable solvent, such as 1,4-dioxane, toluene, ethanol, water and mixtures thereof, at an elevated temperature. The selection of catalyst, base, solvent and reaction conditions (i.e., time, temperature, pressure, choice of atmosphere, etc.) are known to those skilled in the art.

[0100] Intermediates of formula (A11), in which n is zero and E is defined above, which are intermediates of formula (A24), may be prepared from intermediates of formula (A20) and (A22), followed by deprotection of the amine protecting group (PG2) in intermediates of formula (A23).

[0101] In the procedure of the above scheme, the cross-coupling of intermediates of formula (A20) and (A22) to give intermediates of formula (A23) can be accomplished using the conditions described above for the 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 the deprotection of intermediates of formula (A18) to give intermediates of formula (A15).

[0102] Intermediates of formula (A21) and (A22), where X2represents a reactive moiety capable of undergoing a transition metal catalysed cross-coupling reaction (e.g., halide, triflate, boronic acid and boronic ester) and B is defined according to the scope of the present invention, are commercially available, or can be prepared according to methodologies known to those skilled in the art.

[0103] Intermediates of formula (A20) where X1represents a pinacol boronic ester, which are intermediates of formula (A25), can be prepared from intermediates of formula (A26) by a process involving first protection of the acid functionality with a suitable protecting group (E) to give intermediates of formula (A27), followed by protection of the amine functionality in (A27) with a suitable protecting group (PG2) to give intermediates of formula (A28) and then by a cross-coupling reaction with bis(pinacolato)diboron to give intermediates of formula (A25).

[0104] In the procedure of the above scheme, protection of the acid functionality in intermediates of formula (A26) with a suitable protecting group (E) to give intermediates of formula (A27) can be accomplished by reacting together intermediates of formula (A26) and a C1-6alkyl alcohol (e.g.,methanol or ethanol) with removal of water either physically, e.g. by azeotropical water removal or chemically by using a dehydrating agent. Protection of the amine functionality in intermediates of formula (A27) with a suitable protecting group (PG2) to give intermediates of formula (A28) can be accomplished using the conditions described above for protection of the amine functionality in intermediates of formula (A6) to give intermediates of formula (A7). Conversion of the bromine functionality in intermediates of formula (A28) to the pinacol boronic ester functionality in (A25) can be accomplished using the conditions described above for the cross-coupling of intermediates of formula (A20) and (A21) to give intermediates of formula (A17).

[0105] The synthesis of intermediate β-amino acids of formula (A26), can be accomplished using well known procedures described in the 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 (Z5and Z6are C), pyridazin-3(2H)-one (Z5is N and Z6is C) and pyrimidin-2(1H)-one (Z5is C and Z6is N) intermediates, used in the synthesis of intermediates of formula (A10), are commercially available or can be readily prepared according to methodologies known to those skilled in the art. For example, substituted intermediates of formula (A29), may be prepared from intermediates of formula (A30), wherein the ring may be further substituted with one or more optional substituents as described herein.

[0107] In the procedure of the above scheme, the aldehyde functionality in intermediates 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 near room temperature to give intermediates of formula (A31). Cleavage ofthe enol ether functionality in intermediates 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 intermediates of formula (A32). Reductive amination of the aldehyde functionality in intermediates of formula (A32) with the amine functionality in intermediates of formula (A33) gives intermediates of formula (A29). The reductive amination may be conducted under acidic or neutral conditions (i.e., with or without acid present, 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 mixtures thereof.

[0108] Intermediates of formula (A30) and (A33) are commercially available, or readily available through synthesis procedures known in the art.

[0109] Intermediates of formula (A32) can also be prepared from intermediates of formula (A33), in which X3represents a triflate or halide group, by a process involving first a transition metal catalysed cross-coupling reaction with trans-2-ethoxyvinylboronic acid pinacol ester to give intermediates of formula (A34), using the conditions described above for the cross-coupling of intermediates of formula (A20) and (A21) to give intermediates of formula (A17), followed by cleavage of the enol ether functionality in intermediates of formula (A34) to give intermediates of formula (A32) using the conditions described above for the conversion of intermediates of formula (A31) to intermediates of formula (A32).

[0110] Intermediates of formula (A33) are commercially available, or readily available through synthesis procedures known in the art.

[0111] Substituted 2-oxopyridin-1(2H)-yl (Z5and Z6are C), pyridazin-3(2H)-one (Z5is N and Z6is C) and pyrimidin-2(1H)-one (Z5is C and Z6is N) intermediates of formula (A35), may be prepared from intermediates of formula (A33), wherein the ring may be further substituted with one or more optional substituents as described herein and X3represents a triflate or halide group.

[0112] In the procedure of the above scheme, the cross-coupling of intermediates of formula (A33) and (A36) to give intermediates of formula (A37) can be accomplished in the presenceof a suitable catalyst, such as Pd(PPh3)4or 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 an elevated temperature. Intermediates of formula (A35) may be prepared from intermediates of formula (A37), by reduction of the triple bond. The reduction may be accomplished by catalytic hydrogenation with hydrogen in the presence of a noble metal catalyst such as Pt, Pd, Rh, Ru or Raney nickel. The hydrogenation reaction is conducted in a solvent such as methanol, ethanol, tetrahydrofuran or mixtures thereof.

[0113] Intermediates of formula (A36) are commercially available, or readily available through synthesis procedures known in the art. Pharmaceutical Compositions

[0114] The compounds of the invention will normally, but not necessarily, be formulated into pharmaceutical compositions prior to administration to a patient. Therefore, according to a further aspect of the invention there is provided a pharmaceutical composition which comprises a compound of Formula I as defined hereinbefore, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0115] The pharmaceutical compositions of the invention may be prepared and packaged in bulk form wherein a safe and effective amount of a compound of the invention can be extracted and then given to the patient such as with powders or syrups. Alternatively, the pharmaceutical compositions of the invention may be prepared and packaged in unit dosage form wherein each physically discrete unit contains a safe and effective amount of a compound of the invention. When prepared in unit dosage form, the pharmaceutical compositions of the invention typically contain from 1 mg to 1000 mg.

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

[0117] In a convenient 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 comprise one or more of the following excipients: sterile diluent (e.g. water, saline, oils,glycerine, propylene glycol, polyethylene glycols, or other pharmaceutically acceptable solvents); buffer agent (e.g. acetates, citrates, phosphates, or tonicity adjusters such as sodium chloride or dextrose); chelating agent (e.g. edta); antibacterial agent (e.g. methyl parabens or benzyl alcohol); or antioxidant (e.g. ascorbic acid or sodium bisulfite). In a convenient embodiment, the pharmaceutical composition of the present invention is in a form suitable for intravenous or intraperitoneal administration and comprises phosphate buffered saline or physiological saline. Conveniently, the parenteral composition is enclosed within ampoules, vials, or syringes made from either glass or plastic.

[0118] As used herein, "pharmaceutically-acceptable excipient" means a pharmaceutically acceptable material, composition or vehicle involved in giving form or consistency to the pharmaceutical composition. Each excipient must be compatible with the other ingredients of the pharmaceutical composition when commingled such that interactions which would substantially reduce the efficacy of the compound of the invention when administered to a patient and interactions which would result in pharmaceutical compositions that are not pharmaceutically acceptable are avoided. In addition, each excipient must be of sufficiently high purity to render it pharmaceutically-acceptable.

[0119] Suitable pharmaceutically-acceptable excipients will vary depending upon the particular dosage form chosen. In addition, suitable pharmaceutically-acceptable excipients may be chosen for a particular function that they may serve in the composition. For example, certain pharmaceutically-acceptable excipients may be chosen for their ability to facilitate the production of uniform dosage forms. Certain pharmaceutically-acceptable excipients may be chosen for their ability to facilitate the production of stable dosage forms. Certain pharmaceutically-acceptable excipients may be chosen for their ability to facilitate the carrying or transporting of the compound or compounds of the invention once administered to the patient from one organ, or portion of the body, to another organ, or portion of the body. Certain pharmaceutically-acceptable excipients may be chosen for their ability to enhance 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, coloring agents, anticaking agents, humectants, chelating agents, plasticizers, viscosity increasing agents, antioxidants, preservatives, stabilizers, surfactants, and buffering agents. The person skilled in the art will appreciate that certain pharmaceutically-acceptable excipients may serve more than one function and 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] Persons skilled in the art possess the knowledge and skill to enable them to select suitable pharmaceutically-acceptable excipients in appropriate amounts for use in the invention. In addition, there are a number of resources that are available to the skilled artisan which describe pharmaceutically-acceptable excipients 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 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, from 0.5 mg to 0.5 g of active agent (more suitably from 0.5 to 100 mg, for example from 1 to 30 mg) compounded with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight of the total composition.

[0124] The size of the dose for therapeutic or prophylactic purposes of a compound of the formula I will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, according to well-known principles of medicine.

[0125] In using a compound of the invention for therapeutic or prophylactic purposes it will generally be administered so that a daily dose in the range, for example, 0.1 mg / kg to 75 mg / kg body weight is received, given if required in divided doses. In general, lower doses will be administered when a parenteral route is employed. Thus, for example, for intravenous or intraperitoneal administration, a dose in the range, for example, 0.1 mg / kg to 30 mg / kg body weight will generally be used. Similarly, for administration by inhalation, a dose in the range, for example, 0.05 mg / kg to 25 mg / kg body weight will be used. Oral administration may also be suitable, particularly in tablet form. Typically, unit dosage forms will contain about 0.5 mg to 0.5 g of a compound of this invention. Routes of Administration

[0126] The compounds of the invention or pharmaceutical composition comprising the active compound may be administered to a subject by any convenient route of administration, whether systemically / peripherally or topically (i.e. at the site of desired action).

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

[0128] In a preferred embodiment, a compound of the invention as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, is administered orally, intravenously, subcutaneously or intramuscularly. Therapeutic Uses and Applications

[0129] The compounds of the invention are inhibitors of the α4β7 integrin. As a consequence, 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 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 the treatment of a disease or disorder mediated by inhibition of α4β7.

[0132] In another aspect, the present 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 diseases or disorders mediated by α4β7 inhibition.

[0133] In another aspect, the present invention relates to a method of treating a disease or disorder mediated by inhibition of α4β7, said 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 that the compounds of Formula I and their pharmaceutically acceptable salts may be used to treat are inflammatory bowel diseases such as ulcerative colitis or Crohn’s disease, eosinophilic gastrointestinal diseases, and pouchitis.

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

[0136] In another aspect, the present 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 diseases such as ulcerative colitis or Crohn’s disease.

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

[0138] In another aspect, the present invention provides a method of inhibiting α4β7 in vitro, said 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, said 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 of inhibiting α4β7 in vitro and / or in vivo, said method comprising contacting a cell with an effective amount of a compound as defined herein, or a pharmaceutically acceptable salt thereof. Combination Therapy

[0141] The compounds of the invention may be administered alone as a monotherapy or may administered in combination with one or more additional therapeutic agents. The selection of the one or more additional therapeutic agents will of course vary depending on the disease or condition to be treated and its severity.

[0142] It is commonplace to use combination therapies to treat certain medical conditions.

[0143] According to a particular aspect of the 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 hereinbefore, or a pharmaceutically acceptable salt thereof, and another therapeutic agent.

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

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

[0146] Herein, where the term “combination” is used it is to be understood that this refers to simultaneous, separate or sequential administration. In one aspect of the invention “combination” refers to simultaneous administration. In another aspect of the invention “combination” refers to separate administration. In a further aspect of the invention “combination” refers to sequential administration. Where the administration is sequential or separate, the delay in administering the second component should not be such as to lose the beneficial effect of the combination.

[0147] According to a further aspect of the invention there is provided a pharmaceutical composition which comprises a compound of the 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 a further compound of the present invention. Therefore, in an embodiment, there is provided a pharmaceutical composition which comprises 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 a compound of the present invention (e.g. as one of two or more active agents as part of double or triple combinations) include, but are not limited to, the following: i) Aminosalicylates (5-ASAs), including sulphasalazine, mesalazine, balsalazide and olsalazine; ii) Steroids, including prednisolone, hydrocortisone, methylprednisolone, beclomethasone dipropionate, 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) Anti-diarrhoeals, including loperamide, codeine phosphate and diphenoxylate x) Antispasmodics, including mebeverine, hyoscine butylbromide and alverine citrate xi) Antibiotics, including metronidazole, ampicillin, ciprofloxacin

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

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

[0152] Such combination therapies employ the compounds of this invention within the dosage range described herein and the other pharmaceutically active agent within approved dosage ranges and / or the dosage such as described in the relevant publication reference. EXAMPLES

[0153] Methods for preparing the compounds of this invention are illustrated in the following Examples. Starting materials are made according to procedures known in the art or as illustrated herein or are available commercially. Commercial reagents were used without further purification. Where no reaction temperature is included, the reaction was performed at ambient temperature which is typically 17–27 °C.

[0154] A person skilled in the art will appreciate that reaction temperatures, reaction times and reagent quantities may be varied from those stated herein.

[0155] Flash chromatography carried out using Combiflash® Nextgen 300+ and automated reverse-phase chromatography carried out on Interchim Puriflash® 4100

[0156] Where compounds described in the invention are characterized by1H NMR spectroscopy, Bruker 500 MHz spectrometer instrument or Bruker Ultrashield 400 MHz spectrometer. Where no temperature is included, the spectra were recorded at ambient temperature. Chemical shift values are expressed in parts per million (ppm). The followingabbreviations are used for the multiplicity of the NMR signals: s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet, br=broad.

[0157] Where compounds described in the invention are characterized by LCMS data, retention time and molecular weight are determined using the conditions listed below. Method 1: Waters Acquity HT with diode array (210-350 nm) and ZQ mass detector. Column: YMC Triart C185 µm 2.0 x 50 mm (Flow 0.8 mL / min) at 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 with diode array (210-350 nm) and QDa mass detector. Column: Acquity UPLC CSH C181.7 µm 2.1 x 50 mm (Flow 1.0 mL / min) at 50 °C. Conditions: Water with 0.05% formic acid [eluent A], MeCN [eluent B].2% B 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 with diode array (210-350 nm) and QDa mass detector. Column: Acquity UPLC BEH C181.7 µm 2.1 x 50 mm (Flow 0.8 mL / min) at 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 with diode array (210-350 nm) and QDa mass detector. Column: Acquity UPLC BEH C181.7 µm 2.1 x 50 mm (Flow 0.8 mL / min) at 50 °C. Conditions: Water with 0.05% ammonia [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 with diode array (210-350 nm) and QDa mass detector. Column: Acquity UPLC BEH C181.7 µm 2.1 x 50 mm (Flow 1.0 mL / min) at 50 °C. Conditions: Water with 0.05% ammonia [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 with diode array (210-350 nm) and QDa mass detector. Column: Acquity UPLC BEH C181.7 µm 2.1 x 50 mm (Flow 0.8 mL / min) at 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 with diode array (210-350 nm) and QDa mass detector. Column: Acquity UPLC BEH C181.7 µm 2.1 x 50 mm (Flow 0.8 mL / min) at 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 with diode array (210-350 nm) and QDa mass detector. Column: Acquity UPLC BEH C181.7 µm 2.1 x 50 mm (Flow 1.0 mL / min) at 50 °C. Conditions: Water with 0.1% formic acid [eluent A], MeCN [eluent B].2% B 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 with diode array (210-350 nm) and QDa mass detector. Column: Acquity UPLC BEH C181.7 µm 2.1 x 50 mm (Flow 1.0 mL / min) at 50 °C. Conditions: Water with 0.1% formic acid [eluent A], MeCN [eluent B].50% B 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 with diode array (210-350 nm) and QDa mass detector. Column: Acquity UPLC BEH C181.7 µm 2.1 x 50 mm (Flow 0.6 mL / min) at 50 °C. Conditions: Water with 0.1% ammonia [eluent A], MeCN [eluent B].2% B 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 with diode array (210-350 nm) and QDa mass detector. Column: Acquity UPLC BEH C181.7 µm 2.1 x 50 mm (Flow 0.6 mL / min) at 50 °C. Conditions: Water with 0.1% ammonia [eluent A], MeCN [eluent B].2% B 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 with diode array (210-350 nm) and QDa mass detector. Column: Acquity UPLC BEH C181.7 µm 2.1 x 50 mm (Flow 0.8 mL / min) at 50 °C. Conditions: Water with 0.1% ammonia [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 with diode array (210-350 nm) and QDa mass detector. Column: Acquity UPLC BEH C181.7 µm 2.1 x 50 mm (Flow 1.0 mL / min) at 50 °C. Conditions: Water with 0.1% formic acid [eluent A], MeCN [eluent B].2% B 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 with diode array (210-350 nm) and QDa mass detector. Column: Acquity UPLC BEH C181.7 µm 2.1 x 50 mm (Flow 1.0 mL / min) at 50 °C. Conditions: Water with 0.1% ammonia [eluent A], MeCN [eluent B].5% B 0.5 min, gradient: 5 - 95% B over 6 min, hold at 95% B for 1 min. Method 15: Waters Acquity H class UPLC with diode array (210-350 nm) and QDa mass detector. Column: Acquity UPLC BEH C181.7 µm 2.1 x 50 mm (Flow 0.8 mL / min) at 50 °C. Conditions: Water with 0.1% ammonia [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 with diode array (210-350 nm) and QDa mass detector. Column: Acquity UPLC BEH C181.7 µm 2.1 x 50 mm (Flow 1.0 mL / min) at 50 °C. Conditions: Water with 0.1% formic acid [eluent A], MeCN [eluent B].5% B 0.5 min, gradient: 5 - 95% B over 6 min, hold at 95% B for 1 min. Method 17: Waters Acquity H class UPLC with diode array (210-350 nm) and QDa mass detector. Column: Acquity UPLC BEH C181.7 µm 2.1 x 50 mm (Flow 0.8 mL / min) at 50 °C. Conditions: Water with 0.05% ammonia [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 with diode array (210-350 nm) and QDa mass detector. Column: Acquity UPLC BEH C181.7 µm 2.1 x 50 mm (Flow 0.8 mL / min) at 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 with diode array (210-350 nm) and QDa mass detector. Column: Acquity UPLC BEH C181.7 µm 2.1 x 50 mm (Flow 1.0 mL / min) at 50 °C. Conditions: Water with 0.1% ammonia [eluent A], MeCN [eluent B].0% B 0.5 min, gradient: 0 - 98% B over 6 min, hold at 98% B for 1 min. Method 20: Waters Acquity H class UPLC with diode array (210-350 nm) and QDa mass detector. Column: Acquity UPLC BEH C181.7 µm 2.1 x 50 mm (Flow 1.0 mL / min) at 50 °C. Conditions: Water with 0.1% formic acid [eluent A], MeCN [eluent B].2% B 0.5 min, gradient: 2 - 98% B over 6 min, hold at 98% B for 1 min. Method 21: Waters Acquity H class UPLC with diode array (210-350 nm) and QDa mass detector. Column: Acquity UPLC BEH C181.7 µm 2.1 x 50 mm (Flow 1.0 mL / min) at 50 °C. Conditions: Water with 0.1% ammonia [eluent A], MeCN [eluent B].0% B 0.5 min, gradient: 0 - 95% B over 6 min, hold at 95% B for 1 min. Method 22: Waters Acquity H class UPLC with diode array (210-350 nm) and QDa mass detector. Column: Acquity UPLC BEH C181.7 µm 2.1 x 50 mm (Flow 0.8 mL / min) at 50 °C. Conditions: Water with 0.1% ammonia [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 with diode array (210-350 nm) and QDa mass detector. Column: Acquity UPLC BEH C181.7 µm 2.1 x 50 mm (Flow 0.6 mL / min) at 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 with diode array (210-350 nm) and QDa mass detector. Column: Acquity UPLC BEH C181.7 µm 2.1 x 50 mm (Flow 0.8 mL / min) at 50 °C. Conditions: Water with 0.1% formic acid [eluent A], MeCN [eluent B].0% B 0.5 min, gradient: 0 - 95% B over 6 min, hold at 95% B for 1 min. Method 25: Waters Acquity H class UPLC with diode array (210-350 nm) and QDa mass detector. Column: Acquity UPLC BEH C181.7 µm 2.1 x 50 mm (Flow 0.8 mL / min) at 50 °C. Conditions: Water with 0.1% ammonia [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 with diode array (210-350 nm) and QDa mass detector. Column: Acquity UPLC BEH C181.7 µm 2.1 x 50 mm (Flow 0.6 mL / min) at 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 with diode array (210-350 nm) and QDa mass detector. Column: Acquity UPLC BEH C181.7 µm 2.1 x 50 mm (Flow 0.8 mL / min) at 50 °C. Conditions: Water with 0.1% ammonia [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 with diode array (210-350 nm) and QDa mass detector. Column: Acquity UPLC BEH C181.7 µm 2.1 x 50 mm (Flow 0.6 mL / min) at 50 °C. Conditions: Water with 0.1% ammonia [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 with diode array (210-350 nm) and QDa mass detector. Column: Acquity UPLC BEH C181.7 µm 2.1 x 50 mm (Flow 0.6 mL / min) at 50 °C. Conditions: Water with 0.1% formic acid [eluent A], MeCN [eluent B].2% B 0.5 min, gradient: 2 - 98% B over 6 min, hold at 98% B for 1 min.

[0158] Preparative HPLC was performed using Waters 2545 Binary Gradient Module with 2998 PDA and 2767 Sample Manager, Waters SFO module. AbbreviationsSynthesis of Intermediates Intermediate 1: Methyl (S)-3-(3-bromophenyl)-3-((tert-butoxycarbonyl)amino)propanoate

[0159] 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) was added Boc anhydride (9.86 g, 45.2 mmol) and the reaction mixture stirred for 20 h at RT. The reaction mixture was diluted with water and the crude product extracted into DCM. The combined organics were washed with water, brine, dried over MgSO4, filtered and concentrated under reduced pressure to provide the title compound (15.5 g).1H 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). Intermediate 2: Methyl (S)-3-((tert-butoxycarbonyl)amino)-3-(3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)phenyl)propanoate

[0160] 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 the solution was then added potassium acetate (9.07 g, 92.5 mmol) followed by Pd(dppf)Cl2(2.71 g, 3.70 mmol) and the reaction mixture 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 MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by flashchromatography (silica gel, eluting 50% EtOAc in petroleum ether) to provide the title compound (7.0 g). LCMS (Method 1): 3.55 min, 406.1 [M+H]+. Intermediate 3: Methyl (S)-3-((tert-butoxycarbonyl)amino)-3-(2'-hydroxy-6'-methyl-[1,1'- biphenyl]-3-yl)propanoate

[0161] 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 NaHCO3(0.80 g, 7.56 mmol) in toluene (25 mL) and ethanol (5 mL) and water (5.5 mL) was degassed with nitrogen. To this was added Pd(PPh3)4(0.21 g, 0.18 mmol) and the reaction mixture stirred at 85 °C for 16 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, eluting 20 - 50% EtOAc in petroleum ether) to provide the title compound (1.12 g). LCMS (Method 2): 2.07 min, 408.1 [M+Na]+. Intermediate 4: Methyl (S)-3-amino-3-(2'-hydroxy-6'-methyl-[1,1'-biphenyl]-3-yl)propanoate hydrochloride

[0162] 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 RT for 2 h. The mixture was concentrated under reduced pressure to provide the title compound (0.15 g). LCMS (Method 2): 1.31 min, 286.2 [M+H]+. Intermediate 5: Methyl (S)-3-((S)-2-((tert-butoxycarbonyl)amino)pent-4-enamido)-3-(2'- hydroxy-6'-methyl-[1,1'-biphenyl]-3-yl)propanoate

[0163] 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) was added DIPEA (0.83 mL, 4.74 mmol), HOBt (0.44 g, 4.74 mmol) and EDCI (0.55 g, 2.85 mmol) and the mixture was stirred at RT 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, eluting 30 - 50% EtOAc in petroleum ether) to provide the title compound (0.78 g). LCMS (Method 3): 1.63 min, 427.1 [M-tBu+H]+. 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

[0164] 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 continued at reflux 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, eluting 30-50% EtOAc in petroleum ether) to provide the title compound (0.68 g). LCMS (Method 3): 1.90 min, 537.2 [M+H]+. Intermediate 7: Methyl 2-((9S,12S)-9-((tert-butoxycarbonyl)amino)-26-methyl-10-oxo-3-oxa- 11-aza-1(1,3),2(1,2)-dibenzenacyclododecaphan-6-en-12-yl)acetate

[0165] 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, and ethyl vinyl ether (0.05 mL, 0.51 mmol) was added and concentrated under reduced pressure. The crude product was purified by flash chromatography (24 g silica gel, eluting 30-50% EtOAc in petroleum ether) to provide the title compound (0.25 g). LCMS (Method 3): 1.78 min, 509.2 [M+H]+. Intermediate 8: Methyl 2-((9S,12S)-9-((tert-butoxycarbonyl)amino)-26-methyl-10-oxo-3-oxa- 11-aza-1(1,3),2(1,2)-dibenzenacyclododecaphane-12-yl)acetate

[0166] 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 RT for 2 h. The mixture was filtered through Celite®, washing with MeOH and the filtrate was concentrated under reduced pressure to provide the title compound (0.22 g). LCMS (Method 3): 1.79 min, 511.1 [M+H]+. Intermediate 9: Methyl 2-((9S,12S)-9-amino-26-methyl-10-oxo-3-oxa-11-aza-1(1,3),2(1,2)- dibenzenacyclododecaphane-12-yl)acetate hydrochloride

[0167] 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 RT for 1.5 h. The mixture was concentrated under reduced pressure to provide the title compound (0.22 g). LCMS (Method 2): 1.26 min, 411.2 [M+H]+. Intermediate 10: Methyl 2-((9S,12S)-9-acetamido-26-methyl-10-oxo-3-oxa-11-aza- 1(1,3),2(1,2)-dibenzenacyclododecaphane-12-yl)acetate

[0168] 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 RT for 20 min. The mixture was concentrated under reduced pressure. The crude product was purified by flash chromatography (12 g silica gel, eluting 0 - 10% MeOH in DCM) to provide the title compound (0.15 g). LCMS (Method 3): 1.53 min, 453.2 [M+H]+. Intermediate 11: Methyl (S)-3-(2'-(allyloxy)-6'-methyl-[1,1'-biphenyl]-3-yl)-3-((S)-2-((tert- butoxycarbonyl)amino)pent-4-enamido)propanoate

[0169] Prepared in an analogous manner to Intermediate 6 using Intermediate 5 (0.72 g, 1.48 mmol), K2CO3(0.51 g, 3.71 mmol) and allyl bromide (0.26 mL, 2.97 mmol) in MeCN (20 mL) at RT for 72 h. Purified by flash chromatography (24 g silica gel, eluting 30 - 50% EtOAcin petroleum ether) to provide the title compound (0.60 g). LCMS (Method 3): 1.84 min, 523.2 [M+H]+. Intermediate 12: Methyl 2-((8S,11S)-8-((tert-butoxycarbonyl)amino)-26-methyl-9-oxo-3-oxa- 10-aza-1(1,3),2(1,2)-dibenzenacycloundecaphan-5-en-11-yl)acetate

[0170] Prepared in an analogous manner to Intermediate 7 using Intermediate 11 (0.24 g, 0.46 mmol) in DCE (2 mL) and Grubbs II (39 mg, 0.05 mmol) in DCE (2 mL) at 40 °C for 4 h. Quenched with ethyl vinyl ether (0.04 mL, 0.46 mmol). Purified by flash chromatography (24 g silica gel, eluting 30-50% EtOAc in petroleum ether) to provide the title compound (0.23 g). LCMS (Method 3): 1.70 min, 495.1 [M+H]+. Intermediate 13: Methyl 2-((8S,11S)-8-((tert-butoxycarbonyl)amino)-26-methyl-9-oxo-3-oxa- 10-aza-1(1,3),2(1,2)-dibenzenacycloundecaphane-11-yl)acetate

[0171] Prepared in an analogous manner to Intermediate 8 using Intermediate 12 (0.23 g, 0.47 mmol) and 5% palladium on carbon (50 mg) in MeOH (5 mL) under a hydrogen atmosphere at RT for 2 h to provide the title compound (0.18 g). LCMS (Method 3): 1.71 min, 497.1 [M+H]+. Intermediate 14: Methyl 2-((8S,11S)-8-amino-26-methyl-9-oxo-3-oxa-10-aza-1(1,3),2(1,2)- dibenzenacycloundecaphane-11-yl)acetate hydrochloride

[0172] 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 RT for 1.5 h. The mixture was concentrated under reduced pressure to provide the title compound (0.16 g). LCMS (Method 3): 1.19 min, 397.2 [M+H]+. Intermediate 15: Methyl 2-((8S,11S)-8-acetamido-26-methyl-9-oxo-3-oxa-10-aza- 1(1,3),2(1,2)-dibenzenacycloundecaphane-11-yl)acetate

[0173] Prepared in an analogous manner to Intermediate 10 using 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) at RT for 30 min. Purified by flash chromatography (12 g silica gel, eluting 0 - 10% MeOH in DCM) to provide the title compound (0.12 g). LCMS (Method 3): 1.45 min, 439.1 [M+H]+. 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

[0174] Prepared in an analogous manner to Intermediate 6 using 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) at RT for 72 h. Purified by flash chromatography (24 g silica gel, eluting 30 - 50% EtOAc in petroleum ether) to provide the title compound (0.59 g). LCMS (Method 3): 1.96 min, 551.2 [M+H]+.Intermediate 17: Methyl 2-((10S,13S)-10-((tert-butoxycarbonyl)amino)-26-methyl-11-oxo-3- oxa-12-aza-1(1,3),2(1,2)-dibenzenacyclotridecaphan-7-en-13-yl)acetate

[0175] Prepared in an analogous manner to Intermediate 7 using Intermediate 16 (0.24 g, 0.43 mmol) in DCE (3 mL) and Grubbs II (36 mg, 0.04 mmol) in DCE (3 mL) at 40 °C for 4 h. Quenched with ethyl vinyl ether (2.0 mL, 20.1 mmol). Purified by flash chromatography (24 g silica gel, eluting 30-50% EtOAc in petroleum ether) to provide the title compound (0.21 g). LCMS (Method 3): 1.82 min, 523.2 [M+H]+. Intermediate 18: Methyl 2-((10S,13S)-10-((tert-butoxycarbonyl)amino)-26-methyl-11-oxo-3- oxa-12-aza-1(1,3),2(1,2)-dibenzenacyclotridecaphane-13-yl)acetate

[0176] Prepared in an analogous manner to Intermediate 8 using Intermediate 17 (0.21 g, 0.41 mmol) and 5% palladium on carbon (43 mg) in MeOH (5 mL) under a hydrogen atmosphere at RT for 2 h to provide the title compound (0.21 g). LCMS (Method 3): 1.86 min, 525.2 [M+H]+. Intermediate 19: Methyl 2-((10S,13S)-10-amino-26-methyl-11-oxo-3-oxa-12-aza- 1(1,3),2(1,2)-dibenzenacyclotridecaphane-13-yl)acetate hydrochloride

[0177] A suspension of Intermediate 18 (0.21 g, 0.39 mmol) in 4 M HCl in 1,4-dioxane (6 mL) was stirred at RT for 1.5 h. The mixture was concentrated under reduced pressure to provide the title compound (0.18 g). LCMS (Method 3): 1.26 min, 425.2 [M+H]+. Intermediate 20: Methyl 2-((10S,13S)-10-acetamido-26-methyl-11-oxo-3-oxa-12-aza- 1(1,3),2(1,2)-dibenzenacyclotridecaphane-13-yl)acetate

[0178] Prepared in an analogous manner to Intermediate 10 using 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) at RT for 30 min. Purified by flash chromatography (12 g silica gel, eluting 0 - 10% MeOH in DCM) to provide the title compound (96 mg). LCMS (Method 3): 1.59 min, 467.2 [M+H]+. 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

[0179] Prepared in an analogous manner to Intermediate 5 using 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) at RT for 4 h. Purified by flash chromatography (24 g silica gel, eluting 30-50% EtOAc in petroleum ether) to provide the title compound (0.24 g). LCMS (Method 3): 1.68 min, 497.1 [M+H]+. 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

[0180] Prepared in an analogous manner to Intermediate 6 using 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) at reflux for 72 h. Purified by flash chromatography (24 g silica gel, eluting 30- 50% EtOAc in petroleum ether) to provide the title compound (86 mg). LCMS (Method 3): 1.99 min, 565.3 [M+H]+. Intermediate 23: Methyl 2-((10S,13S)-10-((tert-butoxycarbonyl)amino)-26,8-dimethyl-11-oxo- 3-oxa-12-aza-1(1,3),2(1,2)-dibenzenacyclotridecaphan-7-en-13-yl)acetate

[0181] Prepared in an analogous manner to Intermediate 7 using Intermediate 22 (54 mg, 0.10 mmol) in DCE (45 mL) and Grubbs II (8.1 mg, 0.01 mmol) at 40 °C for 4 h. Quenched with ethyl vinyl ether (0.45 mL, 4.68 mmol). Purified by flash chromatography (24 g silica gel, eluting 30-50% EtOAc in petroleum ether) to provide the title compound (21 mg). LCMS (Method 4): 1.89 min, 537.1 [M+H]+. Intermediate 24: Methyl 2-((10S,13S)-10-((tert-butoxycarbonyl)amino)-26,8-dimethyl-11-oxo- 3-oxa-12-aza-1(1,3),2(1,2)-dibenzenacyclotridecaphane-13-yl)acetate

[0182] Prepared in an analogous manner to Intermediate 8 using Intermediate 23 (21 mg, 0.04 mmol) and 5% palladium on carbon (4 mg) in MeOH (5 mL) under a hydrogen atmosphere at RT for 3 h to provide the title compound (0.21 g). LCMS (Method 4): 1.92 min, 539.2 [M+H]+. Intermediate 25: Methyl 2-((10S,13S)-10-amino-26,8-dimethyl-11-oxo-3-oxa-12-aza- 1(1,3),2(1,2)-dibenzenacyclotridecaphane-13-yl)acetate hydrochloride

[0183] A suspension of Intermediate 24 (21 g, 0.39 mmol) in 4 M HCl in 1,4-dioxane (2 mL) was stirred at RT for 1.5 h. The mixture was concentrated under reduced pressure to provide the title compound (18 mg). LCMS (Method 4): 1.62 min, 439.2 [M+H]+. Intermediate 26: Methyl 2-((10S,13S)-10-acetamido-26,8-dimethyl-11-oxo-3-oxa-12-aza- 1(1,3),2(1,2)-dibenzenacyclotridecaphane-13-yl)acetate

[0184] Prepared in an analogous manner to Intermediate 10 using Intermediate 25 (18 mg, 0.04 mmol), triethylamine (12 µL, 0.09 mmol), acetyl chloride (3 µL, 0.04 mmol) in DCM (5 mL) at RT for 30 min. Purified by flash chromatography (12 g silica gel, eluting 0 - 10% MeOH in DCM) to provide the title compound (19 mg). LCMS (Method 4): 2.08 min, 481.2 [M+H]+. Intermediate 27: Methyl (S)-3-((tert-butoxycarbonyl)amino)-3-(5'-hydroxy-2'-methyl-[1,1'- biphenyl]-3-yl)propanoate

[0185] Prepared in an analogous manner to Intermediate 3 using Intermediate 2 (1.0 g, 1.80 mmol), 3-bromo-4-methylphenol (0.31 g, 0.91 mmol, CAS 60710-39-6), Na2CO3(0.80 g,7.56 mmol) and Pd(PPh3)4(95 mg, 0.05 mmol) in toluene (10.2 mL), ethanol (2 mL) and water (2 mL) at 85 °C for 16 h. Purified by flash chromatography (40 g silica gel, eluting 5 - 20% EtOAc in petroleum ether then 100% EtOAc) to provide the title compound (0.64 g). LCMS (Method 5): 1.48 min, 408.1 [M+Na]+. Intermediate 28: Methyl (S)-3-((tert-butoxycarbonyl)amino)-3-(2'-methyl-5'-(pent-4-en-1- yloxy)-[1,1'-biphenyl]-3-yl)propanoate

[0186] Prepared in an analogous manner to Intermediate 6 using 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) at reflux for 24 h to provide the title compound (0.37 g). LCMS (Method 5): 1.94 min, 452.4 [M-H]-. Intermediate 29: Methyl (S)-3-amino-3-(2'-methyl-5'-(pent-4-en-1-yloxy)-[1,1'-biphenyl]-3- yl)propanoate hydrochloride

[0187] 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 RT for 2 h. The mixture was concentrated under reduced pressure to provide the title compound (0.26 g). LCMS (Method 5): 1.71 min, 354.3 [M+H]+. 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

[0188] Prepared in an analogous manner to Intermediate 5 using Intermediate 29 (0.23 g, 0.59 mmol), N-Boc-(S)-allylglycine (0.13 g, 0.59 mmol, CAS 90600-20-7), 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) at RT for 16 h. Purified by flash chromatography (24 g silica gel, eluting 0-50% EtOAc in petroleum ether) to provide the title compound (0.14 g). LCMS (Method 4): 1.88 min, 551.4 [M+H]+. Intermediate 31: Methyl 2-((10S,13S)-10-((tert-butoxycarbonyl)amino)-26-methyl-11-oxo-3- oxa-12-aza-1,2(1,3)-dibenzenacyclotridecaphan-7-en-13-yl)acetate

[0189] Prepared in an analogous manner to Intermediate 7 using Intermediate 30 (0.13 g, 0.24 mmol) in DCE (50 mL) and Grubbs II (20 mg, 0.02 mmol) in DCE (11 mL) at 40 °C for 5 h. Quenched with ethyl vinyl ether (3.0 mL, 31.3 mmol). Purified by flash chromatography (24 g silica gel, eluting 20 - 40% EtOAc in petroleum ether) to provide the title compound (93 mg). LCMS (Method 4): 1.69 and 1.73 min, 523.4 [M+H]+. Intermediate 32: Methyl 2-((10S,13S)-10-((tert-butoxycarbonyl)amino)-26-methyl-11-oxo-3- oxa-12-aza-1,2(1,3)-dibenzenacyclotridecaphane-13-yl)acetate

[0190] Prepared in an analogous manner to Intermediate 8 using Intermediate 31 (93 mg, 0.13 mmol) and 5% palladium on carbon (14 mg) in MeOH (1.4 mL) under a hydrogenatmosphere at RT for 2 h to provide the title compound (47 mg). LCMS (Method 4): 1.73 min, 525.4 [M+H]+. Intermediate 33: Methyl 2-((10S,13S)-10-amino-26-methyl-11-oxo-3-oxa-12-aza-1,2(1,3)- dibenzenacyclotridecaphane-13-yl)acetate hydrochloride

[0191] 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 h. The mixture was concentrated under reduced pressure to provide the title compound (38 mg). LCMS (Method 4): 1.42 min, 425.3 [M+H]+. Intermediate 34: Methyl 2-((10S,13S)-10-acetamido-26-methyl-11-oxo-3-oxa-12-aza- 1,2(1,3)-dibenzenacyclotridecaphane-13-yl)acetate

[0192] Prepared in an analogous manner to Intermediate 10 using 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) at RT for 1 h to provide the title compound (37 mg). LCMS (Method 4): 1.44 min, 467.3 [M+H]+. 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

[0193] Prepared in an analogous manner to Intermediate 6 using 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) at RT for 72 h. Purified by flash chromatography (24 g silica gel, eluting 30-50% EtOAc in petroleum ether) to provide the title compound (0.11 g). LCMS (Method 4): 1.90 min, 537.2 [M+H]+. Intermediate 36: Methyl 2-((8S,11S)-8-((tert-butoxycarbonyl)amino)-26,6-dimethyl-9-oxo-3- oxa-10-aza-1(1,3),2(1,2)-dibenzenacycloundecaphan-5-en-11-yl)acetate

[0194] Prepared in an analogous manner to Intermediate 7 using Intermediate 35 (0.11 g, 0.20 mmol) in DCE (98 mL) and Grubbs II (17 mg, 0.02 mmol) at 40 °C for 4 h. Purified by flash chromatography (24 g silica gel, eluting 30-50% EtOAc in petroleum ether) to provide the title compound (50 mg). LCMS (Method 4): 1.77 min, 509.0 [M+H]+. Intermediate 37: Methyl 2-((8S,11S)-8-((tert-butoxycarbonyl)amino)-26,6-dimethyl-9-oxo-3- oxa-10-aza-1(1,3),2(1,2)-dibenzenacycloundecaphane-11-yl)acetate

[0195] Prepared in an analogous manner to Intermediate 8 using Intermediate 36 (50 mg, 0.10 mmol) and 5% palladium on carbon (11 mg) in MeOH (5 mL) under a hydrogen atmosphere at RT for 4 h to provide the title compound (46 mg). LCMS (Method 4): 1.77 min, 511.3 [M+H]+.Intermediate 38: Methyl 2-((8S,11S)-8-amino-26,6-dimethyl-9-oxo-3-oxa-10-aza- 1(1,3),2(1,2)-dibenzenacycloundecaphane-11-yl)acetate hydrochloride

[0196] A suspension of Intermediate 37 (46 mg, 0.09 mmol) in 4 M HCl in 1,4-dioxane (2.0 mL) was stirred at RT for 1.5 h. The mixture was concentrated under reduced pressure to provide the title compound (40 mg). LCMS (Method 4): 1.50 min, 411.2 [M+H]+. Intermediate 39: Methyl 2-((8S,11S)-8-acetamido-26,6-dimethyl-9-oxo-3-oxa-10-aza- 1(1,3),2(1,2)-dibenzenacycloundecaphane-11-yl)acetate

[0197] Prepared in an analogous manner to Intermediate 10 using 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) at RT for 30 min. Purified by flash chromatography (12 g silica gel, eluting 0 - 10% MeOH in DCM) to provide the title compound (30 mg). LCMS (Method 4): 1.84 min, 453.2 [M+H]+. Intermediate 40: Methyl (S)-3-((S)-2-((tert-butoxycarbonyl)(methyl)amino)pent-4-enamido)- 3-(2'-hydroxy-6'-methyl-[1,1'-biphenyl]-3-yl)propanoate

[0198] Prepared in an analogous manner to Intermediate 5 using 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) at RT for 4 h, to provide the title compound (0.18 g). LCMS (Method 3): 1.73 min, 497.2 [M+H]+. 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

[0199] Prepared in an analogous manner to Intermediate 6 using 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) at reflux for 16 h. Purified by flash chromatography (24 g silica gel, eluting 30 - 50% EtOAc in petroleum ether) to provide the title compound (0.12 g). LCMS (Method 4): 2.04 min, 565.3 [M+H]+. Intermediate 42: Methyl 2-((10S,13S)-10-((tert-butoxycarbonyl)(methyl)amino)-26-methyl-11- oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzenacyclotridecaphan-7-en-13-yl)acetate

[0200] Prepared in an analogous manner to Intermediate 7 using Intermediate 41 (0.10 g, 0.17 mmol) in DCE (85 mL) and Grubbs II (14 mg, 0.17 mmol) at 40 °C for 4 h. Purified by flash chromatography (12 g XTYPE cartridge, eluting 10-40% EtOAc in petroleum ether) to provide the title compound (91 mg). LCMS (Method 4): 1.90 min, 537.3 [M+H]+. Intermediate 43: Methyl 2-((10S,13S)-10-((tert-butoxycarbonyl)(methyl)amino)-26-methyl-11- oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzenacyclotridecaphane-13-yl)acetate

[0201] Prepared in an analogous manner to Intermediate 8 using Intermediate 42 (91 mg, 0.17 mmol) and 5% palladium on carbon (18 mg) in MeOH (10 mL) under a hydrogen atmosphere at RT for 3 h to provide the title compound (90 mg). LCMS (Method 4): 1.94 min, 539.3 [M+H]+. Intermediate 44: Methyl 2-((10S,13S)-26-methyl-10-(methylamino)-11-oxo-3-oxa-12-aza- 1(1,3),2(1,2)-dibenzenacyclotridecaphane-13-yl)acetate hydrochloride

[0202] A suspension of Intermediate 43 (90 mg, 0.17 mmol) in 4 M HCl in 1,4-dioxane (3.0 mL) was stirred at RT for 1.5 h. The mixture was concentrated under reduced pressure to provide the title compound (79 mg). LCMS (Method 4): 1.48 min, 439.4 [M+H]+. Intermediate 45: Methyl 2-((10S,13S)-26-methyl-10-(N-methylacetamido)-11-oxo-3-oxa-12- aza-1(1,3),2(1,2)-dibenzenacyclotridecaphane-13-yl)acetate

[0203] Prepared in an analogous manner to Intermediate 10 using 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) at RT for 30 min, to provide the title compound (80 mg). LCMS (Method 4): 1.56 min, 481.4 [M+H]+. Intermediate 46: Methyl (S)-3-((tert-butoxycarbonyl)amino)-3-(2'-methyl-6'-vinyl-[1,1'- biphenyl]-3-yl)propanoate

[0204] Prepared in an analogous manner to Intermediate 3 using Intermediate 2 (1.1 g, 2.58 mmol), 2-bromo-1-methyl-3-vinylbenzene (0.59 g, 2.83 mmol, CAS 1835-81-0), K2CO3 (0.71 g, 5.16 mmol) and Pd(dppf)Cl2 (0.11 g, 0.15 mmol) in 1,4-dioxane (19 mL), and water (6.4 mL) at 90 °C for 3 h. Purified by flash chromatography (40 g silica gel, eluting 100% DCM) to provide the title compound (0.76 g). LCMS (Method 4): 1.83 min, 418.3 [M+Na]+. Intermediate 47: Methyl (S)-3-amino-3-(2'-methyl-6'-vinyl-[1,1'-biphenyl]-3-yl)propanoate hydrochloride

[0205] A suspension of Intermediate 46 (0.76 g, 1.69 mmol) in 4 M HCl in 1,4-dioxane (10 mL) was stirred at RT for 2 h. The mixture was concentrated under reduced pressure to provide the title compound (0.56 g). LCMS (Method 4): 1.65 min, 296.0 [M+H]+. 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

[0206] Prepared in an analogous manner to Intermediate 5 using 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) at RT for 4 h. Purified by flash chromatography (40 g silica gel,eluting 0-10% EtOAc in DCM) to provide the title compound (0.10 g). LCMS (Method 5): 2.14 min, 463.2 [M-Boc+H]+. Intermediate 49: Methyl 2-((3S,6S)-6-((tert-butoxycarbonyl)(methyl)amino)-16-methyl-5-oxo- 4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphan-12-en-3-yl)acetate

[0207] Prepared in an analogous manner to Intermediate 7 using Intermediate 48 (0.20 g, 0.32 mmol) in DCE (15 mL) and Grubbs II (27 mg, 0.04 mmol) at 60 °C for 16 h, quenching with ethyl vinyl ether (3.04 mL, 31.7 mmol). Purified by flash chromatography (silica gel, eluting 5% EtOAc in DCM) to provide the title compound (0.11 g). LCMS (Method 4): 1.98 min, 535.5 [M+H]+. Intermediate 50: Methyl 2-((3S,6S)-6-((tert-butoxycarbonyl)(methyl)amino)-16-methyl-5-oxo- 4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3-yl)acetate

[0208] Prepared in an analogous manner to Intermediate 8 using Intermediate 49 (91 mg, 0.17 mmol) and 5% palladium on carbon (18 mg) in MeOH (10 mL) under a hydrogen atmosphere at RT for 3 h to provide the title compound (90 mg). LCMS (Method 4): 1.94 min, 537.2 [M+H]+. Intermediate 51: Methyl 2-((3S,6S)-16-methyl-6-(methylamino)-5-oxo-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetate hydrochloride

[0209] A suspension of Intermediate 50 (91 mg, 0.17 mmol) in 4 M HCl in 1,4-dioxane (1.5 mL) was stirred at RT for 1 h. The mixture was concentrated under reduced pressure to provide the title compound (79 mg). LCMS (Method 4): 1.66 min, 437.5 [M+H]+. Intermediate 52: Methyl 2-((3S,6S)-16-methyl-6-(N-methylacetamido)-5-oxo-4-aza- 1(1,2),2(1,3)-dibenzenacyclotridecaphane-3-yl)acetate

[0210] Prepared in an analogous manner to Intermediate 10 using 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) at RT for 2 h, to provide the title compound (77 mg). LCMS (Method 4): 1.83 min, 479.3 [M+H]+. Intermediate 53: Methyl (S)-3-(2'-(but-3-en-1-yloxy)-6'-methyl-[1,1'-biphenyl]-3-yl)-3-((tert- butoxycarbonyl)amino)propanoate

[0211] Prepared in an analogous manner to Intermediate 6 using 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) at reflux for 16 h. Purified by flash chromatography (25 g XTYPE cartridge, eluting 0 - 50% EtOAc in petroleum ether) to provide the title compound (1.0 g). LCMS (Method 3): 1.93 min, 462.2 [M+Na]+.Intermediate 54: Methyl (S)-3-amino-3-(2'-(but-3-en-1-yloxy)-6'-methyl-[1,1'-biphenyl]-3- yl)propanoate hydrochloride

[0212] A suspension of Intermediate 53 (1.0 g, 2.28 mmol) in 4 M HCl in 1,4-dioxane (53 mL) was stirred at RT for 1 h. The mixture was concentrated under reduced pressure to provide the title compound (0.85 g). LCMS (Method 3): 1.19 min, 340.3 [M+H]+. 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

[0213] Prepared in an analogous manner to Intermediate 5 using 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) at RT for 5 h. Purified by flash chromatography (25 g silica gel, eluting 30-100% EtOAc in petroleum ether) to provide the title compound (0.80 g). LCMS (Method 3): 1.68 min, 452.4 [M+H]+. 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

[0214] 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 stirred at RT for 1 h. The mixture was washed with 2 M aqueous HCl, dried over Na2SO4, filtered and concentrated under reduced pressure, to provide the title compound (0.94 g). LCMS (Method 3): 1.82 min, 530.1 [M+H]+. 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

[0215] 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 stirred at 95 °C for 1 h. Additional K2CO3 (0.37 g, 2.66 mmol) was added, and the mixture stirred at 95 °C for 2 h. The mixture was cooled, filtered and the filtrate concentrated under reduced pressure. The crude product was purified by flash chromatography (24 g silica gel, eluting 0-100% EtOAc in petroleum ether) to provide the title compound (0.33 g). LCMS (Method 2): 2.28 min, 551.3 [M+Na]+. Intermediate 58: Methyl 2-((10S,13S)-26-methyl-11-oxo-10-(2-oxopiperidin-1(2H)-yl)-3-oxa- 12-aza-1(1,3),2(1,2)-dibenzenacyclotridecaphan-6-en-13-yl)acetate

[0216] Prepared in an analogous manner to Intermediate 7 using Intermediate 57 (0.33 g, 0.62 mmol) in DCE (31 mL) and Grubbs II (53 mg, 0.06 mmol) at 40 °C for 1 h, quenching with ethyl vinyl ether (0.06 mL, 0.62 mmol). Purified by flash chromatography (25 g silica gel,eluting 0-100% EtOAc in petroleum ether) to provide the title compound (0.10 g). LCMS (Method 4): 1.66 min, 501.2 [M+H]+. Intermediate 59: Methyl 2-((10S,13S)-26-methyl-11-oxo-10-(2-oxopyridin-1(2H)-yl)-3-oxa-12- aza-1(1,3),2(1,2)-dibenzenacyclotridecaphane-13-yl)acetate

[0217] Prepared in an analogous manner to Intermediate 8 using Intermediate 58 (0.10 g, 0.20 mmol) and 5% palladium on carbon (21 mg) in MeOH (5 mL) under a hydrogen atmosphere at RT for 2 h to provide the title compound (75 mg). LCMS (Method 3): 1.70 min, 503.2 [M+H]+. 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

[0218] Prepared in an analogous manner to Intermediate 57 using 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) at 95 °C for 2 h. Purified by flash chromatography (24 g silica gel, eluting 0-100% EtOAc in petroleum ether) to provide the title compound (0.20 g). LCMS (Method 3): 1.94 min, 597.3 [M+H]+. Intermediate 61: Methyl 2-((10S,13S)-26-methyl-11-oxo-10-(2-oxo-4-(trifluoromethyl)pyridin- 1(2H)-yl)-3-oxa-12-aza-1(1,3),2(1,2)-dibenzenacyclotridecaphan-6-en-13-yl)acetate

[0219] Prepared in an analogous manner to Intermediate 7 using Intermediate 60 (0.20 g, 0.34 mmol) in DCE (17 mL) and Grubbs II (28 mg, 0.03 mmol) at 40 °C for 1 h. Purified by flash chromatography (24 g silica gel, eluting 0-100% EtOAc in petroleum ether) to provide the title compound (0.10 g). LCMS (Method 3): 1.84 min, 569.2 [M+H]+. Intermediate 62: Methyl 2-((10S,13S)-26-methyl-11-oxo-10-(2-oxo-4-(trifluoromethyl)-pyridin- 1(2H)-yl)-3-oxa-12-aza-1(1,3),2(1,2)-dibenzenacyclotridecaphane-13-yl)acetate

[0220] Prepared in an analogous manner to Intermediate 8 using Intermediate 61 (0.10 g, 0.20 mmol) and 5% palladium on carbon (10 mg) in MeOH (5 mL) under a hydrogen atmosphere at RT for 1 h to provide the title compound (0.10 g). LCMS (Method 3): 1.87 min, 571.2 [M+H]+. 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

[0221] Prepared in an analogous manner to Intermediate 5 using 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 (10mL) at RT for 5 h, to provide the title compound (0.11 g). LCMS (Method 3): 1.72 min, 438.2 [M+H]+. 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

[0222] Prepared in an analogous manner to Intermediate 56 using 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) at RT for 10 min. Purified by flash chromatography (12 g silica gel, eluting 0-50% EtOAc in petroleum ether) to provide the title compound (75 mg). LCMS (Method 3): 1.78 min, 516.2 [M+H]+. 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

[0223] 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 RT. 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 and diluted with EtOAc, washed with water, dried over Na2SO4, filtered and the filtrate concentrated under reduced pressure. The crude product was purified by flash chromatography (12 g silica gel, eluting 50-100% EtOAc in petroleum ether) to provide the title compound (30 mg). LCMS (Method 3): 2.23 min, 515.2 [M+H]+. Intermediate 66: Methyl 2-((9S,12S)-26-methyl-10-oxo-9-(2-oxopyridin-1(2H)-yl)-3-oxa-11- aza-1(1,3),2(1,2)-dibenzenacyclododecaphan-6-en-12-yl)acetate

[0224] Prepared in an analogous manner to Intermediate 7 using Intermediate 65 (45 mg, 0.09 mmol) in DCE (4.4 mL) and Grubbs II (7.4 mg, 8.7 µmol) at 40 °C for 2 h. Purified by flash chromatography (14 g XTYPE cartridge, eluting 100% EtOAc) to provide the title compound (5 mg). LCMS (Method 3): 1.50 min, 487.4 [M+H]+. Intermediate 67: Methyl 2-((9S,12S)-26-methyl-10-oxo-9-(2-oxopiperidin-1-yl)-3-oxa-11-aza- 1(1,3),2(1,2)-dibenzenacyclododecaphane-12-yl)acetate

[0225] Prepared in an analogous manner to Intermediate 8 using Intermediate 66 (5 mg, 0.01 mmol) and platinum oxide (1 mg, 4.4 µmol) in MeOH (5 mL) under a hydrogen atmosphere at RT for 2 h to provide the title compound (5 mg). LCMS (Method 3): 1.66 min, 493.3 [M+H]+. Intermediate 68: Methyl 2-((10R,13S)-10-hydroxy-26-methyl-11-oxo-3-oxa-12-aza- 1(1,3),2(1,2)-dibenzenacyclotridecaphan-6-en-13-yl)acetate

[0226] Prepared in an analogous manner to Intermediate 7 using Intermediate 55 (550 mg, 1.22 mmol) in DCE (58 mL) and Grubbs II (0.10 g, 0.12 mmol) at 40 °C for 4 h. Purified by flash chromatography (40 g silica gel, eluting 50-100% EtOAc in petroleum ether) to provide the title compound (0.32 g). LCMS (Method 3): 1.58 min, 424.3 [M+H]+. Intermediate 69: Methyl 2-((10R,13S)-26-methyl-10-((methylsulfonyl)oxy)-11-oxo-3-oxa-12- aza-1(1,3),2(1,2)-dibenzenacyclotridecaphan-6-en-13-yl)acetate

[0227] 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 stirred at RT for 1 h. The mixture was concentrated under reduced pressure and the crude product purified by flash chromatography (40 g silica gel, eluting 20-100% EtOAc in petroleum ether) to provide the title compound (0.33 g). LCMS (Method 3): 1.68 min, 502.1 [M+H]+. Intermediate 70: Methyl 2-((10S,13S)-10-azido-26-methyl-11-oxo-3-oxa-12-aza- 1(1,3),2(1,2)-dibenzenacyclotridecaphan-6-en-13-yl)acetate

[0228] 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 stirred at 90 °C for 72 h. The mixture was diluted with EtOAc and water. The aqueous was extracted with EtOAc then the organics washed with brine and concentrated under reduced pressure. The crude product was purified by flash chromatography (12 g silica gel, eluting 20-50% EtOAc in petroleum ether) to provide the title compound (0.12 g). LCMS (Method 4): 1.69 and 1.77 min, 449.1 [M+H]+. Intermediate 71: Methyl 2-((10S,13S)-10-amino-26-methyl-11-oxo-3-oxa-12-aza- 1(1,3),2(1,2)-dibenzenacyclotridecaphane-13-yl)acetate

[0229] Prepared in an analogous manner to Intermediate 8 using Intermediate 70 (0.12 g, 0.24 mmol) and 10% palladium on carbon (11 mg) in MeOH (8 mL) under a hydrogen atmosphere at RT for 2 h to provide the title compound (52 mg). LCMS (Method 4): 1.27 min, 425.2 [M+H]+. Intermediate 72: 4-(((10S,13S)-13-(2-Methoxy-2-oxoethyl)-26-methyl-11-oxo-3-oxa-12-aza- 1(1,3),2(1,2)-dibenzenacyclotridecaphane-10-yl)amino)butanoic acid

[0230] 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) was added STAB (26 mg, 0.12 mmol) and the mixture stirred at RT for 15 h. The mixture was diluted with water (2 mL) and extracted with 10% MeOH in DCM. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flashchromatography (12 g silica gel, eluting 50-100% EtOAc in petroleum ether then 20% MeOH in DCM) to provide the title compound (12 mg). LCMS (Method 4): 1.63 min, 511.2 [M+H]+. Intermediate 73: Methyl (S)-3-(2'-(allyloxy)-6'-methyl-[1,1'-biphenyl]-3-yl)-3-((tert- butoxycarbonyl)amino)propanoate

[0231] Prepared in an analogous manner to Intermediate 6 using Intermediate 3 (1.0 g, 2.59 mmol), K2CO3(0.39 g, 2.85 mmol) and allyl bromide (0.25 mL, 2.85 mmol) in MeCN (50 mL) at 50 °C for 16 h to provide the title compound (1.1 g). LCMS (Method 4): 1.86 min, 448.1 [M+Na]+. Intermediate 74: Methyl (S)-3-(2'-(allyloxy)-6'-methyl-[1,1'-biphenyl]-3-yl)-3- aminopropanoate hydrochloride

[0232] A suspension of Intermediate 73 (1.1 g, 2.58 mmol) in 4 M HCl in 1,4-dioxane (50 mL) was stirred at RT for 2 h. The mixture was concentrated under reduced pressure to provide the title compound (0.93 g). LCMS (Method 3): 1.22 min, 326.1 [M+H]+. Intermediate 75: Methyl (S)-3-(2'-(allyloxy)-6'-methyl-[1,1'-biphenyl]-3-yl)-3-((R)-2- hydroxypent-4-enamido)propanoate

[0233] Prepared in an analogous manner to Intermediate 5 using 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) at RT for 16 h. Purified by flash chromatography (24 g silica gel, eluting 50-100% EtOAc in petroleum ether) to provide the title compound (0.13 g). LCMS (Method 3): 1.63 min, 424.2 [M+H]+. Intermediate 76: Methyl (S)-3-(2'-(allyloxy)-6'-methyl-[1,1'-biphenyl]-3-yl)-3-((R)-2- ((methylsulfonyl)oxy)pent-4-enamido)propanoate

[0234] Prepared in an analogous manner to Intermediate 56 using 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) at RT for 10 min. Purified by flash chromatography (24 g silica gel, eluting 0-60% EtOAc in petroleum ether) to provide the title compound (0.45 g). LCMS (Method 3): 1.62 min, 524.3 [M+Na]+. 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

[0235] Prepared in an analogous manner to Intermediate 65 using 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) at 80 °C for 16 h. Purified by flash chromatography (12g silica gel, eluting 50-100% EtOAc in petroleum ether) to provide the title compound (0.25 g). LCMS (Method 3): 1.71 min, 501.2 [M+H]+. Intermediate 78: Methyl 2-((8S,11S)-26-methyl-9-oxo-8-(2-oxopyridin-1(2H)-yl)-3-oxa-10- aza-1(1,3),2(1,2)-dibenzenacycloundecaphan-5-en-11-yl)acetate

[0236] Prepared in an analogous manner to Intermediate 7 using Intermediate 77 (0.23 g, 0.45 mmol) in DCE (23 mL) and Grubbs II (38 mg, 0.05 mmol) at 40 °C for 2 h. Purified by flash chromatography (12 g silica gel, eluting 50-100% EtOAc in petroleum ether) to provide the title compound (0.20 g). LCMS (Method 3): 1.56 min, 473.2 [M+H]+. Intermediate 79: Methyl 2-((8S,11S)-26-methyl-9-oxo-8-(2-oxopyridin-1(2H)-yl)-3-oxa-10- aza-1(1,3),2(1,2)-dibenzenacycloundecaphane-11-yl)acetate

[0237] Prepared in an analogous manner to Intermediate 8 using Intermediate 78 (0.20 g, 0.42 mmol) and 10% palladium on carbon (12 mg) in MeOH (5 mL) and THF (5 mL) under a hydrogen atmosphere at RT for 2 h. Purified by flash chromatography (40 g silica gel, eluting 50-100% EtOAc in petroleum ether) to provide the title compound (0.10 g). LCMS (Method 3): 1.57 min, 475.2 [M+H]+. Intermediate 80: Methyl (S)-3-((tert-butoxycarbonyl)amino)-3-(4'-fluoro-2'-hydroxy-6'-methyl- [1,1'-biphenyl]-3-yl)propanoate

[0238] Prepared in an analogous manner to Intermediate 3 using Intermediate 2 (0.80 g, 1.68 mmol), 2-bromo-5-fluoro-3-methylphenol (0.41 g, 1.68 mmol, CAS 1807192-21-7), Na2CO3 (0.53 g, 5.03 mmol) and Pd(PPh3)4 (0.09 g, 0.08 mmol) in toluene (14.8 mL) ethanol (3.1 mL) and water (3.1 mL) at 85 °C for 8 h. Purified by flash chromatography (40 g silica gel, eluting 0-20% EtOAc in petroleum ether) to provide the title compound (0.42 g). LCMS (Method 3): 1.66 min, 426.1 [M+Na]+. 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

[0239] Prepared in an analogous manner to Intermediate 6 using 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) at reflux for 16 h. Purified by flash chromatography (12 g silica gel, eluting 0- 60% EtOAc in petroleum ether) to provide the title compound (0.35 g). LCMS (Method 6): 1.93 min, 494.4 [M+Na]+. Intermediate 82: Methyl (S)-3-amino-3-(4'-fluoro-2'-methyl-6'-(pent-4-en-1-yloxy)-[1,1'- biphenyl]-3-yl)propanoate hydrochloride

[0240] A suspension of Intermediate 81 (0.35 g, 0.74 mmol) in 4 M HCl in 1,4-dioxane (5 mL) was stirred at RT for 1 h. The mixture was concentrated under reduced pressure to provide the title compound (0.30 g). LCMS (Method 3): 1.54 min, 372.2 [M+H]+. 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

[0241] Prepared in an analogous manner to Intermediate 5 using 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) at RT for 16 h, to provide the title compound (0.13 g). LCMS (Method 7): 2.29 min, 470.2 [M+H]+. 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

[0242] Prepared in an analogous manner to Intermediate 56 using 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) at RT for 10 min. Purified by flash chromatography (24 g silica gel, eluting 0-60% EtOAc in petroleum ether) to provide the title compound (0.20 g). LCMS (Method 3): 1.86 min, 548.3 [M+H]+. 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

[0243] Prepared in an analogous manner to Intermediate 65 using 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) at 80 °C for 16 h. Purified by flash chromatography (12 g silica gel, eluting 50-100% EtOAc in petroleum ether) to provide the title compound (35 mg). LCMS (Method 3): 1.84 min, 547.2 [M+H]+. Intermediate 86: Methyl 2-((10S,13S)-24-fluoro-26-methyl-11-oxo-10-(2-oxopyridin-1(2H)-yl)- 3-oxa-12-aza-1(1,3),2(1,2)-dibenzenacyclotridecaphan-7-en-13-yl)acetate

[0244] Prepared in an analogous manner to Intermediate 7 using Intermediate 85 (35 mg, 0.06 mmol) in DCE (3.2 mL) and Grubbs II (5.4 mg, 6.4 µmol) at 40 °C for 0.5 h. Purified by flash chromatography (4 g silica gel, eluting 50-100% EtOAc in petroleum ether) to provide the title compound (20 mg). LCMS (Method 3): 1.71 min, 519.2 [M+H]+. Intermediate 87: Methyl 2-((10S,13S)-24-fluoro-26-methyl-11-oxo-10-(2-oxopyridin-1(2H)-yl)- 3-oxa-12-aza-1(1,3),2(1,2)-dibenzenacyclotridecaphane-13-yl)acetate

[0245] Prepared in an analogous manner to Intermediate 8 using Intermediate 86 (20 mg, 0.04 mmol) and 10% palladium on carbon (0.4 mg) in MeOH (1 mL) and THF (1 mL) under a hydrogen atmosphere at RT for 8 h, to provide the title compound (20 mg). LCMS (Method 3): 1.75 min, 521.3 [M+H]+. 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

[0246] Prepared in an analogous manner to Intermediate 65 using 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) at 80 °C for 16 h. Purified by flash chromatography (40 g silica gel, eluting 50-100% EtOAc in petroleum ether) to provide the title compound (25 mg). LCMS (Method 7): 2.51 min, 547.2 [M+H]+. Intermediate 89: Methyl 2-((10S,13S)-10-(5-fluoro-2-oxopyridin-1(2H)-yl)-26-methyl-11-oxo- 3-oxa-12-aza-1(1,3),2(1,2)-dibenzenacyclotridecaphan-6-en-13-yl)acetate

[0247] Prepared in an analogous manner to Intermediate 7 using Intermediate 88 (25 mg, 0.05 mmol) in DCE (5 mL) and Grubbs II (7.8 mg, 9.1 µmol) at 40 °C for 2 h. Purified by flash chromatography (12 g silica gel, eluting 30-100% EtOAc in petroleum ether) to provide the title compound (14 mg). LCMS (Method 6): 1.61 min, 519.2 [M+H]+. Intermediate 90: Methyl 2-((10S,13S)-10-(5-fluoro-2-oxopyridin-1(2H)-yl)-26-methyl-11-oxo- 3-oxa-12-aza-1(1,3),2(1,2)-dibenzenacyclotridecaphane-13-yl)acetate

[0248] Prepared in an analogous manner to Intermediate 8 using Intermediate 89 (14 mg, 0.02 mmol) and 10% palladium on carbon (0.2 mg) in MeOH (1.5 mL) under a hydrogen atmosphere at RT for 24 h, to provide the title compound (10 mg). LCMS (Method 3): 1.77 min, 521.3 [M+H]+. Intermediate 91: Methyl 3-(5-bromopyridin-3-yl)-3-((tert-butoxycarbonyl)amino)-propanoate

[0249] 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) was added ammonium acetate (8.29 g, 108 mmol) and the mixture stirred at 75 °C for 24 h. The mixture was cooled to RT and the solids filtered, washing 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 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 stirred at RT for 6 h. The mixture was washed with water (2 mL) and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by dry flashchromatography (silica gel, eluting 5-35% EtOAc in petroleum ether) to provide the title compound (14.7 g). LCMS (Method 4): 1.42 min, 359.1 [M+H]+. Intermediate 92: Methyl 3-((tert-butoxycarbonyl)amino)-3-(5-(2-hydroxy-6- methylphenyl)pyridin-3-yl)propanoate

[0250] 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 the solution was then added potassium acetate (2.73 g, 27.8 mmol) followed by Pd(dppf)Cl2(0.41 g, 0.56 mmol) and the reaction mixture stirred at 100 °C for 1 h. The mixture was cooled then a degassed solution of Na2CO3 (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 h. The mixture was cooled and filtered through Celite®, washing with EtOAc and water. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (120 g silica gel, eluting 0-100% EtOAc in petroleum ether) to provide the title compound (2.6 g). LCMS (Method 6): 1.16 min, 387.4 [M+H]+. Intermediate 93: Methyl 3-((tert-butoxycarbonyl)amino)-3-(5-(2-methyl-6-(pent-4-en-1- yloxy)phenyl)pyridin-3-yl)propanoate

[0251] Prepared in an analogous manner to Intermediate 6 using 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) at reflux for 6 h. Purified by flash chromatography (80 g silica gel, eluting 0- 60% EtOAc in petroleum ether) to provide the title compound (2.00 g). LCMS (Method 3): 1.77 min, 455.2 [M+H]+. Intermediate 94: Methyl 3-amino-3-(5-(2-methyl-6-(pent-4-en-1-yloxy)phenyl)pyridin-3- yl)propanoate hydrochloride

[0252] A suspension of Intermediate 93 (2.00 g, 4.40 mmol) in 4 M HCl in 1,4-dioxane (62 mL) was stirred at RT for 1 h. The mixture was concentrated under reduced pressure to provide the title compound (1.90 g). LCMS (Method 6): 1.42 min, 355.4 [M+H]+. 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

[0253] Prepared in an analogous manner to Intermediate 5 using 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) at RT for 2 h. Purified by flash chromatography (80 g silica gel, eluting 50-100% EtOAcin petroleum ether) to provide the title compound (0.48 g) as the second diastereomer eluted. LCMS (Method 4): 1.55 min, 453.2 [M+H]+. Intermediate 96: Methyl (S)-3-(5-(2-methyl-6-(pent-4-en-1-yloxy)phenyl)pyridin-3-yl)-3-((R)- 2-((methylsulfonyl)oxy)pent-4-enamido)propanoate

[0254] Prepared in an analogous manner to Intermediate 56 using 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) at RT for 10 min. Purified by flash chromatography (40 g silica gel, eluting 0-50% EtOAc in petroleum ether) to provide the title compound (0.38 g). LCMS (Method 3): 1.59 min, 531.2 [M+H]+. 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

[0255] Prepared in an analogous manner to Intermediate 65 using 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) at 80 °C for 16 h. Purified by flash chromatography (12 g silica gel, eluting 50-100% EtOAc in petroleum ether) to provide the title compound (0.12 g). LCMS (Method 3): 1.54 min, 530.3 [M+H]+. Intermediate 98: Methyl 2-((10S,13S)-26-methyl-11-oxo-10-(2-oxopyridin-1(2H)-yl)-3-oxa-12- aza-1(3,5)-pyridina-2(1,2)-benzenacyclotridecaphan-7-en-13-yl)acetate

[0256] Prepared in an analogous manner to Intermediate 7 using Intermediate 97 (0.12 g, 0.23 mmol) in DCE (9 mL) and Grubbs II (38 mg, 0.05 mmol) at 40 °C for 24 h. Additional Grubbs II (19 mg, 0.02 mmol) was added and heated at 40 °C for 15 h. Purified by flash chromatography (40 g silica gel, eluting 30-100% EtOAc in petroleum ether) to provide the title compound (60 mg). LCMS (Method 3): 1.35 min, 502.2 [M+H]+. Intermediate 99: Methyl 2-((10S,13S)-26-methyl-11-oxo-10-(2-oxopyridin-1(2H)-yl)-3-oxa-12- aza-1(3,5)-pyridina-2(1,2)-benzenacyclotridecaphane-13-yl)acetate

[0257] Prepared in an analogous manner to Intermediate 8 using Intermediate 98 (43 mg, 0.09 mmol) and platinum oxide (1.9 mg) in MeOH (1.5 mL) under a hydrogen atmosphere at RT for 3.5 h, to provide the title compound (35 mg). LCMS (Method 3): 1.40 min, 504.2 [M+H]+- note also contaminated with lactam, 508.3 in LCMS. Intermediate 100: 2-((10S,13S)-26-Methyl-11-oxo-10-(2-oxopyridin-1(2H)-yl)-3-oxa-12-aza- 1(3,5)-pyridina-2(1,2)-benzenacyclotridecaphane-13-yl)acetic acid

[0258] A mixture of Intermediate 99 (53 mg, 0.10 mmol) was dissolved in MeOH (2 mL), THF (1 mL) and water (1 mL) then lithium hydroxide (2.5 mg, 0.10 mmol) was added and thesolution stirred at RT for 4 h. The solution was adjusted to pH 4 with 2 M aqueous HCl and then the mixture was concentrated under reduced pressure. The crude product was purified by flash chromatography (32 g C18, eluting 0-60% MeCN in 1% aqueous formic acid) to provide the title compound (12 mg), contaminated with lactam. LCMS (Method 3): 1.21 min, 490.1 [M+H]+; 1.23 min, 494.2 [M+H]+lactam. Intermediate 101: 5-(4-Fluoro-2-hydroxy-6-methylphenyl)nicotinaldehyde

[0259] Prepared in an analogous manner 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), Na2CO3 (2.32 g, 21.9 mmol) and Pd(PPh3)4 (0.38 g, 0.33 mmol) in toluene (52 mL), ethanol (13 mL) and water (13 mL) at 85 °C for 8 h. Purified by dry flash chromatography (silica gel, eluting 50% EtOAc in petroleum ether) to provide the title compound (1.37 g). LCMS (Method 3): 1.25 min, 232.0 [M+H]+. Intermediate 102: (R,E)-N-((5-(4-Fluoro-2-hydroxy-6-methylphenyl)pyridin-3-yl)methylene)- 2-methylpropane-2-sulfinamide

[0260] 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) then the mixture was stirred at 60 °C for 2 h. The mixture was diluted with water and extracted into EtOAc. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (12 g silica gel, eluting 50 – 100% EtOAc in petroleum ether) to provide the title compound (0.75 g). LCMS (Method 3): 1.48 min, 335.1 [M+H]+. 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

[0261] Prepared in an analogous manner to Intermediate 6 using 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) at reflux for 18 h. Extra K2CO3 (0.62 g, 4.49 mmol) and 5-bromopent-1-ene (0.53 mL, 4.49 mmol) was added and heating continued for 5 h. Purified by flash chromatography (24 g silica gel, eluting 0 - 50% EtOAc in petroleum ether) to provide the title compound (0.85 g). LCMS (Method 3): 1.90 min, 403.1 [M+H]+. 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

[0262] 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 h. The mixture was cooledto RT then ethyl bromoacetate (0.59 mL, 5.30 mmol) was added and the mixture placed in a sonic bath at 40 °C for 15 min. 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 then the mixture was stirred at RT for 1 h. The mixture was diluted with water and extracted into EtOAc. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to provide the title compound (0.80 g). LCMS (Method 3): 1.69 min, 491.1 [M+H]+. Intermediate 105: Ethyl (S)-3-amino-3-(5-(4-fluoro-2-methyl-6-(pent-4-en-1- yloxy)phenyl)pyridin-3-yl)propanoate hydrochloride

[0263] To a suspension of Intermediate 104 (0.80 g, 1.63 mmol) in DCM (1.1 mL) was added 4 M HCl in 1,4-dioxane (2.45 mL) and this was stirred at RT for 1 h. The mixture was concentrated under reduced pressure to provide the title compound (0.63 g). LCMS (Method 3): 1.31 min, 387.1 [M+H]+. 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

[0264] Prepared in an analogous manner to Intermediate 5 using 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 RT for 4 h, to provide the title compound (0.55 g) as the second diastereomer eluted. LCMS (Method 3): 1.57 min, 485.2 [M+H]+. 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)pent-4-enamido)propanoate

[0265] Prepared in an analogous manner to Intermediate 56 using 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) at RT for 30 min. Purified by flash chromatography (24 g silica gel, eluting 0-10% MeOH in DCM) to provide the title compound (0.52 g). LCMS (Method 6): 1.57 min, 563.5 [M+H]+. 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

[0266] Prepared in an analogous manner to Intermediate 65 using 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) at 80 °C for 10 h. Purified by flash chromatography (24 g silica gel, eluting 50-100% EtOAc in petroleum ether) to provide the title compound (0.14 g). LCMS (Method 3): 1.62 min, 562.3 [M+H]+.Intermediate 109: Ethyl 2-((10S,13S)-24-fluoro-26-methyl-11-oxo-10-(2-oxopyridin-1(2H)-yl)- 3-oxa-12-aza-1(3,5)-pyridina-2(1,2)-benzenacyclotridecaphan-7-en-13-yl)acetate

[0267] Prepared in an analogous manner to Intermediate 7 using Intermediate 108 (0.13 g, 0.22 mmol) in DCE (9 mL) and Grubbs II (19 mg, 0.02 mmol) 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. Purified by flash chromatography (24 g silica gel, eluting 50-100% EtOAc in petroleum ether) to provide the title compound (80 mg). LCMS (Method 3): 1.43 min, 534.2 [M+H]+. Intermediate 110: Ethyl 2-((10S,13S)-24-fluoro-26-methyl-11-oxo-10-(2-oxopyridin-1(2H)-yl)- 3-oxa-12-aza-1(3,5)-pyridina-2(1,2)-benzenacyclotridecaphane-13-yl)acetate

[0268] Prepared in an analogous manner to Intermediate 8 using Intermediate 109 (80 mg, 0.15 mmol) and 10% palladium on carbon (10 mg) in MeOH (2 mL) under a hydrogen atmosphere at RT for 4 h, to provide the title compound (10 mg). LCMS (Method 6): 1.40 min, 536.5 [M+H]+. Intermediate 111: Methyl (S)-3-((tert-butoxycarbonyl)amino)-3-(2'-methyl-6'-(pent-4-en-1- yloxy)-[1,1'-biphenyl]-3-yl)propanoate

[0269] Prepared in an analogous manner to Intermediate 6 using 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) at reflux for 8 h. Extra K2CO3 (0.95 g, 6.91 mmol) and 5-bromopent-1-ene (0.82 mL, 6.91 mmol) was added and heating continued for 4 h. Extra K2CO3 (0.48 g, 3.45 mmol) and 5-bromopent-1-ene (0.41 mL, 3.45 mmol) was added and heating continued for 4 h. Purified by flash chromatography (120 g silica gel, eluting 0 - 30% EtOAc in petroleum ether) to provide the title compound (2.63 g). LCMS (Method 6): 1.92 min, 454.5 [M+H]+. Intermediate 112: Methyl (S)-3-amino-3-(2'-methyl-6'-(pent-4-en-1-yloxy)-[1,1'-biphenyl]-3- yl)propanoate hydrochloride

[0270] A suspension of Intermediate 111 (2.79 g, 5.79 mmol) in 4 M HCl in 1,4-dioxane (60 mL) was stirred at RT for 1 h. The mixture was concentrated under reduced pressure to provide the title compound (3.06 g). LCMS (Method 6): 1.20 min, 354.4 [M+H]+. 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

[0271] Prepared in an analogous manner to Intermediate 5 using 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) inMeCN (0.10 L) at RT for 18 h, to provide the title compound (3.98 g). LCMS (Method 6): 1.68 min, 452.4 [M+H]+. 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

[0272] Prepared in an analogous manner to Intermediate 56 using 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) at RT 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 RT 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 RT for 18 h. Purified by flash chromatography (24 g silica gel, eluting 0-10% MeOH in DCM) to provide the title compound (1.76 g). LCMS (Method 3): 1.83 min, 530.2 [M+H]+. 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

[0273] Prepared in an analogous manner to Intermediate 65 using 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) at 80 °C for 18 h. Purified by flash chromatography (40 g silica gel, eluting 30-100% EtOAc in petroleum ether) and reverse phase chromatography (32 g C18, eluting 30-90% MeCN in 1% aqueous formic acid) to provide the title compound (16 mg). LCMS (Method 3): 1.76 min, 547.2 [M+H]+. Intermediate 116: Methyl 2-((10S,13S)-10-(4-fluoro-2-oxopyridin-1(2H)-yl)-26-methyl-11-oxo- 3-oxa-12-aza-1(1,3),2(1,2)-dibenzenacyclotridecaphan-7-en-13-yl)acetate

[0274] Prepared in an analogous manner to Intermediate 7 using Intermediate 115 (16 mg, 0.03 mmol) in DCE (3.3 mL) and Grubbs II (2.5 mg, 3 µmol) at RT for 5 h. Purified by flash chromatography (4 g silica gel, eluting 0-100% EtOAc in petroleum ether) to provide the title compound (10 mg). LCMS (Method 3): 1.59 min, 519.2 [M+H]+. Intermediate 117: Methyl 2-((10S,13S)-10-(4-fluoro-2-oxopyridin-1(2H)-yl)-26-methyl-11-oxo- 3-oxa-12-aza-1(1,3),2(1,2)-dibenzenacyclotridecaphane-13-yl)acetate

[0275] Prepared in an analogous manner to Intermediate 8 using Intermediate 116 (10 mg, 0.02 mmol) and 10% palladium on carbon (0.2 mg) in MeOH (1.5 mL) under a hydrogen atmosphere at RT for 5 h, to provide the title compound (10 mg). LCMS (Method 3): 1.63 min, 521.3 [M+H]+. 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

[0276] Prepared in an analogous manner to Intermediate 65 using 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) at 80 °C for 2 h. Additional K2CO3(52 mg, 0.38 mmol) was added and stirred at 80 °C for 2 h then an additional K2CO3(52 mg, 0.38 mmol) was added and stirred at 80 °C for 12 h. Purified by flash chromatography (40 g silica gel, eluting 15-100% EtOAc in petroleum ether) and to provide the title compound (0.15 g). LCMS (Method 3): 1.84 min, 597.3 [M+H]+. Intermediate 119: Methyl 2-((10S,13S)-26-methyl-11-oxo-10-(2-oxo-5-(trifluoromethyl)- pyridin-1(2H)-yl)-3-oxa-12-aza-1(1,3),2(1,2)-dibenzenacyclotridecaphan-7-en-13-yl)acetate

[0277] Prepared in an analogous manner to Intermediate 7 using Intermediate 118 (0.15 g, 0.23 mmol) in DCE (26 mL) and Grubbs II (19 mg, 0.03 mmol) at RT for 4 h. Purified by flash chromatography (25 g silica gel, eluting 0-100% EtOAc in petroleum ether) to provide the title compound (90 mg). LCMS (Method 3): 1.73 min, 569.3 [M+H]+. Intermediate 120: Methyl 2-((10S,13S)-26-methyl-11-oxo-10-(2-oxo-5-(trifluoromethyl)- pyridin-1(2H)-yl)-3-oxa-12-aza-1(1,3),2(1,2)-dibenzenacyclotridecaphane-13-yl)acetate

[0278] Prepared in an analogous manner to Intermediate 8 using Intermediate 119 (90 mg, 0.15 mmol) and 10% palladium on carbon (1.6 mg) in MeOH (12 mL) under a hydrogen atmosphere at RT for 5 h, to provide the title compound (82 mg). LCMS (Method 3): 1.78 min, 571.2 [M+H]+. Intermediate 121: (2-(Benzyloxy)-6-methylphenyl)boronic acid

[0279] 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 heated to 47 °C then the remainder of the solution was added over 5 min. Additional THF (4 mL) was added and the mixture stirred at 47 °C for 2 h until the majority of magnesium was consumed. The mixture was cooled to RT. 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 min. The mixture was stirred at - 30 °C for 2 h. The mixture was adjusted to pH 4 with 2 M aqueous HCl and the mixture was stirred at RT for 30 min. The mixture was extracted with DCM then the organics were washed with water, brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was recrystallised from diethyl ether / petroleum ether, filtered and dried under vacuum to provide 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 then purified by flash chromatography (80 g silica gel, eluting 20% EtOAc in petroleum ether).Intermediate 122: (R,E)-N-(5-Bromo-2-fluoro-3-methylbenzylidene)-2-methylpropane-2- sulfinamide

[0280] Prepared in an analogous manner to Intermediate 102 using 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, to provide the title compound (90 mg). LCMS (Method 7): 2.29 min, 322.0 [M+H]+. Intermediate 123: Ethyl (S)-3-(5-bromo-2-fluoro-3-methylphenyl)-3-(((R)-tert- butylsulfinyl)amino)propanoate

[0281] Prepared in an analogous manner 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, then Intermediate 122 (1.95 g, 6.09 mmol) in THF (25 mL) at RT for 16 h. Purified by flash chromatography (80 g silica gel, eluting 1-10% MeOH in DCM) to provide the title compound (1.55 g). LCMS (Method 8): 2.07 min, 410.3 [M+H]+. Intermediate 124: Ethyl (S)-3-(2'-(benzyloxy)-4-fluoro-5,6'-dimethyl-[1,1'-biphenyl]-3-yl)-3- (((R)-tert-butylsulfinyl)amino)propanoate

[0282] Prepared in an analogous manner to Intermediate 3 using 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) at 85 °C for 2.5 h. Purified by flash chromatography (40 g silica gel, eluting 50% EtOAc in petroleum ether) to provide the title compound (1.41 g). LCMS (Method 7): 2.49 min, 526.2 [M+H]+. Intermediate 125: Ethyl (S)-3-amino-3-(2'-(benzyloxy)-4-fluoro-5,6'-dimethyl-[1,1'-biphenyl]- 3-yl)propanoate hydrochloride

[0283] 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 RT for 2 h. The mixture was concentrated under reduced pressure to provide the title compound (0.98 g). LCMS (Method 8): 1.70 min, 422.4 [M+H]+. Intermediate 126: Ethyl (S)-3-(2'-(benzyloxy)-4-fluoro-5,6'-dimethyl-[1,1'-biphenyl]-3-yl)-3- ((tert-butoxycarbonyl)amino)propanoate

[0284] 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 stirred for 16 h at RT. The reaction mixture was diluted with DCM and 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, eluting 20-40% EtOAc in petroleum ether) to provide the title compound (0.75 g). LCMS (Method 8): 2.56 min, 520.5 [M-H]-. Intermediate 127: Ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(4-fluoro-2'-hydroxy-5,6'- dimethyl-[1,1'-biphenyl]-3-yl)propanoate

[0285] To a stirred solution of Intermediate 126 (0.68 g, 1.29 mmol) in ethanol (25 mL) was 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 for 2 h at reflux. Additional ammonium formate (1.63 g, 25.9 mmol) was added and heating continued for 1.5 h. Additional 10% palladium on carbon (0.28 g, 0.26 mmol) was added and heating continued for 2 h. The mixture was cooled to RT, diluted with EtOAc and water and filtered through Celite®. The organic layer was separated and the aqueous extracted with EtOAc. The combined organics were dried over Na2SO4, filtered and concentrated under reduced pressure to provide the title compound (0.52 g). LCMS (Method 8): 2.19 min, 430.5 [M-H]-. 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

[0286] Prepared in an analogous manner to Intermediate 6 using 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) at reflux for 8 h. Extra K2CO3 (0.19 g, 1.35 mmol) and 5-bromopent-1-ene (0.13 mL, 1.12 mmol) was added and heating continued for 4 h. Extra K2CO3 (0.16 g, 1.12 mmol) was added and heating continued for 5 h, to provide the title compound (0.53 g). LCMS (Method 8): 2.63 min, 522.5 [M+Na]+. 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

[0287] To a suspension of Intermediate 128 (0.53 g, 0.98 mmol) in 1,4-dioxane (5 mL) was added 4 M HCl in 1,4-dioxane (4.9 mL) and this was stirred at RT for 3 h. The mixture was concentrated under reduced pressure to provide the title compound (0.43 g). LCMS (Method 8): 1.71 min, 400.4 [M+H]+. 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

[0288] Prepared in an analogous manner to Intermediate 5 using 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) at RT 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 stirring at RT for 3 h. Purifiedby flash chromatography (24 g silica gel, eluting 25-50% EtOAc in petroleum ether) to provide the title compound (0.27 g). LCMS (Method 6): 1.83 min, 498.5 [M+H]+. 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

[0289] Prepared in an analogous manner to Intermediate 56 using 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) at RT for 0.5 h, to provide the title compound (0.31 g). LCMS (Method 3): 1.84 min, 576.3 [M+H]+. 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

[0290] Prepared in an analogous manner to Intermediate 65 using 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) at 85 °C for 1 h. Additional K2CO3 (0.17 g, 1.19 mmol) was added and stirred at 95 °C for 9 h. Purified by flash chromatography (12 g silica gel, eluting 0-100% EtOAc in petroleum ether) and to provide the title compound (0.14 g). LCMS (Method 3): 1.82 min, 575.3 [M+H]+. Intermediate 133: Ethyl 2-((10S,13S)-14-fluoro-15,26-dimethyl-11-oxo-10-(2-oxopyridin- 1(2H)-yl)-3-oxa-12-aza-1(1,3),2(1,2)-dibenzenacyclotridecaphan-7-en-13-yl)acetate

[0291] Prepared in an analogous manner to Intermediate 7 using Intermediate 132 (0.14 g, 0.24 mmol) in DCE (0.11 L) and Grubbs II (20.7 mg, 0.02 mmol) at 40 °C for 4 h. Purified by flash chromatography (24 g silica gel, eluting 50-80% EtOAc in petroleum ether) to provide the title compound (0.10 g). LCMS (Method 8): 2.22 min, 547.5 [M+H]+. Intermediate 134: Ethyl 2-((10S,13S)-14-fluoro-15,26-dimethyl-11-oxo-10-(2-oxopyridin- 1(2H)-yl)-3-oxa-12-aza-1(1,3),2(1,2)-dibenzenacyclotridecaphane-13-yl)acetate

[0292] Prepared in an analogous manner to Intermediate 8 using Intermediate 133 (0.10 g, 0.18 mmol) and 10% palladium on carbon (19.5 mg) in MeOH (4 mL) under a hydrogen atmosphere at RT for 0.5 h, to provide the title compound (97 mg). LCMS (Method 9): 4.65 min, 549.6 [M+H]+. Intermediate 135: 5-(2-Methoxyvinyl)pyridin-2(1H)-one

[0293] 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) was added potassium tert-butoxide (1 M in THF, 50.8 mL, 50.8 mmol) dropwise, and the mixture was stirred at RT for 15 min.6-Oxo-1H- pyridine-3-carbaldehyde (2.50 g, 20.3 mmol) was added as a solution in THF (16.5 mL) andthe mixture stirred for at RT for 16 h. The reaction mixture was diluted with water and the crude product extracted into EtOAc 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 (32 g C18, eluting 0-50% MeCN in water, 0.1% ammonia) to provide the title compound (0.93 g). LCMS (Method 4): 0.81 and 0.86 min, 152.0 [M+H]+. Intermediate 136: 5-(2,2-Dihydroxyethyl)pyridin-2(1H)-one

[0294] A suspension of Intermediate 135 (0.30 g, 1.97 mmol) in formic acid (5.22 mL, 138 mmol) was stirred at 70 °C for 2 h. The mixture was concentrated under reduced pressure to provide the title compound (0.27 g).1H 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). Intermediate 137: 5-(2-(Dimethylamino)ethyl)pyridin-2(1H)-one

[0295] 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 RT for 30 min. STAB (1.25 g, 5.91 mmol) was added and the mixture stirred at RT 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 stirred at RT for 6 h. The mixture was filtered and the filtrate concentrated under reduced pressure. The crude product was purified by catch and release chromatography (5 g SCX, eluting MeOH followed by 1 M ammonia in MeOH) to provide the title compound (0.24 g). LCMS (Method 4): 0.86 min, 167.0 [M+H]+. 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

[0296] Prepared in an analogous manner to Intermediate 65 using 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) at 90 °C for 10 h. Additional K2CO3 (0.13 g, 0.94 mmol) was added and stirred at 90 °C for 40 h. Purified by flash chromatography (24 g silica gel, eluting 5-10% MeOH in DCM with 0.5% ammonia in MeOH) to provide the title compound (0.09 g). LCMS (Method 5): 2.10 min, 600.1 [M+H]+. Intermediate 139: Methyl 2-((10S,13S)-10-(5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)- yl)-26-methyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzenacyclotridecaphan-7-en-13- yl)acetate

[0297] Prepared in an analogous manner to Intermediate 7 using Intermediate 138 (89 mg, 0.15 mmol) in DCE (64 mL) and Grubbs II (12.6 mg, 14.8 µmol) 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. Purified by flashchromatography (12 g silica gel, eluting 5-10% MeOH in DCM with 0.1% ammonia in MeOH) to provide the title compound (66 mg). LCMS (Method 5): 2.07 min, 570.5 [M-H]-. Intermediate 140: Methyl 2-((10S,13S)-10-(5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)- yl)-26-methyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzenacyclotridecaphane-13-yl)acetate

[0298] Prepared in an analogous manner to Intermediate 8 using Intermediate 139 (48 mg, 0.08 mmol) and 10% palladium on carbon (9 mg) in MeOH (8 mL) under a hydrogen atmosphere at RT for 15 min. Additional 10% palladium on carbon (9 mg) added and stirred under hydrogen at RT for 20 min, to provide the title compound (67 mg). LCMS (Method 10): 4.33 min, 572.5 [M-H]-. 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)pent-4-enamido)propanoate

[0299] Prepared in an analogous manner to Intermediate 65 using 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) at 90 °C for 16 h. Purified by flash chromatography (40 g silica gel, eluting 0-20% MeOH in DCM) to provide the title compound (0.14 g). LCMS (Method 11): 2.10 min, 572.1 [M+H]+. Intermediate 142: Methyl 2-((8S,11S)-8-(5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)- 26-methyl-9-oxo-3-oxa-10-aza-1(1,3),2(1,2)-dibenzenacycloundecaphan-5-en-11-yl)acetate

[0300] Prepared in an analogous manner to Intermediate 7 using Intermediate 141 (0.14 g, 0.24 mmol) in DCE (50 mL) and Grubbs II (20 mg, 24.5 µmol) at 40 °C for 96 h. Purified by flash chromatography (25 g silica gel, eluting 0-10% MeOH in DCM) to provide the title compound (0.14 g). LCMS (Method 5): 2.07 min, 544.3 [M+H]+. Intermediate 143: Methyl 2-((8S,11S)-8-(5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)- 26-methyl-9-oxo-3-oxa-10-aza-1(1,3),2(1,2)-dibenzenacycloundecaphane-11-yl)acetate

[0301] Prepared in an analogous manner to Intermediate 8 using Intermediate 142 (0.14 g, 0.18 mmol) and 10% palladium on carbon (19 mg) in MeOH (5 mL) under a hydrogen atmosphere at RT for 5 h. Purified by flash chromatography (12 g silica gel, eluting 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 RT for 15 min, to provide the title compound (12 mg). LCMS (Method 5): 1.95 min, 546.3 [M+H]+. Intermediate 144: Methyl (S)-3-(4'-bromo-2'-hydroxy-6'-methyl-[1,1'-biphenyl]-3-yl)-3-((tert- butoxycarbonyl)amino)propanoate

[0302] Prepared in an analogous manner to Intermediate 3 using Intermediate 2 (0.40 g, 0.99 mmol), 5-bromo-2-iodo-3-methylphenol (0.31 g, 0.99 mmol, CAS 2091225-92-0), Na2CO3(0.26 g, 2.48 mmol) and Pd(dppf)Cl2(81 mg, 0.10 mmol) in 1,4-dioxane (9.3 mL), andwater (3.1 mL) at 55 °C for 2.5 h. Purified by flash chromatography (12 g silica gel, eluting 0- 35% EtOAc in petroleum ether) to provide the title compound (0.38 g). LCMS (Method 6): 1.66 min, 486.2 [M+Na]+. 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

[0303] Prepared in an analogous manner to Intermediate 6 using 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) at reflux for 18 h, to provide the title compound (0.34 g). LCMS (Method 6): 2.03 min, 556.2 [M+Na]+. Intermediate 146: Methyl (S)-3-amino-3-(4'-bromo-2'-methyl-6'-(pent-4-en-1-yloxy)-[1,1'- biphenyl]-3-yl)propanoate hydrochloride

[0304] 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 RT for 3 h. The mixture was concentrated under reduced pressure to provide the title compound (0.43 g). LCMS (Method 12): 1.86 min, 456.1 [M+Na]+. 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

[0305] Prepared in an analogous manner to Intermediate 5 using 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) at RT for 18 h. Purified by flash chromatography (12 g silica gel, eluting 15-55% EtOAc in petroleum ether) to provide 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). 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

[0306] Prepared in an analogous manner to Intermediate 56 using 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) at RT for 18 h. Purified by flash chromatography (12 g silica gel, eluting 15-55% EtOAc in petroleum ether) to provide the title compound (0.45 g). LCMS (Method 4): 1.99 min, 606.1 [M-H]-. 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

[0307] Prepared in an analogous manner to Intermediate 65 using Intermediate 148 (0.45 g, 0.67 mmol), pyridin-2-ol (0.14 g, 1.48 mmol) and K2CO3(0.28 g, 2.02 mmol) in MeCN (10 mL) at 90 °C for 16 h. Purified by flash chromatography (12 g silica gel, eluting 10-100% EtOAc in petroleum ether) to provide the title compound (0.15 g).1H 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). Intermediate 150: Methyl 2-((10S,13S)-24-bromo-26-methyl-11-oxo-10-(2-oxopyridin-1(2H)- yl)-3-oxa-12-aza-1(1,3),2(1,2)-dibenzenacyclotridecaphan-7-en-13-yl)acetate

[0308] Prepared in an analogous manner to Intermediate 7 using Intermediate 149 (0.17 g, 0.28 mmol) in DCE (30 mL) and Grubbs II (24 mg, 28.4 µmol) at 40 °C for 4 h. Purified by flash chromatography (25 g silica gel, eluting 50-100% EtOAc in petroleum ether) to provide the title compound (90 mg). LCMS (Method 4): 1.84 min, 581.0 [M+H]+. Intermediate 151: Methyl 2-((10S,13S)-24-(3,6-dihydro-2H-pyran-4-yl)-26-methyl-11-oxo-10- (2-oxopyridin-1(2H)-yl)-3-oxa-12-aza-1(1,3),2(1,2)-dibenzenacyclotridecaphan-7-en-13- yl)acetate

[0309] 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 stirred at 80 °C for 16 h. 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 provide the title compound (0.13 g). LCMS (Method 4): 1.68 min, 583.2 [M+H]+. Intermediate 152: 2-((10S,13S)-24-(3,6-Dihydro-2H-pyran-4-yl)-26-methyl-11-oxo-10-(2- oxopyridin-1(2H)-yl)-3-oxa-12-aza-1(1,3),2(1,2)-dibenzenacyclotridecaphan-7-en-13- yl)acetic acid

[0310] 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 stirred at RT for 2 h. Additional lithium hydroxide (7.9 mg, 0.33 mmol) was added and stirring continued at RT for 3 h. The mixture was concentrated under reduced pressure and the residue 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 provide the title compound (70 mg). LCMS (Method 4): 1.12 min, 569.1 [M+H]+.Intermediate 153: Methyl 2-((10S,13S)-26-methyl-11-oxo-10-(2-oxopyridin-1(2H)-yl)-24- (tetrahydro-2H-pyran-4-yl)-3-oxa-12-aza-1(1,3),2(1,2)-dibenzenacyclotridecaphane-13- yl)acetate

[0311] Prepared in an analogous manner to Intermediate 8 using Intermediate 152 (70 mg, 0.12 mmol) and 10% palladium on carbon (13 mg) in MeOH (5 mL) under a hydrogen atmosphere at RT for 24 h, to provide the title compound (63 mg). LCMS (Method 12): 1.60 min, 587.4 [M+H]+. Intermediate 154: Benzyl (S)-3'-(1-((tert-butoxycarbonyl)amino)-3-methoxy-3-oxopropyl)-6- methyl-[1,1'-biphenyl]-2-carboxylate

[0312] Prepared in an analogous manner to Intermediate 3 using Intermediate 2 (0.38 g, 0.94 mmol), benzyl 2-bromo-3-methylbenzoate (0.26 g, 0.86 mmol, CAS 291289-66-2), Na2CO3 (0.18 g, 1.71 mmol) and Pd(dppf)Cl2 (63 mg, 0.09 mmol) in 1,4-dioxane (3 mL), and water (1.8 mL) at 85 °C for 16 h. Purified by flash chromatography (24 g silica gel, eluting 5- 35% EtOAc in petroleum ether) to provide the title compound (0.25 g). LCMS (Method 4): 1.91 min, 404.1 [M-Boc+H]+. Intermediate 155: (S)-3'-(1-((tert-Butoxycarbonyl)amino)-3-methoxy-3-oxopropyl)-6-methyl- [1,1'-biphenyl]-2-carboxylic acid

[0313] Prepared in an analogous manner to Intermediate 8 using Intermediate 154 (0.25 g, 0.49 mmol) and 10% palladium on carbon (52 mg) in THF (15 mL) under a hydrogen atmosphere at RT for 16 h, to provide the title compound (0.19 g). LCMS (Method 3): 1.56 min, 314.0 [M-Boc+H]+. Intermediate 156: Methyl (S)-3-(2'-(allylcarbamoyl)-6'-methyl-[1,1'-biphenyl]-3-yl)-3-((tert- butoxycarbonyl)amino)propanoate

[0314] Prepared in an analogous manner to Intermediate 5 using 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) at RT for 16 h, to provide the title compound (0.33 g). LCMS (Method 3): 1.59 min, 353.1 [M-Boc+H]+. Intermediate 157: Methyl (S)-3-(2'-(allylcarbamoyl)-6'-methyl-[1,1'-biphenyl]-3-yl)-3- aminopropanoate hydrochloride

[0315] A suspension of Intermediate 156 (83 mg, 0.18 mmol) in 4 M HCl in 1,4-dioxane (2 mL) was stirred at RT for 1.5 h. The mixture was concentrated under reduced pressure to provide the title compound (71 mg). LCMS (Method 3): 1.07 min, 353.1 [M+H]+. Intermediate 158: Methyl (S)-3-(2'-(allylcarbamoyl)-6'-methyl-[1,1'-biphenyl]-3-yl)-3-((S)-2- ((tert-butoxycarbonyl)amino)pent-4-enamido)propanoate

[0316] Prepared in an analogous manner to Intermediate 5 using Intermediate 157 (71 mg, 0.18 mmol), N-Boc-L-allylglycine (39 mg, 0.18 mmol, CAS 90600-20-7), DIPEA (64 µL, 0.37 mmol), HOBt (28 mg, 0.18 mmol) and EDCI (42 mg, 0.22 mmol) in DMF (2 mL) at RT for 18 h, to provide the title compound (77 mg). LCMS (Method 3): 1.58 min, 550.2 [M+H]+. Intermediate 159: Methyl 2-((3S,6S)-6-((tert-butoxycarbonyl)amino)-16-methyl-5,12-dioxo- 4,11-diaza-1(1,2),2(1,3)-dibenzenacyclododecaphan-8-en-3-yl)acetate

[0317] Prepared in an analogous manner to Intermediate 7 using Intermediate 158 (77 mg, 0.14 mmol) in DCE (5 mL) and Grubbs II (12 mg, 14 µmol) at 40 °C for 4 h. Purified by flash chromatography (12 g silica gel, eluting 50-100% EtOAc in petroleum ether) to provide the title compound (51 mg). LCMS (Method 3): 1.42 min, 522.1 [M+H]+. Intermediate 160: Methyl 2-((3S,6S)-6-((tert-butoxycarbonyl)amino)-16-methyl-5,12-dioxo- 4,11-diaza-1(1,2),2(1,3)-dibenzenacyclododecaphane-3-yl)acetate

[0318] Prepared in an analogous manner to Intermediate 8 using Intermediate 159 (55 mg, 0.11 mmol) and 10% palladium on carbon (11 mg) in MeOH (10 mL) under a hydrogen atmosphere at RT for 3 h, to provide the title compound (47 mg). LCMS (Method 3): 1.40 min, 524.2 [M+H]+. Intermediate 161: Methyl 2-((3S,6S)-6-amino-16-methyl-5,12-dioxo-4,11-diaza-1(1,2),2(1,3)- dibenzenacyclododecaphane-3-yl)acetate hydrochloride

[0319] A suspension of Intermediate 160 (47 mg, 0.09 mmol) in 4 M HCl in 1,4-dioxane (2 mL) was stirred at RT for 1.5 h. The mixture was concentrated under reduced pressure to provide the title compound (41 mg). LCMS (Method 3): 1.05 min, 424.2 [M+H]+. Intermediate 162: Methyl 2-((3S,6S)-6-acetamido-16-methyl-5,12-dioxo-4,11-diaza- 1(1,2),2(1,3)-dibenzenacyclododecaphane-3-yl)acetate

[0320] Prepared in an analogous manner to Intermediate 10 using Intermediate 161 (41 mg, 0.09 mmol), triethylamine (27 µL, 0.20 mmol), acetyl chloride (7 µL, 0.10 mmol) in DCM (2 mL) at RT for 1 h. Purified by flash chromatography (12 g silica gel, eluting 0-10% MeOH in DCM) to provide the title compound (20 mg). LCMS (Method 3): 1.15 min, 466.2 [M+H]+. Intermediate 163: Methyl (S)-3-(2'-(but-3-en-1-ylcarbamoyl)-6'-methyl-[1,1'-biphenyl]-3-yl)-3- ((tert-butoxycarbonyl)amino)propanoate

[0321] Prepared in an analogous manner to Intermediate 5 using 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) at RT for 16 h. Purified by flash chromatography (12 g silica gel, eluting 50–100% EtOAc in petroleum ether) to provide the title compound (83 mg). LCMS (Method 3): 1.63 min, 367.1 [M-Boc+H]+.Intermediate 164: Methyl (S)-3-amino-3-(2'-(but-3-en-1-ylcarbamoyl)-6'-methyl-[1,1'- biphenyl]-3-yl)propanoate hydrochloride

[0322] A suspension of Intermediate 163 (83 mg, 0.18 mmol) in 4 M HCl in 1,4-dioxane (2 mL) was stirred at RT for 1.5 h. The mixture was concentrated under reduced pressure to provide the title compound (72 mg). LCMS (Method 3): 1.11 min, 367.1 [M+H]+. 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

[0323] Prepared in an analogous manner to Intermediate 5 using Intermediate 164 (72 mg, 0.18 mmol), N-Boc-L-allylglycine (39 mg, 0.18 mmol, CAS 90600-20-7), DIPEA (62 µL, 0.36 mmol), HOBt (27 mg, 0.18 mmol) and EDCI (41 mg, 0.21 mmol) in DMF (2 mL) at RT for 4 h, to provide the title compound (67 mg). LCMS (Method 3): 1.57 min, 564.2 [M+H]+. Intermediate 166: Methyl 2-((3S,6S)-6-((tert-butoxycarbonyl)amino)-16-methyl-5,13-dioxo- 4,12-diaza-1(1,2),2(1,3)-dibenzenacyclotridecaphan-8-en-3-yl)acetate

[0324] Prepared in an analogous manner to Intermediate 7 using Intermediate 165 (67 mg, 0.12 mmol) in DCE (4 mL) and Grubbs II (10 mg, 12 µmol) 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. Purified by flash chromatography (12 g silica gel, eluting 50-100% EtOAc in petroleum ether) to provide the title compound (44 mg). LCMS (Method 4): 1.47 min, 536.2 [M+H]+. Intermediate 167: Methyl 2-((3S,6S)-6-((tert-butoxycarbonyl)amino)-16-methyl-5,13-dioxo- 4,12-diaza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3-yl)acetate

[0325] Prepared in an analogous manner to Intermediate 8 using Intermediate 166 (44 mg, 0.08 mmol) and 10% palladium on carbon (8.7 mg) in MeOH (10 mL) under a hydrogen atmosphere at RT for 2 h, to provide the title compound (36 mg). LCMS (Method 4): 1.53 min, 538.2 [M+H]+Intermediate 168: Methyl 2-((3S,6S)-6-amino-16-methyl-5,13-dioxo-4,12-diaza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetate hydrochloride

[0326] A suspension of Intermediate 167 (36 mg, 0.07 mmol) in 4 M HCl in 1,4-dioxane (2 mL) was stirred at RT for 1.5 h. The mixture was concentrated under reduced pressure to provide the title compound (32 mg). LCMS (Method 4): 1.17 min, 438.2 [M+H]+. Intermediate 169: Methyl 2-((3S,6S)-6-acetamido-16-methyl-5,13-dioxo-4,12-diaza- 1(1,2),2(1,3)-dibenzenacyclotridecaphane-3-yl)acetate

[0327] Prepared in an analogous manner to Intermediate 10 using Intermediate 168 (32 mg, 0.07 mmol), triethylamine (21 µL, 0.15 mmol), acetyl chloride (5 µL, 0.07 mmol) in DCM(5 mL) at RT for 0.5 h. Purified by flash chromatography (12 g silica gel, eluting 0-10% MeOH in DCM) to provide the title compound (39 mg). LCMS (Method 4): 1.11 min, 480.2 [M+H]+. Intermediate 170: Methyl (S)-3-((tert-butoxycarbonyl)amino)-3-(2'-(hex-5-en-1-yloxy)-6'- methyl-[1,1'-biphenyl]-3-yl)propanoate

[0328] Prepared in an analogous manner to Intermediate 6 using 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) at reflux for 18 h. Purified by flash chromatography (12 g silica gel, eluting 0-50% EtOAc in petroleum ether) to provide the title compound (0.14 g). LCMS (Method 4): 2.05 min, 368.2 [M-Boc+H]+. Intermediate 171: Methyl (S)-3-amino-3-(2'-(hex-5-en-1-yloxy)-6'-methyl-[1,1'-biphenyl]-3- yl)propanoate hydrochloride

[0329] A suspension of Intermediate 170 (0.14 g, 0.31 mmol) in 4 M HCl in 1,4-dioxane (3 mL) was stirred at RT for 1 h. The mixture was concentrated under reduced pressure to provide the title compound (0.13 g). LCMS (Method 4): 1.85 min, 368.2 [M+H]+. 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

[0330] Prepared in an analogous manner to Intermediate 5 using Intermediate 171 (0.13 g, 0.33 mmol), N-Boc-L-allylglycine (71 mg, 0.33 mmol, CAS 90600-20-7), DIPEA (0.17 mL, 1.00 mmol), HOBt (51 mg, 0.33 mmol) and EDCI (76 mg, 0.40 mmol) in DMF (2 mL) at RT for 4 h, to provide the title compound (0.18 g). LCMS (Method 4): 2.02 min, 565.3 [M+H]+. Intermediate 173: Methyl 2-((11S,14S,E)-11-((tert-butoxycarbonyl)amino)-26-methyl-12-oxo- 3-oxa-13-aza-1(1,3),2(1,2)-dibenzenacyclotetradecaphan-8-en-14-yl)acetate

[0331] Prepared in an analogous manner to Intermediate 7 using Intermediate 172 (0.17 g, 0.30 mmol) in DCE (0.15 L) and Grubbs II (30 mg, 0.12 mmol) at 40 °C for 2.5 h. Purified by flash chromatography (12 g silica gel, eluting 0-50% EtOAc in petroleum ether) to provide the title compound (0.11 g). LCMS (Method 4): 1.91 min, 537.1 [M+H]+. Intermediate 174: Methyl 2-((11S,14S,E)-11-amino-26-methyl-12-oxo-3-oxa-13-aza- 1(1,3),2(1,2)-dibenzenacyclotetradecaphan-8-en-14-yl)acetate hydrochloride

[0332] A suspension of Intermediate 173 (30 mg, 0.06 mmol) in 4 M HCl in 1,4-dioxane (3 mL) was stirred at RT for 1 h. The mixture was concentrated under reduced pressure to provide the title compound (26 mg). LCMS (Method 4): 1.62 min, 437.1 [M+H]+. Intermediate 175: Methyl 2-((11S,14S,E)-11-acetamido-26-methyl-12-oxo-3-oxa-13-aza- 1(1,3),2(1,2)-dibenzenacyclotetradecaphan-8-en-14-yl)acetate

[0333] Prepared in an analogous manner to Intermediate 10 using Intermediate 174 (28 mg, 0.06 mmol), triethylamine (18 µL, 0.13 mmol), acetyl chloride (5 µL, 0.07 mmol) in DCM (3 mL) at RT for 1 h, to provide the title compound (28 mg). LCMS (Method 4): 1.65 min, 479.3 [M+H]+. Intermediate 176: Methyl 2-((11S,14S)-11-((tert-butoxycarbonyl)amino)-26-methyl-12-oxo-3- oxa-13-aza-1(1,3),2(1,2)-dibenzenacyclotetradecaphane-14-yl)acetate

[0334] Prepared in an analogous manner to Intermediate 8 using Intermediate 173 (80 mg, 0.15 mmol) and 10% palladium on carbon (16 mg) in MeOH (19 mL) under a hydrogen atmosphere at RT for 3 h, to provide the title compound (77 mg). LCMS (Method 12): 1.82 min, 539.4 [M+H]+. Intermediate 177: Methyl 2-((11S,14S)-11-amino-26-methyl-12-oxo-3-oxa-13-aza- 1(1,3),2(1,2)-dibenzenacyclotetradecaphane-14-yl)acetate hydrochloride

[0335] A suspension of Intermediate 176 (77 mg, 0.14 mmol) in 4 M HCl in 1,4-dioxane (7.7 mL) was stirred at RT for 1 h. The mixture was concentrated under reduced pressure to provide the title compound (77 mg). LCMS (Method 4): 1.66 min, 439.2 [M+H]+. Intermediate 178: Methyl 2-((11S,14S)-11-acetamido-26-methyl-12-oxo-3-oxa-13-aza- 1(1,3),2(1,2)-dibenzenacyclotetradecaphane-14-yl)acetate

[0336] Prepared in an analogous manner to Intermediate 10 using Intermediate 177 (68 mg, 0.14 mmol), triethylamine (44 µL, 0.32 mmol), acetyl chloride (11 µL, 0.16 mmol) in DCM (5 mL) at RT for 1 h, to provide the title compound (69 mg). LCMS (Method 4): 1.69 min, 481.2 [M+H]+. Intermediate 179: Methyl 3-((tert-butoxycarbonyl)amino)-3-(5-(4-fluoro-2-hydroxy-6- methylphenyl)pyridin-3-yl)propanoate

[0337] Prepared in an analogous manner to Intermediate 92 using 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)Cl2 (51 mg, 0.07 mmol) in 1,4-dioxane (6.5 mL) at 100 °C for 1 h, then Na2CO3 (0.30 g, 2.78 mmol) in water (6.6 mL) and 2-bromo-5-fluoro-3-methylphenol (0.34 g, 1.67 mmol, CAS 1807192-21-7) were added followed by heating at 100 °C for 2 h. Purified by flash chromatography (12 g silica gel, eluting 40-100% EtOAc in petroleum ether) to provide the title compound (0.34 g). LCMS (Method 12): 1.26 min, 405.4 [M+H]+. Intermediate 180: Methyl 3-((tert-butoxycarbonyl)amino)-3-(5-(4-fluoro-2-methyl-6-(pent-4- en-1-yloxy)phenyl)pyridin-3-yl)propanoate

[0338] Prepared in an analogous manner to Intermediate 6 using 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) at reflux for 3 h. Purified by flash chromatography (12 g silica gel, eluting 0 - 50% EtOAc in petroleum ether) to provide the title compound (0.14 g). LCMS (Method 4): 1.83 min, 473.3 [M+H]+. Intermediate 181: Methyl 3-amino-3-(5-(4-fluoro-2-methyl-6-(pent-4-en-1- yloxy)phenyl)pyridin-3-yl)propanoate hydrochloride

[0339] 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 RT for 2 h. The mixture was concentrated under reduced pressure to provide the title compound (0.16 g). LCMS (Method 4): 1.57 min, 373.2 [M+H]+. 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

[0340] Prepared in an analogous manner to Intermediate 5 using 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) at RT for 3 h. Purified by flash chromatography (12 g silica gel, eluting 0-70% EtOAc in petroleum ether) to provide the title compound (0.14 g). LCMS (Method 4): 1.88 min, 584.3 [M+H]+. Intermediate 183: Methyl 2-((10S)-10-((tert-butoxycarbonyl)(methyl)amino)-24-fluoro-26- methyl-11-oxo-3-oxa-12-aza-1(3,5)-pyridina-2(1,2)-benzenacyclotridecaphan-7-en-13- yl)acetate

[0341] Prepared in an analogous manner to Intermediate 7 using Intermediate 182 (0.14 g, 0.25 mmol) in DCE (141 mL) and Grubbs II (25 mg, 0.03 mmol) at 40 °C for 48 h. Purified by flash chromatography (12 g silica gel, eluting 0-7% MeOH in DCM) to provide the title compound (64 mg). LCMS (Method 4): 1.78 min, 556.3 [M+H]+. Intermediate 184: Methyl 2-((10S)-10-((tert-butoxycarbonyl)(methyl)amino)-24-fluoro-26- methyl-11-oxo-3-oxa-12-aza-1(3,5)-pyridina-2(1,2)-benzenacyclotridecaphane-13-yl)acetate

[0342] Prepared in an analogous manner to Intermediate 8 using Intermediate 183 (64 mg, 0.12 mmol) and 10% palladium on carbon (12 mg) in MeOH (12 mL) under a hydrogen atmosphere at RT for 1 h, to provide the title compound (54 mg). LCMS (Method 4): 1.83 and 1.85 min, 558.3 [M+H]+. Intermediate 185: Methyl 2-((10S)-24-fluoro-26-methyl-10-(methylamino)-11-oxo-3-oxa-12- aza-1(3,5)-pyridina-2(1,2)-benzenacyclotridecaphane-13-yl)acetate hydrochloride

[0343] A suspension of Intermediate 184 (54 mg, 0.10 mmol) in 4 M HCl in 1,4-dioxane (2 mL) was stirred at RT for 2 h. The mixture was concentrated under reduced pressure to provide the title compound (0.16 g). LCMS (Method 4): 1.48 and 1.56 min, 458.3 [M+H]+. Intermediate 186: Methyl 2-((10S)-24-fluoro-26-methyl-10-(N-methylacetamido)-11-oxo-3- oxa-12-aza-1(3,5)-pyridina-2(1,2)-benzenacyclotridecaphane-13-yl)acetate

[0344] Prepared in an analogous manner to Intermediate 10 using Intermediate 185 (49 mg, 0.10 mmol), triethylamine (30 µL, 0.22 mmol), acetyl chloride (8 µL, 0.11 mmol) in DCM (1 mL) at RT for 2 h, to provide the title compound (49 mg). LCMS (Method 7): 1.77 min, 500.3 [M+H]+. 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

[0345] Prepared in an analogous manner to Intermediate 65 using 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) at 90 °C for 2 h. Additional K2CO3 (76 mg, 0.55 mmol) was added and stirred at 90 °C for 16 h. Purified by flash chromatography (4 g silica gel, eluting 5-10% MeOH in DCM with 0.5% ammonia in MeOH) to provide the title compound (50 mg). LCMS (Method 14): 5.01 min, 618.3 [M+H]+. Intermediate 188: Methyl 2-((10S,13S)-10-(5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)- yl)-24-fluoro-26-methyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzenacyclotridecaphan-7-en- 13-yl)acetate

[0346] Prepared in an analogous manner to Intermediate 7 using Intermediate 187 (50 mg, 0.06 mmol) in DCE (30 mL) and Grubbs II (5.3 mg, 6.2 µmol) at 40 °C for 4 h. Additional Grubbs II (2.6 mg, 3.1 µmol) was added and heating continued at 40 °C for 45 min. Purified by flash chromatography (4 g silica gel, eluting 5-10% MeOH in DCM with 0.5% ammonia) to provide the title compound (20 mg). LCMS (Method 15): 2.29 min, 590.2 [M+H]+. Intermediate 189: Methyl 2-((10S,13S)-10-(5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)- yl)-24-fluoro-26-methyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzenacyclotridecaphane-13- yl)acetate

[0347] Prepared in an analogous manner to Intermediate 8 using Intermediate 188 (17 mg, 0.03 mmol) and 10% palladium on carbon (3 mg) in MeOH (2.4 mL) under a hydrogen atmosphere at RT for 15 min, to provide the title compound (15 mg). LCMS (Method 15): 2.36 min, 592.2 [M+H]+. Intermediate 190: 5-(2-(Pyrrolidin-1-yl)ethyl)pyridin-2(1H)-one

[0348] Prepared in an analogous manner to Intermediate 137 using Intermediate 136 (0.71 g, 4.59 mmol), pyrrolidine (1.13 mL, 13.8 mmol) in MeOH (7 mL), DCM (56 mL) and 4 Å molecular sieves at RT for 30 min, then STAB (2.92 g, 13.8 mmol) at RT for 18 h. Purified by flash chromatography (40 g silica gel, eluting 0-201 M ammonia MeOH in DCM) then by reverse phase chromatography (38 g C18, 0-50% MeCN in 0.1% aqueous ammonia) to provide the title compound (0.34 g). LCMS (Method 12): 0.82 min, 193.1 [M+H]+. 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)pent-4-enamido)propanoate

[0349] Prepared in an analogous manner to Intermediate 65 using 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) at 80 °C for 22 h. Purified by flash chromatography (25 g silica gel, eluting 0-10% MeOH in DCM) to provide the title compound (49 mg). LCMS (Method 8): 1.70 min, 624.7 [M- H]-. Intermediate 192: Methyl 2-((10S,13S)-26-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)-dibenzenacyclotridecaphan-7-en-13- yl)acetate

[0350] Prepared in an analogous manner to Intermediate 7 using Intermediate 191 (49 mg, 0.08 mmol) in DCE (39 mL) and Grubbs II (6.7 mg, 7.8 µmol) at 40 °C for 3 h. Additional Grubbs II (6.7 mg, 7.8 µmol) was added and heating continued at 40 °C for 6 h. Purified by flash chromatography (12 g silica gel, eluting 8% MeOH in DCM with 0.5% ammonia) to provide the title compound (23 mg). LCMS (Method 8): 1.56 min, 596.6 [M-H]-. Intermediate 193: Methyl 2-((10S,13S)-26-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)-dibenzenacyclotridecaphane-13- yl)acetate

[0351] Prepared in an analogous manner to Intermediate 8 using Intermediate 192 (47 mg, 0.06 mmol) and 10% palladium on carbon (6.4 mg) in MeOH (4 mL) under a hydrogen atmosphere at RT for 40 min. Additional 10% palladium on carbon (6.4 mg) was added and stirring continued under a hydrogen atmosphere at RT for 40 min, to provide the title compound (35 mg). LCMS (Method 11): 2.52 min, 598.6 [M-H]-. 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

[0352] Prepared in an analogous manner to Intermediate 57 using 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) at 95 °C for 1 h. Additional K2CO3(0.37 g, 2.66 mmol) was addedand heating continued for 2 h. Purified by flash chromatography (24 g silica gel, eluting 0 - 100% EtOAc in petroleum ether) to provide the title compound (0.32 g). LCMS (Method 17): 2.40 min, 580.3 [M+H]+. Intermediate 195: Methyl 2-((10S,13S)-26-methyl-11-oxo-10-(4-oxoquinazolin-3(4H)-yl)-3- oxa-12-aza-1(1,3),2(1,2)-dibenzenacyclotridecaphan-6-en-13-yl)acetate

[0353] Prepared in an analogous manner to Intermediate 7 using Intermediate 194 (0.35 g, 0.61 mmol) in DCE (31 mL) and Grubbs II (51 mg, 0.06 mmol) at 40 °C for 1 h. Quenched with ethyl vinyl ether (0.06 mL, 0.61 mmol). Purified by flash chromatography (25 g silica gel, eluting 0-100% EtOAc in petroleum ether) to provide the title compound (0.17 g). LCMS (Method 3): 1.75 min, 552.2 [M+H]+. Intermediate 196: Methyl 2-((10S,13S)-26-methyl-11-oxo-10-(4-oxoquinazolin-3(4H)-yl)-3- oxa-12-aza-1(1,3),2(1,2)-dibenzenacyclotridecaphane-13-yl)acetate

[0354] Prepared in an analogous manner to Intermediate 8 using Intermediate 195 (0.17 g, 0.31 mmol) and 10% palladium on carbon (32 mg) in MeOH (5 mL) under a hydrogen atmosphere at RT for 2 h to provide the title compound (0.12 g). LCMS (Method 15): 2.24 min, 554.2 [M+H]+. Intermediate 197: (E)-5-(2-Ethoxyvinyl)-3-fluoro-2-methoxypyridine

[0355] 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 the solution was then added K2CO3 (2.15 g, 15.5 mmol) followed by Pd(PPh3)4 (0.30 g, 0.26 mmol) and the reaction mixture 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 MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel 40 g, eluting 0-80% EtOAc in petroleum ether) to provide the title compound (0.94 g). LCMS (Method 4): 1.48 min, 198.0 [M+H]+. Intermediate 198: 2-(5-Fluoro-6-methoxypyridin-3-yl)acetaldehyde

[0356] 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 provide the title compound (0.12 g). LCMS (Method 4): 1.04 min, 169.9 [M+H]+. Intermediate 199: 2-(5-Fluoro-6-methoxypyridin-3-yl)-N,N-dimethylethan-1-amine

[0357] Prepared in an analogous manner to Intermediate 137 using Intermediate 198 (0.25 g, 1.49 mmol), dimethylamine (2 M in THF, 0.89 mL, 1.78 mmol), triethylamine (0.41 mL, 2.97mmol) in DCM (9.2 mL) and 4 Å molecular sieves at RT for 3 h, then STAB (0.63 g, 2.97 mmol) at RT for 18 h. Purified by flash chromatography (4 g silica gel, eluting 0-10% 1 M ammonia MeOH in DCM) then by reverse phase chromatography (32 g C18, 5-60% MeCN in 0.1% aqueous ammonia) to provide the title compound (63 mg).1H 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). Intermediate 200: 5-(2-(Dimethylamino)ethyl)-3-fluoropyridin-2(1H)-one

[0358] 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 h. The mixture was cooled and concentrated under reduced pressure. The crude product was purified by catch and release chromatography (1 g SCX, eluting MeOH followed by 1 M ammonia in MeOH) to provide the title compound (40 mg).1H 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). 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

[0359] Prepared in an analogous manner to Intermediate 65 using Intermediate 114 (0.17 g, 0.33 mmol), Intermediate 200 (50 g, 0.27 mmol) and K2CO3 (75 mg, 0.54 mmol) in MeCN (3.5 mL) at 85 °C for 18 h. Purified by flash chromatography (25 g silica gel, eluting 0-8% MeOH in DCM with 0.5% ammonia in MeOH) to provide the title compound (58 mg).1H 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. Intermediate 202: Methyl 2-((10S,13S)-10-(5-(2-(dimethylamino)ethyl)-3-fluoro-2- oxopyridin-1(2H)-yl)-26-methyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)- dibenzenacyclotridecaphan-7-en-13-yl)acetate

[0360] Prepared in an analogous manner to Intermediate 7 using Intermediate 201 (58 mg, 0.10 mmol) in DCE (45 mL) and Grubbs II (8 mg, 0.10 mmol) at 40 °C for 18 h. Additional Grubbs II (8 mg, 0.10 mmol) was added at 40 °C for 24 h. Purified by flash chromatography (25 g silica gel, eluting 5-8% MeOH in DCM containing 0.5% ammonia) to provide the title compound (18 mg). LCMS (Method 18): 1.23 min, 590.2 [M+H]+. Intermediate 203: Methyl 2-((10S,13S)-10-(5-(2-(dimethylamino)ethyl)-3-fluoro-2- oxopyridin-1(2H)-yl)-26-methyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)- dibenzenacyclotridecaphane-13-yl)acetate

[0361] Prepared in an analogous manner to Intermediate 8 using Intermediate 202 (18 mg, 0.03 mmol) and 10% palladium on carbon (3.2 mg) in MeOH (2.5 mL) under a hydrogen atmosphere at RT for 2 h to provide the title compound (17 mg). LCMS (Method 18): 1.25 min, 592.2 [M+H]+. 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

[0362] Prepared in an analogous manner to Intermediate 6 using 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) at reflux for 16 h. Extra K2CO3 (0.38 g, 2.78 mmol) and 4-bromobut-1-ene (0.28 mL, 2.78 mmol) was added and heating continued for 7 h. Extra K2CO3 (0.38 g, 2.78 mmol) and 4-bromobut-1-ene (0.28 mL, 2.78 mmol) was added and heating continued for 18 h. Purified by flash chromatography (25 g silica gel, eluting 0-50% EtOAc in petroleum ether) to provide the title compound (0.49 g).1H 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). 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

[0363] 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 RT for 2 h. The mixture was concentrated under reduced pressure to provide the title compound (0.43 g). LCMS (Method 18): 1.25 min, 386.1 [M+H]+. 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

[0364] Prepared in an analogous manner to Intermediate 5 using 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) at RT for 4 h. Purified by flash chromatography (25 g silica gel, eluting 30 - 100% EtOAc in petroleum ether) to provide the title compound (0.25 g).1H 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). 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

[0365] Prepared in an analogous manner to Intermediate 56 using 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) at RT for 1 h, to provide the title compound (0.12 g).1H 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). 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)hex-5-enamido)propanoate

[0366] Prepared in an analogous manner to Intermediate 65 using Intermediate 137 (40 mg, 0.24 mmol), Intermediate 207 (0.11 g, 0.18 mmol) and K2CO3 (76 mg, 0.55 mmol) in MeCN (2.4 mL) at 85 °C for 18 h. Purified by flash chromatography (25 g silica gel, eluting 2- 8% MeOH in DCM with 0.5% ammonia in MeOH) to provide 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. Intermediate 209: Ethyl 2-((10S,13S)-10-(5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)- 14-fluoro-15,26-dimethyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzenacyclotridecaphan-6-en- 13-yl)acetate

[0367] Prepared in an analogous manner to Intermediate 7 using Intermediate 208 (41 mg, 0.06 mmol) in DCE (30 mL) and Grubbs II (5.4 mg, 6.4 µmol) at 40 °C for 18 h. Purified by flash chromatography (12 g silica gel, eluting 5 - 8% MeOH in DCM containing 0.5% ammonia) to provide the title compound (18 mg). LCMS (Method 18): 2.00 min, 618.3 [M+H]+. Intermediate 210: Ethyl 2-((10S,13S)-10-(5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)- 14-fluoro-15,26-dimethyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzenacyclotridecaphane-13- yl)acetate

[0368] Prepared in an analogous manner to Intermediate 8 using Intermediate 209 (18 mg, 0.03 mmol) and 10% palladium on carbon (3.2 mg) in MeOH (3.1 mL) under a hydrogen atmosphere at RT for 2 h to provide the title compound (14 mg). LCMS (Method 18): 2.02 min, 620.3 [M+H]+. Intermediate 211: Methyl (S)-3-((tert-butoxycarbonyl)amino)-3-(2'-hydroxy-4’-6'-dimethyl- [1,1'-biphenyl]-3-yl)propanoate

[0369] Prepared in an analogous manner to Intermediate 3 using Intermediate 2 (1.51 g, 3.73 mmol), 2-bromo-3,5-dimethylphenol (0.75 g, 3.73 mmol, CAS 125237-08-3), Na2CO3(1.19 g, 11.2 mmol) and Pd(dppf)Cl2(0.14 g, 0.19 mmol) in 1,4-dioxane (30 mL), and water (15 mL) at 80 °C for 16 h. Purified by flash chromatography (40 g silica gel, eluting 10-80% EtOAc in petroleum ether) to provide the title compound (0.45 g). LCMS (Method 4): 1.65 min, 422.1 [M+Na]+. Intermediate 212: Methyl (S)-3-((tert-butoxycarbonyl)amino)-3-(2',4'-dimethyl-6'-(pent-4-en- 1-yloxy)-[1,1'-biphenyl]-3-yl)propanoate

[0370] Prepared in an analogous manner to Intermediate 6 using 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) at reflux for 24 h to provide the title compound (0.47 g). LCMS (Method 4): 2.03 min, 490.0 [M+Na]+. Intermediate 213: Methyl (S)-3-amino-3-(2',4'-dimethyl-6'-(pent-4-en-1-yloxy)-[1,1'- biphenyl]-3-yl)propanoate hydrochloride

[0371] 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 RT for 3 h. The mixture was concentrated under reduced pressure to provide the title compound (0.39 g). LCMS (Method 4): 1.83 min, 368.1 [M+H]+. 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

[0372] Prepared in an analogous manner to Intermediate 5 using 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) at RT for 18 h. Purified by flash chromatography (40 g silica gel, eluting 5-80% EtOAc in petroleum ether) to provide the title compound (0.33 g). LCMS (Method 11): 2.27 min, 466.0 [M+H]+. 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

[0373] Prepared in an analogous manner to Intermediate 56 using 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) at RT for 2 h, to provide the title compound (0.33 g). LCMS (Method 4): 1.97 min, 544.1 [M+H]+. 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

[0374] Prepared in an analogous manner to Intermediate 65 using 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) at 90 °C for 18 h. Purified by flash chromatography (12 g silica gel, eluting 0-50% EtOAc in petroleum ether) to provide the title compound (94 mg). LCMS (Method 11): 2.45 min, 612.7 [M-H]-. Intermediate 217: Methyl 2-((10S,13S)-10-(5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)- yl)-24,26-dimethyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzenacyclotridecaphan-7-en-13- yl)acetate

[0375] Prepared in an analogous manner to Intermediate 7 using Intermediate 216 (0.18 g, 0.29 mmol) in DCE (40 mL) and Grubbs II (25 mg, 0.03 mmol) at 40 °C for 4 h. Purified by flash chromatography (25 g silica gel, eluting 5-65% 9:1 MeOH in DCM containing 0.5% ammonia, in DCM) to provide the title compound (0.11 g). LCMS (Method 11): 2.24 min, 584.6 [M-H]-. Intermediate 218: Methyl 2-((10S,13S)-10-(5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)- yl)-24,26-dimethyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzenacyclotridecaphane-13- yl)acetate

[0376] Prepared in an analogous manner to Intermediate 8 using Intermediate 217 (95 mg, 0.16 mmol) and 10% palladium on carbon (17 mg) in MeOH (2 mL) under a hydrogen atmosphere at RT for 18 h to provide the title compound (80 mg). LCMS (Method 4): 1.93 min, 588.2 [M+H]+. Intermediate 219: (R,E)-N-(5-Bromo-2-fluorobenzylidene)-2-methylpropane-2-sulfinamide

[0377] Prepared in an analogous manner to Intermediate 102 using 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) at 40 °C for 2.5 h, to provide the title compound (3.75 g). LCMS (Method 11): 2.10 min, 306.0 [M+H]+. Intermediate 220: Ethyl (S)-3-(5-bromo-2-fluorophenyl)-3-(((R)-tert- butylsulfinyl)amino)propanoate

[0378] Prepared in an analogous manner to Intermediate 104 using 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) at 60 °C for 1 h, then Intermediate 219 (3.75 g, 12.2 mmol) in THF (15 mL) at RT for 1.5 h. Purified by flash chromatography (80 g silica gel, eluting 5-80% EtOAc in petroleum ether) to provide the title compound (4.45 g). LCMS (Method 11): 1.94 min, 392.2 [M-H]-.Intermediate 221: Ethyl (S)-3-amino-3-(5-bromo-2-fluorophenyl)propanoate hydrochloride

[0379] 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 RT for 3 h. The mixture was concentrated under reduced pressure to provide the title compound (3.21 g). LCMS (Method 11): 1.68 min, 290.4 [M+H]+. Intermediate 222: Ethyl (S)-3-(5-bromo-2-fluorophenyl)-3-((tert- butoxycarbonyl)amino)propanoate

[0380] 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 stirred for 20 h at RT. The reaction mixture was diluted with DCM and 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, eluting 5-35% EtOAc in petroleum ether) to provide the title compound (2.08 g). LCMS (Method 11): 2.12 min, 412.1 [M+Na]+. 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

[0381] Prepared in an analogous manner 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)Cl2 (0.37 g, 0.51 mmol) in 1,4-dioxane (20 mL) at 90 °C for 2 h. Purified by flash chromatography (silica gel, eluting 6:1 EtOAc / petroleum ether) to provide the title compound (2.12 g).1H 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). Intermediate 224: Ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(4-fluoro-2'-hydroxy-6'-methyl- [1,1'-biphenyl]-3-yl)propanoate

[0382] Prepared in an analogous manner to Intermediate 3 using Intermediate 223 (1.05 g, 2.40 mmol), 2-bromo-3-methylphenol (0.45 g, 2.40 mmol, CAS 22061-78-5), Na2CO3(0.64 g, 6.00 mmol) and Pd(dppf)Cl2 (98 mg, 0.12 mmol) in 1,4-dioxane (18 mL), and water (9 mL) at 90 °C for 16 h. Purified by flash chromatography (40 g silica gel, eluting 6:1 EtOAc / petroleum ether) to provide the title compound (0.69 g). LCMS (Method 4): 1.78 min, 440.0 [M+Na]+. 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

[0383] Prepared in an analogous manner to Intermediate 6 using 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) at reflux for 24 h to provide the title compound (0.70 g). LCMS (Method 4): 2.10 min, 508.1 [M+Na]+. Intermediate 226: Ethyl (S)-3-amino-3-(4-fluoro-2'-methyl-6'-(pent-4-en-1-yloxy)-[1,1'- biphenyl]-3-yl)propanoate hydrochloride

[0384] 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 RT for 3 h. The mixture was concentrated under reduced pressure to provide the title compound (0.61 g). LCMS (Method 12): 1.74 min, 386.3 [M+H]+. 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

[0385] Prepared in an analogous manner to Intermediate 5 using 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) at RT for 18 h. Purified by flash chromatography (12 g silica gel, eluting 15-55% EtOAc in petroleum ether) to provide the title compound (0.47 g).1H 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). 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

[0386] Prepared in an analogous manner to Intermediate 56 using 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) at RT for 1 h, to provide the title compound (0.48 g). LCMS (Method 12): 1.78 min, 562.6 [M+H]+. 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

[0387] Prepared in an analogous manner to Intermediate 65 using 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) at 90 °C for 16 h. Purified by flash chromatography (4 g silica gel, eluting 0-20% 0.1% ammonia in MeOH in DCM) to provide the title compound (0.15 g). LCMS (Method 6): 1.35 min, 632.4 [M+H]+.Intermediate 230: Ethyl 2-((10S,13S)-10-(5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)- 14-fluoro-26-methyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzenacyclotridecaphan-7-en-13- yl)acetate

[0388] Prepared in an analogous manner to Intermediate 7 using Intermediate 229 (0.16 g, 0.25 mmol) in DCE (33 mL) and Grubbs II (21 mg, 0.03 mmol) at 40 °C for 18 h. Additional Grubbs II (21 mg, 0.03 mmol) was added and stirred at 40 °C for 24 h. Purified by flash chromatography (12 g silica gel, eluting 0-10% MeOH in DCM) to provide the title compound (0.10 g). LCMS (Method 15): 2.39 min, 604.3 [M+H]+. Intermediate 231: Ethyl 2-((10S,13S)-10-(5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)- 14-fluoro-26-methyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzenacyclotridecaphane-13- yl)acetate

[0389] Prepared in an analogous manner to Intermediate 8 using Intermediate 230 (0.10 g, 0.10 mmol) and 10% palladium on carbon (11 mg) in ethanol (5 mL) under a hydrogen atmosphere at RT for 5 h to provide the title compound (17 mg). LCMS (Method 11): 2.26 min, 606.5 [M+H]+. Intermediate 232: Ethyl (S)-3-amino-3-(5-bromo-3-methyl-2-fluorophenyl)propanoate hydrochloride

[0390] 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 RT for 3 h. The mixture was concentrated under reduced pressure and triturated in petroleum ether to provide the title compound (3.26 g). LCMS (Method 12): 1.41 min, 304.1 [M+H]+. Intermediate 233: Ethyl (S)-3-(5-bromo-2-fluoro-3-methylphenyl)-3-((tert- butoxycarbonyl)amino)propanoate

[0391] 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 stirred for 2 h at RT. The reaction mixture was diluted with DCM and 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, eluting 0-30% EtOAc in petroleum ether) to provide the title compound (3.11 g). LCMS (Method 4): 1.78 min, 305.8 [M-Boc+H]+. 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

[0392] Prepared in an analogous manner to Intermediate 2 using 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)Cl2(0.48 g, 0.66 mmol) in 1,4-dioxane (43 mL) at 90 °C for 16 h. Purified by flash chromatography (40 g silica gel, eluting 0-50% EtOAc in petroleum ether) to provide the title compound (2.98 g).1H 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). Intermediate 235: Ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(4,4'-difluoro-2'-hydroxy-5,6'- dimethyl-[1,1'-biphenyl]-3-yl)propanoate

[0393] Prepared in an analogous manner 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), Na2CO3 (2.11 g, 19.9 mmol) and Pd(dppf)Cl2 (0.36 g, 0.50 mmol) in 1,4-dioxane (180 mL), and water (45 mL) at 85 °C for 20 h. Purified by dry flash chromatography (silica gel, eluting 0-30% EtOAc in petroleum ether) to provide the title compound (1.15 g).1H 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) – OH not observed. 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

[0394] Prepared in an analogous manner to Intermediate 6 using 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) at reflux for 16 h to provide the title compound (0.86 g). LCMS (Method 4): 2.16 min, 418.1 [M-Boc+H]+. 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

[0395] A suspension of Intermediate 236 (0.86 g, 1.67 mmol) in 4 M HCl in 1,4-dioxane (5 mL) was stirred at RT for 2 h. The mixture was concentrated under reduced pressure to provide the title compound (0.64 g).1H 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). 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

[0396] Prepared in an analogous manner to Intermediate 5 using 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) at RT for 16 h. Purified by flash chromatography (12 g silica gel, eluting 5-80% EtOAc in petroleum ether) to provide 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. 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

[0397] Prepared in an analogous manner to Intermediate 56 using 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) at RT for 1 h, to provide the title compound (0.64 g). LCMS (Method 12): 1.84 min, 592.5 [M-H]-. 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

[0398] Prepared in an analogous manner to Intermediate 65 using Intermediate 239 (0.50 g, 0.80 mmol), Intermediate 137 (0.17 g, 1.04 mmol) and K2CO3 (0.33 g, 2.40 mmol) in MeCN (23 mL) at 90 °C for 16 h. Purified by flash chromatography (40 g silica gel, eluting 0-10% 0.1% ammonia in MeOH in DCM) to provide the title compound (0.11 g).1H 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). Intermediate 241: Ethyl 2-((10S,13S)-10-(5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)- 14,24-difluoro-15,26-dimethyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzenacyclotridecaphan- 7-en-13-yl)acetate

[0399] Prepared in an analogous manner to Intermediate 7 using Intermediate 240 (0.11 g, 0.12 mmol) in DCE (79 mL) and Grubbs II (10.6 mg, 0.01 mmol) 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. Purified by flash chromatography (12 g silica gel, eluting 0-10% 2 M ammonia MeOH in DCM) and again (12 gsilica gel 8% (0.5% ammonia in MeOH) in DCM) to provide the title compound (48 mg). LCMS (Method 13): 2.33 min, 634.6 [M-H]-. Intermediate 242: Ethyl 2-((10S,13S)-10-(5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)- 14,24-difluoro-15,26-dimethyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzenacyclotridecaphane- 13-yl)acetate

[0400] Prepared in an analogous manner to Intermediate 8 using Intermediate 241 (48 mg, 0.06 mmol) and 10% palladium on carbon (6.1 mg) in MeOH (6.3 mL) under a hydrogen atmosphere at RT for 36 h to provide the title compound (30 mg). LCMS (Method 16): 3.50 min, 638.1 [M+H]+. Intermediate 243: 5-(2-(3-fluoroazetidin-1-yl)ethyl)pyridin-2(1H)-one

[0401] Prepared in an analogous manner to Intermediate 137 using 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 at RT for 2 h, then STAB (2.92 g, 13.8 mmol) at RT for 2 h. Purified by flash chromatography (12 g silica gel, eluting 0- 20% 1 M ammonia MeOH in DCM) then by reverse phase chromatography (38 g C180-50% MeCN in 0.1% aqueous ammonia) to provide the title compound (0.28 g).1H 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). 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

[0402] Prepared in an analogous manner to Intermediate 65 using 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) at 85 °C for 18 h. Additional K2CO3 (0.16 g, 1.13 mmol) was added and heated at 85 °C for 24 h. Purified by flash chromatography (24 g silica gel, eluting 2-10% (0.1% ammonia in MeOH) in DCM) to provide the title compound (69 mg). LCMS (Method 13): 1.66 min, 628.6 [M-H]-. Intermediate 245: Methyl 2-((10S,13S)-10-(5-(2-(3-fluoroazetidin-1-yl)ethyl)-2-oxopyridin- 1(2H)-yl)-26-methyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzenacyclotridecaphan-7-en-13- yl)acetate

[0403] Prepared in an analogous manner to Intermediate 7 using Intermediate 244 (69 mg, 0.11 mmol) in DCE (55 mL) and Grubbs II (9.3 mg, 0.01 mmol) at 40 °C for 24 h. Purified by flash chromatography (12 g silica gel, eluting 2-10% 2 M ammonia MeOH in DCM) to provide the title compound (54 mg). LCMS (Method 13): 1.54 min, 600.6 [M-H]-.Intermediate 246: Methyl 2-((10S,13S)-10-(5-(2-(3-fluoroazetidin-1-yl)ethyl)-2-oxopyridin- 1(2H)-yl)-26-methyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzenacyclotridecaphane-13- yl)acetate

[0404] Prepared in an analogous manner to Intermediate 8 using Intermediate 245 (54 mg, 0.08 mmol) and 10% palladium on carbon (8 mg) in MeOH (5 mL) under a hydrogen atmosphere at RT for 40 min. Additional 10% palladium on carbon (8 mg) was added and stirred under a hydrogen atmosphere at RT for 40 min to provide the title compound (48 mg). LCMS (Method 16): 3.17 min, 602.6 [M-H]-. Intermediate 247: (R)-5-(2-(3-Fluoropyrrolidin-1-yl)ethyl)pyridin-2(1H)-one

[0405] Prepared in an analogous manner to Intermediate 137 using 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 at RT for 3 h, then STAB (3.36 g, 15.0 mmol) at RT for 18 h. Purified by flash chromatography (12 g silica gel, eluting 0-20% 1 M ammonia MeOH in DCM) then by reverse phase chromatography (38 g C18, 0-50% MeCN in 0.1% aqueous ammonia) to provide the title compound (0.28 g).1H 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). 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

[0406] Prepared in an analogous manner to Intermediate 65 using 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) at 85 °C for 18 h. Purified by flash chromatography (24 g silica gel, eluting 2-10% (0.1% ammonia MeOH) in DCM) to provide the title compound (0.15 g). LCMS (Method 13): 1.71 min, 644.6 [M+H]+. Intermediate 249: Methyl 2-((10S,13S)-10-(5-(2-((R)-3-fluoropyrrolidin-1-yl)ethyl)-2- oxopyridin-1(2H)-yl)-26-methyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)- dibenzenacyclotridecaphan-7-en-13-yl)acetate

[0407] Prepared in an analogous manner to Intermediate 7 using Intermediate 248 (0.15 g, 0.11 mmol) in DCE (0.11 L) and Grubbs II (19.1 mg, 0.02 mmol) 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. Purified by flash chromatography (24 g silica gel, eluting 2-8% 2 M ammonia MeOH in DCM) to provide the title compound (91 mg). LCMS (Method 16): 3.12 min, 614.7 [M-H]-.Intermediate 250: Methyl 2-((10S,13S)-10-(5-(2-((R)-3-fluoropyrrolidin-1-yl)ethyl)-2- oxopyridin-1(2H)-yl)-26-methyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)- dibenzenacyclotridecaphane-13-yl)acetate

[0408] Prepared in an analogous manner to Intermediate 8 using Intermediate 249 (91 mg, 0.14 mmol) and 10% palladium on carbon (14.8 mg) in MeOH (8 mL) under a hydrogen atmosphere at RT for 40 min. Additional 10% palladium on carbon (14.8 mg) was added and stirred under a hydrogen atmosphere at RT for 40 min to provide the title compound (72 mg). LCMS (Method 16): 4.33 min, 616.6 [M-H]-. Intermediate 251: 5-(2-(3-Methoxyazetidin-1-yl)ethyl)pyridin-2(1H)-one

[0409] Prepared in an analogous manner to Intermediate 137 using 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 at RT for 2 h, then STAB (3.21 g, 15.2 mmol) at RT for 18 h. Purified by flash chromatography (40 g silica gel, eluting 0-20% 1 M ammonia MeOH in DCM) then by reverse phase chromatography (38 g C18, 0-50% MeCN in 0.1% aqueous ammonia) to provide the title compound (0.35 g).1H 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). 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

[0410] Prepared in an analogous manner to Intermediate 65 using 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) at 85 °C for 18 h. Purified by flash chromatography (24 g silica gel, eluting 4-10% (0.1% ammonia MeOH) in DCM) to provide the title compound (97 mg). LCMS (Method 13): 1.70 min, 640.6 [M-H]-. Intermediate 253: Methyl 2-((10S,13S)-10-(5-(2-(3-methoxyazetidin-1-yl)ethyl)-2-oxopyridin- 1(2H)-yl)-26-methyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzenacyclotridecaphan-7-en-13- yl)acetate

[0411] Prepared in an analogous manner to Intermediate 7 using Intermediate 252 (97 mg, 0.14 mmol) in DCE (75 mL) and Grubbs II (12.1 mg, 0.02 mmol) at 40 °C for 18 h. Additional Grubbs II (6 mg, 0.01 mmol) was added and heated at 40 °C for 6 h. Purified by flash chromatography (24 g silica gel, eluting 2-8% 2 M ammonia MeOH in DCM) to provide the title compound (42 mg). LCMS (Method 16): 3.12 min, 612.6 [M-H]-.Intermediate 254: Methyl 2-((10S,13S)-10-(5-(2-(3-methoxyazetidin-1-yl)ethyl)-2-oxopyridin- 1(2H)-yl)-26-methyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzenacyclotridecaphane-13- yl)acetate

[0412] Prepared in an analogous manner to Intermediate 8 using Intermediate 253 (42 mg, 0.06 mmol) and 10% palladium on carbon (6.4 mg) in MeOH (5 mL) under a hydrogen atmosphere at RT for 40 min. Additional 10% palladium on carbon (6.4 mg) was added and stirred under a hydrogen atmosphere at RT for 40 min to provide the title compound (40 mg). LCMS (Method 16): 3.18 min, 616.2 [M+H]+. Intermediate 255: (E)-5-(2-Ethoxyvinyl)-2-methoxy-4-(trifluoromethyl)pyridine

[0413] Prepared in an analogous manner to Intermediate 197 using 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), K2CO3 (3.64 g, 26.4 mmol) and Pd(PPh3)4 (0.51 g, 0.44 mmol) in 1,4-dioxane (27 mL) and water (6 mL) at 100 °C for 3 h. Purified by flash chromatography (40 g silica gel, eluting 0-20% 1 M ammonia MeOH in DCM) then by reverse phase chromatography (40 g silica gel, 0-60% MeCN in petroleum ether) to provide the title compound (1.81 g). LCMS (Method 4): 1.72 min, 247.9 [M+H]+. Intermediate 256: 2-(6-Methoxy-4-(trifluoromethyl)pyridin-3-yl)ethane-1,1-diol

[0414] A solution of Intermediate 255 (0.50 g, 1.82 mmol) in TFA (2.2 mL) was stirred at 20 °C for 2 h. The mixture was cooled and concentrated under reduced pressure to provide the title compound (0.43 g).1H 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). Intermediate 257: 2-(6-Methoxy-4-(trifluoromethyl)pyridin-3-yl)-N,N-dimethylethan-1-amine

[0415] Prepared in an analogous manner to Intermediate 137 using 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) in DCM (15 mL) and 4 Å molecular sieves at RT for 16 h, then STAB (0.77 g, 3.63 mmol) at RT for 6 h. Purified by flash chromatography (12 g silica gel, eluting 0-6% MeOH in DCM) then by flash chromatography (20 g C18, 0–100% MeCN in 0.1 M aqueous ammonia) to provide the title compound (0.29 g). LCMS (Method 4): 1.48 min, 249.0 [M+H]+. Intermediate 258: 5-(2-(Dimethylamino)ethyl)-4-(trifluoromethyl)pyridin-2(1H)-one

[0416] 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 (1 gSCX, eluting MeOH followed by 1 M ammonia in MeOH) to provide the title compound (0.15 g). LCMS (Method 4): 1.00 min, 234.9 [M+H]+. 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

[0417] Prepared in an analogous manner to Intermediate 65 using 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) at 85 °C for 18 h. Purified by flash chromatography (24 g silica gel, eluting 2-8% (0.1% ammonia MeOH) in DCM) and again (24 g silica gel, eluting 2.5% (0.1% ammonia MeOH) in DCM) to provide the title compound (0.10 g). LCMS (Method 13): 1.70 min, 666.7 [M-H]-. Intermediate 260: Methyl 2-((10S,13S)-10-(5-(2-(dimethylamino)ethyl)-2-oxo-4- (trifluoromethyl)pyridin-1(2H)-yl)-26-methyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)- dibenzenacyclotridecaphan-7-en-13-yl)acetate

[0418] Prepared in an analogous manner to Intermediate 7 using Intermediate 259 (0.10 g, 0.15 mmol) in DCE (75 mL) and Grubbs II (12.7 mg, 0.02 mmol) 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. Purified by flash chromatography (24 g silica gel, eluting 0-10% 2 M ammonia MeOH in DCM) to provide the title compound (44 mg). LCMS (Method 16): 3.18 min, 638.5 [M-H]-. Intermediate 261: Methyl 2-((10S,13S)-10-(5-(2-(dimethylamino)ethyl)-2-oxo-4- (trifluoromethyl)pyridin-1(2H)-yl)-26-methyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)- dibenzenacyclotridecaphane-13-yl)acetate

[0419] Prepared in an analogous manner to Intermediate 8 using Intermediate 260 (44 mg, 0.06 mmol) and 10% palladium on carbon (6.5 mg) in MeOH (3 mL) under a hydrogen atmosphere at RT for 1 h. Purified flash chromatography (24 g silica gel, eluting 0-10% 2 M ammonia MeOH in DCM) to provide the title compound (35 mg). LCMS (Method 7): 1.59 min, 642.2 [M+H]+. Intermediate 262: 5-(2-(Azetidin-1-yl)ethyl)pyridin-2(1H)-one

[0420] Prepared in an analogous manner to Intermediate 137 using Intermediate 136 (0.78 g, 5.05 mmol), azetidine (0.68 mL, 10.1 mmol), triethylamine (1.41 mL, 10.1 mmol) in DCM (15 mL) and 4 Å molecular sieves at RT for 2 h, then STAB (3.21 g, 15.2 mmol) at RT for 2 h. Purified by flash chromatography (40 g silica gel, eluting 0-20% MeOH in DCM) then by flash chromatography (38 g C18, 0–50% MeCN in 0.1 M aqueous ammonia) to provide the title compound (0.39 g).1H NMR (400 MHz; CD3OD) δ: 7.53 (dd, 1H), 7.26 (d, 1H), 6.52 (d, 1H), 3.25 (t, 4H), 2.62 (t, 2H), 2.44 (t, 2H), 2.14 – 2.07 (m, 2H).Intermediate 263: (R,E)-N-(3-Bromo-5-methylbenzylidene)-2-methylpropane-2-sulfinamide

[0421] Prepared in an analogous manner to Intermediate 102 using 5-bromo-3-methyl- benzaldehyde (2.50 g, 12.6 mmol, CAS 188813-04-9), (R)-2-methylpropane-2-sulfinimide (1.67 g, 13.8 mmol, CAS 196929-78-9) and titanium ethoxide (4.30 g, 18.8 mmol) in THF (20 mL) at 40 °C for 2.5 h, to provide the title compound (3.65 g). LCMS (Method 11): 2.22 min, 302.1 [M+H]+. Intermediate 264: Ethyl (S)-3-(5-bromo-3-methylphenyl)-3-(((R)-tert- butylsulfinyl)amino)propanoate

[0422] Prepared in an analogous manner to Intermediate 104 using zinc (3.9 g, 60.4 mmol) chlorotrimethylsilane (0.31 mL, 2.42 mmol) and ethyl bromoacetate (3.35 mL, 30.2 mmol) in THF (72 mL) at 60 °C for 1 h, then Intermediate 263 (3.65 g, 12.1 mmol) in THF (72 mL) at RT for 1.5 h. Purified by flash chromatography (80 g silica gel, eluting 5-80% EtOAc in petroleum ether) to provide the title compound (3.98 g). LCMS (Method 11): 2.05 min, 390.1 [M+H]+. Intermediate 265: Ethyl (S)-3-amino-3-(3-bromo-5-methylphenyl)propanoate hydrochloride

[0423] A suspension of Intermediate 264 (3.98 g, 10.2 mmol) in 4 M HCl in 1,4-dioxane (5 mL) was stirred at RT for 3 h. The mixture was concentrated under reduced pressure to provide the title compound (2.95 g). LCMS (Method 11): 1.79 min, 286.4 [M+H]+. Intermediate 266: Ethyl (S)-3-(3-bromo-5-methylphenyl)-3-((tert- butoxycarbonyl)amino)propanoate

[0424] To a stirred suspension of Intermediate 265 (2.80 g, 8.68 mmol) and Boc anhydride (2.08 g, 9.55 mmol) in DCM (85 mL) was added triethylamine (1.82 mL, 13.0 mmol) and the mixture stirred for 20 h at RT. The reaction mixture was diluted with DCM and 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, eluting 5-35% EtOAc in petroleum ether) to provide the title compound (1.95 g). LCMS (Method 11): 2.21 min, 408.1 [M+Na]+. Intermediate 267: Ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(3-methyl-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate

[0425] Prepared in an analogous manner to Intermediate 2 using Intermediate 266 (1.85 g, 4.79 mmol), bis(pinacolato)diboron (1.46 g, 5.75 mmol), and Pd(dppf)Cl2(0.35 g, 0.48 mmol) in 1,4-dioxane (19 mL) at 90 °C for 16 h. Purified by dry flash chromatography (silica gel, eluting 1:6 EtOAc / petroleum ether) to provide the title compound (2.06 g).1H NMR (400MHz; CDCl3) δ: 7.46 – 7.44 (m, 2H), 7.14 (s, 1H), 5.29 (br s, 1H), 5.04 – 4.92 (br m, 1H), 4.07 – 3.92 (m, 2H), 2.83 – 2.65 (m, 2H), 2.26 (s, 3H), 1.35 (s, 9H), 1.26 (s, 12H), 1.11 (t, 3H). Intermediate 268: Ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(2'-hydroxy-5,6'-dimethyl-[1,1'- biphenyl]-3-yl)propanoate

[0426] Prepared in an analogous manner to Intermediate 3 using Intermediate 267 (1.00 g, 2.31 mmol), 2-bromo-3-methylphenol (0.43 g, 7.31 mmol, CAS 22061-78-5), Na2CO3 (0.61 g, 5.77 mmol) and Pd(dppf)Cl2 (94 mg, 0.12 mmol) in 1,4-dioxane (88 mL), and water (18 mL) at 90 °C for 20 h. Purified by dry flash chromatography (silica gel, eluting 1:5 EtOAc / petroleum ether) to provide the title compound (0.61 g). LCMS (Method 4): 1.82 min, 436.0 [M+Na]+. Intermediate 269: Ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(2',5-dimethyl-6'-(pent-4-en-1- yloxy)-[1,1'-biphenyl]-3-yl)propanoate

[0427] Prepared in an analogous manner to Intermediate 6 using Intermediate 268 (0.61 g, 1.47 mmol), K2CO3 (0.62 g, 1.91 mmol) and 5-bromopent-1-ene (0.21 mL, 1.77 mmol) in MeCN (15 mL) at reflux for 16 h to provide the title compound (0.60 g). LCMS (Method 4): 2.13 min, 504.1 [M+Na]+. Intermediate 270: Ethyl (S)-3-amino-3-(2',5-dimethyl-6'-(pent-4-en-1-yloxy)-[1,1'-biphenyl]- 3-yl)propanoate hydrochloride

[0428] A suspension of Intermediate 269 (0.60 g, 1.24 mmol) in 4 M HCl in 1,4-dioxane (4.6 mL) was stirred at RT for 3 h. The mixture was concentrated under reduced pressure to provide the title compound (0.51 g). LCMS (Method 12): 1.78 min, 404.3 [M+Na]+. Intermediate 271: Ethyl (S)-3-(2',5-dimethyl-6'-(pent-4-en-1-yloxy)-[1,1'-biphenyl]-3-yl)-3- ((R)-2-hydroxypent-4-enamido)propanoate

[0429] Prepared in an analogous manner to Intermediate 5 using Intermediate 270 (0.52 g, 1.23 mmol), (2R)-2-hydroxypent-4-enoic acid (0.22 g, 1.85 mmol, CAS 413622-10-3), DIPEA (0.88 mL, 4.93 mmol), HOBt (0.20 g, 1.48 mmol) and EDCI (0.35 g, 1.85 mmol) in MeCN (6 mL) and DMF (1 mL) at RT for 16 h. Purified by flash chromatography (12 g silica gel, eluting 15-55% EtOAc in petroleum ether) to provide the title compound (0.41 g).1H NMR (400 MHz; CDCl3) δ: 7.36 (d, 1H), 7.11 (t, 1H), 6.98 (s, 1H), 6.87 (d, 2H), 6.80 (d, 1H), 6.71 (d, 1H), 5.79 – 5.56 (m, 2H), 5.42 – 5.32 (m, 1H), 5.15 – 5.04 (m, 2H), 4.90 – 4.79 (m, 2H), 4.10 (dd, 1H), 4.00 (q, 2H), 3.79 (t, 2H), 2.86 (dd, 1H), 2.75 (dd, 1H), 2.58 (dt, 1H), 2.29 (s, 3H), 1.98 (s, 3H), 1.90 (q, 2H), 1.61 – 1.52 (m, 2H), 1.10 (t, 3H) – OH and NH not observed. Intermediate 272: Ethyl (S)-3-(2',5-dimethyl-6'-(pent-4-en-1-yloxy)-[1,1'-biphenyl]-3-yl)-3- ((R)-2-((methylsulfonyl)oxy)pent-4-enamido)propanoate

[0430] Prepared in an analogous manner to Intermediate 56 using Intermediate 271 (0.41 g, 0.86 mmol), triethylamine (0.24 mL, 1.72 mmol) and methanesulfonyl chloride (0.10 mL, 1.29 mmol) in DCM (1 mL) at RT for 2 h, to provide the title compound (0.45 g). LCMS (Method 12): 1.81 min, 559.4 [M+H]+. Intermediate 273: Ethyl (S)-3-((S)-2-(5-(2-(azetidin-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)pent-4- enamido)-3-(2',5-dimethyl-6'-(pent-4-en-1-yloxy)-[1,1'-biphenyl]-3-yl)propanoate

[0431] Prepared in an analogous manner to Intermediate 65 using Intermediate 272 (0.37 g, 0.66 mmol), Intermediate 262 (0.14 g, 0.80 mmol) and K2CO3 (0.26 g, 1.99 mmol) in MeCN (7.4 mL) at 85 °C for 30 h. Purified by flash chromatography (12 g silica gel, eluting 0-20% (0.1% ammonia MeOH) in DCM) to provide the title compound (0.10 g). LCMS (Method 6): 1.34 min, 640.5 [M+H]+. Intermediate 274: Ethyl 2-((10S,13S)-10-(5-(2-(azetidin-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)- 15,26-dimethyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzenacyclotridecaphan-7-en-13- yl)acetate

[0432] Prepared in an analogous manner to Intermediate 7 using Intermediate 273 (0.10 g, 0.15 mmol) in DCE (75 mL) and Grubbs II (13 mg, 0.02 mmol) at 40 °C for 18 h. Additional Grubbs II (13 mg, 0.02 mmol) was added and heated at 40 °C for 24 h. Purified by flash chromatography (12 g silica gel, eluting 0-10% 2 M ammonia MeOH in DCM) to provide the title compound (13 mg). LCMS (Method 13): 1.63 min, 612.5 [M+H]+. Intermediate 275: Ethyl 2-((10S,13S)-10-(5-(2-(azetidin-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)- 15,26-dimethyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzenacyclotridecaphane-13-yl)acetate

[0433] Prepared in an analogous manner to Intermediate 8 using Intermediate 274 (13 mg, 0.02 mmol) and 10% palladium on carbon (2 mg) in MeOH (1.5 mL) under a hydrogen atmosphere at RT for 1 h. Additional 10% palladium on carbon (2 mg) was added and stirred under a hydrogen atmosphere at RT for 2 h. Purified flash chromatography (4 g silica gel, eluting 0-10% 2 M ammonia MeOH in DCM) to provide the title compound (10 mg). LCMS (Method 13): 1.65 min, 614.5 [M+H]+. Intermediate 276: (R)-3-Fluoro-5-(2-(3-fluoropyrrolidin-1-yl)ethyl)-2-methoxypyridine

[0434] Prepared in an analogous manner to Intermediate 137 using Intermediate 198 (0.17 g, 1.01 mmol), (R)-3-fluoropyrrolidine hydrochloride (0.15 g, 1.22 mmol, CAS 136725-55-8), triethylamine (0.28 mL, 2.03 mmol) in DCM (6.6 mL) and 4 Å molecular sieves at RT for 5 h, then STAB (0.43 g, 2.03 mmol) at RT for 18 h. Purified by reverse phase chromatography (20 g C18, 5-70% MeCN in 0.1% aqueous ammonia) to provide the title compound (70 mg). LCMS (Method 11): 0.86 min, 242.9 [M+H]+.Intermediate 277: (R)-3-Fluoro-5-(2-(3-fluoropyrrolidin-1-yl)ethyl)pyridin-2(1H)-one

[0435] A solution of Intermediate 276 (70 mg, 0.29 mmol) in 33% HBr in AcOH (1.0 mL, 5.78 mmol) was stirred at 85 °C for 2 h. The mixture was cooled and concentrated under reduced pressure. The crude product was purified by reverse-phase chromatography (20 g C18, 2-60% MeCN in 0.1% aqueous ammonia)to provide the title compound (53 mg). LCMS (Method 7): 0.98 min, 228.9 [M+H]+. Intermediate 278: Ethyl (S)-3-(4,4'-difluoro-2',5-dimethyl-6'-(pent-4-en-1-yloxy)-[1,1'- biphenyl]-3-yl)-3-((S)-2-(3-fluoro-5-(2-((R)-3-fluoropyrrolidin-1-yl)ethyl)-2-oxopyridin-1(2H)- yl)pent-4-enamido)propanoate

[0436] Prepared in an analogous manner to Intermediate 65 using Intermediate 239 (0.27 g, 0.45 mmol), Intermediate 277 (98 mg, 0.43 mmol) and K2CO3 (0.18 g, 1.29 mmol) in MeCN (3 mL) at 85 °C for 30 h. Purified by flash chromatography (24 g silica gel, eluting 0-10% (0.1% ammonia MeOH) in DCM) to provide the title compound (0.11 g). LCMS (Method 11): 1.84 min, 724.7 [M-H]-. Intermediate 279: Ethyl 2-((10S,13S)-14,24-difluoro-10-(3-fluoro-5-(2-((R)-3-fluoropyrrolidin- 1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-15,26-dimethyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)- dibenzenacyclotridecaphan-7-en-13-yl)acetate

[0437] Prepared in an analogous manner to Intermediate 7 using Intermediate 278 (0.11 g, 0.15 mmol) in DCE (70 mL) and Grubbs II (13 mg, 0.02 mmol) at 40 °C for 5 h. Additional Grubbs II (13 mg, 0.02 mmol) was added and heated at 40 °C for 18 h. Purified by flash chromatography (12 g silica gel, eluting 0-10% 2 M ammonia MeOH in DCM) to provide the title compound (85 mg). LCMS (Method 11): 2.27 min, 698.5 [M+H]+. Intermediate 280: Ethyl 2-((10S,13S)-14,24-difluoro-10-(3-fluoro-5-(2-((R)-3-fluoropyrrolidin- 1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-15,26-dimethyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)- dibenzenacyclotridecaphane-13-yl)acetate

[0438] Prepared in an analogous manner to Intermediate 8 using Intermediate 279 (85 mg, 0.12 mmol) and 10% palladium on carbon (13 mg) in ethanol (10 mL) under a hydrogen atmosphere at RT for 8 h, to provide the title compound (80 mg). LCMS (Method 15): 2.41 min, 700.3 [M+H]+. Intermediate 281: 3-Fluoro-5-(2-(3-fluoroazetidin-1-yl)ethyl)-2-methoxypyridine

[0439] Prepared in an analogous manner to Intermediate 137 using Intermediate 198 (1.29 g, 7.60 mmol), 3-fluoroazetidine hydrochloride (1.02 g, 9.12 mmol, CAS 617718-46-4), triethylamine (2.12 mL, 15.2 mmol) in DCM (40 mL) and 4 Å molecular sieves at RT for 6 h,then STAB (3.22 g, 15.2 mmol) at RT for 18 h. Purified by flash chromatography (25 g silica gel, 0-4% 2 M ammonia MeOH in DCM) to provide the title compound (0.49 g).1H NMR (400 MHz, CDCl3) δ 7.72 (d, 1H), 7.18 (dd, 1H), 5.27 – 5.03 (m, 1H), 3.96 (s, 3H), 3.96 – 3.83 (m, 2H), 3.35 – 3.18 (m, 2H), 2.79 (t, 2H), 2.64 (t, 2H). Intermediate 282: 3-Fluoro-5-(2-(3-fluoroazetidin-1-yl)ethyl)pyridin-2(1H)-one

[0440] A solution of Intermediate 281 (0.53 g, 2.33 mmol) in 33% HBr in AcOH (6.0 mL, 35.0 mmol) was stirred at 85 °C for 2 h. The mixture was cooled and concentrated under reduced pressure. The crude product was purified by catch and release chromatography (10 g SCX, eluting MeOH followed by 1 M ammonia in MeOH) then by reverse-phase chromatography (32 g C18, 5-50% MeCN in 0.1% aqueous ammonia) to provide the title compound (0.22 g). LCMS (Method 4): 0.77 min, 214.9 [M+H]+. Intermediate 283: Ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(4-fluoro-2'-hydroxy-4',5,6'- trimethyl-[1,1'-biphenyl]-3-yl)propanoate

[0441] Prepared in an analogous manner to Intermediate 3 using Intermediate 234 (3.00 g, 6.65 mmol), 2-bromo-3,5-dimethylphenol (1.34 g, 6.65 mmol, CAS 125237-08-3), Na2CO3 (2.11 g, 19.9 mmo...

Claims

Claims 1. A compound of Formula I, or a pharmaceutically acceptable salt thereof: (I) wherein: A is an aromatic ring and Z1, Z2, Z3and Z4are independently N or CR2; B is aryl, 5- to 10-membered heteroaryl, C3-10cycloalkyl, or 4- to 10-membered heterocyclyl; wherein B is optionally substituted with one to five substituents independently selected from C1-5alkyl, halo, cyano, hydroxyl, NR3R4, C1-5alkoxy, C1-5haloalkyl, C1-5haloalkoxy, C1-4alkylene-O-C1-4alkyl, C3-10cycloalkyl, and 4- to 10- membered heterocyclyl; L is C3-8alkylene, C3-8alkenylene, or C3-8alkynylene, wherein one, two or three methylene groups in L are optionally substituted with -O-, -S-, -C(O)-, or -N(R5)-; and wherein L is optionally substituted with one to five substituents independently selected from C1-5alkyl, halo, hydroxyl, C1-5alkoxy, C1-5haloalkyl, C1-5haloalkoxy, and NR6R7; R1is 4- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, aryl, C3-10cycloalkyl, or NR8C(O)R9; wherein: i) each of 4- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, aryl, and C3-10cycloalkyl is optionally substituted with one to five substituents independently selected from C1-5alkyl, halo, oxo, cyano, C1-5alkoxy, C1-5haloalkyl, C1-5haloalkoxy, C1-4alkylene-O-C1-4alkyl, C1-4alkylene-OH, C3-6cycloalkyl, 4- to 6-membered heterocyclyl, and C1-4alkylene-NR10R11; and 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; R2at each occurrence is independently selected from H, halo, cyano, hydroxyl, C1-5alkyl, C1-5alkoxy, C1-5haloalkyl, C1-5haloalkoxy, C1-4alkylene-O-C1-4alkyl, C3-6cycloalkyl and 4-6 membered heterocyclyl;R3and R4are independently selected from H, C1-5alkyl, C1-5haloalkyl, and C3-10cycloalkyl; R5, R6and R7are independently H or C1-5alkyl; R8is H, C1-6alkyl, C2-6haloalkyl, C2-4alkylene-O-C1-4alkyl; C3-6cycloalkyl, 4- to 6- membered heterocyclyl, or C2-5alkylene-NR12R13; R9is C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, C1-6haloalkoxy, C2-4alkylene-O-C1-4alkyl, C3-6cycloalkyl, 4- to 6-membered heterocyclyl, NR14R15or C1-5alkylene-NR16R17; R10and R11are independently H, C1-5alkyl, C1-5haloalkyl or -C1-4alkylene-O-C1-4alkyl; or R10and R11, taken together with the nitrogen to which they are attached, form a 4- to 6- membered heterocyclyl ring optionally substituted with one to four groups independently selected from halo, C1-5alkyl, C1-5alkoxy, C1-5haloalkyl, and C1-5haloalkoxy; and R12, R13, R14, R15, R16, and R17are independently H, C1-5alkyl, or C1-5haloalkyl; or R12and R13, R14and R15, or R16and R17, taken together with the nitrogen atoms to which they are attached, independently form a 4- to 6-membered heterocyclyl ring optionally substituted with one to four groups independently selected from halo and C1-5alkyl.

2. The compound according to claim 1, wherein the compound has a structure according to either formula IA or formula IB:or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 1 or claim 2, wherein Z1, Z2, Z3and Z4are all CR2.

4. The compound according to claim 1 or claim 2, wherein one of Z1, Z2, Z3and Z4is N and the other three are CR2.

5. The compound according to any one of claims 1 to 4, wherein R2at each occurrence is independently selected from H, halo, cyano, hydroxyl, C1-5alkyl, C1-5alkoxy, C1-5haloalkyl, and C3-6cycloalkyl.

6. The compound according to claim 5, wherein R2at each occurrence is independently selected from H, fluoro, chloro, methyl, ethyl, trifluoromethyl, and cyclopropyl.

7. The compound according to claim 1 or claim 2, wherein A is selected from:wherein ‘b’ is the point of attachment to the B ring.

8. The compound according to any one of claims 1 to 7, wherein B is aryl, or 5- to 6- membered heteroaryl; wherein B is optionally substituted with one to four substituents independently selected from C1-3alkyl, halo, cyano, hydroxyl, NR3R4, C1-5alkoxy, C1-5haloalkyl, C1-5haloalkoxy, C1-4alkylene-O-C1-4alkyl, C3-7cycloalkyl, and 4- to 10- membered heterocyclyl.

9. The compound according to any one of claims 1 to 7, wherein B is phenyl, optionally substituted with one to four substituents independently selected from C1-3alkyl, halo, cyano, C1-5alkoxy, C1-5haloalkyl, C3-7cycloalkyl, and 4- to 10-membered heterocyclyl.

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

11. The compound according to any one of claims 1 to 7, wherein B is selected from:wherein ‘a’ is the point of attachment to the A ring and ‘l’ is the point of attachment to the linker L.

12. The compound according to any one of claims 1 to 11, wherein L is C3-8alkylene, or C3-8alkenylene, wherein one, two or three methylene groups in L are optionally substituted with -O-, -S-, -C(O)-, or -N(R5)-; and wherein L is optionally substituted with one to five substituents independently selected from C1-5alkyl, halo, hydroxyl, C1-5alkoxy, C1-5haloalkyl, C1-5haloalkoxy, and NR6R7.

13. The compound according to any one of claims 1 to 11, wherein L is C5-8alkylene, or C5-8alkenylene, wherein one, two or three methylene groups in L are optionally substituted with -O-, -C(O)-, or -N(R5)-; and wherein L is optionally substituted with one to five substituents independently selected from C1-5alkyl, halo, hydroxyl, C1-5alkoxy, and C1-5haloalkyl.

14. The compound according to any one of claims 1 to 11, wherein L is C5-8alkylene, wherein one or two methylene groups in L are optionally substituted with -O-, -C(O)-, or -N(R5)-; and wherein L is optionally substituted with one to three independently selected C1-5alkyl substituents.

15. The compound according to any one of claims 1 to 11, wherein L is selected from:wherein ‘b’ is the point of attachment to the B ring.

16. The compound according to any one of claims 1 to 15, wherein R1is 4- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, aryl, C3-10cycloalkyl, or NR8C(O)R9; wherein: i) each of 4- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, aryl, and C3-10cycloalkyl is optionally substituted with one to five substituents independently selected from C1-5alkyl, halo, oxo, cyano, C1-5alkoxy, C1-5haloalkyl, C1-5haloalkoxy, C1-4alkylene-O-C1-4alkyl, C3-6cycloalkyl, 4- to 6-membered heterocyclyl, and C1-4alkylene- NR10R11; and 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.

17. The compound according to any one of claims 1 to 15, wherein R1is 4- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, or -NR8C(O)R9; wherein:i) each of 4- to 10-membered heterocyclyl, and 5- to 10-membered heteroaryl is optionally substituted with one to five substituents independently selected from C1-5alkyl, halo, oxo, cyano, C1-5alkoxy, C1-5haloalkyl, C1-5haloalkoxy, C1-4alkylene-O- C1-4alkyl, C3-6cycloalkyl, 4- to 6-membered heterocyclyl, and C1-4alkylene-NR10R11; and 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.

18. The compound according to any one of claims 1 to 15, wherein R1is 5- to 6-membered heterocyclyl; optionally substituted with one to five substituents independently selected from C1-5alkyl, halo, oxo, cyano, C1-5alkoxy, C1-5haloalkyl, C1-5haloalkoxy, C1-4alkylene- O-C1-4alkyl, C3-6cycloalkyl, 4- to 6-membered heterocyclyl, and C1-4alkylene-NR10R11; optionally containing one or two carbon-carbon double bonds; and optionally fused to a phenyl ring.

19. The compound according to any one of claims 1 to 15, wherein R1is selected from:optionally substituted with one to three substituents independently selected from C1-5alkyl, halo, oxo, cyano, C1-5alkoxy, C1-5haloalkyl, C1-5haloalkoxy, C1-4alkylene-O-C1-4alkyl, C1-4alkylene-OH, C3-6cycloalkyl, 4- to 6-membered heterocyclyl, and C1-4alkylene- NR10R11.

20. The compound according to any one of claims 1 to 15, wherein R1is selected from:wherein R18is selected from hydrogen, C1-5alkyl, halo, C1-5alkoxy, C1-5haloalkyl, and C3-6cycloalkyl; and R19is selected from hydrogen, halo, C1-4alkylene-O-C1-4alkyl, C1-4alkylene-OH, and C1-4alkylene-NR10R11.

21. The compound according to any one of claims 1 to 15, wherein R1is NR8C(O)R9, and R8is H or C1-6alkyl.

22. The compound according to any one of claims 1 to 15 or claim 21, wherein R1is NR8C(O)R9, and R9is C1-6alkyl.

23. The compound according to any one of claims 1 to 22, wherein R10and R11are independently H or C1-5alkyl.

24. The compound according to any one of claims 1 to 22, wherein R10and R11, taken together with the nitrogen to which they are attached, form a 4- to 6-membered heterocyclyl ring optionally substituted with one to four groups independently selected from halo, C1-5alkyl, C1-5alkoxy, and C1-5haloalkyl.

25. A compound selected from one of the following compounds, or a pharmaceutically acceptable salt thereof: 2-((9S,12S)-9-Acetamido-26-methyl-10-oxo-3-oxa-11-aza-1(1,3),2(1,2)- dibenzenacyclododecaphane-12-yl)acetic acid; 2-((8S,11S)-8-Acetamido-26-methyl-9-oxo-3-oxa-10-aza-1(1,3),2(1,2)- dibenzenacycloundecaphane-11-yl)acetic acid; 2-((10S,13S)-10-Acetamido-26-methyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)- dibenzenacyclotridecaphane-13-yl)acetic acid; 2-((10S,13S)-10-Acetamido-26,8-dimethyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)- dibenzenacyclotridecaphane-13-yl)acetic acid; 2-((10S,13S)-10-acetamido-26-methyl-11-oxo-3-oxa-12-aza-1,2(1,3)- dibenzenacyclotridecaphane-13-yl)acetic acid; 2-((8S,11S)-8-Acetamido-26,6-dimethyl-9-oxo-3-oxa-10-aza-1(1,3),2(1,2)- dibenzenacycloundecaphane-11-yl)acetic acid; 2-((10S,13S)-26-Methyl-10-(N-methylacetamido)-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)- dibenzenacyclotridecaphane-13-yl)acetic acid; 2-((3S,6S)-16-Methyl-6-(N-methylacetamido)-5-oxo-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid;2-((10S,13S)-26-methyl-11-oxo-10-(2-oxopyridin-1(2H)-yl)-3-oxa-12-aza-1(1,3),2(1,2)- dibenzenacyclotridecaphane-13-yl)acetic acid; 2-((10S,13S)-26-Methyl-11-oxo-10-(2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-3-oxa-12- aza-1(1,3),2(1,2)-dibenzenacyclotridecaphane-13-yl)acetic acid; 2-((10S,13S)-26-Methyl-11-oxo-10-(2-oxopiperidin-1-yl)-3-oxa-12-aza-1(1,3),2(1,2)- dibenzenacyclotridecaphane-13-yl)acetic acid; 2-((9S,12S)-26-Methyl-10-oxo-9-(2-oxopiperidin-1-yl)-3-oxa-11-aza-1(1,3),2(1,2)- dibenzenacyclododecaphane-12-yl)acetic acid; 2-((10S,13S)-26-Methyl-11-oxo-10-(2-oxopyrrolidin-1-yl)-3-oxa-12-aza-1(1,3),2(1,2)- dibenzenacyclotridecaphane-13-yl)acetic acid; 2-((8S,11S)-26-Methyl-9-oxo-8-(2-oxopyridin-1(2H)-yl)-3-oxa-10-aza-1(1,3),2(1,2)- dibenzenacycloundecaphane-11-yl)acetic acid; 2-((10S,13S)-24-fluoro-26-methyl-11-oxo-10-(2-oxopyridin-1(2H)-yl)-3-oxa-12-aza- 1(1,3),2(1,2)-dibenzenacyclotridecaphane-13-yl)acetic acid; 2-((10S,13S)-10-(5-Fluoro-2-oxopyridin-1(2H)-yl)-26-methyl-11-oxo-3-oxa-12-aza- 1(1,3),2(1,2)-dibenzenacyclotridecaphane-13-yl)acetic acid; 2-((10S,13S)-26-Methyl-11-oxo-10-(2-oxopiperidin-1-yl)-3-oxa-12-aza-1(3,5)-pyridina- 2(1,2)-benzenacyclotridecaphane-13-yl)acetic acid; 2-((10S,13S)-24-Fluoro-26-methyl-11-oxo-10-(2-oxopyridin-1(2H)-yl)-3-oxa-12-aza- 1(3,5)-pyridina-2(1,2)-benzenacyclotridecaphane-13-yl)acetic acid; 2-((10S,13S)-10-(4-Fluoro-2-oxopyridin-1(2H)-yl)-26-methyl-11-oxo-3-oxa-12-aza- 1(1,3),2(1,2)-dibenzenacyclotridecaphane-13-yl)acetic acid; 2-((10S,13S)-26-Methyl-11-oxo-10-(2-oxo-5-(trifluoromethyl)pyridin-1(2H)-yl)-3-oxa-12- aza-1(1,3),2(1,2)-dibenzenacyclotridecaphane-13-yl)acetic acid; 2-((10S,13S)-14-Fluoro-15,26-dimethyl-11-oxo-10-(2-oxopyridin-1(2H)-yl)-3-oxa-12-aza- 1(1,3),2(1,2)-dibenzenacyclotridecaphane-13-yl)acetic acid; 2-((10S,13S)-10-(5-(2-(Dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-26-methyl-11-oxo- 3-oxa-12-aza-1(1,3),2(1,2)-dibenzenacyclotridecaphane-13-yl)acetic acid; 2-((8S,11S)-8-(5-(2-(Dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-26-methyl-9-oxo-3- oxa-10-aza-1(1,3),2(1,2)-dibenzenacycloundecaphane-11-yl)acetic acid; 2-((10S,13S)-26-Methyl-11-oxo-10-(2-oxopyridin-1(2H)-yl)-24-(tetrahydro-2H-pyran-4- yl)-3-oxa-12-aza-1(1,3),2(1,2)-dibenzenacyclotridecaphane-13-yl)acetic acid; 2-((3S,6S)-6-Acetamido-16-methyl-5,12-dioxo-4,11-diaza-1(1,2),2(1,3)- dibenzenacyclododecaphane-3-yl)acetic acid; 2-((3S,6S)-6-Acetamido-16-methyl-5,13-dioxo-4,12-diaza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((11S,14S,E)-11-acetamido-26-methyl-12-oxo-3-oxa-13-aza-1(1,3),2(1,2)- dibenzenacyclotetradecaphan-8-en-14-yl)acetic acid; 2-((11S,14S)-11-Acetamido-26-methyl-12-oxo-3-oxa-13-aza-1(1,3),2(1,2)- dibenzenacyclotetradecaphane-14-yl)acetic acid; 2-((10S,13S)-24-Fluoro-26-methyl-10-(N-methylacetamido)-11-oxo-3-oxa-12-aza- 1(3,5)-pyridina-2(1,2)-benzenacyclotridecaphane-13-yl)acetic acid;2-((10S,13S)-10-(5-(2-(Dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-24-fluoro-26- methyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzenacyclotridecaphane-13-yl)acetic acid; 2-((10S,13S)-26-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)-dibenzenacyclotridecaphane-13-yl)acetic acid; 2-((10S,13S)-24-Fluoro-26-methyl-10-(N-methylacetamido)-11-oxo-3-oxa-12-aza- 1(3,5)-pyridina-2(1,2)-benzenacyclotridecaphane-13-yl)acetic acid; 2-((10S,13S)-26-Methyl-11-oxo-10-(4-oxoquinazolin-3(4H)-yl)-3-oxa-12-aza- 1(1,3),2(1,2)-dibenzenacyclotridecaphane-13-yl)acetic acid; 2-((10S,13S)-10-(5-(2-(Dimethylamino)ethyl)-3-fluoro-2-oxopyridin-1(2H)-yl)-26-methyl- 11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzenacyclotridecaphane-13-yl)acetic acid; 2-((10S,13S)-10-(5-(2-(Dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-14-fluoro-15,26- dimethyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzenacyclotridecaphane-13-yl)acetic acid; 2-((10S,13S)-10-(5-(2-(Dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-24,26-dimethyl-11- oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzenacyclotridecaphane-13-yl)acetic acid; 2-((10S,13S)-10-(5-(2-(Dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-14-fluoro-26- methyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzenacyclotridecaphane-13-yl)acetic acid; 2-((10S,13S)-10-(5-(2-(Dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-14,24-difluoro- 15,26-dimethyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzenacyclotridecaphane-13- yl)acetic acid; 2-((10S,13S)-10-(5-(2-(3-Fluoroazetidin-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-26-methyl- 11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzenacyclotridecaphane-13-yl)acetic acid; 2-((10S,13S)-10-(5-(2-((R)-3-Fluoropyrrolidin-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-26- methyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzenacyclotridecaphane-13-yl)acetic acid; 2-((10S,13S)-10-(5-(2-(3-Methoxyazetidin-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-26-methyl- 11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzenacyclotridecaphane-13-yl)acetic acid; 2-((10S,13S)-10-(5-(2-(Dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)- 26-methyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzenacyclotridecaphane-13-yl)acetic acid; 2-((10S,13S)-10-(5-(2-(Azetidin-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-15,26-dimethyl-11- oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzenacyclotridecaphane-13-yl)acetic acid; 2-((10S,13S)-14,24-Difluoro-10-(3-fluoro-5-(2-((R)-3-fluoropyrrolidin-1-yl)ethyl)-2- oxopyridin-1(2H)-yl)-15,26-dimethyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)- dibenzenacyclotridecaphane-13-yl)acetic acid; 2-((10S,13S)-14-Fluoro-10-(3-fluoro-5-(2-(3-fluoroazetidin-1-yl)ethyl)-2-oxopyridin- 1(2H)-yl)-15,24,26-trimethyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)- dibenzenacyclotridecaphane-13-yl)acetic acid; 2-((10S,13S)-14,24-Difluoro-10-(3-fluoro-5-(2-(3-fluoroazetidin-1-yl)ethyl)-2-oxopyridin- 1(2H)-yl)-15,26-dimethyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)- dibenzenacyclotridecaphane-13-yl)acetic acid;2-((10S,13S)-10-(5-(2-(Dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)- 14-fluoro-15,24,26-trimethyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)- dibenzenacyclotridecaphane-13-yl)acetic acid; 2-((10S,13S)-14,24-Difluoro-10-(5-(2-(3-methoxyazetidin-1-yl)ethyl)-2-oxo-4- (trifluoromethyl)pyridin-1(2H)-yl)-15,26-dimethyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)- dibenzenacyclotridecaphane-13-yl)acetic acid; 2-((10S,13S)-10-(5-(2-(Dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)- 14,24-difluoro-15,26-dimethyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)- dibenzenacyclotridecaphane-13-yl)acetic acid 2-((10S,13S)-15-cyclopropyl-10-(5-(2-(dimethylamino)ethyl)-2-oxo-4- (trifluoromethyl)pyridin-1(2H)-yl)-12,14-difluoro-24,26-dimethyl-11-oxo-3-oxa-12-aza- 1(1,3),2(1,2)-dibenzenacyclotridecaphane-13-yl)acetic acid; 2-((10S,13S)-14-fluoro-15,24,26-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)- dibenzenacyclotridecaphane-13-yl)acetic acid; 2-((10S,13S)-14,24-difluoro-15,26-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)- dibenzenacyclotridecaphane-13-yl)acetic acid; 2-((10S,13S)-10-(5-(2-(dimethylamino)ethyl)-4-methyl-2-oxopyridin-1(2H)-yl)-14-fluoro- 15,24,26-trimethyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzenacyclotridecaphane-13- yl)acetic acid; 2-((10S,13S)-24-cyclopropyl-10-(5-(2-(dimethylamino)ethyl)-2-oxo-4- (trifluoromethyl)pyridin-1(2H)-yl)-14-fluoro-15,26-dimethyl-11-oxo-3-oxa-12-aza- 1(1,3),2(1,2)-dibenzenacyclotridecaphane-13-yl)acetic acid; 2-((10S,13S)-10-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)- 14-fluoro-24,26-dimethyl-11-oxo-15-(trifluoromethyl)-3-oxa-12-aza-1(1,3),2(1,2)- dibenzenacyclotridecaphane-13-yl)acetic acid; 2-((8S,11S)-8-(5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-24-fluoro-26-methyl-9- oxo-3-oxa-10-aza-1(1,3),2(1,2)-dibenzenacycloundecaphane-11-yl)acetic acid; 2-((10S,13S)-10-(5-(2-(azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-15- cyclopropyl-12,14-difluoro-24,26-dimethyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)- dibenzenacyclotridecaphane-13-yl)acetic acid; 2-((10S,13S)-10-(5-(3-(dimethylamino)propyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)- yl)-14-fluoro-15,24,26-trimethyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)- dibenzenacyclotridecaphane-13-yl)acetic acid; 2-((10S,13S)-15-cyclopropyl-10-(5-(2-(dimethylamino)ethyl)-2-oxo-4- (trifluoromethyl)pyridin-1(2H)-yl)-14-fluoro-24,26-dimethyl-11-oxo-3-oxa-12-aza- 1(1,3),2(1,2)-dibenzenacyclotridecaphane-13-yl)acetic acid; 2-((10S,13S)-14-fluoro-15,24,26-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)- dibenzenacyclotridecaphane-13-yl)acetic acid; 2-((10S,13S)-15-cyclopropyl-10-(5-(2-(dimethylamino)ethyl)-2-oxo-4- (trifluoromethyl)pyridin-1(2H)-yl)-14,25-difluoro-24,26-dimethyl-11-oxo-3-oxa-12-aza- 1(1,3),2(1,2)-dibenzenacyclotridecaphane-13-yl)acetic acid;2-((10S,13S)-10-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)- 12,14-difluoro-15,24,26-trimethyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)- dibenzenacyclotridecaphane-13-yl)acetic acid; 2-((10S,13S)-15-cyclopropyl-10-(5-(3-(dimethylamino)propyl)-2-oxo-4- (trifluoromethyl)pyridin-1(2H)-yl)-12,14-difluoro-24,26-dimethyl-11-oxo-3-oxa-12-aza- 1(1,3),2(1,2)-dibenzenacyclotridecaphane-13-yl)acetic acid; 2-((3S,6S)-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-24- fluoro-14,16-dimethyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotetradecaphane-3-yl)acetic acid; 2-((3S,6S)-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-24- fluoro-14,16-dimethyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-24- fluoro-14,16-dimethyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclododecaphane-3-yl)acetic acid; 2-((10S,13S)-15-Cyclopropyl-14-fluoro-24,26-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)- dibenzenacyclotridecaphane-13-yl)acetic acid; 2-((10S,13S)-15-Cyclopropyl-10-(5-(3-(dimethylamino)propyl)-2-oxo-4- (trifluoromethyl)pyridin-1(2H)-yl)-14-fluoro-24,26-dimethyl-11-oxo-3-oxa-12-aza- 1(1,3),2(1,2)-dibenzenacyclotridecaphane-13-yl)acetic acid; 2-((10S,13S)-15-Cyclopropyl-10-(5-(2-(diethylamino)ethyl)-2-oxo-4- (trifluoromethyl)pyridin-1(2H)-yl)-14-fluoro-24,26-dimethyl-11-oxo-3-oxa-12-aza- 1(1,3),2(1,2)-dibenzenacyclotridecaphane-13-yl)acetic acid; 2-((3S,6S)-25-Cyclopropyl-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4- (trifluoromethyl)pyridin-1(2H)-yl)-24-fluoro-14,16-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-25-Cyclopropyl-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4- (trifluoromethyl)pyridin-1(2H)-yl)-24-fluoro-14,16-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)- dibenzenacyclododecaphane-3-yl)acetic acid; 2-((10S,13S)-14,24-Difluoro-26-methyl-11-oxo-10-(2-oxo-5-(2-(pyrrolidin-1-yl)ethyl)-4- (trifluoromethyl)pyridin-1(2H)-yl)-15-(trifluoromethyl)-3-oxa-12-aza-1(1,3),2(1,2)- dibenzenacyclotridecaphane-13-yl)acetic acid; 2-((10S,13S)-24-Cyclopentyl-15-cyclopropyl-10-(5-(2-(dimethylamino)ethyl)-2-oxo-4- (trifluoromethyl)pyridin-1(2H)-yl)-14-fluoro-26-methyl-11-oxo-3-oxa-12-aza- 1(1,3),2(1,2)-dibenzenacyclotridecaphane-13-yl)acetic acid; 2-((10S,13S)-15-Cyclopropyl-10-(5-(3-(diethylamino)propyl)-2-oxo-4- (trifluoromethyl)pyridin-1(2H)-yl)-14-fluoro-24,26-dimethyl-11-oxo-3-oxa-12-aza- 1(1,3),2(1,2)-dibenzenacyclotridecaphane-13-yl)acetic acid; 2-((3S,6S)-25-Cyclopropyl-6-(5-(3-(dimethylamino)propyl)-2-oxo-4- (trifluoromethyl)pyridin-1(2H)-yl)-24-fluoro-14,16-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-14-Cyclopropyl-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4- (trifluoromethyl)pyridin-1(2H)-yl)-24-fluoro-16,25-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid;2-((3S,6S)-14-Cyclopropyl-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4- (trifluoromethyl)pyridin-1(2H)-yl)-24-fluoro-16,25-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)- dibenzenacyclododecaphane-3-yl)acetic acid; 2-((3S,6S)-25-Cyclopropyl-6-(5-(2-(dimethylamino)ethyl)-3-fluoro-2-oxopyridin-1(2H)- yl)-24-fluoro-14,16-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3- yl)acetic acid; 2-((10S,13S)-15,24-Dicyclopropyl-10-(5-(2-(dimethylamino)ethyl)-2-oxo-4- (trifluoromethyl)pyridin-1(2H)-yl)-14-fluoro-26-methyl-11-oxo-3-oxa-12-aza- 1(1,3),2(1,2)-dibenzenacyclotridecaphane-13-yl)acetic acid; 2-((9S,12S)-15,24-Dicyclopropyl-9-(5-(2-(dimethylamino)ethyl)-2-oxo-4- (trifluoromethyl)pyridin-1(2H)-yl)-14-fluoro-26-methyl-10-oxo-3-oxa-11-aza- 1(1,3),2(1,2)-dibenzenacyclododecaphane-12-yl)acetic acid; 2-((10S,13S)-15-Cyclopropyl-10-(5-(2-(dimethylamino)ethyl)-2-oxo-4- (trifluoromethyl)pyridin-1(2H)-yl)-14-fluoro-24,25,26-trimethyl-11-oxo-3-oxa-12-aza- 1(1,3),2(1,2)-dibenzenacyclotridecaphane-13-yl)acetic acid; 2-((9S,12S)-15-Cyclopropyl-9-(5-(2-(dimethylamino)ethyl)-2-oxo-4- (trifluoromethyl)pyridin-1(2H)-yl)-14-fluoro-24,25,26-trimethyl-10-oxo-3-oxa-11-aza- 1(1,3),2(1,2)-dibenzenacyclododecaphane-12-yl)acetic acid; 2-((3S,6S)-25-Cyclopropyl-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4- (trifluoromethyl)pyridin-1(2H)-yl)-14-fluoro-16,24-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-25-Cyclopropyl-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4- (trifluoromethyl)pyridin-1(2H)-yl)-14,24-difluoro-16-methyl-5-oxo-4-aza-1(1,2),2(1,3)- dibenzenacyclododecaphane-3-yl)acetic acid; 2-((10S,13S)-15-Cyclopropyl-10-(5-(2-(dimethylamino)ethyl)-2-oxo-4- (trifluoromethyl)pyridin-1(2H)-yl)-14-fluoro-26-methyl-11-oxo-24-(trifluoromethyl)-3-oxa- 12-aza-1(1,3),2(1,2)-dibenzenacyclotridecaphane-13-yl)acetic acid; 2-((9S,12S)-15-Cyclopropyl-9-(5-(2-(dimethylamino)ethyl)-2-oxo-4- (trifluoromethyl)pyridin-1(2H)-yl)-14-fluoro-26-methyl-10-oxo-24-(trifluoromethyl)-3-oxa- 11-aza-1(1,3),2(1,2)-dibenzenacyclododecaphane-12-yl)acetic acid; 2-((3S,6S)-6-(5-(2-(Azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-24- fluoro-14,16-dimethyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-25-Cyclopropyl-14,24-difluoro-6-(5-(2-(3-fluoroazetidin-1-yl)ethyl)-2-oxo-4- (trifluoromethyl)pyridin-1(2H)-yl)-16-methyl-5-oxo-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-25-Cyclopropyl-14,24-difluoro-6-(5-(2-(3-fluoroazetidin-1-yl)ethyl)-2-oxo-4- (trifluoromethyl)pyridin-1(2H)-yl)-16-methyl-5-oxo-4-aza-1(1,2),2(1,3)- dibenzenacyclododecaphane-3-yl)acetic acid; 2-((3S,6S)-14-Cyclopropyl-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4- (trifluoromethyl)pyridin-1(2H)-yl)-24-fluoro-16-methyl-5-oxo-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-14-Cyclopropyl-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4- (trifluoromethyl)pyridin-1(2H)-yl)-24-fluoro-16-methyl-5-oxo-4-aza-1(1,2),2(1,3)- dibenzenacyclododecaphane-3-yl)acetic acid;2-((3S,6S)-6-(5-(2-(Dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-24- fluoro-14,16-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-6-(5-(2-(Dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-24- fluoro-14,16-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclododecaphane-3- yl)acetic acid; 2-((3S,6S)-25-Cyclopropyl-6-(5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-24- fluoro-14,16-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-25-Cyclopropyl-6-(5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-24- fluoro-14,16-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclododecaphane-3- yl)acetic acid; 2-((3S,6S)-6-(5-(2-(Dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-24- fluoro-14,16,25-trimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3- yl)acetic acid; 2-((3S,6S)-6-(5-(2-(Dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-24- fluoro-14,16,25-trimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclododecaphane-3- yl)acetic acid; 2-((10S,13S)-10-(5-(3-(Dimethylamino)propyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)- yl)-14-fluoro-24,26-dimethyl-11-oxo-15-(trifluoromethyl)-3-oxa-12-aza-1(1,3),2(1,2)- dibenzenacyclotridecaphane-13-yl)acetic acid; 2-((3S,6S)-25-Cyclopropyl-24-fluoro-6-(5-(2-(3-fluoroazetidin-1-yl)ethyl)-2-oxo-4- (trifluoromethyl)pyridin-1(2H)-yl)-14,16-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((10S,13S)-10-(5-(2-(Azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-14- fluoro-24,26-dimethyl-11-oxo-15-(trifluoromethyl)-3-oxa-12-aza-1(1,3),2(1,2)- dibenzenacyclotridecaphane-13-yl)acetic acid; 2-((3S,6S)-6-(5-(3-(Dimethylamino)propyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-24- fluoro-14,16-dimethyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((10S,13S)-10-(5-(2-(Azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-15- cyclopropyl-14-fluoro-24,26-dimethyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)- dibenzenacyclotridecaphane-13-yl)acetic acid; 2-((3S,6S)-6-(5-(2-(Azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-25- cyclopropyl-24-fluoro-14,16-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-6-(5-(2-(Azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-25- cyclopropyl-14,24-difluoro-16-methyl-5-oxo-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-6-(5-(2-(Azetidin-1-yl)ethyl)-3-fluoro-2-oxopyridin-1(2H)-yl)-25-cyclopropyl- 24-fluoro-14,16-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3- yl)acetic acid; 2-((3S,6S)-25-Cyclopropyl-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4- (trifluoromethyl)pyridin-1(2H)-yl)-24-fluoro-14-methyl-5-oxo-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid;2-((3S,6S)-25-Cyclopropyl-6-(5-(3-(dimethylamino)propyl)-2-oxo-4- (trifluoromethyl)pyridin-1(2H)-yl)-14,24-difluoro-16-methyl-5-oxo-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-25-Cyclopropyl-6-(5-(2-(dimethylamino)ethyl)-3-fluoro-2-oxopyridin-1(2H)- yl)-14,24-difluoro-16-methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3- yl)acetic acid; 2-((3S,6S)-25-Cyclopropyl-6-(5-(2-(dimethylamino)ethyl)-4-methyl-2-oxopyridin-1(2H)- yl)-14,24-difluoro-16-methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3- yl)acetic acid; 2-((3S,6S)-25-Cyclopropyl-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4- (trifluoromethyl)pyridin-1(2H)-yl)-24-fluoro-16-methyl-5-oxo-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-25-Cyclopropyl-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4- (trifluoromethyl)pyridin-1(2H)-yl)-24-fluoro-16-methyl-5-oxo-4-aza-1(1,2),2(1,3)- dibenzenacyclododecaphane-3-yl)acetic acid; 2-((3S,6S)-25-Cyclopropyl-24-fluoro-6-(3-fluoro-5-(2-(3-fluoroazetidin-1-yl)ethyl)-2- oxopyridin-1(2H)-yl)-14,16-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((10S,13S)-15-Cyclopropyl-14-fluoro-10-(4-methoxy-2-oxopyridin-1(2H)-yl)-24,26- dimethyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzenacyclotridecaphane-13-yl)acetic acid; 2-((3S,6S)-6-(5-(2-(Azetidin-1-yl)ethyl)-4-methyl-2-oxopyridin-1(2H)-yl)-25-cyclopropyl- 24-fluoro-14,16-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3- yl)acetic acid; 2-((3S,6S)-6-(5-(2-(Dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)- 14,24-difluoro-16-methyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-6-(5-(2-(Dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)- 14,24-difluoro-16-methyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclododecaphane-3-yl)acetic acid; 2-((3S,6S)-25-Cyclopropyl-14,24-difluoro-6-(5-(3-(3-fluoroazetidin-1-yl)propyl)-2-oxo-4- (trifluoromethyl)pyridin-1(2H)-yl)-16-methyl-5-oxo-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-6-(5-(2-(Azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-24- fluoro-14,16,25-trimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3- yl)acetic acid; 2-((3S,6S)-6-(5-(3-(Dimethylamino)propyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-24- fluoro-14,16,25-trimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3- yl)acetic acid; 2-((3S,6S)-25-Cyclopropyl-14,24-difluoro-6-(5-(2-(3-methoxyazetidin-1-yl)ethyl)-2-oxo-4- (trifluoromethyl)pyridin-1(2H)-yl)-16-methyl-5-oxo-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-25-Cyclopropyl-14,24-difluoro-6-(5-(2-(3-methoxyazetidin-1-yl)ethyl)-2-oxo-4- (trifluoromethyl)pyridin-1(2H)-yl)-16-methyl-5-oxo-4-aza-1(1,2),2(1,3)- dibenzenacyclododecaphane-3-yl)acetic acid;2-((3S,6S)-6-(5-(2-(Azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-25- cyclopropyl-24-fluoro-16-methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane- 3-yl)acetic acid; 2-((3S,6S)-25-Cyclopropyl-6-(5-(2-(dimethylamino)ethyl)-4-methyl-2-oxopyridin-1(2H)- yl)-24-fluoro-14,16-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3- yl)acetic acid; 2-((3S,6S)-25-Cyclopropyl-6-(5-(2-(dimethylamino)ethyl)-4-methyl-2-oxopyridin-1(2H)- yl)-24-fluoro-14,16-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclododecaphane-3- yl)acetic acid; 2-((10S,13S)-15-cyclopropyl-14-fluoro-10-(4-fluoro-2-oxopyridin-1(2H)-yl)-24,26- dimethyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzenacyclotridecaphane-13-yl)acetic acid; 2-((3S,6S)-25-Cyclopropyl-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4- (trifluoromethyl)pyridin-1(2H)-yl)-14,16-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-6-(5-(2-(Azetidin-1-yl)ethyl)-4-methyl-2-oxopyridin-1(2H)-yl)-25-cyclopropyl- 14,24-difluoro-16-methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3- yl)acetic acid; 2-((3S,6S)-25-Cyclopropyl-14,24-difluoro-16-methyl-6-(4-methyl-2-oxopyridin-1(2H)-yl)- 5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-24-Chloro-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin- 1(2H)-yl)-14,16-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3- yl)acetic acid; 2-((3S,6S)-25-Cyclopropyl-6-(5-(3-(dimethylamino)propyl)-4-methyl-2-oxopyridin-1(2H)- yl)-14,24-difluoro-16-methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3- yl)acetic acid; 2-((3S,6S)-6-(5-(2-(Azetidin-1-yl)ethyl)-3-fluoro-2-oxopyridin-1(2H)-yl)-25-cyclopropyl- 14,24-difluoro-16-methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3- yl)acetic acid; 2-((3S,6S)-25-Cyclopropyl-6-(4-cyclopropyl-5-(2-(dimethylamino)ethyl)-2-oxopyridin- 1(2H)-yl)-24-fluoro-14,16-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-14,24-Difluoro-6-(3-(2-(3-fluoroazetidin-1-yl)ethyl)-6-oxo-4- (trifluoromethyl)pyridazin-1(6H)-yl)-16,25-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-25-Cyclopropyl-6-(5-(3-(dimethylamino)propyl)-4-methyl-2-oxopyridin-1(2H)- yl)-24-fluoro-14,16-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3- yl)acetic acid; 2-((3S,6S)-25-Cyclopropyl-6-(5-(3-(dimethylamino)propyl)-2-oxo-4- (trifluoromethyl)pyridin-1(2H)-yl)-24-fluoro-16-methyl-5-oxo-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-25-Cyclopropyl-6-(5-(3-(dimethylamino)propyl)-3-fluoro-2-oxopyridin-1(2H)- yl)-24-fluoro-14,16-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3- yl)acetic acid;2-((3S,6S)-25-Cyclopropyl-6-(4-cyclopropyl-5-(2-(dimethylamino)ethyl)-2-oxopyridin- 1(2H)-yl)-14,24-difluoro-16-methyl-5-oxo-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-25-Cyclopropyl-6-(5-(3-(dimethylamino)propyl)-3-fluoro-2-oxopyridin-1(2H)- yl)-14,24-difluoro-16-methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3- yl)acetic acid; 2-((3S,6S)-25-Cyclopropyl-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4- (trifluoromethyl)pyridin-1(2H)-yl)-14,16,24-trifluoro-5-oxo-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-25-Cyclopropyl-24-fluoro-6-(5-(3-(3-fluoroazetidin-1-yl)propyl)-2-oxo-4- (trifluoromethyl)pyridin-1(2H)-yl)-14,16-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-6-(5-(2-(Azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-14,24- difluoro-16-methyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-6-(5-(2-(Diethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-14,24- difluoro-16-methyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-6-(5-(3-(Dimethylamino)propyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)- 14,24-difluoro-16-methyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-6-(5-(3-(Azetidin-1-yl)propyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-25- cyclopropyl-14,24-difluoro-16-methyl-5-oxo-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-25-Cyclopropyl-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4- (trifluoromethyl)pyridin-1(2H)-yl)-14,22,24-trifluoro-16-methyl-5-oxo-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-6-(5-(2-(Dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)- 14,24-difluoro-16,25-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3- yl)acetic acid; 2-((3S,6S)-6-(5-(2-(Diethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-14,24- difluoro-16,25-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3- yl)acetic acid; 2-((3S,6S)-6-(5-(2-(Azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-14,24- difluoro-16,25-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3- yl)acetic acid; 2-((3S,6S)-16-Chloro-25-cyclopropyl-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4- (trifluoromethyl)pyridin-1(2H)-yl)-24-fluoro-5-oxo-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-25-Cyclopropyl-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4- (trifluoromethyl)pyridin-1(2H)-yl)-14-fluoro-16-methyl-5-oxo-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-6-(5-(3-(Azetidin-1-yl)propyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-14,24- difluoro-16-methyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid;2-((3S,6S)-6-(5-(2-(Dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-24- fluoro-14,16,25-trimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphan-8-en-3- yl)acetic acid; 2-((3S,6S)-6-(4-(Difluoromethyl)-5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)- 14,24-difluoro-16-methyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-6-(5-(2-(Dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)- 14,24,25-trifluoro-16-methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3- yl)acetic acid; 2-((3S,6S)-25-Chloro-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin- 1(2H)-yl)-14,24-difluoro-16-methyl-5-oxo-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-6-(5-(2-(Azetidin-1-yl)ethyl)-3-methyl-2-oxopyridin-1(2H)-yl)-25-cyclopropyl- 14,24-difluoro-16-methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3- yl)acetic acid; 2-((10S,13S)-14,24-Difluoro-15,26-dimethyl-11-oxo-10-(3-oxo-2-azaspiro[4.5]decan-2- yl)-3-oxa-12-aza-1(1,3),2(1,2)-dibenzenacyclotridecaphane-13-yl)acetic acid; 2-((10S,13S)-15-Cyclopropyl-10-(5-(2-(dimethylamino)ethyl)-2-oxo-4- (trifluoromethyl)pyridin-1(2H)-yl)-14-fluoro-23,24,26-trimethyl-11-oxo-3-oxa-12-aza- 1(1,3),2(1,2)-dibenzenacyclotridecaphane-13-yl)acetic acid; 2-((3S,6S)-6-(5-(2-(Dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-14- fluoro-16-methyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)- 14,16,24-trifluoro-26-methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3- yl)acetic acid; 2-((3S,6S)-6-(5-(2-(Dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-14- fluoro-16,25-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-6-(5-(2-(Dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)- 14,22-difluoro-16-methyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((10S,13S)-15-Cyclopropyl-10-(5-(3-(dimethylamino)propyl)-2-oxo-4- (trifluoromethyl)pyridin-1(2H)-yl)-14,23,24-trifluoro-26-methyl-11-oxo-3-oxa-12-aza- 1(1,3),2(1,2)-dibenzenacyclotridecaphane-13-yl)acetic acid; 2-((3S,6S)-6-(5-(2-(Dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)- 14,24-difluoro-16,8-dimethyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-6-(5-(2-(Dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)- 14,24-difluoro-16,8-dimethyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclododecaphane-3-yl)acetic acid; 2-((3S,6S)-6-(5-(2-(Dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)- 14,24-difluoro-16,26-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3- yl)acetic acid;2-((10S,13S)-14,24-Difluoro-15,26-dimethyl-10-(3-methyl-2-oxotetrahydropyrimidin- 1(2H)-yl)-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzenacyclotridecaphane-13-yl)acetic acid; 2-((3S,6S)-14,24-Difluoro-6-(5-(2-(3-methoxyazetidin-1-yl)ethyl)-2-oxo-4- (trifluoromethyl)pyridin-1(2H)-yl)-16-methyl-5-oxo-25-(trifluoromethyl)-4-aza- 1(1,2),2(1,3)-dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-6-(5-(2-(Ethyl(methyl)amino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)- yl)-14,24-difluoro-16-methyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-6-(5-(3-(Dimethylamino)propyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)- 14,24-difluoro-16,25-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3- yl)acetic acid; 2-((3S,6S)-14,24-Difluoro-6-(5-(2-(3-fluoroazetidin-1-yl)ethyl)-2-oxo-4- (trifluoromethyl)pyridin-1(2H)-yl)-16-methyl-5-oxo-25-(trifluoromethyl)-4-aza- 1(1,2),2(1,3)-dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-6-(5-(3-(Azetidin-1-yl)propyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-14,24- difluoro-16,25-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3- yl)acetic acid; 2-((3S,6S)-6-(5-(2-(Dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)- 14,16,24,25-tetrafluoro-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3- yl)acetic acid; 2-((3S,6S)-6-(5-(2-(Dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)- 14,16,24,25-tetrafluoro-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclododecaphane-3- yl)acetic acid; 2-((3S,6S)-14,24-Difluoro-16-methyl-5-oxo-6-(2-oxo-5-(2-(pyrrolidin-1-yl)ethyl)-4- (trifluoromethyl)pyridin-1(2H)-yl)-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-14,24-Difluoro-16-methyl-5-oxo-6-(3-oxo-3,4-dihydroisoquinolin-2(1H)-yl)-25- (trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-14,24-Difluoro-16,25-dimethyl-5-oxo-6-(3-oxo-2-azaspiro[4.5]decan-2-yl)-4- aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-6-(5-(2-(Dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)- 14,24-difluoro-16,9-dimethyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-6-(5-(2-(Dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)- 14,16,24-trifluoro-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-14,24,25-Trifluoro-16-methyl-5-oxo-6-(3-oxo-2-azaspiro[4.5]decan-2-yl)-4- aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((10S,13S)-10-(4,4-Dimethyl-2-oxopyrrolidin-1-yl)-14,24-difluoro-15,26-dimethyl-11- oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzenacyclotridecaphane-13-yl)acetic acid; 2-((3S,6S)-14,24-Difluoro-16-methyl-5-oxo-6-(3-oxo-2-azaspiro[4.4]nonan-2-yl)-25- (trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3-yl)acetic acid;2-((3S,6S)-25-Cyclopropyl-14,24-difluoro-16-methyl-5-oxo-6-(3-oxo-2,8- diazaspiro[4.5]decan-2-yl)-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-25-Cyclopropyl-14,24-difluoro-16-methyl-5-oxo-6-(8-methyl-3-oxo-2,8- diazaspiro[4.5]decan-2-yl)-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-14,24-Difluoro-6-(3-fluoro-5-(2-(3-fluoroazetidin-1-yl)ethyl)-2-oxopyridin- 1(2H)-yl)-16-methyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-14,24-Difluoro-6-(5-(2-(3-methoxyazetidin-1-yl)ethyl)-2-oxo-4- (trifluoromethyl)pyridin-1(2H)-yl)-16,25-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-6-(5-Bromo-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-14,24-difluoro-16- methyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3- yl)acetic acid; 2-((3S,6S)-6-(5-(3-(Dimethylamino)propyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)- 14,24,25-trifluoro-16-methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3- yl)acetic acid; 2-((3S,6S)-6-(5-(3-(Dimethylamino)propyl)-2-oxopyridin-1(2H)-yl)-14,24-difluoro-16- methyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3- yl)acetic acid; 2-((3S,6S)-6-(5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-16-methyl-5-oxo-4-aza- 1(1,2),2(1,3)-dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-14,24-Difluoro-16-methyl-5-oxo-6-(3-oxo-8-oxa-2-azaspiro[4.5]decan-2-yl)- 25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-6-(5-(2-(Dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-16- ethyl-14,24-difluoro-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-6-(5-(3-(Dimethylamino)propyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)- 14,16,24-trifluoro-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-14,24,25-Trifluoro-16-methyl-6-(1-methyl-2-oxo-1,3-diazaspiro[4.5]decan-3- yl)-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-25-Cyclopropyl-24-fluoro-14,16-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)- dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((10S,13S)-10-(5-(2-(Dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)- 14,24-difluoro-26,7-dimethyl-11-oxo-15-(trifluoromethyl)-3-oxa-12-aza-1(1,3),2(1,2)- dibenzenacyclotridecaphane-13-yl)acetic acid; 2-((10S,13S)-10-(5-(2-(Dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)- 14,24-difluoro-26,4-dimethyl-11-oxo-15-(trifluoromethyl)-3-oxa-12-aza-1(1,3),2(1,2)- dibenzenacyclotridecaphane-13-yl)acetic acid; 2-((3S,6S)-14,24-Difluoro-16-methyl-6-(5-(2-morpholinoethyl)-2-oxo-4- (trifluoromethyl)pyridin-1(2H)-yl)-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid;2-((3S,6S)-6-(3-(2-(Azetidin-1-yl)ethyl)-6-oxo-5-(trifluoromethyl)pyridazin-1(6H)-yl)-25- cyclopropyl-14,24-difluoro-16-methyl-5-oxo-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-25-Cyclopropyl-14,24-difluoro-6-(3-(2-(3-fluoroazetidin-1-yl)ethyl)-6-oxo-5- (trifluoromethyl)pyridazin-1(6H)-yl)-16-methyl-5-oxo-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-6-(3-(2-(Azetidin-1-yl)ethyl)-6-oxo-5-(trifluoromethyl)pyridazin-1(6H)-yl)- 14,24-difluoro-16-methyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-6-(3-(2-(Azetidin-1-yl)ethyl)-5-methyl-6-oxopyridazin-1(6H)-yl)-25- cyclopropyl-14,24-difluoro-16-methyl-5-oxo-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-6-(3-(3-(Dimethylamino)propyl)-6-oxo-5-(trifluoromethyl)pyridazin-1(6H)-yl)- 14,24-difluoro-16-methyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-14,24-Difluoro-6-(3-(2-(3-fluoroazetidin-1-yl)ethyl)-5-methyl-6-oxopyridazin- 1(6H)-yl)-16-methyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-14,24-Difluoro-6-(3-(2-(3-methoxyazetidin-1-yl)ethyl)-5-methyl-6- oxopyridazin-1(6H)-yl)-16-methyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-6-(3-(2-(Azetidin-1-yl)ethyl)-5-methyl-6-oxopyridazin-1(6H)-yl)-14,24- difluoro-16-methyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-6-(3-(3-(Dimethylamino)propyl)-5-methyl-6-oxopyridazin-1(6H)-yl)-14,24- difluoro-16-methyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-6-(3-(3-(Dimethylamino)propyl)-6-oxo-4-(trifluoromethyl)pyridazin-1(6H)-yl)- 14,24-difluoro-16-methyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-14,24-Difluoro-6-(3-(2-(3-fluoroazetidin-1-yl)ethyl)-6-oxo-4- (trifluoromethyl)pyridazin-1(6H)-yl)-16-methyl-5-oxo-25-(trifluoromethyl)-4-aza- 1(1,2),2(1,3)-dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-6-(3-(3-(Dimethylamino)propyl)-6-oxo-4-(trifluoromethyl)pyridazin-1(6H)-yl)- 14,24-difluoro-16,25-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3- yl)acetic acid; 2-((3S,6S)-25-Cyclopropyl-6-(3-(3-(dimethylamino)propyl)-6-oxo-4- (trifluoromethyl)pyridazin-1(6H)-yl)-14,24-difluoro-16-methyl-5-oxo-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-6-(3-(3-(Azetidin-1-yl)propyl)-6-oxo-4-(trifluoromethyl)pyridazin-1(6H)-yl)- 14,24-difluoro-16-methyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-25-Cyclopropyl-14,24-difluoro-6-(3-(2-(3-methoxyazetidin-1-yl)ethyl)-6-oxo-4- (trifluoromethyl)pyridazin-1(6H)-yl)-16-methyl-5-oxo-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid;2-((3S,6S)-25-Cyclopropyl-14,24-difluoro-6-(3-(2-(3-fluoroazetidin-1-yl)ethyl)-6-oxo-4- (trifluoromethyl)pyridazin-1(6H)-yl)-16-methyl-5-oxo-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-25-Cyclopropyl-14,24-difluoro-6-(5-(3-hydroxypropyl)-2-oxo-4- (trifluoromethyl)pyridin-1(2H)-yl)-16-methyl-5-oxo-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-14,24-Difluoro-6-(3-(2-(3-methoxyazetidin-1-yl)ethyl)-6-oxo-4- (trifluoromethyl)pyridazin-1(6H)-yl)-16-methyl-5-oxo-25-(trifluoromethyl)-4-aza- 1(1,2),2(1,3)-dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-14,16,24-Trifluoro-6-(5-(2-morpholinoethyl)-2-oxo-4-(trifluoromethyl)pyridin- 1(2H)-yl)-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3- yl)acetic acid; 2-((3S,6S)-6-(5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-14,24-difluoro-16- methyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3- yl)acetic acid; 2-((3S,6S)-6-(3-(2-(Dimethylamino)ethyl)-6-oxo-4-(trifluoromethyl)pyridazin-1(6H)-yl)- 14,24-difluoro-16-methyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-25-Cyclopropyl-14,24-difluoro-6-(3-(2-(3-fluoroazetidin-1-yl)ethyl)-5-methyl-6- oxopyridazin-1(6H)-yl)-16-methyl-5-oxo-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-14,24-Difluoro-6-(3-(2-(3-methoxyazetidin-1-yl)ethyl)-6-oxo-4- (trifluoromethyl)pyridazin-1(6H)-yl)-16,25-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-25-Cyclopropyl-14,16,24-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)- dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-6-(3-(3-(Dimethylamino)propyl)-6-oxo-4-(trifluoromethyl)pyridazin-1(6H)-yl)- 14,24,25-trifluoro-16-methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3- yl)acetic acid; 2-((3S,6S)-25-Cyclopropyl-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4- (trifluoromethyl)pyridin-1(2H)-yl)-13,14,24-trifluoro-16-methyl-5-oxo-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-6-(3-(2-(Azetidin-1-yl)ethyl)-6-oxo-4-(trifluoromethyl)pyridazin-1(6H)-yl)- 14,24-difluoro-16-methyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-25-Cyclopropyl-6-(3-(2-(dimethylamino)ethyl)-6-oxo-4- (trifluoromethyl)pyridazin-1(6H)-yl)-14,16,24-trifluoro-5-oxo-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-6-(3-(2-(Azetidin-1-yl)ethyl)-6-oxo-4-(trifluoromethyl)pyridazin-1(6H)-yl)- 14,24-difluoro-16,25-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3- yl)acetic acid; 2-((3S,6S)-25-Cyclopropyl-6-(5-(2-(dimethylamino)ethyl)-4-methyl-2-oxopyrimidin- 1(2H)-yl)-14,24-difluoro-16-methyl-5-oxo-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid;2-((3S,6S)-6-(5-(2-(3-Methoxyazetidin-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-16-methyl-5- oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3-yl)acetic acid; and 2-((3S,6S)-6-(5-(2-(3-Fluoroazetidin-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-16-methyl-5-oxo- 4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3-yl)acetic acid.

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 diseases or disorders 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. A method of treating a disease or disorders mediated by α4β7, said method 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 of treating inflammatory bowel diseases, such as ulcerative colitis or Crohn’s disease, said method 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