Therapeutic compounds

Abstract

The present invention relates to compounds that are α4β7 integrin inhibitors. 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 example Natalizumab (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. Clinical trials with orally delivered small molecules are underway or have completed, but there remains a need for more selective molecules with an improved dosing frequency.

[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” ofa 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 or display 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] The phrase “compound of the invention” means those compounds which are disclosed herein, as referred to in the claims and also in the Examples prepared in the experimental section. Compounds of the Invention

[0022] In a first aspect, the present invention provides a compound, or a pharmaceutically acceptable salt thereof, selected from: 2-((3S,6S)-6-(5-(2-(Dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-14,16-difluoro-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-fluoro-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)-14,16,24- trifluoro-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3- yl)acetic acid; 2-((3S,6S)-14,16,24-Trifluoro-6-(5-(2-(3-methoxyazetidin-1-yl)ethyl)-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)-14,24-Difluoro-6-(5-(2-(3-fluoro-3-methylazetidin-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-(Dimethylamino)ethyl)-2-oxopyridin-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-(3-(3-(Dimethylamino)propyl)-6-oxo-4-(trifluoromethyl)pyridazin-1(6H)-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)-6-(5-(2-(Dimethylamino)ethyl)-3-methyl-2-oxopyrazin-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-(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)-14,16,24-Trifluoro-6-(5-(2-(3-fluoroazetidin-1-yl)ethyl)-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-(Dimethylamino)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-((10S,13S)-10-(5-(2-(Azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-15- cyclopropyl-14,24-difluoro-26-methyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)- dibenzenacyclotridecaphane-13-yl)acetic acid; 2-((3S,6S)-6-(3-(2-(Dimethylamino)ethyl)-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)-14,24-Difluoro-6-(3-(2-(3-fluoro-3-methylazetidin-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)-6-(5-(2-(Dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-14,16,24- trifluoro-25-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-oxopyridazin-1(6H)-yl)-14-fluoro-16-methyl-5- oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-14,16,24-Trifluoro-6-(3-(2-(3-methoxyazetidin-1-yl)ethyl)-6-oxo-4- (trifluoromethyl)pyridazin-1(6H)-yl)-25-methyl-5-oxo-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-6-(5-(2-(Dimethylamino)ethyl)-3-methyl-2-oxopyrazin-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)-16,25-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)-3-methyl-2-oxopyrazin-1(2H)- 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-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin- 1(2H)-yl)-14,16,24-trifluoro-5-oxo-12-oxa-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- fluoro-16,25-dimethyl-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)- 14,16,24-trifluoro-25-methyl-5-oxo-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- 16,25-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)-14,24- difluoro-16,25,8-trimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclododecaphane-3-yl)acetic acid; 2-((3S,6S)-6-(5-Cyclopropyl-3-(2-(3-fluoroazetidin-1-yl)ethyl)-6-oxopyridazin-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)-6-(3-(2-(Azetidin-1-yl)ethyl)-5-cyclopropyl-6-oxopyridazin-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)-14,24-Difluoro-6-(3-(2-(3-fluoroazetidin-1-yl)ethyl)-5-methyl-6-oxopyridazin-1(6H)- yl)-16,25-dimethyl-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)-5-methyl-6-oxopyridazin-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)-6-(5-(3-(Dimethylamino)propyl)-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)-14-Fluoro-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)-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)-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)-6-(5-(3-(Dimethylamino)propyl)-2-oxopyrazin-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)-4-methyl-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-(3-(Dimethylamino)propyl)-4-methyl-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)-24-Fluoro-6-(5-(2-(3-methoxyazetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin- 1(2H)-yl)-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-(3-(Difluoromethyl)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-(3-(Dimethylamino)-2-methylpropyl)-4-methyl-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)-14,24-Difluoro-6-(5-(2-(3-(methoxymethyl)azetidin-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)-14,24-Difluoro-16-methyl-5-oxo-6-(2-oxo-4-(trifluoromethyl)-5-(2-(3- (trifluoromethyl)azetidin-1-yl)ethyl)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-6-(5-(2-(3-methoxyazetidin-1-yl)ethyl)-2-oxo-4- (trifluoromethyl)pyridin-1(2H)-yl)-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-(3-Ethoxyazetidin-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-(3-(Dimethylamino)propyl)-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)-6-(5-(2-(Dimethylamino)ethyl)-1-methyl-2-oxo-1,2-dihydropyridin-3-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-Cyclobutyl-14,24-difluoro-6-(5-(2-(3-methoxyazetidin-1-yl)ethyl)-4-methyl-2- oxopyrimidin-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-(5-(3-(3-methoxyazetidin-1-yl)propyl)-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)-25-Chloro-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-Chloro-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-Chloro-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)-14,24-Difluoro-6-(5-(3-(3-methoxyazetidin-1-yl)propyl)-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)-24-Fluoro-6-(5-(2-(3-fluoroazetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin- 1(2H)-yl)-16-methyl-5-oxo-14,25-bis(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-6-(4-(Difluoromethyl)-5-(2-(3-methoxyazetidin-1-yl)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-(3-(Azetidin-1-yl)propyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-25-chloro- 14,24-difluoro-16-methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-6-(4-(Difluoromethyl)-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)-14,16,24-trifluoro-6-(5-(3-(3-methoxyazetidin-1-yl)propyl)-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)-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-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)-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-Difluoro-6-(5-(3-(3-fluoroazetidin-1-yl)propyl)-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)-25-(Difluoromethyl)-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-(Difluoromethyl)-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)-6-(5-(3-(Azetidin-1-yl)propyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-25- (difluoromethyl)-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-(3-(Azetidin-1-yl)propyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-14,16,24- trifluoro-25-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)-4-(difluoromethyl)-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)-14,24-Difluoro-16,25-dimethyl-6-(5-((1-methylazetidin-3-yl)methyl)-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)-14,24-Difluoro-16,25-dimethyl-6-(5-((1-methylpiperidin-4-yl)methyl)-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)-25-Chloro-6-(5-(3-(dimethylamino)-2-methylpropyl)-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-(3-(Dimethylamino)-2-methylpropyl)-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)-2-methylpropyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)- yl)-14,16,24-trifluoro-25-methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3- yl)acetic acid; 2-((3S,6S)-25-(Difluoromethyl)-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)-6-(5-(3-(Dimethylamino)-2-methylpropyl)-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)-14,16,24-Trifluoro-6-(5-(2-(3-fluoroazetidin-1-yl)ethyl)-2-oxo-4- (trifluoromethyl)pyridin-1(2H)-yl)-25-methyl-5-oxo-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-24-Fluoro-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-(3-(Dimethylamino)propyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-24- fluoro-16-methyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane- 3-yl)acetic acid; 2-((3S,6S)-25-Chloro-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)-25-Cyclopropyl-14-fluoro-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)-14,24-Difluoro-6-(5-(3-(3-fluoroazetidin-1-yl)propyl)-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)-14-Cyano-24-fluoro-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-(2-(Dimethylamino)ethyl)-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-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)-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)- 14,24-difluoro-16,9-dimethyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacycloundecaphane-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)-16,25,9-trimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphan-9-en-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)-16,25,9-trimethyl-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)-16,25,8-trimethyl-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)-3-methyl-2,4-dioxo-3,4- dihydropyrimidin-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-(Dimethylamino)ethyl)-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-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-(3-(Dimethylamino)-2-methylpropyl)-3-methyl-2,4-dioxo-3,4- dihydropyrimidin-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-16,9-dimethyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacycloundecaphane-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)- dibenzenacycloundecaphane-3-yl)acetic acid; 2-((3S,6S)-6-(5-(3-(Dimethylamino)propyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-14,16,24- trifluoro-8-methyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacycloundecaphane-3-yl)acetic acid; 2-((9S,12S)-9-(5-(2-(Dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-24-fluoro-26-methyl-10-oxo- 3-oxa-11-aza-1(1,3),2(1,2)-dibenzenacyclododecaphane-12-yl)acetic acid; 2-((11S,14S)-11-(5-(2-(Dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-24-fluoro-26-methyl-12- oxo-3-oxa-13-aza-1(1,3),2(1,2)-dibenzenacyclotetradecaphane-14-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)-16,9-dimethyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacycloundecaphane-3-yl)acetic acid; 2-((9S,12S)-9-(5-(2-(Dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-26-methyl-10-oxo-3-oxa- 11-aza-1(1,3),2(1,2)-dibenzenacyclododecaphane-12-yl)acetic acid; and 2-((11S,14S)-11-(5-(2-(Dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-26-methyl-12-oxo-3-oxa- 13-aza-1(1,3),2(1,2)-dibenzenacyclotetradecaphane-14-yl)acetic acid.

[0023] 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.

[0024] 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 a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture”.

[0025] 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 thedetermination 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 α4β7 inhibition activity.

[0026] 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.

[0027] 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 α4β7 inhibition activity.

[0028] 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 α4β7 inhibition activity.

[0029] 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.

[0030] 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 inventioncontains 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.

[0031] Accordingly, the present invention includes those compounds of the invention 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 invention 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 invention may be a synthetically-produced compound or a metabolically-produced compound.

[0032] A suitable pharmaceutically acceptable pro-drug of a compound of the invention 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.

[0033] 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.

[0034] A suitable pharmaceutically acceptable pro-drug of a compound of the invention that possesses a carboxy group is, for example, an in vivo cleavable ester thereof. An in vivo cleavable ester of a compound of the invention 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 C1-6alkylesters 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.

[0035] A suitable pharmaceutically acceptable pro-drug of a compound of the invention 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 invention 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 include aminomethyl, 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.

[0036] A suitable pharmaceutically acceptable pro-drug of a compound of the invention 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.

[0037] A suitable pharmaceutically acceptable pro-drug of a compound of the invention 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.

[0038] The in vivo effects of a compound of the invention 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 invention. As stated hereinbefore, the in vivo effects of a compound of the invention may also be exerted by way of metabolism of a precursor compound (a pro-drug).

[0039] It shall also be appreciated that compounds of the invention 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

[0040] 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 compounds of the invention, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, or deuterated analogue thereof, may be accomplished as described in the following examples.

[0041] 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.

[0042] 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.

[0043] Necessary starting materials may be obtained by standard procedures of organic chemistry. Alternatively, necessary starting materials are obtainable by analogous procedures to those illustrated which are within the ordinary skill of an organic chemist.

[0044] 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.

[0045] 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.

[0046] 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.

[0047] 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, for example, 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.

[0048] 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 the invention can be prepared by the methods given in the experimental section, or by analogous methods. Pharmaceutical Compositions

[0049] 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 the invention as defined hereinbefore, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0050] 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 theinvention. When prepared in unit dosage form, the pharmaceutical compositions of the invention typically contain from 1 mg to 1000 mg.

[0051] 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).

[0052] 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.

[0053] 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.

[0054] 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 theproduction 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.

[0055] 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.

[0056] 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).

[0057] 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).

[0058] 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.

[0059] The size of the dose for therapeutic or prophylactic purposes of a compound of the invention 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.

[0060] 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

[0061] 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).

[0062] 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.

[0063] 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

[0064] 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.

[0065] 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.

[0066] 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.

[0067] 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.

[0068] 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.

[0069] Examples of inflammatory diseases that the compounds of the invention 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.

[0070] 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.

[0071] 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.

[0072] 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.

[0073] 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.

[0074] 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.

[0075] 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

[0076] 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.

[0077] It is commonplace to use combination therapies to treat certain medical conditions.

[0078] 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.

[0079] 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.

[0080] 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.

[0081] 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.

[0082] According to a further aspect of the invention there is provided a pharmaceutical composition which comprises a compound of the invention, or a pharmaceutically acceptablesalt thereof in combination with one or more additional therapeutic agents in association with a pharmaceutically acceptable diluent or carrier.

[0083] 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.

[0084] 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

[0085] 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.

[0086] 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.

[0087] 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

[0088] 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.

[0089] A person skilled in the art will appreciate that reaction temperatures, reaction times and reagent quantities may be varied from those stated herein.

[0090] Flash chromatography carried out using Combiflash® Nextgen 300+ and automated reverse-phase chromatography carried out on Interchim Puriflash® 4100.

[0091] 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 following abbreviations are used for the multiplicity of the NMR signals: s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet, br=broad.

[0092] Where compounds described in the invention are characterized by LCMS data, retention time and molecular weight are determined using the conditions listed below. 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 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 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 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 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 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 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 30: 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 - 10% B over 1.7 min, 10 – 95% over 0.4 min, hold at 95% B for 0.4 min. Method 31: 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 - 98% B over 4.0 min, hold at 98% B for 0.8 min. Method 32: Waters Acquity I-Class Plus (Waters Acquity PDA 210 – 400 nm and Waters Acquity SQ detector). Column: X-Bridge C18, 130 Å, 5 µm, 100 x 4.6 mm (Flow 1.0 mL / min) at 40 °C. Conditions: 10 mM NH4HCO3 in water [eluent A], MeCN [eluent B]. Gradient: 10 - 95% B over 8 min, hold at 95% B for 3 min. Method 34: 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 30 mm (Flow 0.85 mL / min) at 45 °C. Conditions: Water with 0.1% formic acid [eluent A], MeCN [eluent B]. Gradient: 3 - 98% B over 1.6 min, hold at 98% B for 0.7 min. Method 35: 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 30 mm (Flow 0.85 mL / min) at 45 °C. Conditions: Water with 0.1% formic acid [eluent A], MeCN [eluent B]. Gradient: 3 - 98% B over 1.2 min, hold at 98% B for 0.4 min. Method 36: Waters Acquity I-Class Plus (Waters Acquity PDA 210 – 400 nm and Waters Acquity SQ detector). Column: X-Bridge C18, 130 Å, 3.5 µm, 50 x 4.6 mm (Flow 1.0 mL / min) at 40 °C. Conditions: 10 mM NH4HCO3 in water [eluent A], MeCN [eluent B]. Gradient: 0 - 95% B over 2 min, hold at 95% B for 2 min.

[0093] Preparative HPLC was performed using Waters 2545 Binary Gradient Module with 2998 PDA and 2767 Sample Manager, Waters SFO module. Abbreviations AcOH Acetic acid BINAP [1-(2-diphenylphosphanyl-1-naphthyl)-2-naphthyl]-diphenyl-phosphane Boc tert-Butyloxycarbonyl Co(acac)2 Cobalt (II) acetylacetonate Cs2CO3 Cesium carbonate DCE 1,2-Dichloroethane DCM Dichloromethane DIPEA N,N-Diisopropylethylamine DME 1,2-Dimethoxyethane DMF N,N-Dimethylformamide DMSO DimethylsulfoxideEDCI N-Ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride EtOAc Ethyl acetate [13-Bis(26-di-i-propylphenyl)imidazolidin-2-ylidene]2-[[1-(methoxy(methyl)amino)- GreenCat 1-oxopropan-2-yl]oxy]benzylideneruthenium(II) dichloride Benzylidene[1,3-bis(2,4,6-trimethylphenyl)-2- Grubbs II imidazolidinylidene]dichloro(tricyclohexylphosphine)ruthenium h Hour(s) 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid HATU hexafluorophosphate HBr Hydrogen bromide HCl Hydrogen chloride HOBt Hydroxybenzotriazole HPLC High Performance Liquid Chromatography IPA Isopropyl alcohol K2CO3 Potassium carbonate K3PO4 Potassium phosphate LCMS Liquid Chromatography Mass Spectrometry LDA Lithium diisopropylamide MeCN Acetonitrile MeOH Methanol MgSO4 Magnesium sulfate min Minute(s) Na2CO3 Sodium carbonate NaHCO3 Sodium bicarbonate Na2SO4 Sodium sulfate NH4HCO3 Ammonium bicarbonate NH4Cl Ammonium chloride NMR Nuclear Magnetic Resonance Pd2(dba)3 Tris(dibenzylideneacetone)dipalladium(0) Pd(dppf)Cl2 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloride Pd(dtbpf)Cl2 [1,1′-Bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) Pd(PPh3)4 Tetrakis(triphenylphosphine)palladium(0) Pd(PPh3)2Cl2 Dichlorobis(triphenylphosphine)palladium(II) RT Room temperature RuPhos 2-Dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl (2-Dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2′-amino-1,1- RuPhosPdG3 biphenyl)]palladium(II) methanesulfonate SPhos 2-Dicyclohexylphosphino-2′,6′-dimethoxybiphenyl STAB Sodium triacetoxyborohydride TBAB Tetrabutylammonium bromide TBAF Tetrabutylammonium fluoride trihydrate tBu Tertiary butyl TFA Trifluoroacetic acid THF Tetrahydrofuran Xantphos 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene Chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′- XPhosPdG2 biphenyl)]palladium(II) Synthesis of Intermediates Intermediate 1: Methyl (S)-3-((tert-butoxycarbonyl)amino)-3-(2'-chloro-4',6'-difluoro-[1,1'- biphenyl]-3-yl)propanoate

[0094] A mixture of methyl (S)-3-((tert-butoxycarbonyl)amino)-3-(3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)phenyl)propanoate (1.60 g, 3.95 mmol, CAS 2378703-25-2), 2-bromo-1- chloro-3,5-difluorobenzene (1.08 g, 4.74 mmol, CAS 1020198-58-6), potassium formate (0.33g, 3.95 mmol) and K3PO4(2.51 g, 11.8 mmol) in toluene (32 mL) and water (8 mL) was degassed with nitrogen. To this was added Pd(dtbpf)Cl2(0.13 g, 0.20 mmol) and the mixture stirred at 70 °C for 2 h. The mixture was filtered through Celite®, 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 (40 g silica gel, 0-25% EtOAc in petroleum ether) to provide the title compound (1.61 g). LCMS (Method 15): 2.35 min, 448.1 [M+Na]+. Intermediate 2: Methyl (S)-3-((tert-butoxycarbonyl)amino)-3-(2',4'-difluoro-6'-(hex-5-en-1-yl)- [1,1'-biphenyl]-3-yl)propanoate

[0095] Prepared in an analogous manner to Intermediate 1 using Intermediate 1 (1.40 g, 3.29 mmol), 5-hexenylboronic acid (0.72 g, 5.59 mmol, CAS 1072952-16-9), K2CO3 (1.63 g, 9.86 mmol), palladium acetate (74 mg, 0.33 mmol) and SPhos (0.27 g, 0.66 mmol) in toluene (37 mL) and water (9 mL) at 90 °C for 1.5 h. Purified by flash chromatography (40 g silica gel, 0-30% EtOAc in petroleum ether) to provide the title compound (1.54 g). LCMS (Method 15): 2.69 min, 374.3 [M-Boc+H]+. Intermediate 3: Methyl (S)-3-amino-3-(2',4'-difluoro-6'-(hex-5-en-1-yl)-[1,1'-biphenyl]-3- yl)propanoate hydrochloride

[0096] A suspension of Intermediate 2 (1.54 g, 2.99 mmol) in 4 M HCl in 1,4-dioxane (7.5 mL) was stirred at RT for 1 h. The mixture was concentrated under reduced pressure to provide the title compound (1.36 g). LCMS (Method 15): 2.41 min, 374.1 [M+H]+. Intermediate 4: Methyl (S)-3-(2',4'-difluoro-6'-(hex-5-en-1-yl)-[1,1'-biphenyl]-3-yl)-3-((R)-2- hydroxypent-4-enamido)propanoate

[0097] To a solution of Intermediate 3 (1.36 g, 2.72 mmol) and (2R)-2-hydroxypent-4-enoic acid (0.51 g, 4.16 mmol, CAS 413622-10-3) in MeCN (15 mL) was added DIPEA (1.45 mL, 8.16 mmol), HOBt (0.37 g, 2.72 mmol) and EDCI (0.62 g, 3.26 mmol) and the mixture was stirred at RT for 16 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 (40 g silica gel, 0-100% EtOAc in petroleum ether) to provide the title compound (0.98 g). LCMS (Method 11): 2.41 min, 472.1 [M+H]+. Intermediate 5: Methyl (S)-3-(2',4'-difluoro-6'-(hex-5-en-1-yl)-[1,1'-biphenyl]-3-yl)-3-((R)-2- ((methylsulfonyl)oxy)pent-4-enamido)propanoate

[0098] To a solution of Intermediate 4 (0.13 g, 0.26 mmol) and triethylamine (73 µL, 0.52 mmol) in DCM (2.6 mL) was added methanesulfonyl chloride (30 µL, 0.39 mmol) and themixture 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 (0.14 g). LCMS (Method 15): 2.53 min, 550.2 [M+H]+. Intermediate 6: Methyl (S)-3-(2',4'-difluoro-6'-(hex-5-en-1-yl)-[1,1'-biphenyl]-3-yl)-3-((S)-2-(5- (2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)pent-4-

[0099] To a solution of Intermediate 5 (0.43 g, 0.73 mmol) and 5-(2- (dimethylamino)ethyl)pyridin-2(1H)-one (0.13 g, 0.80 mmol, CAS 2378704-50-6) in MeCN (7.3 mL) was added K2CO3 (0.30 g, 2.19 mmol) and the mixture stirred at 85 °C for 16 h. The mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered and the filtrate concentrated under reduced pressure. The crude product was purified by flash chromatography (24 g silica gel, 0-10% (0.5% ammonia MeOH) in DCM) to provide the title compound (0.21 g). LCMS (Method 15): 2.53 min, 620.3 [M+H]+. Intermediate 7: Methyl 2-((3S,6S)-6-(5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)- 14,16-difluoro-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphan-8-en-3-yl)acetate

[0100] To a solution of Intermediate 6 (0.28 g, 0.45 mmol) in DCE (0.23 L) with bubbling nitrogen through, was added Grubbs II (38 mg, 0.05 mmol) and the mixture was stirred at 50 °C for 3 h. The mixture was cooled and concentrated under reduced pressure. The crude product was purified by flash chromatography (25 g silica gel, 0-10% (0.5% ammonia MeOH) in DCM) to provide the title compound (0.23 g). LCMS (Method 15): 2.33 min, 592.2 [M+H]+. Intermediate 8: Methyl 2-((3S,6S)-6-(5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)- 14,16-difluoro-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3-yl)acetate

[0101] A solution of Intermediate 7 (0.23 g, 0.31 mmol) in MeOH (6 mL) was added 10% palladium on carbon (33 mg) and the mixture was stirred under a hydrogen atmosphere at RT for 5 h. The mixture was filtered through Celite®, washed with MeOH, and concentrated under reduced pressure. The crude product was purified by flash chromatography (25 g silica gel, 0-10% (0.5% ammonia MeOH) in DCM) to provide the title compound (0.20 g). LCMS (Method 15): 2.41 min, 594.3 [M+H]+. Intermediate 9: Methyl (S)-3-((tert-butoxycarbonyl)amino)-3-(4'-fluoro-2'-hydroxy-6'-methyl- [1,1'-biphenyl]-3-yl)propanoate

[0102] Prepared in an analogous manner to Intermediate 1 using methyl (S)-3-((tert- butoxycarbonyl)amino)-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate (1.60 g, 3.95 mmol, CAS 2378703-25-2), 2-bromo-5-fluoro-3-methylphenol (0.41 g, 1.68mmol, 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, 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 10: Methyl (S)-3-((tert-butoxycarbonyl)amino)-3-(4'-fluoro-2'-methyl-6'- (((trifluoromethyl)sulfonyl)oxy)-[1,1'-biphenyl]-3-yl)propanoate

[0103] To a solution of Intermediate 9 (4.12 g, 9.50 mmol) in DCM (81 mL) was added phenyl triflimide (3.39 g, 9.50 mmol, CAS 37595-74-7) and Cs2CO3 (3.71 g, 11.4 mmol) then the mixture was stirred at RT for 16 h. The mixture was diluted with water and extracted into DCM. The organic layer was washed with water, brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (40 g silica gel, 0-20% EtOAc in petroleum ether) to provide the title compound (5.4 g). LCMS (Method 15): 2.48 min, 436.0 [M-Boc+H]+. Intermediate 11: Methyl (S)-3-((tert-butoxycarbonyl)amino)-3-(4'-fluoro-2'-(hex-5-en-1-yl)-6'- methyl-[1,1'-biphenyl]-3-yl)propanoate

[0104] Prepared in an analogous manner to Intermediate 1 using Intermediate 10 (5.2 g, 9.13 mmol), 5-hexenylboronic acid (1.75 g, 13.7 mmol, CAS 1072952-16-9), K2CO3 (3.79 g, 27.4 mmol), palladium acetate (0.20 g, 0.91 mmol) and RuPhos (0.64 g, 1.37 mmol) in toluene (0.13 L) and water (33 mL) at 90 °C for 1.5 h. Purified by flash chromatography (80 g silica gel, 0-30% EtOAc in petroleum ether) to provide the title compound (4.12 g). LCMS (Method 15): 2.77 min, 370.1 [M-Boc+H]+. Intermediate 12: Methyl (S)-3-amino-3-(4'-fluoro-2'-(hex-5-en-1-yl)-6'-methyl-[1,1'-biphenyl]- 3-yl)propanoate hydrochloride

[0105] A suspension of Intermediate 11 (4.12 g, 8.51 mmol) in 4 M HCl in 1,4-dioxane (21 mL) was stirred at RT for 1 h. The mixture was concentrated under reduced pressure to provide the title compound (3.69 g). LCMS (Method 15): 2.47 min, 370.1 [M+H]+. Intermediate 13: Methyl (S)-3-(4'-fluoro-2'-(hex-5-en-1-yl)-6'-methyl-[1,1'-biphenyl]-3-yl)-3- ((R)-2-hydroxypent-4-enamido)propanoate

[0106] Prepared in an analogous manner to Intermediate 4 using Intermediate 12 (3.69 g, 8.36 mmol), (2R)-2-hydroxypent-4-enoic acid (1.56 g, 12.8 mmol, CAS 413622-10-3), DIPEA (4.47 mL, 25.1 mmol), HOBt (1.13 g, 8.35 mmol) and EDCI (1.92 g, 10.0 mmol) in MeCN (15 mL) at RT for 16 h. Purified by flash chromatography (40 g silica gel, 0-100% EtOAc in petroleum ether) to provide the title compound (3.31 g). LCMS (Method 11): 2.50 min, 468.2 [M+H]+.Intermediate 14: Methyl (S)-3-(4'-fluoro-2'-(hex-5-en-1-yl)-6'-methyl-[1,1'-biphenyl]-3-yl)-3- ((R)-2-((methylsulfonyl)oxy)pent-4-enamido)propanoate

[0107] Prepared in an analogous manner to Intermediate 5 using Intermediate 13 (2.0 g, 3.85 mmol), triethylamine (1.07 mL, 7.70 mmol) and methanesulfonyl chloride (0.44 mL, 5.77 mmol) in DCM (39 mL) at RT for 1 h, to provide the title compound (2.52 g). LCMS (Method 15): 2.59 min, 546.2 [M+H]+. Intermediate 15: Methyl (S)-3-((S)-2-(5-bromo-2-oxopyridin-1(2H)-yl)pent-4-enamido)-3-(4'- fluoro-2'-(hex-5-en-1-yl)-6'-methyl-[1,1'-biphenyl]-3-yl)propanoate

[0108] Prepared in an analogous manner to Intermediate 6 using Intermediate 14 (1.68 g, 3.08 mmol), 5-bromo-1H-pyridin-2-one (0.59 g, 3.39 mmol, CAS 13466-38-1) and K2CO3 (1.28 g, 9.24 mmol) in MeCN (31 mL) at reflux for 16 h. Purified by flash chromatography (40 g silica gel, 0-100% EtOAc in petroleum ether) to provide the title compound (0.51 g). LCMS (Method 15): 2.72 min, 625.1 [M+H]+. Intermediate 16: Methyl 2-((3S,6S)-6-(5-bromo-2-oxopyridin-1(2H)-yl)-14-fluoro-16-methyl-5- oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphan-8-en-3-yl)acetate

[0109] Prepared in an analogous manner to Intermediate 7 using Intermediate 15 (0.51 g, 0.82 mmol) and Grubbs II (69 mg, 0.08 mmol) in DCE (0.42 L) at 50 °C for 1.5 h. Purified by flash chromatography (24 g silica gel, 0-100% EtOAc in petroleum ether) to provide the title compound (0.43 g). LCMS (Method 11): 2.58 min, 597.1 [M+H]+. Intermediate 17: Methyl 2-((3S,6S)-6-(5-(3-(dimethylamino)prop-1-yn-1-yl)-2-oxopyridin- 1(2H)-yl)-14-fluoro-16-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphan-8-en-3- yl)acetate

[0110] A mixture of Intermediate 16 (0.13 g, 0.19 mmol), Pd(PPh3)2Cl2 (9.2 mg, 13 µmol) and copper(I) iodide (2.5 mg, 13 µmol) in MeCN (3.8 mL) was degassed with nitrogen. Triethylamine (0.18 mL, 1.31 mmol) and N,N-dimethylpropargylamine (0.14 mL, 1.31 mmol) were added and the mixture stirred at 80 °C for 16 h. The mixture was filtered and concentrated under reduced pressure. The crude was purified by flash chromatography (25 g silica gel, 0- 5% (0.5% ammonia MeOH) in DCM) and catch and release chromatography (5 g SCX, MeOH followed by 1 M ammonia in MeOH) to provide the title compound (56 mg). LCMS (Method 15): 2.50 min, 598.3 [M+H]+. Intermediate 18: Methyl 2-((3S,6S)-6-(5-(3-(dimethylamino)propyl)-2-oxopyridin-1(2H)-yl)-14- fluoro-16-methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3-yl)acetate

[0111] Prepared in an analogous manner to Intermediate 8 using Intermediate 17 (89 mg, 0.15 mmol) and 10% palladium on carbon (16 mg) in MeOH (3 mL) under a hydrogenatmosphere at RT for 3 h. Purified by catch and release chromatography (5 g SCX, MeOH followed by 1 M ammonia in MeOH) to provide the title compound (65 mg). LCMS (Method 15): 2.59 min, 604.4 [M+H]+. Intermediate 19: Ethyl (S)-3-amino-3-(5-bromo-2-fluoro-3- (trifluoromethyl)phenyl)propanoate

[0112] A suspension of ethyl (S)-3-(5-bromo-2-fluoro-3-(trifluoromethyl)phenyl)-3- (((R)-tert-butylsulfinyl)amino)propanoate (24.4 g, 52.7 mmol, CAS 2640364-18-5) in 4 M HCl in 1,4-dioxane (33 mL) was stirred at RT for 2 h. The mixture was concentrated under reduced pressure, dissolved in saturated aqueous NaHCO3 and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to provide the title compound (15.0 g). LCMS (Method 22): 1.56 min, 359.9 [M+H]+. Intermediate 20: Ethyl (S)-3-(5-bromo-2-fluoro-3-(trifluoromethyl)phenyl)-3-((tert- butoxycarbonyl)amino)propanoate

[0113] To a stirred suspension of Intermediate 19 (14.1 g, 35.4 mmol) and Boc anhydride (9.28 g, 42.5 mmol) in DCM (0.18 L) was added DIPEA (9.26 mL, 53.2 mmol) and the mixture stirred at RT for 72 h. The mixture was diluted with DCM and washed with 1 M aqueous HCl, brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was triturated in petroleum ether and filtered to provide the title compound (12.7 g). LCMS (Method 22): 1.86 min, 357.9 [M-Boc+H]+. Intermediate 21: Ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(2'-chloro-4,4',6'-trifluoro-5- (trifluoromethyl)-[1,1'-biphenyl]-3-yl)propanoate

[0114] A solution of 2-bromo-1-chloro-3,5-difluorobenzene (7.86 g, 34.6 mmol, CAS 1020198-58-6), bis(pinacolato)diboron (9.66 g, 38.0 mmol) and potassium acetate (7.63 g, 77.8 mmol) in toluene (95 mL) was degassed with nitrogen. Pd(dppf)Cl2 (0.51 g, 0.69 mmol) was added and the mixture stirred at 110 °C for 9 h. The mixture was cooled, filtered through Celite® and concentrated under reduced pressure. The residue was dissolved in toluene (92 mL) then a degassed with nitrogen. Intermediate 20 (8.25 g, 17.3 mmol), a solution of K3PO4 (12.8 g, 60.5 mmol) in water (24 mL) and XPhosPdG2 (0.68 g, 0.86 mmol) were added and the mixture was stirred at 110 °C for 3 h. The mixture was cooled and filtered through Celite®, washing with EtOAc and water. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (120 g silica gel, 0-10% EtOAc in petroleum ether) to provide the title compound (6.30 g). LCMS (Method 15): 2.63 min, 426.0 [M-Boc+H]+.Intermediate 22: Ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(2',4,4'-trifluoro-6'-(hex-5-en-1- yl)-5-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)propanoate

[0115] an analogous manner to Intermediate 1 using Intermediate 21 (6.30 g, 8.39 mmol), 5-hexenylboronic acid (1.82 g, 14.3 mmol, CAS 1072952-16-9), K2CO3(3.38 g, 25.2 mmol), palladium acetate (0.19 g, 0.84 mmol) and SPhos (0.69 g, 1.68 mmol) in toluene (0.11 L) and water (28 mL) at 90 °C for 3 h. Purified by flash chromatography (120 g silica gel, 0-10% EtOAc in petroleum ether) to provide the title compound (5.10 g). LCMS (Method 15): 2.88 min, 474.1 [M-Boc+H]+. Intermediate 23: Ethyl (S)-3-amino-3-(2',4,4'-trifluoro-6'-(hex-5-en-1-yl)-5-(trifluoromethyl)- [1,1'-biphenyl]-3-yl)propanoate hydrochloride

[0116] A suspension of Intermediate 22 (5.10 g, 7.11 mmol) in 4 M HCl in 1,4-dioxane (12 mL) was stirred at RT for 3.5 h. The mixture was concentrated under reduced pressure to provide the title compound (6.40 g). LCMS (Method 15): 2.70 min, 474.1 [M+H]+. Intermediate 24: Ethyl (S)-3-((R)-2-hydroxypent-4-enamido)-3-(2',4,4'-trifluoro-6'-(hex-5-en- 1-yl)-5-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)propanoate

[0117] Preparedanalogous manner to Intermediate 4 using Intermediate 23 (6.40 g, 7.28 mmol), (2R)-2-hydroxypent-4-enoic acid (1.35 g, 11.6 mmol, CAS 413622-10-3), DIPEA (3.80 mL, 21.8 mmol), HOBt (1.08 g, 8.01 mmol) and EDCI (1.70 g, 10.9 mmol) in MeCN (63 mL) at RT for 20 h. Purified by flash chromatography (120 g silica gel, 0-50% EtOAc in petroleum ether) to provide the title compound (3.60 g). LCMS (Method 15): 2.63 min, 572.2 [M+H]+. Intermediate 25: Ethyl (S)-3-((R)-2-((methylsulfonyl)oxy)pent-4-enamido)-3-(2',4,4'-trifluoro- 6'-(hex-5-en-1-yl)-5-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)propanoate

[0118] Prepared in anmanner to Intermediate 5 using Intermediate 24 (1.58 g, 2.76 mmol), triethylamine (0.77 mL, 5.53 mmol) and methanesulfonyl chloride (0.32 mL, 4.15 mmol) in DCM (30 mL) at RT for 4 h, to provide the title compound (2.60 g). LCMS (Method 15): 2.69 min, 650.2 [M+H]+. Intermediate 26: Ethyl (S)-3-((S)-2-(5-bromo-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)pent- 4-enamido)-3-(2',4,4'-trifluoro-6'-(hex-5-en-1-yl)-5-(trifluoromethyl)-[1,1'-biphenyl]-3- yl)propanoate

[0119] Prepared in an analogous manner to Intermediate 6 using Intermediate 25 (2.60 g, 3.08 mmol), 5-bromo-4-(trifluoromethyl)pyridin-2-ol (0.75 g, 3.08 mmol, CAS 109919- 32-6) and K2CO3(1.16 g, 8.41 mmol) in MeCN (32 mL) at reflux for 17 h. Additional 5-bromo- 4-(trifluoromethyl)pyridin-2-ol (75 mg, 0.31 mmol) and K2CO3(0.12 g, 0.84 mmol) were addedand heating continued for 3 h. Purified by flash chromatography (120 g silica gel, 0-20% EtOAc in petroleum ether) to provide the title compound (0.68 g). LCMS (Method 15): 2.87 min, 795.2 [M+H]+. Intermediate 27: Ethyl 2-((3S,6S)-6-(5-bromo-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)- 14,16,24-trifluoro-5-oxo-25--4-aza-1(1,2),2(1,3)-8- en-3-yl)acetate

[0120] Prepared in an analogous manner to Intermediate 7 using Intermediate 26 (0.67 g, 0.79 mmol) and Grubbs II (67 mg, 0.08 mmol) in DCE (0.46 L) at 50 °C for 2 h. Purified by flash chromatography (25 g silica gel, 0-30% EtOAc in petroleum ether) to provide the title compound (0.53 g). LCMS (Method 15): 2.80 min, 769.1 [M+H]+. Intermediate 28: Ethyl 2-((3S,6S)-6-(5-bromo-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)acetate

[0121] Prepared in an analogous manner to Intermediate 8 using Intermediate 27 (0.43 g, 0.47 mmol) and 10% palladium on carbon (50 mg) in EtOAc (47 mL) under a hydrogen atmosphere at RT for 2 h. Purified by flash chromatography (12 g silica gel, 0-30% EtOAc in petroleum ether) to provide the title compound (0.33 g). LCMS (Method 27): 2.58 min, 771.0 [M+H]+. Intermediate 29: Ethyl 2-((3S,6S)-6-(5-((E)-2-ethoxyvinyl)-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)acetate

[0122] A mixture of Intermediate 28 (0.33 g, 0.39 mmol), trans-2-ethoxyvinylboronic acid pinacol ester (85 mg, 0.43 mmol, CAS 1201905-61-4) and Na2CO3 (82 mg, 0.77 mmol) in 1,4-dioxane (13 mL) and water (4 mL) was degassed with nitrogen. To this was added Pd(dppf)Cl2 (28 mg, 0.04 mmol) and the mixture stirred at 90 °C for 1 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 (25 g silica gel, 0-30% EtOAc in petroleum ether) to provide the title compound (0.23 g). LCMS (Method 15): 2.86 min, 761.3 [M+H]+. Intermediate 30: Ethyl 2-((3S,6S)-14,16,24-trifluoro-5-oxo-6-(2-oxo-5-(2-oxoethyl)-4- (trifluoromethyl)pyridin-1(2H)-yl)-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetate

[0123] A solution of Intermediate 29 (0.16 g, 0.21 mmol) in DCM (4.2 mL) and TFA (0.45 mL) was stirred at RT for 3 h. The mixture was concentrated under reduced pressure to provide the title compound (0.16 g). LCMS (Method 22): 2.66 min, 733.2 [M+H]+. Intermediate 31: Ethyl 2-((3S,6S)-6-(5-(2-(azetidin-1-yl)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)acetate

[0124] A solution of Intermediate 30 (0.16 g, 84 µmol) and azetidine (7 µL, 0.10 mmol) in DCM (1.0 mL) was stirred at RT for 1 h. STAB (35 mg, 0.17 mmol) was added and the mixture stirred at RT for 20 h. The mixture was concentrated under reduced pressure and the crude product was purified by catch and release chromatography (10 g SCX, MeOH followed by 1 M ammonia in MeOH) to provide the title compound (49 mg). LCMS (Method 15): 2.82 min, 774.3 [M+H]+. Intermediate 32: Ethyl 2-((3S,6S)-14,16,24-trifluoro-6-(5-(2-(3-methoxyazetidin-1-yl)ethyl)-2- oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetate

[0125] Prepared in an analogous manner to Intermediate 31 using Intermediate 30 (0.14 g, 70 µmol), 3-methoxyazetidine hydrochloride (10 mg, 80 µmol, CAS 148644-09-1) and triethylamine (39 µL, 0.28 mmol) in DCM (0.7 mL) at RT for 1 h, followed by STAB (30 mg, 0.14 mmol) at RT for 18 h. Purified by catch and release chromatography (10 g SCX, MeOH followed by 1 M ammonia in MeOH) to provide the title compound (44 mg). LCMS (Method 27): 2.82 min, 804.3 [M+H]+. Intermediate 33: 2-Fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3- (trifluoromethyl)benzaldehyde

[0126] A solution of 5-bromo-2-fluoro-3-(trifluoromethyl)benzaldehyde (6.0 g, 22.1 mmol, CAS 1291487-26-7) and bis(pinacolato)diboron (6.75 g, 26.6 mmol) in 1,4-dioxane (90 mL) was degassed with nitrogen. To the solution was then added potassium acetate (4.35 g, 44.3 mmol) and Pd(dppf)Cl2 (0.90 g, 1.11 mmol) then the mixture was stirred at 95 °C for 20 h. The mixture was cooled and filtered through Celite®, washing with EtOAc and water. The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, DCM) to provide the title compound (7.0 g).1H NMR (400 MHz; CDCl3) δ: 10.40 (s, 1H), 8.50 (d, 1H), 8.27 (d, 1H), 1.35 (s, 12H). Intermediate 34: 4,4'-Difluoro-2'-hydroxy-6'-methyl-5-(trifluoromethyl)-[1,1'-biphenyl]-3- carbaldehyde

[0127] Prepared in an analogous manner to Intermediate 1 using Intermediate 33 (1.20 g, 3.77 mmol), 2-bromo-5-fluoro-3-methylphenol (0.70 g, 3.42 mmol, CAS 1807192-21- 7), K3PO4(1.45 g, 6.85 mmol), palladium acetate (77 mg, 0.34 mmol) and tricyclohexyl phosphine (96 mg, 0.34 mmol) in toluene (9 mL) and water (4.6 mL) at 85 °C for 3 h. Additional palladium acetate (77 mg, 0.34 mmol) and tricyclohexyl phosphine (96 mg, 0.34 mmol) were added and heating continued at 85 °C for 18 h. Purified by flash chromatography (40 g silica gel, 0-10% MeOH in DCM) to provide the title compound (0.45 g).1H NMR (400 MHz; CDCl3) δ: 10.26 (s, 1H), 7.87 – 7.80 (m, 1H), 7.70 – 7.63 (m, 1H), 6.33 (d, 1H), 6.25 – 6.20 (m, 1H), 2.14 (s, 3H) – OH not observed. Intermediate 35: 4,4'-Difluoro-3'-formyl-6-methyl-5'-(trifluoromethyl)-[1,1'-biphenyl]-2-yl trifluoromethanesulfonate

[0128] Prepared in an analogous manner to Intermediate 10 using Intermediate 34 (2.11 g, 6.67 mmol), phenyl triflimide (2.38 g, 6.67 mmol, CAS 37595-74-7) and Cs2CO3 (2.61 g, 8.01 mmol) in DCM (40 mL) at RT for 2 h. Purified by flash chromatography (25 g silica gel, 20–80% EtOAc in petroleum ether) to provide the title compound (2.09 g).1H NMR (400 MHz; CDCl3) δ: 10.45 (s, 1H), 7.96 (dd, 1H), 7.75 (dd, 1H), 7.11 (dd, 1H), 7.03 (dd, 1H), 2.17 (s, 3H). Intermediate 36: 4,4'-Difluoro-2'-(hex-5-en-1-yl)-6'-methyl-5-(trifluoromethyl)-[1,1'-biphenyl]- 3-carbaldehyde

[0129] Prepared in an analogous manner to Intermediate 1 using Intermediate 35 (2.09 g, 4.65 mmol), 5-hexenylboronic acid (0.89 g, 6.98 mmol, CAS 1072952-16-9), K2CO3 (1.93 g, 14.0 mmol), palladium acetate (0.10 g, 0.47 mmol) and RuPhos (0.33 g, 0.70 mmol) in toluene (42 mL) and water (5 mL) at 100 °C for 2 h. Purified by flash chromatography (40 g silica gel, 0-60% EtOAc in petroleum ether) to provide the title compound (1.38 g).1H NMR (400 MHz; CDCl3) δ: 10.46 (s, 1H), 7.85 (dd, 1H), 7.64 (dd, 1H), 6.84 (d, 2H), 5.73 – 5.62 (m, 1H), 4.95 – 4.87 (m, 2H), 2.27 – 2.22 (m, 2H), 1.97 (s, 3H), 1.91 (q, 2H), 1.43 – 1.37 (m, 2H), 1.27 – 1.23 (m, 2H). Intermediate 37: (R,Z)-N-((4,4'-Difluoro-2'-(hex-5-en-1-yl)-6'-methyl-5-(trifluoromethyl)-[1,1'- biphenyl]-3-yl)methylene)-2-methylpropane-2-sulfinamide

[0130] To a solution of Intermediate 36 (1.37 g, 3.59 mmol) in THF (24 mL) was added (R)-2-methylpropane-2-sulfinamide (0.48 g, 3.94 mmol, CAS 196929-78-9) and titanium ethoxide (1.23 g, 5.38 mol) then the mixture was stirred at 40 °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, to provide the title compound (1.57 g).1H NMR (400 MHz; CDCl3) δ: 8.96 (s, 1H), 7.98 – 7.93 (m, 1H), 7.53 (dd, 1H), 6.85 (dd, 2H), 5.73 –5.61 (m, 1H), 4.95 – 4.83 (m, 2H), 2.32 – 2.24 (m, 2H), 2.01 (s, 3H), 1.95 – 1.88 (m, 2H), 1.44 – 1.39 (m, 2H), 1.28 – 1.25 (m, 11H). Intermediate 38: Ethyl (S)-3-(((R)-tert-butylsulfinyl)amino)-3-(4,4'-difluoro-2'-(hex-5-en-1-yl)- 6'-methyl-5-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)propanoate

[0131] To a suspension of zinc (1.06 g, 16.1 mmol) in THF (12 mL) was added chlorotrimethylsilane (82 µL, 0.65 mmol) and stirred at 60 °C for 1 h. The mixture was cooled to RT then ethyl bromoacetate (0.90 mL, 8.07 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 37 (1.57 g, 3.22 mmol) in THF (12 mL) was added then the mixture was stirred at RT 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. Purified by flash chromatography (40 g silica gel, 0-80% EtOAc in petroleum ether) to provide the title compound (1.01 g). LCMS (Method 15): 2.82 min, 574.2 [M+H]+. Intermediate 39: Ethyl (S)-3-amino-3-(4,4'-difluoro-2'-(hex-5-en-1-yl)-6'-methyl-5- (trifluoromethyl)-[1,1'-biphenyl]-3-yl)propanoate

[0132] A suspension of Intermediate 38 (1.01 g, 1.76 mmol) in 4 M HCl in 1,4-dioxane (8.8 mL) was stirred at RT for 1 h. The mixture was concentrated under reduced pressure and purified by catch and release chromatography (5 g SCX, MeOH followed by 3.5 M ammonia in MeOH) to provide the title compound (0.83 g). LCMS (Method 15): 2.72 min, 470.2 [M+H]+. Intermediate 40: Ethyl (S)-3-(4,4'-difluoro-2'-(hex-5-en-1-yl)-6'-methyl-5-(trifluoromethyl)- [1,1'-biphenyl]-3-yl)-3-((R)-2-hydroxypent-4-enamido)propanoate Prepared in an analogous manner to Intermediate 4 using Intermediate 39 (0.83 g, 1.76 mmol), (2R)-2-hydroxypent-4-enoic acid (0.31 g, 2.64 mmol, CAS 413622-10-3), DIPEA (0.92 mL, 5.28 mmol), HOBt (0.26 g, 1.94 mmol) and EDCI (0.41 g, 2.64 mmol) in MeCN (24 mL) at RT for 18 h. Purified by flash chromatography (12 g silica gel, 0-100% EtOAc in petroleum ether) to provide the title compound (0.41 g). LCMS (Method 7): 2.68 min, 568.2 [M+H]+. Intermediate 41: Ethyl (S)-3-(4,4'-difluoro-2'-(hex-5-en-1-yl)-6'-methyl-5-(trifluoromethyl)- [1,1'-biphenyl]-3-yl)-3-((R)-2-((methylsulfonyl)oxy)pent-4-enamido)propanoate Prepared in an analogous manner to Intermediate 5 using Intermediate 40 (0.41 g, 0.72 mmol), triethylamine (0.20 mL, 1.44 mmol) and methanesulfonyl chloride (83 µL, 1.08 mmol) in DCM (8 mL) at 0 °C for 1 h, to provide the title compound (0.51 g). LCMS (Method 15): 2.73 min, 646.1 [M+H]+.Intermediate 42: Ethyl (S)-3-((S)-2-(5-bromo-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)pent- 4-enamido)-3-(4,4'-difluoro-2'-(hex-5-en-1-yl)-6'-methyl-5-(trifluoromethyl)-[1,1'-biphenyl]-3- yl)propanoate

[0135] Prepared in an analogous manner to Intermediate 6 using Intermediate 41 (1.75 g, 2.70 mmol), 5-bromo-4-(trifluoromethyl)pyridin-2-ol (0.72 g, 2.97 mmol, CAS 109919- 32-6) and K2CO3(1.12 g, 8.11 mmol) in MeCN (35 mL) at reflux for 16 h. Purified by flash chromatography (40 g silica gel, 0-60% EtOAc in petroleum ether) to provide the title compound (1.03 g). LCMS (Method 15): 2.88 min, 793.1 [M+H]+. Intermediate 43: Ethyl 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)- dibenzenacyclotridecaphan-8-en-3-yl)acetate

[0136] Prepared in an analogous manner to Intermediate 7 using Intermediate 42 (1.03 g, 1.30 mmol) and Grubbs II (0.11 g, 0.13 mmol) in DCE (0.64 L) at 50 °C for 1 h. Purified by flash chromatography (24 g silica gel, 0-40% EtOAc in petroleum ether) to provide the title compound (0.78 g). LCMS (Method 15): 2.83 min, 765.1 [M+H]+. Intermediate 44: Ethyl 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)acetate

[0137] Prepared in an analogous manner to Intermediate 8 using Intermediate 43 (0.22 g, 0.28 mmol) and 10% palladium on carbon (32 mg) in EtOAc (15 mL) under a hydrogen atmosphere at RT for 1.5 h. Purified by flash chromatography (25 g silica gel, 0-50% EtOAc in petroleum ether) to provide the title compound (0.23 g). LCMS (Method 19): 5.93 min, 765.3 [M+H]+. Intermediate 45: Ethyl 2-((3S,6S)-6-(5-((E)-2-ethoxyvinyl)-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)acetate

[0138] Prepared in an analogous manner to Intermediate 29 using Intermediate 44 (0.23 g, 0.30 mmol), trans-2-ethoxyvinylboronic acid pinacol ester (62 mg, 0.31 mmol, CAS 1201905-61-4), Pd(dppf)Cl2(25 mg, 0.03 mmol) and Na2CO3(64 mg, 0.60 mmol) in 1,4- dioxane (3 mL) and water (1 mL) at 90 °C for 3 h. Purified by flash chromatography (12 g silica gel, 0-50% EtOAc in petroleum ether) to provide the title compound (0.13 g). LCMS (Method 19): 5.98 min, 755.6 [M-H]-.Intermediate 46: Ethyl 2-((3S,6S)-14,24-difluoro-6-(5-(2-(3-fluoro-3-methylazetidin-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)acetate

[0139] A solution of Intermediate 45 (0.10 g, 0.12 mmol) in DCM (6 mL) and TFA (0.20 mL) was stirred at RT for 1.5 h. The mixture was concentrated under reduced pressure then dissolved in DCM (6 mL).3-Fluoro-3-methyl-azetidine hydrochloride (26 mg, 0.30 mmol, CAS 1427379-42-7), triethylamine (75 µL, 0.56 mmol) and 4 Å molecular sieves were added and stirred at RT for 15 min. STAB (25 mg, 0.36 mmol) was added and stirred at RT for 25 h. The mixture was filtered and concentrated under reduced pressure. The crude product was purified by catch and release chromatography (10 g SCX, MeOH followed by 3.5 M ammonia in MeOH) to provide the title compound (36 mg). LCMS (Method 21): 6.02 min, 802.3 [M+H]+. Intermediate 47: Methyl 2-((3S,6S)-6-(5-((E)-2-ethoxyvinyl)-2-oxopyridin-1(2H)-yl)-14-fluoro- 16-methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphan-8-en-3-yl)acetate

[0140] Prepared in an analogous manner to Intermediate 29 using Intermediate 16 (0.20 g, 0.29 mmol), trans-2-ethoxyvinylboronic acid pinacol ester (60 mg, 0.30 mmol, CAS 1201905-61-4), Pd(dppf)Cl2 (21 mg, 0.03 mmol) and Na2CO3 (61 mg, 0.58 mmol) in 1,4- dioxane (6 mL) and water (1.5 mL) at 90 °C for 16 h. Purified by flash chromatography (12 g silica gel, 20-100% EtOAc in petroleum ether) to provide the title compound (50 mg). LCMS (Method 15): 2.58 min, 587.3 [M+H]+. Intermediate 48: Methyl 2-((3S,6S)-6-(5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-14- fluoro-16-methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphan-8-en-3-yl)acetate

[0141] Prepared in an analogous manner to Intermediate 46 using Intermediate 47 (67 mg, 85 µmol), in DCM (2 mL) and TFA (0.26 mL) at RT for 3 h. Then dimethylamine (2 M in THF, 51 µL, 0.10 mmol), triethylamine (36 µL, 0.26 mmol) in DCM (2 mL) with 4 Å molecular sieves at RT for 1 h, followed by STAB (90 mg, 0.43 mmol) at RT for 16 h. Purified by catch and release chromatography (10 g SCX, MeOH followed by 3.5 M ammonia in MeOH) to provide the title compound (33 mg). LCMS (Method 22): 2.45 min, 588.3 [M+H]+. Intermediate 49: Methyl 2-((3S,6S)-6-(5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-14- fluoro-16-methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3-yl)acetate

[0142] Prepared in an analogous manner to Intermediate 8 using Intermediate 48 (33 mg, 51 µmol) and 10% palladium on carbon (5.4 mg) in MeOH (2 mL) under a hydrogen atmosphere at RT for 1.5 h. Purified by catch and release chromatography (10 g SCX, MeOH followed by 3.5 M ammonia in MeOH) to provide the title compound (24 mg). LCMS (Method 15): 2.49 min, 590.3 [M+H]+.Intermediate 50: 6-Chloro-5-(trifluoromethyl)pyridazin-3(2H)-one

[0143] To a solution of 3,6-dichloro-4-(trifluoromethyl)pyridazine (0.85 g, 3.92 mmol, CAS 1057672-68-0) in 1,4-dioxane (5 mL) and water (4.5 mL) was added sodium hydroxide (0.17 g, 4.31 mmol) and the mixture was stirred at 40 °C for 1 h. The mixture was acidified with 2 M aqueous HCl and extracted into EtOAc. The organic layer was washed with water, brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (40 g silica gel, 0–4% MeOH in DCM) to provide the title compound (0.61 g).1H NMR (400 MHz; DMSO-d6) δ: 13.83 (br s, 1H), 8.06 (s, 1H). Intermediate 51: Ethyl (S)-3-((S)-2-(3-chloro-6-oxo-4-(trifluoromethyl)pyridazin-1(6H)- yl)pent-4-enamido)-3-(2',4,4'-trifluoro-6'-(hex-5-en-1-yl)-5-(trifluoromethyl)-[1,1'-biphenyl]-3- yl)propanoate

[0144] Prepared in an analogous manner to Intermediate 6 using Intermediate 25 (0.58 g, 0.90 mmol), Intermediate 50 (0.18 g, 0.90 mmol) and K2CO3 (0.29 g, 2.07 mmol) in MeCN (10 mL) at reflux for 18 h. Purified by flash chromatography (12 g silica gel, 0-40% EtOAc in petroleum ether) to provide the title compound (0.24 g). LCMS (Method 15): 2.88 min, 752.2 [M+H]+. Intermediate 52: Ethyl 2-((3S,6S)-6-(3-chloro-6-oxo-4-(trifluoromethyl)pyridazin-1(6H)-yl)- 14,16,24-trifluoro-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphan-8- en-3-yl)acetate

[0145] Prepared in an analogous manner to Intermediate 7 using Intermediate 51 (0.36 g, 0.48 mmol) and Grubbs II (41 mg, 48 µmol) in DCE (0.16 L) at 50 °C for 2 h. Purified by flash chromatography (24 g silica gel, 0-40% EtOAc in petroleum ether) to provide the title compound (0.23 g). LCMS (Method 15): 2.79 min, 724.2 [M+H]+. Intermediate 53: Ethyl 2-((3S,6S)-6-(3-chloro-6-oxo-4-(trifluoromethyl)pyridazin-1(6H)-yl)- 14,16,24-trifluoro-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane- 3-yl)acetate

[0146] Prepared in an analogous manner to Intermediate 8 using Intermediate 52 (0.19 mg, 0.26 mmol) and 10% palladium on carbon (27 mg) in EtOAc (26 mL) under a hydrogen atmosphere at RT for 3 h. Purified by flash chromatography (12 g silica gel, 0-40% EtOAc in petroleum ether) to provide the title compound (0.19 g). LCMS (Method 15): 2.81 min, 726.1 [M+H]+. Intermediate 54: Ethyl 2-((3S,6S)-6-(3-(3-(dimethylamino)prop-1-yn-1-yl)-6-oxo-4- (trifluoromethyl)pyridazin-1(6H)-yl)-14,16,24-trifluoro-5-oxo-25-(trifluoromethyl)-4-aza- 1(1,2),2(1,3)-dibenzenacyclotridecaphane-3-yl)acetate

[0147] Prepared in an analogous manner to Intermediate 17 using Intermediate 53 (0.19 g, 0.26 mmol), Pd(PPh3)2Cl2(13 mg, 18 µmol), copper(I) iodide (3.5 mg, 18 µmol), triethylamine (0.25 mL, 1.82 mmol) and N,N-dimethylpropargylamine (0.20 mL, 1.82 mmol) in MeCN (5 mL) at 80 °C for 16 h. Purified by catch and release chromatography (10 g SCX, MeOH followed by 3.5 M ammonia in MeOH) to provide the title compound (0.11 g). LCMS (Method 15): 2.72 min, 773.2 [M+H]+. Intermediate 55: Ethyl 2-((3S,6S)-6-(3-(3-(dimethylamino)propyl)-6-oxo-4- (trifluoromethyl)pyridazin-1(6H)-yl)-14,16,24-trifluoro-5-oxo-25-(trifluoromethyl)-4-aza- 1(1,2),2(1,3)-dibenzenacyclotridecaphane-3-yl)acetate

[0148] Prepared in an analogous manner to Intermediate 8 using Intermediate 54 (90 mg, 0.12 mmol) and 10% palladium on carbon (24 mg) in ethanol (3 mL) under a hydrogen atmosphere at RT for 7 h. Purified by catch and release chromatography (1 g SCX, MeOH followed by 3.5 M ammonia in MeOH) to provide the title compound (49 mg). LCMS (Method 15): 2.81 min, 777.3 [M+H]+. Intermediate 56: Ethyl (S)-3-((S)-2-(5-bromo-3-methyl-2-oxopyrazin-1(2H)-yl)pent-4- enamido)-3-(4,4'-difluoro-2'-(hex-5-en-1-yl)-6'-methyl-5-(trifluoromethyl)-[1,1'-biphenyl]-3- yl)propanoate

[0149] Prepared in an analogous manner to Intermediate 6 using Intermediate 41 (0.50 g, 0.78 mmol), 5-bromo-3-methyl-1H-pyrazin-2-one (0.18 g, 0.93 mmol, CAS 100047- 56-1) and K2CO3 (0.32 g, 2.33 mmol) in MeCN (11 mL) at reflux for 16 h. Purified by flash chromatography (25 g silica gel, 0-30% EtOAc in petroleum ether) to provide the title compound (0.28 g). LCMS (Method 15): 2.88 min, 740.2 [M+H]+. Intermediate 57: Ethyl 2-((3S,6S)-6-(5-bromo-3-methyl-2-oxopyrazin-1(2H)-yl)-14,24- difluoro-16-methyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphan- 8-en-3-yl)acetate

[0150] Prepared in an analogous manner to Intermediate 7 using Intermediate 56 (0.32 g, 0.43 mmol) and Grubbs II (36 mg, 43 µmol) in DCE (0.20 L) at 50 °C for 1 h. Purified by flash chromatography (24 g silica gel, 0-40% EtOAc in petroleum ether) to provide the title compound (0.24 g). LCMS (Method 15): 2.80 min, 712.1 [M+H]+. Intermediate 58: Ethyl 2-((3S,6S)-6-(5-((E)-2-ethoxyvinyl)-3-methyl-2-oxopyrazin-1(2H)-yl)- 14,24-difluoro-16-methyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphan-8-en-3-yl)acetate

[0151] Prepared in an analogous manner to Intermediate 29 using Intermediate 57 (0.15 g, 0.21 mmol), trans-2-ethoxyvinylboronic acid pinacol ester (49 mg, 0.25 mmol, CAS1201905-61-4), Pd(dppf)Cl2(15 mg, 21 µmol) and Na2CO3(44 mg, 0.41 mmol) in toluene (15 mL) and water (3 mL) at 90 °C for 6 h. Purified by flash chromatography (25 g silica gel, 0- 25% EtOAc in petroleum ether) to provide the title compound (82 mg). LCMS (Method 15): 2.81 min, 702.3 [M+H]+. Intermediate 59: Ethyl 2-((3S,6S)-6-(5-(2-(dimethylamino)ethyl)-3-methyl-2-oxopyrazin- 1(2H)-yl)-14,24-difluoro-16-methyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphan-8-en-3-yl)acetate

[0152] Prepared in an analogous manner to Intermediate 46 using Intermediate 58 (82 mg, 0.12 mmol) in DCM (4 mL) and TFA (0.18 mL) at RT for 2 h. Then dimethylamine (2 M in THF, 70 µL, 0.14 mmol), triethylamine (49 µL, 0.35 mmol) in DCM (5 mL) with 4 Å molecular sieves at RT for 1 h, followed by STAB (50 mg, 0.23 mmol) at RT for 16 h. Purified by catch and release chromatography (SCX, MeOH followed by 3.5 M ammonia in MeOH) to provide the title compound (28 mg). LCMS (Method 15): 2.72 min, 703.3 [M+H]+. Intermediate 60: Ethyl 2-((3S,6S)-6-(5-(2-(dimethylamino)ethyl)-3-methyl-2-oxopyrazin- 1(2H)-yl)-14,24-difluoro-16-methyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetate

[0153] Prepared in an analogous manner to Intermediate 8 using Intermediate 59 (28 mg, 0.03 mmol) and 10% palladium on carbon (3.3 mg) in ethanol (2 mL) under a hydrogen atmosphere at RT for 3 h. Purified by flash chromatography (4 g silica gel, 0-5% MeOH in DCM) to provide the title compound (15 mg). LCMS (Method 15): 2.68 min, 705.3 [M+H]+. Intermediate 61: 5-Fluoro-2-iodo-3-methylphenol

[0154] To a suspension of sodium hydride (60% dispersion in oil, 8.0 g, 0.20 mol) in toluene (0.10 L) at 0 °C was added a solution of 3-fluoro-5-methylphenol (12.5 g, 99.1 mmol, CAS 216976-31-7) in toluene (50 mL) and stirred at 0 °C for 30 min. A solution of iodine (25.2 g, 99.3 mmol) in toluene (0.45 L) was added over 70 mins at 0 °C then stirred at RT for 30 min. The mixture was acidified to pH 5 with 2 M aqueous HCl then extracted with EtOAc. The organics were washed with water, brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (120 g silica gel, 0-20% EtOAc in petroleum ether) to provide the title compound (12.5 g).1H NMR (400 MHz; CDCl3) δ: 6.64 – 6.59 (m, 2H), 5.53 (d, 1H), 2.43 (s, 3H). Intermediate 62: 4,4'-Difluoro-2'-hydroxy-5,6'-dimethyl-[1,1'-biphenyl]-3-carbaldehyde

[0155] Prepared in an analogous manner to1 using Intermediate 61 (5.0 g, 17.4 mmol), 2-fluoro-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzaldehyde (4.80 g, 17.4 mmol, CAS 2121513-83-3), K3PO4(7.41 g, 34.9 mmol),palladium acetate (0.39 g, 1.75 mmol) and tricyclohexyl phosphine (0.49 g, 1.75 mmol) in toluene (80 mL) and water (11 mL) at 100 °C for 6 h. Purified by flash chromatography (40 g silica gel, 0-10% MeOH in DCM) to provide the title compound (2.89 g).1H NMR (400 MHz; CDCl3) δ: 10.36 (s, 1H), 7.57 (d, 1H), 7.36 (d, 1H), 6.61 – 6.50 (m, 2H), 5.13 (s, 1H), 2.39 (d, 3H), 2.02 (s, 3H). Intermediate 63: 4,4'-Difluoro-3'-formyl-5',6-dimethyl-[1,1'-biphenyl]-2-yl trifluoromethanesulfonate

[0156] Prepared in an analogous manner to Intermediate 10 using Intermediate 62 (3.34 g, 12.7 mmol), phenyl triflimide (4.55 g, 12.7 mmol, CAS 37595-74-7) and Cs2CO3 (4.98 g, 15.3 mmol) in DCM (51 mL) at RT for 2 h. Purified by flash chromatography (80 g silica gel, 0–15% EtOAc in petroleum ether) to provide the title compound (4.43 g).1H NMR (400 MHz; CDCl3) δ: 10.40 (s, 1H), 7.55 (dd, 1H), 7.33 (dd, 1H), 7.07 (dd, 1H), 6.98 (dd, 1H), 2.39 (d, 3H), 2.15 (s, 3H). Intermediate 64: 4,4'-Difluoro-2'-(hex-5-en-1-yl)-5,6'-dimethyl-[1,1'-biphenyl]-3-carbaldehyde

[0157] Prepared in an analogous manner tousing Intermediate 63 (2.23 g, 5.66 mmol), 5-hexenylboronic acid (1.09 g, 8.48 mmol, CAS 1072952-16-9), K2CO3 (2.35 g, 17.0 mmol), palladium acetate (0.13 g, 0.57 mmol) and RuPhos (0.46 g, 0.85 mmol) in toluene (51 mL) and water (6 mL) at 100 °C for 2 h. Purified by flash chromatography (40 g silica gel, 0-20% EtOAc in petroleum ether) to provide the title compound (1.0 g).1H NMR (400 MHz; CDCl3) δ: 10.41 (s, 1H), 7.45 (dd, 1H), 7.22 (dd, 1H), 6.83 – 6.78 (m, 2H), 5.74 – 5.63 (m, 1H), 4.94 – 4.87 (m, 2H), 2.38 (d, 3H), 2.28 – 2.24 (m, 2H), 1.97 (s, 3H), 1.91 (q, 2H), 1.42 – 1.35 (m, 2H), 1.28 – 1.22 (m, 2H). Intermediate 65: (R,Z)-N-((4,4'-Difluoro-2'-(hex-5-en-1-yl)-5,6'-dimethyl-[1,1'-biphenyl]-3- yl)methylene)-2-2-sulfinamide

[0158] Prepared in an analogous manner to Intermediate 37 using Intermediate 64 (1.72 g, 5.24 mmol), (R)-2-methylpropane-2-sulfinamide (0.70 g, 5.76 mmol, CAS 196929-78- 9) and titanium ethoxide (1.79 g, 7.85 mmol) in THF (30 mL) at 40 °C for 2 h, to provide the title compound (2.26 g).1H NMR (400 MHz; CDCl3) δ: 8.94 (s, 1H), 7.58 – 7.53 (m, 1H), 7.10 (dd, 1H), 6.82 (dd, 2H), 5.75 – 5.61 (m, 1H), 4.94 – 4.85 (m, 2H), 2.36 (d, 3H), 2.33 – 2.26 (m, 2H), 2.00 (s, 3H), 1.91 (t, 2H), 1.45 – 1.39 (m, 2H), 1.27 – 1.23 (m, 11H). Intermediate 66: Ethyl (S)-3-(((R)-tert-butylsulfinyl)amino)-3-(4,4'-difluoro-2'-(hex-5-en-1-yl)- 5,6'-dimethyl-[1,1'-biphenyl]-3-yl)propanoate

[0159] Prepared in an analogous manner to Intermediate 38 using zinc (1.71 g, 26.2 mmol), chlorotrimethylsilane (0.13 mL, 1.05 mmol) and ethyl bromoacetate (1.45 mL, 13.1mmol) in THF (32 mL) at 65 °C for 1 h, then Intermediate 65 (2.26 g, 5.24 mmol) in THF (19 mL) at RT for 2 h. Purified by flash chromatography (40 g silica gel, 0-80% EtOAc in petroleum ether) to provide the title compound (1.86 g). LCMS (Method 15): 2.78 min, 520.2 [M+H]+. Intermediate 67: Ethyl (S)-3-amino-3-(4,4'-difluoro-2'-(hex-5-en-1-yl)-5,6'-dimethyl-[1,1'- biphenyl]-3-yl)propanoate

[0160] A suspension of Intermediate 66 (1.86 g, 3.58 mmol) in 4 M HCl in 1,4-dioxane (18 mL) was stirred at RT for 1 h. The mixture was diluted with water and washed with EtOAc. The aqueous was basified with aqueous NaHCO3 and extracted with EtOAc. The organics were dried over Na2SO4, filtered and concentrated under reduced pressure, to provide the title compound (1.47 g). LCMS (Method 15): 2.67 min, 416.2 [M+H]+. Intermediate 68: Ethyl (S)-3-(4,4'-difluoro-2'-(hex-5-en-1-yl)-5,6'-dimethyl-[1,1'-biphenyl]-3- yl)-3-((R)-2-hydroxypent-4-enamido)propanoate

[0161] Prepared in an analogous manner to Intermediate 4 using Intermediate 67 (1.48 g, 3.56 mmol), (2R)-2-hydroxypent-4-enoic acid (0.64 g, 5.34 mmol, CAS 413622-10-3), DIPEA (1.86 mL, 10.7 mmol), HOBt (0.53 g, 3.92 mmol) and EDCI (0.83 g, 5.34 mmol) in MeCN (36 mL) at RT for 18 h. Purified by flash chromatography (40 g silica gel, 0-60% EtOAc in petroleum ether) to provide the title compound (1.30 g). LCMS (Method 15): 2.62 min, 514.2 [M+H]+. Intermediate 69: Ethyl (S)-3-(4,4'-difluoro-2'-(hex-5-en-1-yl)-5,6'-dimethyl-[1,1'-biphenyl]-3- yl)-3-((R)-2-((methylsulfonyl)oxy)pent-4-enamido)propanoate

[0162] Prepared in an analogous manner to Intermediate 5 using Intermediate 68 (0.85 g, 1.66 mmol), triethylamine (0.46 mL, 3.31 mmol) and methanesulfonyl chloride (0.19 mL, 2.48 mmol) in DCM (17 mL) at RT for 1 h, to provide the title compound (0.96 g). LCMS (Method 15): 2.67 min, 592.2 [M+H]+. Intermediate 76: (R,E)-N-(5-Bromo-2-fluorobenzylidene)-2-methylpropane-2-sulfinamide

[0163] in an analogous manner to Intermediate 37 using 5-bromo-2- fluorobenzaldehyde (2.50 g, 12.3 mmol, CAS 93777-26-5), (R)-2-methylpropane-2- sulfinamide (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 77: Ethyl (S)-3-(5-bromo-2-fluorophenyl)-3-(((R)-tert- butylsulfinyl)amino)propanoate

[0164] Prepared in an analogous manner to Intermediate 38 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 76 (3.75 g, 12.2 mmol) in THF (15 mL) at RT for 1.5 h. Purified by flash chromatography (80 g silica gel, 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 78: Ethyl (S)-3-amino-3-(5-bromo-2-fluorophenyl)propanoate hydrochloride

[0165] A suspension of Intermediate 77 (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 79: Ethyl (S)-3-(5-bromo-2-fluorophenyl)-3-((tert- butoxycarbonyl)amino)propanoate

[0166] Prepared in an analogous manner to Intermediate 20 using Intermediate 78 (3.0 g, 9.19 mmol), Boc anhydride (2.21 g, 10.1 mmol), triethylamine (1.92 mL, 13.8 mmol) in DCM (50 mL) for 20 h at RT. Purified by flash chromatography (80 g silica gel, 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 80: Ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(2-fluoro-5-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)phenyl)propanoate

[0167] Prepared in an analogous manner to Intermediate 33 using Intermediate 79 (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, 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 81: Ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(4,4'-difluoro-2'-hydroxy-6'- methyl-[1,1'-biphenyl]-3-yl)propanoate

[0168] Prepared in an analogous manner to Intermediate 1 using Intermediate 80 (2.62 g, 4.97 mmol), Intermediate 61 (1.88 g, 7.46 mmol), K3PO4(2.11 g, 9.95 mmol), palladium acetate (0.11 g, 0.50 mmol) and tricyclohexyl phosphine (0.14 g, 0.50 mmol) in toluene (37 mL) and water (12 mL) at 100 °C for 2.5 h. Purified by flash chromatography (40 g silica gel, 0-40% EtOAc in petroleum ether) to provide the title compound (1.86 g). LCMS (Method 15): 2.30 min, 434.2 [M-H]-.Intermediate 82: Ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(4,4'-difluoro-2'-methyl-6'- (((trifluoromethyl)sulfonyl)oxy)-[1,1'-biphenyl]-3-yl)propanoate

[0169] Prepared in anmanner to Intermediate 10 using Intermediate 81 (1.86 g, 3.42 mmol), phenyl triflimide (1.22 g, 3.42 mmol, CAS 37595-74-7) and Cs2CO3(1.34 g, 4.10 mmol) in DCM (17 mL) at RT for 1 h. Purified by flash chromatography (40 g silica gel, 0–25% EtOAc in petroleum ether) to provide the title compound (1.92 g). LCMS (Method 15): 2.30 min, 566.2 [M-H]-. Intermediate 83: Ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(4,4'-difluoro-2'-(hex-5-en-1-yl)- 6'-methyl-[1,1'-biphenyl]-3-yl)propanoate

[0170] Prepared in an analogous manner to Intermediate 1 using Intermediate 82 (1.92 g, 3.05 mmol), 5-hexenylboronic acid (0.58 g, 4.57 mmol, CAS 1072952-16-9), K2CO3 (1.26 g, 9.13 mmol), palladium acetate (68 mg, 0.30 mmol) and RuPhos (0.21 g, 0.46 mmol) in toluene (27 mL) and water (3 mL) at 95 °C for 2.5 h. Purified by flash chromatography (80 g silica gel, 0-20% EtOAc in petroleum ether) to provide the title compound (1.32 g). LCMS (Method 15): 2.89 min, 402.2 [M-Boc+H]+. Intermediate 84: Ethyl (S)-3-amino-3-(4,4'-difluoro-2'-(hex-5-en-1-yl)-6'-methyl-[1,1'- biphenyl]-3-yl)propanoate hydrochloride

[0171] A suspension of Intermediate 83 (1.32 g, 2.50 mmol) in 4 M HCl in 1,4-dioxane (19 mL) was stirred at RT for 1 h. The mixture was concentrated under reduced pressure to provide the title compound (1.79 g). LCMS (Method 15): 2.67 min, 402.1 [M+H]+. Intermediate 85: Ethyl (S)-3-(4,4'-difluoro-2'-(hex-5-en-1-yl)-6'-methyl-[1,1'-biphenyl]-3-yl)-3- ((R)-2-hydroxypent-4-enamido)propanoate

[0172] Prepared in an analogous manner to Intermediate 4 using Intermediate 84 (1.79 g, 2.49 mmol), (2R)-2-hydroxypent-4-enoic acid (0.45 g, 3.74 mmol, CAS 413622-10-3), DIPEA (1.30 mL, 7.48 mmol), HOBt (0.46 g, 2.74 mmol) and EDCI (0.58 g, 3.74 mmol) in MeCN (25 mL) at RT for 17 h. Purified by flash chromatography (40 g silica gel, 0-50% EtOAc in petroleum ether) to provide the title compound (0.83 g). LCMS (Method 15): 2.63 min, 500.2 [M+H]+. Intermediate 86: Ethyl (S)-3-(4,4'-difluoro-2'-(hex-5-en-1-yl)-6'-methyl-[1,1'-biphenyl]-3-yl)-3- ((R)-2-((methylsulfonyl)oxy)pent-4-enamido)propanoate

[0173] Prepared in an analogous manner to Intermediate 5 using Intermediate 85 (0.83 g, 1.47 mmol), triethylamine (0.61 mL, 4.40 mmol) and methanesulfonyl chloride (0.17 mL, 2.20 mmol) in DCM (20 mL) at 0 °C for 1 h, to provide the title compound (1.06 g). LCMS (Method 15): 2.66 min, 578.2 [M+H]+.Intermediate 87: Ethyl (S)-3-((S)-2-(3-chloro-6-oxo-4-(trifluoromethyl)pyridazin-1(6H)- yl)pent-4-enamido)-3-(4,4'-difluoro-2'-(hex-5-en-1-yl)-6'-methyl-[1,1'-biphenyl]-3- yl)propanoate

[0174] Prepared in an analogous manner to Intermediate 6 using Intermediate 86 (0.36 g, 1.83 mmol), Intermediate 50 (0.36 g, 1.83 mmol) and K2CO3 (0.63 g, 4.57 mmol) in DMF (15 mL) at 90 °C for 1.5 h. Purified by flash chromatography (40 g silica gel, 0-20% EtOAc in petroleum ether) to provide the title compound (0.79 g). LCMS (Method 15): 2.86 min, 680.1 [M+H]+. Intermediate 88: Ethyl 2-((3S,6S)-6-(3-chloro-6-oxo-4-(trifluoromethyl)pyridazin-1(6H)-yl)- 14,24-difluoro-16-methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphan-8-en-3- yl)acetate

[0175] Prepared in an analogous manner to Intermediate 7 using Intermediate 87 (0.75 g, 1.11 mmol) and Grubbs II (94 mg, 0.11 mmol) in DCE (0.36 L) at 40 °C for 3 h. Purified by flash chromatography (12 g silica gel, 0-30% EtOAc in petroleum ether) to provide the title compound (0.42 g). LCMS (Method 27): 2.18 min, 652.1 [M+H]+. Intermediate 89: Ethyl 2-((3S,6S)-6-(3-(3-(dimethylamino)prop-1-yn-1-yl)-6-oxo-4- (trifluoromethyl)pyridazin-1(6H)-yl)-14,24-difluoro-16-methyl-5-oxo-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphan-8-en-3-yl)acetate

[0176] Prepared in an analogous manner to Intermediate 17 using Intermediate 88 (0.21 g, 0.32 mmol), Pd(PPh3)2Cl2 (16 mg, 23 µmol), copper(I) iodide (4.3 mg, 23 µmol), triethylamine (0.23 g, 2.27 mmol) and N,N-dimethylpropargylamine (0.24 mL, 2.27 mmol) in MeCN (10 mL) at 80 °C for 45 h. Purified by catch and release chromatography (10 g SCX, MeOH followed by 3.5 M ammonia in MeOH) to provide the title compound (75 mg). LCMS (Method 15): 2.60 min, 699.3 [M+H]+. Intermediate 90: Ethyl 2-((3S,6S)-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)acetate

[0177] Prepared in an analogous manner to Intermediate 8 using Intermediate 89 (75 mg, 0.09 mmol), AcOH (5 µL) and 10% palladium on carbon (9.4 mg) in ethanol (10 mL) under a hydrogen atmosphere at RT for 22 h, to provide the title compound (46 mg). LCMS (Method 15): 2.76 min, 705.3 [M+H]+. Intermediate 91: Ethyl 2-((3S,6S)-6-(5-((E)-2-ethoxyvinyl)-2-oxo-4-(trifluoromethyl)pyridin- 1(2H)-yl)-14,16,24-trifluoro-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphan-8-en-3-yl)acetate

[0178] Prepared in an analogous manner to Intermediate 29 using Intermediate 27 (0.20 g, 0.23 mmol), trans-2-ethoxyvinylboronic acid pinacol ester (50 mg, 0.25 mmol, CAS 1201905-61-4), Pd(dppf)Cl2(17 mg, 23 µmol) and Na2CO3(50 mg, 0.47 mmol) in 1,4-dioxane (3 mL) and water (1 mL) at 85 °C for 2 h. Purified by flash chromatography (12 g silica gel, 0- 50% EtOAc in petroleum ether) to provide the title compound (0.15 g). LCMS (Method 21): 5.80 min, 759.2 [M+H]+. Intermediate 92: Ethyl 2-((3S,6S)-14,16,24-trifluoro-6-(5-(2-(3-fluoroazetidin-1-yl)ethyl)-2- oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphan-8-en-3-yl)acetate

[0179] Prepared in an analogous manner to Intermediate 46 using Intermediate 91 (0.15 g, 0.17 mmol) in DCM (5 mL) and TFA (0.40 mL) at RT for 1.5 h. Then 3-fluoroazetidine hydrochloride (22 mg, 0.20 mmol, CAS 617718-46-4), triethylamine (70 µL, 0.50 mmol) in DCM (5 mL) with 4 Å molecular sieves at RT for 15 min, followed by STAB (71 mg, 0.34 mmol) at RT for 21 h. Purified by catch and release chromatography (2 g SCX, MeOH followed by 3.5 M ammonia in MeOH) to provide the title compound (79 mg). LCMS (Method 11): 2.55 min, 790.4 [M+H]+. Intermediate 93: Ethyl 2-((3S,6S)-14,16,24-trifluoro-6-(5-(2-(3-fluoroazetidin-1-yl)ethyl)-2- oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetate

[0180] Prepared in an analogous manner to Intermediate 8 using Intermediate 92 (79 mg, 0.10 mmol) and 10% palladium on carbon (21 mg) in ethanol (3 mL) under a hydrogen atmosphere at RT for 3 h, to provide the title compound (77 mg). LCMS (Method 11): 2.58 min, 792.2 [M+H]+. Intermediate 94: Ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(4,4'-difluoro-2'-(hex-5-en-1-yl)- 5,6'-dimethyl-[1,1'-biphenyl]-3-yl)propanoate

[0181] Prepared in an analogous manner to Intermediate 20 using Intermediate 67 (6.39 g, 7.69 mmol), Boc anhydride (2.01 g, 9.22 mmol), DIPEA (2.0 mL, 11.5 mmol) in DCM (77 mL) at RT for 18 h. Purified by flash chromatography (80 g silica gel, 0-40% EtOAc in petroleum ether) to provide the title compound (6.50 g). LCMS (Method 15): 2.89 min, 416.2 [M-Boc+H]+. Intermediate 95: Ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(4,4'-difluoro-2'-(hex-4-en-1-yl)- 5,6'-dimethyl-[1,1'-biphenyl]-3-yl)propanoate

[0182] A stirred solution of Intermediate 94 (4.40 g, 8.53 mmol) in DMF (11.6 mL) was degassed then Co(acac)2(0.11 g, 0.43 mmol), K2CO3(1.18 g, 8,53 mmol), Hantzsch ester(2.16 g, 8,53 mmol, CAS 1149-23-1) and Xantphos (0.49 g, 0.85 mmol) were added and mixture stirred under 450 nm light irradiation for 4 days. The mixture was diluted with EtOAc and washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (80 g silica gel, 0-30% EtOAc in petroleum ether) to provide the title compound (3.40 g). LCMS (Method 22): 2.23 min, 416.2 [M-Boc+H]+. Intermediate 96: Ethyl (S)-3-amino-3-(4,4'-difluoro-2'-(hex-4-en-1-yl)-5,6'-dimethyl-[1,1'- biphenyl]-3-yl)propanoate hydrochloride

[0183] A suspension of Intermediate 95 (4.08 g, 7.91 mmol) in 4 M HCl in 1,4-dioxane (40 mL) was stirred at RT for 1 h. The mixture was concentrated under reduced pressure to provide the title compound (3.87 g). LCMS (Method 15): 2.67 min, 416.3 [M+H]+. Intermediate 97: Ethyl (S)-3-(4,4'-difluoro-2'-(hex-4-en-1-yl)-5,6'-dimethyl-[1,1'-biphenyl]-3- yl)-3-((R)-2-hydroxyhex-5-enamido)propanoate

[0184] Prepared in an analogous manner to Intermediate 4 using Intermediate 96 (4.60 g, 7.64 mmol), (2R)-2-hydroxyhex-5-enoic acid (1.19 g, 9.17 mmol, CAS 612825-60-2), DIPEA (3.99 mL, 22.9 mmol), HOBt (1.42 g, 8.40 mmol) and EDCI (1.78 g, 11.5 mmol) in MeCN (53 mL) at RT for 36 h. Purified by flash chromatography (40 g silica gel, 0-60% EtOAc in petroleum ether) to provide the title compound (2.24 g). LCMS (Method 15): 2.68 min, 528.3 [M+H]+. Intermediate 98: Ethyl (S)-3-(4,4'-difluoro-2'-(hex-4-en-1-yl)-5,6'-dimethyl-[1,1'-biphenyl]-3- yl)-3-((R)-2-((methylsulfonyl)oxy)hex-5-enamido)propanoate

[0185] Prepared in an analogous manner to Intermediate 5 using Intermediate 97 (1.50 g, 2.84 mmol), triethylamine (0.79 mL, 5.69 mmol) and methanesulfonyl chloride (0.33 mL, 4.26 mmol) in DCM (23 mL) at RT for 1 h, to provide the title compound (1.82 g). LCMS (Method 15): 2.71 min, 606.3 [M+H]+. Intermediate 99: Ethyl (S)-3-((S)-2-(3-chloro-6-oxo-4-(trifluoromethyl)pyridazin-1(6H)-yl)hex- 5-enamido)-3-(4,4'-difluoro-2'-(hex-4-en-1-yl)-5,6'-dimethyl-[1,1'-biphenyl]-3-yl)propanoate

[0186] Prepared in an analogous manner to6 using Intermediate 98 (0.37 g, 0.61 mmol), Intermediate 50 (0.11 g, 0.56 mmol) and K2CO3(0.19 g, 1.40 mmol) in DMF (4 mL) at 80 °C for 3 h. Purified by flash chromatography (25 g silica gel, 0-40% EtOAc in petroleum ether) to provide the title compound (0.24 g). LCMS (Method 15): 2.95 min, 708.2 [M+H]+.Intermediate 100: Ethyl 2-((3S,6S)-6-(3-chloro-6-oxo-4-(trifluoromethyl)pyridazin-1(6H)-yl)- 14,24-difluoro-16,25-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphan-9-en-3- yl)acetate

[0187] Prepared in an analogous manner to Intermediate 7 using Intermediate 99 (0.24 g, 0.34 mmol) and Grubbs II (29 mg, 34 µmol) in DCE (0.11 L) at 50 °C for 2 h. Purified by flash chromatography (12 g silica gel, 0-10% (0.1% ammonia MeOH) in DCM) to provide the title compound (0.19 g). LCMS (Method 15): 2.80 min, 666.2 [M+H]+. Intermediate 101: Ethyl 2-((3S,6S)-6-(3-chloro-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)acetate

[0188] Prepared in an analogous manner to Intermediate 8 using Intermediate 100 (0.47 g, 0.55 mmol) and 10% palladium on carbon (59 mg) in EtOAc (24 mL) under a hydrogen atmosphere at RT for 3 h. Purified by flash chromatography (4 g silica gel, 0-30% EtOAc in petroleum ether) to provide the title compound (0.45 g). LCMS (Method 15): 2.83 min, 668.2 [M+H]+. Intermediate 102: Ethyl 2-((3S,6S)-6-(3-((E)-2-ethoxyvinyl)-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)acetate

[0189] Prepared in an analogous manner to Intermediate 29 using Intermediate 101 (0.40 g, 0.49 mmol), trans-2-ethoxyvinylboronic acid pinacol ester (0.22 g, 1.06 mmol, CAS 1201905-61-4), Pd(dppf)Cl2 (70 mg, 96 µmol) and Na2CO3 (0.11 g, 0.97 mmol) in toluene (5.6 mL) and water (1.9 mL) at 90 °C for 24 h. Purified by flash chromatography (40 g silica gel, 0- 25% EtOAc in petroleum ether), to provide the title compound (0.15 g). LCMS (Method 15): 2.89 min, 704.2 [M+H]+. Intermediate 103: Ethyl 2-((3S,6S)-6-(3-(2-(dimethylamino)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)acetate

[0190] Prepared in an analogous manner to Intermediate 46 using Intermediate 102 (0.15 g, 0.15 mmol) in DCM (2 mL) and TFA (0.24 mL) at RT for 3 h. Then dimethylamine (2 M in THF, 92 µL, 0.19 mmol), triethylamine (64 µL, 0.46 mmol) in DCM (5 mL) with 4 Å molecular sieves at RT for 30 min, followed by STAB (65 mg, 0.31 mmol) at RT for 18 h. Purified by catch and release chromatography (2 g SCX, MeOH followed by 3.5 M ammonia in MeOH) to provide the title compound (59 mg). LCMS (Method 15): 2.77 min, 705.3 [M+H]+.Intermediate 104: (R,E)-N-(3-bromo-5-chloro-2-fluorobenzylidene)-2-methylpropane-2- sulfinamide

[0191] Prepared in an analogous manner to Intermediate 37 using 3-bromo-5-chloro- 2-fluorobenzaldehyde (4.00 g, 16.8 mmol, CAS 1269440-82-5), (R)-2-methylpropane-2- sulfinamide (2.25 g, 18.5 mmol, CAS 196929-78-9) and titanium ethoxide (5.76 g, 25.3 mmol) in THF (40 mL) at 40 °C for 19 h, to provide the title compound (6.15 g). LCMS (Method 22): 1.78 min, 341.8 [M+H]+. Intermediate 105: Ethyl (S)-3-(3-bromo-5-chloro-2-fluorophenyl)-3-(((R)-tert- butylsulfinyl)amino)propanoate

[0192] Prepared in an analogous manner to Intermediate 38 using zinc (5.9 g, 90.3 mmol) chlorotrimethylsilane (0.46 mL, 3.61 mmol) and ethyl bromoacetate (5.0 mL, 45.1 mmol) in THF (0.12 L) at 60 °C for 1 h, then Intermediate 104 (6.15 g, 18.1 mmol) in THF (25 mL) at RT for 18 h. Purified by flash chromatography (80 g silica gel, 0-100% EtOAc in petroleum ether) to provide the title compound (4.04 g). LCMS (Method 22): 1.69 min, 430.2 [M+H]+. Intermediate 106: Ethyl (S)-3-amino-3-(3-bromo-5-chloro-2-fluorophenyl)propanoate

[0193] A suspension of Intermediate 105 (4.04 g, 9.42 mmol) in 4 M HCl in 1,4- dioxane (15 mL) was stirred at RT for 2 h. The mixture was concentrated under reduced pressure then purified by catch and release chromatography (20 g SCX, MeOH followed by 3.5 M ammonia in MeOH) to provide the title compound (2.49 g). LCMS (Method 12): 1.65 min, 323.9 [M+H]+. Intermediate 107: Ethyl (S)-3-(3-bromo-5-chloro-2-fluorophenyl)-3-((tert- butoxycarbonyl)amino)propanoate

[0194] Prepared in an analogous manner to Intermediate 20 using Intermediate 106 (2.49 g, 7.66 mmol), Boc anhydride (2.01 g, 9.20 mmol) and DIPEA (2.00 mL, 11.5 mmol) in DCM (20 mL) for 5 h at RT. Purified by flash chromatography (12 g silica gel, 0-20% EtOAc in petroleum ether) to provide the title compound (1.13 g). LCMS (Method 22): 1.76 min, 323.9 [M-Boc+H]+. Intermediate 108: Ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(5-chloro-3-cyclopropyl-2- fluorophenyl)propanoate

[0195] Prepared in an analogous manner to Intermediate 1 using Intermediate 107 (1.00 g, 2.36 mmol), cyclopropaneboronic acid (0.25 g, 2.94 mmol), K2CO3(0.98 g, 7.06 mmol), Pd(dtbpf)Cl2(77 mg, 0.12 mmol) in toluene (25 mL) at 70 °C for 3 h. Conditions were repeated with cyclopropaneboronic acid (51 mg, 0.59 mmol), K2CO3(0.20 g, 1.41 mmol) andPd(dtbpf)Cl2(15 mg, 0.02 mmol) in toluene (25 mL) at 70 °C for 3 h. Purified by flash chromatography (12 g silica gel, 0-20% EtOAc in petroleum ether) to provide the title compound (0.73 g). LCMS (Method 26): 2.31 min, 286.2 [M-Boc+H]+. Intermediate 109: Ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(3-cyclopropyl-2-fluoro-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate

[0196] Prepared in an analogous manner to Intermediate 33 using Intermediate 108 (0.49 g, 1.12 mmol), bis(pinacolato)diboron (0.57 g, 2.24 mmol), potassium acetate (25 mg, 0.11 mmol) and SPhos (46 mg, 0.11 mmol) in DME (19 mL) at 105 °C for 2 h. Purified by flash chromatography (12 g silica gel, 0-20% EtOAc in petroleum ether) to provide the title compound (0.38 g). LCMS (Method 12): 1.94 min, 378.3 [M-Boc+H]+. Intermediate 110: Ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(5-cyclopropyl-4,4'-difluoro-2'- hydroxy-6'-methyl-[1,1'-biphenyl]-3-yl)propanoate

[0197] in an analogous manner to Intermediate 1 using 2-bromo-5-fluoro- 3-methylphenol (1.29 g, 6.28 mmol, CAS 1807192-21-7), Intermediate 109 (2.50 g, 5.24 mmol), K3PO4 (3.34 g, 15.7 mmol), palladium acetate (0.12 g, 0.52 mmol) and tricyclohexyl phosphine (0.15 g, 0.52 mmol) in toluene (50 mL) and water (10 mL) at 100 °C for 18 h. Purified by flash chromatography (40 g silica gel, 0-40% EtOAc in petroleum ether) to provide the title compound (1.72 g). LCMS (Method 15): 2.42 min, 474.2 [M-H]-. Intermediate 111: Ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(5-cyclopropyl-4,4'-difluoro-2'- methyl-6'-(pent-4-en-1-yloxy)-[1,1'-biphenyl]-3-yl)propanoate

[0198] To a stirred solution of Intermediate 110 (1.37 g, 2.88 mmol) and 5-bromopent- 1-ene (0.49 mL, 4.09 mmol, CAS 1119-51-3) in MeCN (38 mL) was added K2CO3 (0.61 g, 4.41 mmol) and the mixture was heated at reflux for 18 h. The mixture was poured into water and extracted with EtOAc. The organics were dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (40 g silica gel, 0-20% EtOAc in petroleum ether) to provide the title compound (1.44 g). LCMS (Method 27): 2.61 min, 542.3 [M-H]-. Intermediate 112: Ethyl (S)-3-amino-3-(5-cyclopropyl-4,4'-difluoro-2'-methyl-6'-(pent-4-en-1- yloxy)-[1,1'-biphenyl]-3-yl)propanoate hydrochloride

[0199] A suspension of Intermediate 111 (1.44 g, 2.65 mmol) in 4 M HCl in 1,4- dioxane (8 mL) was stirred at RT for 2 h. The mixture was concentrated under reduced pressure to provide the title compound (1.24 g). LCMS (Method 15): 2.66 min, 444.1 [M+H]+. Intermediate 113: Ethyl (S)-3-(5-cyclopropyl-4,4'-difluoro-2'-methyl-6'-(pent-4-en-1-yloxy)- [1,1'-biphenyl]-3-yl)-3-((R)-2-hydroxypent-4-enamido)propanoate

[0200] Prepared in an analogous manner to Intermediate 4 using Intermediate 112 (1.24 g, 2.58 mmol), (2R)-2-hydroxypent-4-enoic acid (0.41 g, 3.53 mmol, CAS 413622-10-3), DIPEA (1.38 mL, 7.75 mmol), HOBt (0.38 g, 2.84 mmol) and EDCI (1.24 g, 2.58 mmol) in MeCN (16 mL) at RT for 16 h. Purified by flash chromatography (25 g silica gel, 0-50% EtOAc in petroleum ether) to provide the title compound (0.80 g). LCMS (Method 15): 2.64 min, 542.2 [M+H]+. Intermediate 114: Ethyl (S)-3-(5-cyclopropyl-4,4'-difluoro-2'-methyl-6'-(pent-4-en-1-yloxy)- [1,1'-biphenyl]-3-yl)-3-((R)-2-((methylsulfonyl)oxy)pent-4-enamido)propanoate

[0201] Prepared in an analogous manner to Intermediate 5 using Intermediate 113 (0.80 g, 1.47 mmol), triethylamine (0.41 mL, 2.94 mmol) and methanesulfonyl chloride (0.17 mL, 2.20 mmol) in DCM (14 mL) at RT for 1 h, to provide the title compound (0.91 g). LCMS (Method 15): 2.70 min, 620.2 [M+H]+. Intermediate 115: Ethyl (S)-3-((S)-2-(5-bromo-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)pent- 4-enamido)-3-(5-cyclopropyl-4,4'-difluoro-2'-methyl-6'-(pent-4-en-1-yloxy)-[1,1'-biphenyl]-3- yl)propanoate

[0202] Prepared in an analogous manner to Intermediate 6 using Intermediate 114 (0.91 g, 1.47 mmol), 5-bromo-4-(trifluoromethyl)pyridin-2-ol (0.43 g, 1.76 mmol, CAS 109919- 32-6) and K2CO3 (0.67 g, 4.85 mmol) in MeCN (10 mL) at reflux for 16 h. Purified by flash chromatography (120 g silica gel, 0-20% EtOAc in petroleum ether) to provide the title compound (0.61 g). LCMS (Method 15): 2.87 min, 765.3 [M-H]-. Intermediate 116: Ethyl 2-((10S,13S)-10-(5-bromo-2-oxo-4-(trifluoromethyl)pyridin-1(2H)- yl)-15-cyclopropyl-14,24-difluoro-26-methyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzenacyclotridecaphan-7-en-13-yl)acetate

[0203] Prepared in an analogous manner to Intermediate 7 using Intermediate 115 (0.61 g, 0.79 mmol) and Grubbs II (67 mg, 79 µmol) in DCE (0.27 L) at 40 °C for 3 h. Purified by flash chromatography (12 g silica gel, 0-30% EtOAc in petroleum ether) to provide the title compound (0.50 g). LCMS (Method 15): 2.76 min, 739.1 [M+H]+. Intermediate 117: Ethyl 2-((10S,13S)-15-cyclopropyl-10-(5-((E)-2-ethoxyvinyl)-2-oxo-4- (trifluoromethyl)pyridin-1(2H)-yl)-14,24-difluoro-26-methyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)- dibenzenacyclotridecaphan-7-en-13-yl)acetate

[0204] Prepared in an analogous manner to Intermediate 29 using Intermediate 116 (0.25 g, 0.34 mmol), trans-2-ethoxyvinylboronic acid pinacol ester (70 mg, 0.35 mmol, CAS 1201905-61-4), Pd(dppf)Cl2(24 mg, 33 µmol) and Na2CO3(72 mg, 0.68 mmol) in 1,4-dioxane (4.5 mL) and water (1.1 mL) at 85 °C for 3 h. Purified by flash chromatography (25 g silica gel,0-20% EtOAc in petroleum ether) to provide the title compound (98 mg). LCMS (Method 15): 2.70 min, 729.3 [M+H]+. Intermediate 118: Ethyl 2-((10S,13S)-10-(5-(2-(azetidin-1-yl)ethyl)-2-oxo-4- (trifluoromethyl)pyridin-1(2H)-yl)-15-cyclopropyl-14,24-difluoro-26-methyl-11-oxo-3-oxa-12- aza-1(1,3),2(1,2)-dibenzenacyclotridecaphan-7-en-13-yl)acetate

[0205] Prepared in an analogous manner to Intermediate 46 using Intermediate 117 (98 mg, 0.13 mmol) in DCM (3 mL) and TFA (0.21 mL) at RT for 2 h. Then azetidine (7.7 mg, 0.13 mmol), triethylamine (56 µL, 0.40 mmol) in DCM (3 mL) with 4 Å molecular sieves at RT for 1 h, followed by STAB (57 mg, 0.27 mmol) at RT for 16 h. Purified by flash chromatography (25 g silica gel, 0-10% MeOH in DCM) to provide the title compound (43 mg). LCMS (Method 15): 2.60 min, 742.4 [M+H]+. Intermediate 119: Ethyl 2-((10S,13S)-10-(5-(2-(azetidin-1-yl)ethyl)-2-oxo-4- (trifluoromethyl)pyridin-1(2H)-yl)-15-cyclopropyl-14,24-difluoro-26-methyl-11-oxo-3-oxa-12- aza-1(1,3),2(1,2)-dibenzenacyclotridecaphane-13-yl)acetate

[0206] Prepared in an analogous manner to Intermediate 8 using Intermediate 118 (0.12 g, 0.16 mmol) and 10% palladium on carbon (17 mg) in ethanol (14 mL) under a hydrogen atmosphere at RT for 8 h. Purified by flash chromatography (12 g silica gel, 0-10% MeOH in DCM) to provide the title compound (97 mg). LCMS (Method 15): 2.71 min, 744.4 [M+H]+. Intermediate 120: Ethyl (S)-3-((S)-2-(3-chloro-6-oxopyridazin-1(6H)-yl)pent-4-enamido)-3- (4,4'-difluoro-2'-(hex-5-en-1-yl)-6'-methyl-5-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)propanoate

[0207] Prepared in an analogous manner to6 using Intermediate 41 (0.54 g, 0.77 mmol), 3-chloro-1H-pyridazin-6-one (0.12 g, 0.92 mmol, CAS 19064-67-6) and K2CO3 (0.32 g, 2.30 mmol) in MeCN (8 mL) at reflux for 21 h. Purified by flash chromatography (25 g silica gel, 0-75% EtOAc in petroleum ether) to provide the title compound (0.45 g). LCMS (Method 21): 5.88 min, 680.2 [M+H]+. Intermediate 121: Ethyl 2-((3S,6S)-6-(3-chloro-6-oxopyridazin-1(6H)-yl)-14,24-difluoro-16- methyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphan-8-en-3- yl)acetate

[0208] Prepared in an analogous manner to Intermediate 7 using Intermediate 120 (0.45 g, 0.63 mmol) and Grubbs II (55 mg, 65 µmol) in DCE (0.30 L) at 50 °C for 2 h. Purified by flash chromatography (12 g silica gel, 0-50% EtOAc in petroleum ether) to provide the title compound (0.39 g). LCMS (Method 21): 5.68 min, 652.1 [M+H]+.Intermediate 122: Ethyl 2-((3S,6S)-6-(3-((E)-2-ethoxyvinyl)-6-oxopyridazin-1(6H)-yl)-14,24- difluoro-16-methyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphan- 8-en-3-yl)acetate

[0209] Prepared in an analogous manner to Intermediate 29 using Intermediate 121 (0.20 g, 0.27 mmol), trans-2-ethoxyvinylboronic acid pinacol ester (56 mg, 0.28 mmol, CAS 1201905-61-4), Pd(dppf)Cl2(22 mg, 27 µmol) and Na2CO3(57 mg, 0.54 mmol) in toluene (9 mL) and water (3 mL) at 140 °C for 30 min under microwave irradiation. Additional trans-2- ethoxyvinylboronic acid pinacol ester (56 mg, 0.28 mmol) added and heated at 140 °C for 15 min under microwave irradiation. Purified by flash chromatography (12 g silica gel, 0-50% EtOAc in petroleum ether), to provide the title compound (0.18 g). LCMS (Method 19): 5.60 min, 686.5 [M-H]-. Intermediate 123: Ethyl 2-((3S,6S)-6-(3-(2-(dimethylamino)ethyl)-6-oxopyridazin-1(6H)-yl)- 14,24-difluoro-16-methyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphan-8-en-3-yl)acetate

[0210] Prepared in an analogous manner to Intermediate 46 using Intermediate 122 (0.18 g, 0.23 mmol) in DCM (10 mL) and TFA (1.4 mL) at RT for 3 h. Then dimethylamine (2 M in THF, 0.15 mL, 1.32 mmol), triethylamine (0.10 mL, 0.72 mmol) in DCM (10 mL) with 4 Å molecular sieves at RT for 15 min, followed by STAB (0.10 g, 0.47 mmol) at RT for 72 h. Purified by catch and release chromatography (10 g SCX, MeOH followed by 1 M ammonia in MeOH) to provide the title compound (82 mg). LCMS (Method 19): 5.48 min, 687.6 [M-H]-. Intermediate 124: Ethyl 2-((3S,6S)-6-(3-(2-(dimethylamino)ethyl)-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)acetate

[0211] Prepared in an analogous manner to Intermediate 8 using Intermediate 123 (82 mg, 0.09 mmol) and 10% palladium on carbon (20 mg) in ethanol (5 mL) under a hydrogen atmosphere at RT for 9 h. Purified by catch and release chromatography (10 g SCX, MeOH followed by 1 M ammonia in MeOH) to provide the title compound (41 mg). LCMS (Method 11): 2.70 min, 689.7 [M+H]+. Intermediate 125: Ethyl 2-((3S,6S)-14,24-difluoro-6-(3-(2-(3-fluoro-3-methylazetidin-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)acetate

[0212] Prepared in an analogous manner to Intermediate 46 using Intermediate 102 (0.16 g, 0.17 mmol) in DCM (2.1 mL) and TFA (0.26 mL) at RT for 4 h. Then 3-fluoro-3- methylazetidine hydrochloride (25 mg, 0.20 mmol), triethylamine (69 µL, 0.50 mmol) in DCM(2.1 mL) with 4 Å molecular sieves at RT for 1 h, followed by STAB (70 mg, 0.33 mmol) at RT for 2 h. Purified by catch and release chromatography (2 g SCX, MeOH followed by 3.5 M ammonia in MeOH) to provide the title compound (80 mg). LCMS (Method 15): 2.77 min, 749.4 [M+H]+. Intermediate 126: (R,E)-N-(5-Bromo-2-fluoro-3-methylbenzylidene)-2-methylpropane-2- sulfinamide

[0213] Prepared in an analogous manner to Intermediate 37 using 5-bromo-2-fluoro- 3-methylbenzaldehyde (1.50 g, 6.91 mmol, CAS 903875-64-9), (R)-2-methylpropane-2- sulfinamide (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 127: Ethyl (S)-3-(5-bromo-2-fluoro-3-methylphenyl)-3-(((R)-tert- butylsulfinyl)amino)propanoate

[0214] Prepared in an analogous manner to Intermediate 38 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 126 (1.95 g, 6.09 mmol) in THF (25 mL) at RT for 16 h. Purified by flash chromatography (80 g silica gel, 1-10% MeOH in DCM) to provide the title compound (1.55 g). LCMS (Method 8): 2.07 min, 410.3 [M+H]+. Intermediate 128: Ethyl (S)-3-amino-3-(5-bromo-3-methyl-2-fluorophenyl)propanoate hydrochloride

[0215] A suspension of Intermediate 127 (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 129: Ethyl (S)-3-(5-bromo-2-fluoro-3-methylphenyl)-3-((tert- butoxycarbonyl)amino)propanoate

[0216] Prepared in an analogous manner to Intermediate 20 using Intermediate 128 (3.22 g, 9.45 mmol), Boc anhydride (2.48 g, 11.3 mmol) and DIPEA (2.5 mL, 14.2 mmol) in DCM (100 mL) for 2 h at RT. Purified by flash chromatography (12 g silica gel, 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 130: 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

[0217] Prepared in an analogous manner to Intermediate 33 using Intermediate 129 (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, 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 131: Ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(2'-chloro-4,4',6'-trifluoro-5- methyl-[1,1'-biphenyl]-3-yl)propanoate

[0218] Prepared in an analogous manner to Intermediate 1 using Intermediate 130 (4.97 g, 9.80 mmol), 2-bromo-1-chloro-3,5-difluorobenzene (2.68 g, 11.8 mmol, CAS 1020198-58-6), K3PO4 (6.24 g, 29.4 mmol), Pd(dtbpf)Cl2 (0.64 g, 0.98 mmol) and potassium formate (1.65 g, 19.6 mmol) in toluene (0.13 L) and water (32 mL) at 70 °C for 3 h. Purified by flash chromatography (120 g silica gel, 0-20% EtOAc in petroleum ether) to provide the title compound (6.16 g). LCMS (Method 15): 2.45 min, 372.3 [M-Boc+H]+. Intermediate 132: Ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(2',4,4'-trifluoro-6'-(hex-5-en-1- yl)-5-methyl-[1,1'-biphenyl]-3-yl)propanoate

[0219] Prepared in an analogous manner to Intermediate 1 using Intermediate 131 (5.16 g, 10.4 mmol), 5-hexenylboronic acid (2.26 g, 4.57 mmol, CAS 1072952-16-9), K2CO3 (4.31 g, 31.2 mmol), palladium acetate (0.23 g, 1.04 mmol) and SPhos (0.85 g, 2.08 mmol) in toluene (0.14 L) and water (34 mL) at 90 °C for 4 h. Purified by flash chromatography (80 g silica gel, 0-20% EtOAc in petroleum ether) to provide the title compound (5.28 g). LCMS (Method 15): 2.70 min, 420.3 [M-Boc+H]+. Intermediate 133: Ethyl (S)-3-amino-3-(2',4,4'-trifluoro-6'-(hex-5-en-1-yl)-5-methyl-[1,1'- biphenyl]-3-yl)propanoate hydrochloride

[0220] A suspension of Intermediate 132 (6.40 g, 12.3 mmol) in 4 M HCl in 1,4- dioxane (31 mL) was stirred at RT for 1.5 h. The mixture was concentrated under reduced pressure to provide the title compound (5.86 g). LCMS (Method 15): 2.60 min, 420.2 [M+H]+. Intermediate 134: Ethyl (S)-3-((R)-2-hydroxypent-4-enamido)-3-(2',4,4'-trifluoro-6'-(hex-5- en-1-yl)-5-methyl-[1,1'-biphenyl]-3-yl)propanoate

[0221] Prepared in an analogous manner to Intermediate 4 using Intermediate 133 (5.60 g, 12.3 mmol), (2R)-2-hydroxypent-4-enoic acid (2.16 g, 18.4 mmol, CAS 413622-10-3), DIPEA (6.42 mL, 36.8 mmol), HOBt (1.83 g, 13.5 mmol) and EDCI (2.86 g, 18.4 mmol) in MeCN (65 mL) at RT for 16 h. Purified by flash chromatography (80 g silica gel, 0-50% EtOAcin petroleum ether) to provide the title compound (3.99 g). LCMS (Method 15): 2.56 min, 518.3 [M+H]+. Intermediate 135: Ethyl (S)-3-((R)-2-((methylsulfonyl)oxy)pent-4-enamido)-3-(2',4,4'- trifluoro-6'-(hex-5-en-1-yl)-5-methyl-[1,1'-biphenyl]-3-yl)propanoate

[0222] Prepared in an analogous manner to Intermediate 5 using Intermediate 134 (0.48 g, 0.83 mmol), triethylamine (0.23 mL, 1.65 mmol) and methanesulfonyl chloride (96 µL, 1.24 mmol) in DCM (5 mL) at RT for 1 h, to provide the title compound (0.58 g). LCMS (Method 15): 2.63 min, 596.2 [M+H]+. Intermediate 136: Ethyl (S)-3-((S)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4- (trifluoromethyl)pyridin-1(2H)-yl)pent-4-enamido)-3-(2',4,4'-trifluoro-6'-(hex-5-en-1-yl)-5- methyl-[1,1'-biphenyl]-3-yl)propanoate

[0223] Prepared in an analogous manner to Intermediate 6 using Intermediate 135 (0.58 g, 0.77 mmol), 5-[2-(dimethylamino)ethyl]-4-(trifluoromethyl)-1H-pyridin-2-one (0.20 g, 0.85 mmol, CAS 2378705-10-1) and K2CO3 (0.32 g, 2.32 mmol) in MeCN (13 mL) at reflux for 18 h. Purified by flash chromatography (40 g silica gel, 0-8% MeOH in DCM) to provide the title compound (0.27 g). LCMS (Method 21): 2.81 min, 734.4 [M+H]+. Intermediate 137: Ethyl 2-((3S,6S)-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4- (trifluoromethyl)pyridin-1(2H)-yl)-14,16,24-trifluoro-25-methyl-5-oxo-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphan-8-en-3-yl)acetate

[0224] Prepared in an analogous manner to Intermediate 7 using Intermediate 136 (0.27 g, 0.34 mmol) and Grubbs II (29 mg, 34 µmol) in DCE (0.19 L) at 50 °C for 1 h. Purified by flash chromatography (40 g silica gel, 0-30% EtOAc in petroleum ether) to provide the title compound (0.25 g). LCMS (Method 15): 2.66 min, 706.3 [M+H]+. Intermediate 138: Ethyl 2-((3S,6S)-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4- (trifluoromethyl)pyridin-1(2H)-yl)-14,16,24-trifluoro-25-methyl-5-oxo-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetate

[0225] Prepared in an analogous manner to Intermediate 8 using Intermediate 137 (0.24 g, 0.25 mmol) and 10% palladium on carbon (27 mg) in ethanol (7 mL) under a hydrogen atmosphere at RT for 4 h. Purified by flash chromatography (12 g silica gel, 0-10% MeOH in DCM) to provide the title compound (0.21 g). LCMS (Method 15): 2.70 min, 708.3 [M+H]+. Intermediate 139: Methyl (S)-3-((S)-2-(3-chloro-6-oxopyridazin-1(6H)-yl)pent-4-enamido)-3- (4'-fluoro-2'-(hex-5-en-1-yl)-6'-methyl-[1,1'-biphenyl]-3-yl)propanoate

[0226] Prepared in an analogous manner to Intermediate 6 using Intermediate 14 (0.50 g, 0.92 mmol), 3-chloro-1H-pyridazin-6-one (0.14 g, 1.11 mmol, CAS 19064-67-6) and K2CO3(0.38 g, 2.77 mmol) in MeCN (9 mL) at reflux for 16 h. Purified by flash chromatography (40 g silica gel, 0-100% EtOAc in petroleum ether) to provide the title compound (0.40 g). LCMS (Method 11): 2.51 min, 578.6 [M-H]-. Intermediate 140: Methyl 2-((3S,6S)-6-(3-chloro-6-oxopyridazin-1(6H)-yl)-14-fluoro-16- methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphan-8-en-3-yl)acetate

[0227] Prepared in an analogous manner to Intermediate 7 using Intermediate 139 (0.40 g, 0.69 mmol) and Grubbs II (58 mg, 69 µmol) in DCE (0.33 L) at 50 °C for 2 h. Purified by flash chromatography (25 g silica gel, 0-100% EtOAc in petroleum ether) to provide the title compound (0.32 g). LCMS (Method 15): 2.47 min, 552.2 [M+H]+. Intermediate 141: Methyl 2-((3S,6S)-6-(3-chloro-6-oxopyridazin-1(6H)-yl)-14-fluoro-16- methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3-yl)acetate

[0228] Prepared in an analogous manner to Intermediate 8 using Intermediate 140 (0.29 g, 0.46 mmol) and 10% palladium on carbon (49 mg) in EtOAc (20 mL) under a hydrogen atmosphere at RT for 21 h. Purified by flash chromatography (25 g silica gel, 0-100% EtOAc in petroleum ether) to provide the title compound (0.20 g). LCMS (Method 21): 5.16 min, 554.2 [M+H]+. Intermediate 142: Methyl 2-((3S,6S)-6-(3-(3-(dimethylamino)prop-1-yn-1-yl)-6-oxopyridazin- 1(6H)-yl)-14-fluoro-16-methyl-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3- yl)acetate

[0229] Prepared in an analogous manner to Intermediate 17 using Intermediate 141 (0.26 g, 0.26 mmol), Pd(PPh3)2Cl2 (13 mg, 18 µmol), copper(I) iodide (3.5 mg, 18 µmol), triethylamine (0.26 mL, 1.85 mmol) and N,N-dimethylpropargylamine (0.20 mL, 1.85 mmol) in MeCN (2.6 mL) at 80 °C for 20 h. Purified by catch and release chromatography (10 g SCX, MeOH followed by 3.5 M ammonia in MeOH) to provide the title compound (0.15 g). LCMS (Method 15): 2.44 min, 601.3 [M+H]+. Intermediate 143: Methyl 2-((3S,6S)-6-(3-(3-(dimethylamino)propyl)-6-oxopyridazin-1(6H)- yl)-14-fluoro-16-methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3-yl)acetate

[0230] Prepared in an analogous manner to Intermediate 8 using Intermediate 142 (0.11 g, 0.16 mmol) and 10% palladium on carbon (17 mg) in IPA (20 mL) under a hydrogen atmosphere at RT for 2 h. Purified by catch and release chromatography (10 g SCX, MeOH followed by 3.5 M ammonia in MeOH) to provide the title compound (77 mg). LCMS (Method 27): 5.05 min, 605.4 [M+H]+.Intermediate 144: Ethyl (S)-3-((S)-2-(3-chloro-6-oxo-4-(trifluoromethyl)pyridazin-1(6H)- yl)pent-4-enamido)-3-(2',4,4'-trifluoro-6'-(hex-5-en-1-yl)-5-methyl-[1,1'-biphenyl]-3- yl)propanoate

[0231] Prepared in an analogous manner to Intermediate 6 using Intermediate 135 (1.99 g, 2.57 mmol), Intermediate 50 (0.56 g, 2.83 mmol) and K2CO3 (1.07 g, 7.72 mmol) in MeCN (35 mL) at reflux for 16 h. Purified by flash chromatography (40 g silica gel, 0-40% EtOAc in petroleum ether) to provide the title compound (1.50 g). LCMS (Method 15): 2.82 min, 698.2 [M+H]+. Intermediate 145: Ethyl 2-((3S,6S)-6-(3-chloro-6-oxo-4-(trifluoromethyl)pyridazin-1(6H)-yl)- 14,16,24-trifluoro-25-methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphan-8-en-3- yl)acetate

[0232] Prepared in an analogous manner to Intermediate 7 using Intermediate 144 (1.50 g, 2.15 mmol) and Grubbs II (0.18 g, 0.21 mmol) in DCE (1.31 L) at 50 °C for 2 h. Purified by flash chromatography (40 g silica gel, 0-40% EtOAc in petroleum ether) to provide the title compound (1.12 g). LCMS (Method 11): 2.59 min, 670.2 [M+H]+. Intermediate 146: Ethyl 2-((3S,6S)-6-(3-chloro-6-oxo-4-(trifluoromethyl)pyridazin-1(6H)-yl)- 14,16,24-trifluoro-25-methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3- yl)acetate

[0233] Prepared in an analogous manner to Intermediate 8 using Intermediate 145 (0.91 g, 1.35 mmol) and 10% palladium on carbon (0.14 g) in EtOAc (60 mL) under a hydrogen atmosphere at RT for 4.5 h. Purified by flash chromatography (25 g silica gel, 0-30% EtOAc in petroleum ether) to provide the title compound (0.91 g). LCMS (Method 15): 2.73 min, 672.2 [M+H]+. Intermediate 147: Ethyl 2-((3S,6S)-6-(3-((E)-2-ethoxyvinyl)-6-oxo-4- (trifluoromethyl)pyridazin-1(6H)-yl)-14,16,24-trifluoro-25-methyl-5-oxo-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetate

[0234] Prepared in an analogous manner to Intermediate 29 using Intermediate 146 (0.25 g, 0.37 mmol), trans-2-ethoxyvinylboronic acid pinacol ester (81 mg, 0.41 mmol, CAS 1201905-61-4), Pd(dppf)Cl2(27 mg, 37 µmol) and Na2CO3(79 mg, 0.74 mmol) in toluene (2.8 mL) and water (1.0 mL) at 90 °C for 6 h. Additional trans-2-ethoxyvinylboronic acid pinacol ester (26 mg, 0.13 mmol) and Pd(dppf)Cl2(27 mg, 37 µmol) were added and the mixture heated at 90 °C for 8 h. Purified by flash chromatography (25 g silica gel, 0-30% EtOAc in petroleum ether) to provide the title compound (0.15 g). LCMS (Method 15): 2.79 min, 708.3 [M+H]+.Intermediate 148: Ethyl 2-((3S,6S)-14,16,24-trifluoro-6-(3-(2-(3-methoxyazetidin-1-yl)ethyl)-6- oxo-4-(trifluoromethyl)pyridazin-1(6H)-yl)-25-methyl-5-oxo-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetate

[0235] Prepared in an analogous manner to Intermediate 46 using Intermediate 147 (0.15 g, 95 µmol), in DCM (1.4 mL) and TFA (0.15 mL) at RT for 2 h. Then 3-methoxyazetidine hydrochloride (7.7 mg, 0.13 mmol, CAS 148644-09-1), triethylamine (40 µL, 0.29 mmol) in DCM (3 mL) with 4 Å molecular sieves at RT for 30 min, followed by STAB (40 mg, 0.19 mmol) at RT for 18 h. Purified by catch and release chromatography (10 g SCX, MeOH followed by 3.5 M ammonia in MeOH) to provide the title compound (38 mg). LCMS (Method 15): 2.61 min, 751.3 [M+H]+. Intermediate 149: Ethyl (S)-3-((S)-2-(5-bromo-3-methyl-2-oxopyrazin-1(2H)-yl)pent-4- enamido)-3-(4,4'-difluoro-2'-(hex-5-en-1-yl)-5,6'-dimethyl-[1,1'-biphenyl]-3-yl)propanoate

[0236] Prepared in an analogous manner to6 using Intermediate 69 (1.10 g, 1.86 mmol), 5-bromo-3-methyl-1H-pyrazin-2-one (0.42 g, 2.23 mmol, CAS 100047- 56-1) and K2CO3 (0.77 g, 5.58 mmol) in MeCN (25 mL) at reflux for 16 h. Purified by flash chromatography (40 g silica gel, 0-30% EtOAc in petroleum ether) to provide the title compound (0.78 g). LCMS (Method 15): 2.82 min, 684.2 [M+H]+. Intermediate 150: Ethyl 2-((3S,6S)-6-(5-bromo-3-methyl-2-oxopyrazin-1(2H)-yl)-14,24- difluoro-16,25-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphan-8-en-3- yl)acetate

[0237] Prepared in an analogous manner to Intermediate 7 using Intermediate 149 (0.89 g, 1.30 mmol) Grubbs II (0.11 g, 0.13 mmol) in DCE (0.44 L) and at 40 °C for 1.5 h. Purified by flash chromatography (40 g silica gel, 0-40% EtOAc in petroleum ether) to provide the title compound (0.49 g). LCMS (Method 15): 2.73 min, 656.2 [M+H]+. Intermediate 151: Ethyl 2-((3S,6S)-6-(5-((E)-2-ethoxyvinyl)-3-methyl-2-oxopyrazin-1(2H)-yl)- 14,24-difluoro-16,25-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphan-8-en-3- yl)acetate

[0238] Prepared in an analogous manner to Intermediate 29 using Intermediate 150 (0.49 g, 0.75 mmol), trans-2-ethoxyvinylboronic acid pinacol ester (0.18 g, 0.90 mmol, CAS 1201905-61-4), Pd(dppf)Cl2(55 mg, 75 µmol) and Na2CO3(0.16 g, 1.49 mmol) in toluene (12 mL) and water (2.5 mL) at 90 °C for 3 h. Purified by flash chromatography (40 g silica gel, 0- 25% EtOAc in petroleum ether) to provide the title compound (0.25 g). LCMS (Method 15): 2.76 min, 648.3 [M+H]+.Intermediate 152: Ethyl 2-((3S,6S)-6-(5-(2-(dimethylamino)ethyl)-3-methyl-2-oxopyrazin- 1(2H)-yl)-14,24-difluoro-16,25-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphan- 8-en-3-yl)acetate

[0239] Prepared in an analogous manner to Intermediate 46 using Intermediate 151 (0.12 g, 0.19 mmol) in DCM (5.9 mL) and TFA (0.29 mL) at RT for 4 h. Then dimethylamine (2 M in THF, 0.11 mL, 0.22 mmol), triethylamine (78 µL, 0.56 mmol) in DCM (7 mL) with 4 Å molecular sieves at RT for 1 h, followed by STAB (79 mg, 0.37 mmol) at RT for 18 h. Purified by catch and release chromatography (10 g SCX, MeOH followed by 3.5 M ammonia in MeOH) to provide the title compound (60 mg). LCMS (Method 15): 2.61 min, 649.3 [M+H]+. Intermediate 153: Ethyl 2-((3S,6S)-6-(5-(2-(dimethylamino)ethyl)-3-methyl-2-oxopyrazin- 1(2H)-yl)-14,24-difluoro-16,25-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetate

[0240] Prepared in an analogous manner to Intermediate 8 using Intermediate 152 (60 mg, 92 µmol) and 10% palladium on carbon (10 mg) in ethanol (6 mL) under a hydrogen atmosphere at RT for 3 h, to provide the title compound (59 mg). LCMS (Method 15): 2.65 min, 651.4 [M+H]+. Intermediate 154: Ethyl (S)-3-((S)-2-(5-bromo-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)pent- 4-enamido)-3-(4,4'-difluoro-2'-(hex-5-en-1-yl)-5,6'-dimethyl-[1,1'-biphenyl]-3-yl)propanoate

[0241] Prepared in an analogous manner to6 using Intermediate 69 (0.53 g, 0.86 mmol), 5-bromo-4-(trifluoromethyl)pyridin-2-ol (0.23 g, 0.94 mmol, CAS 109919- 32-6) and K2CO3 (0.36 g, 2.57 mmol) in MeCN (11 mL) at reflux for 18 h. Purified by flash chromatography (40 g silica gel, 0-40% EtOAc in petroleum ether) to provide the title compound (0.34 g). LCMS (Method 15): 2.88 min, 739.2 [M+H]+. Intermediate 155: Ethyl 2-((3S,6S)-6-(5-bromo-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)- 14,24-difluoro-16,25-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphan-8-en-3- yl)acetate

[0242] Prepared in an analogous manner to Intermediate 7 using Intermediate 154 (0.34 g, 0.47 mmol) and Grubbs II (39 mg, 46 µmol) in DCE (0.19 L) at 50 °C for 2.5 h. Purified by flash chromatography (25 g silica gel, 0-10% MeOH in DCM) to provide the title compound (0.35 g). LCMS (Method 15): 2.80 min, 709.1 [M+H]+. Intermediate 156: Ethyl 2-((3S,6S)-6-(5-((E)-2-ethoxyvinyl)-2-oxo-4-(trifluoromethyl)pyridin- 1(2H)-yl)-14,24-difluoro-16,25-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphan- 8-en-3-yl)acetate

[0243] Prepared in an analogous manner to Intermediate 29 using Intermediate 155 (0.35 g, 0.49 mmol), trans-2-ethoxyvinylboronic acid pinacol ester (0.10 g, 0.51 mmol, CAS 1201905-61-4), Pd(dppf)Cl2(36 mg, 49 µmol) and Na2CO3(0.10 g, 0.98 mmol) in 1,4-dioxane (4.2 mL) and water (1.4 mL) at 85 °C for 1 h. Purified by flash chromatography (40 g silica gel, 0-100% EtOAc in petroleum ether), to provide the title compound (0.23 g). LCMS (Method 15): 2.83 min, 701.3 [M+H]+. Intermediate 157: Ethyl 2-((3S,6S)-14,24-difluoro-6-(5-(2-(3-fluoroazetidin-1-yl)ethyl)-2-oxo- 4-(trifluoromethyl)pyridin-1(2H)-yl)-16,25-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphan-8-en-3-yl)acetate

[0244] Prepared in an analogous manner to Intermediate 46 using Intermediate 156 (93 mg, 0.12 mmol) in DCM (4 mL) and TFA (0.28 mL) at RT for 1 h. Then 3-fluoroazetidine hydrochloride (20 mg, 0.18 mmol, CAS 617718-46-4), triethylamine (50 µL, 0.36 mmol) in DCM (4 mL) with 4 Å molecular sieves at RT for 1 h, followed by STAB (51 mg, 0.24 mmol) at RT for 2 h. Purified by catch and release chromatography (2 g SCX, MeOH followed by 3.5 M ammonia in MeOH) to provide the title compound (46 mg). LCMS (Method 15): 2.70 min, 732.3 [M+H]+. Intermediate 158: Ethyl 2-((3S,6S)-14,24-difluoro-6-(5-(2-(3-fluoroazetidin-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)acetate

[0245] Prepared in an analogous manner to Intermediate 8 using Intermediate 157 (46 mg, 61 µmol) and 10% palladium on carbon (6.5 mg) in ethanol (5 mL) under a hydrogen atmosphere at RT for 3 h. Purified by catch and release chromatography (2 g SCX, MeOH followed by 3.5 M ammonia in MeOH) to provide the title compound (32 mg). LCMS (Method 15): 2.73 min, 734.4 [M+H]+. Intermediate 159: Ethyl 2-((3S,6S)-14,24-difluoro-6-(5-(2-(3-fluoroazetidin-1-yl)ethyl)-3- methyl-2-oxopyrazin-1(2H)-yl)-16,25-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphan-8-en-3-yl)acetate

[0246] Prepared in an analogous manner to Intermediate 46 using Intermediate 151 (0.12 g, 0.19 mmol) in DCM (5.9 mL) and TFA (0.29 mL) at RT for 4 h. Then 3-fluoroazetidine hydrochloride (25 mg, 0.18 mmol, CAS 617718-46-4), triethylamine (78 µL, 0.56 mmol) in DCM (7 mL) with 4 Å molecular sieves at RT for 1 h, followed by STAB (79 mg, 0.37 mmol) at RT for 18 h. Purified by catch and release chromatography (10 g SCX, MeOH followed by 3.5 M ammonia in MeOH) to provide the title compound (82 mg). LCMS (Method 15): 2.57 min, 679.4 [M+H]+.Intermediate 160: Ethyl 2-((3S,6S)-14,24-difluoro-6-(5-(2-(3-fluoroazetidin-1-yl)ethyl)-3- methyl-2-oxopyrazin-1(2H)-yl)-16,25-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetate

[0247] Prepared in an analogous manner to Intermediate 8 using Intermediate 159 (82 mg, 0.12 mmol) and 10% palladium on carbon (13 mg) in ethanol (8 mL) under a hydrogen atmosphere at RT for 3 h, to provide the title compound (74 mg). LCMS (Method 15): 2.59 min, 681.4 [M+H]+. Intermediate 161: Ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(5-cyclopropyl-2',4,4'-trifluoro- 6'-formyl-[1,1'-biphenyl]-3-yl)propanoate

[0248] Prepared in an analogous manner to Intermediate 1 using 2-bromo-3,5- difluoro-benzaldehyde (0.60 g, 2.72 mmol, CAS 1232407-50-9), Intermediate 109 (1.36 g, 2.85 mmol), K3PO4 (1.65 g, 7.76 mmol), XPhosPdG2 (0.20 g, 0.26 mmol) in 1,4-dioxane (42 mL) and water (6 mL) at 150 °C for 20 min under microwave radiation. Purified by flash chromatography (40 g silica gel, 0-30% EtOAc in petroleum ether) to provide the title compound (1.06 g). LCMS (Method 15): 2.48 min, 490.2 [M-H]-. Intermediate 162: Ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(5-cyclopropyl-2',4,4'-trifluoro- 6'-(hydroxymethyl)-[1,1'-biphenyl]-3-yl)propanoate

[0249] To a solution of Intermediate 161 (1.06 g, 1.51 mmol) in ethanol (20 mL) at 0 °C, was added sodium borohydride (46 mg, 1.21 mmol) and the mixture was stirred for 30 min. The mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, water, dried over Na2SO4, filtered and concentrated under reduced pressure and purified by flash chromatography (40 g silica gel, 0-100% EtOAc in petroleum ether) to provide the title compound (0.88 g). LCMS (Method 15): 2.34 min, 394.1 [M-Boc+H]+. Intermediate 163: Ethyl (S)-3-(2'-((allyloxy)methyl)-5-cyclopropyl-4,4',6'-trifluoro-[1,1'- biphenyl]-3-yl)-3-((tert-butoxycarbonyl)amino)propanoate

[0250] A mixture of Intermediate 162 (0.88 g, 1.48 mmol) and BINAP (0.18 g, 0.30 mmol) in THF (40 mL) was degassed with nitrogen. To this was added allyl methyl carbonate (0.67 mL, 5.92 mmol, CAS 35466-83-2) and Pd2(dba)3(68 mg, 74 µmol) and the mixture stirred at 60 °C for 2 h. Additional allyl methyl carbonate (0.67 mL, 5.92 mmol) was added and heating continued at 60 °C for 1 h. The mixture was concentrated under reduced pressure. The crude product was purified by flash chromatography (40 g silica gel, 0-30% EtOAc in petroleum ether) to provide the title compound (0.59 g). LCMS (Method 15): 2.67 min, 434.1 [M-Boc+H]+.Intermediate 164: Ethyl (S)-3-(2'-((allyloxy)methyl)-5-cyclopropyl-4,4',6'-trifluoro-[1,1'- biphenyl]-3-yl)-3-aminopropanoate hydrochloride

[0251] A suspension of Intermediate 163 (0.59 g, 1.00 mmol) in 4 M HCl in 1,4- dioxane (7.5 mL) was stirred at RT for 30 min. The mixture was concentrated under reduced pressure to provide the title compound (0.47 g). LCMS (Method 15): 2.39 min, 434.1 [M+H]+. Intermediate 165: Ethyl (S)-3-(2'-((allyloxy)methyl)-5-cyclopropyl-4,4',6'-trifluoro-[1,1'- biphenyl]-3-yl)-3-((R)-2-hydroxyhex-5-enamido)propanoate

[0252] Prepared in an analogous manner to Intermediate 4 using Intermediate 164 (0.47 g, 1.00 mmol), (2R)-2-hydroxyhex-5-enoic acid (0.19 g, 1.49 mmol, CAS 612825-60-2), DIPEA (0.52 mL, 2.99 mmol), HOBt (0.18 g, 1.10 mmol) and EDCI (0.23 g, 1.49 mmol) in MeCN (10 mL) at RT for 20 h. Purified by flash chromatography (40 g silica gel, 0-50% EtOAc in petroleum ether) to provide the title compound (0.35 g). LCMS (Method 15): 2.34 min, 546.3 [M+H]+. Intermediate 166: Ethyl (S)-3-(2'-((allyloxy)methyl)-5-cyclopropyl-4,4',6'-trifluoro-[1,1'- biphenyl]-3-yl)-3-((R)-2-((methylsulfonyl)oxy)hex-5-enamido)propanoate

[0253] Prepared in an analogous manner to Intermediate 5 using Intermediate 165 (0.32 g, 0.56 mmol), triethylamine (0.23 mL, 1.67 mmol) and methanesulfonyl chloride (65 µL, 0.84 mmol) in DCM (15 mL) at RT for 1 h, to provide the title compound (0.35 g). LCMS (Method 15): 2.51 min, 622.2 [M-H]-. Intermediate 167: Ethyl (S)-3-(2'-((allyloxy)methyl)-5-cyclopropyl-4,4',6'-trifluoro-[1,1'- biphenyl]-3-yl)-3-((S)-2-(5-bromo-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)hex-5-enamido)propanoate

[0254] Prepared in an analogous manner to Intermediate 6 using Intermediate 166 (0.38 g, 0.56 mmol), 5-bromo-4-(trifluoromethyl)pyridin-2-ol (0.20 g, 0.84 mmol, CAS 109919- 32-6) and K2CO3 (0.23 g, 1.67 mmol) in MeCN (15 mL) at reflux for 17 h. Purified by flash chromatography (50 g silica gel, 0-30% EtOAc in petroleum ether) to provide the title compound (0.23 g). LCMS (Method 15): 2.75 min, 771.2 [M+H]+. Intermediate 168: Ethyl 2-((3S,6S)-6-(5-bromo-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-25- cyclopropyl-14,16,24-trifluoro-5-oxo-12-oxa-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphan-9- en-3-yl)acetate

[0255] Prepared in an analogous manner to Intermediate 7 using Intermediate 167 (0.23 g, 0.28 mmol) and Grubbs II (24 mg, 28 µmol) in DCE (0.15 L) at 50 °C for 1 h. Purified by flash chromatography (25 g silica gel, 0-40% EtOAc in petroleum ether) to provide the title compound (0.21 g). LCMS (Method 15): 2.62 min, 741.1 [M+H]+.Intermediate 169: Ethyl 2-((3S,6S)-6-(5-bromo-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-25- cyclopropyl-14,16,24-oxa-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane- 3-yl)acetate

[0256] Prepared in an analogous manner to Intermediate 8 using Intermediate 168 (0.21 g, 0.25 mmol) and 10% palladium on carbon (26 mg) in EtOAc (50 mL) under a hydrogen atmosphere at RT for 1 h, to provide the title compound (0.20 g). LCMS (Method 15): 2.66 min, 745.2 [M+H]+. Intermediate 170: Ethyl 2-((3S,6S)-25-cyclopropyl-6-(5-((E)-2-ethoxyvinyl)-2-oxo-4- (trifluoromethyl)pyridin-1(2H)-yl)-14,16,24-trifluoro-5-oxo-12-oxa-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetate

[0257] Prepared in an analogous manner to Intermediate 29 using Intermediate 169 (0.23 g, 0.23 mmol), trans-2-ethoxyvinylboronic acid pinacol ester (67 mg, 0.34 mmol, CAS 1201905-61-4), Pd(dppf)Cl2 (17 mg, 22 µmol) and Na2CO3 (48 mg, 0.45 mmol) in 1,4-dioxane (6 mL) and water (1.5 mL) at 85 °C for 40 h. Purified by flash chromatography (40 g silica gel, 0-30% EtOAc in petroleum ether), to provide the title compound (74 mg). LCMS (Method 15): 2.68 min, 733.3 [M-H]-. Intermediate 171: Ethyl 2-((3S,6S)-25-cyclopropyl-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4- (trifluoromethyl)pyridin-1(2H)-yl)-14,16,24-trifluoro-5-oxo-12-oxa-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetate

[0258] Prepared in an analogous manner to Intermediate 46 using Intermediate 170 (74 mg, 77 µmol) in DCM (5 mL) and TFA (0.19 mL) at RT for 1 h. Then dimethylamine (2 M in THF, 77 µL, 0.15 mmol), triethylamine (32 µL, 0.23 mmol) in DCM (5 mL) with 4 Å molecular sieves at RT for 15 min, followed by STAB (32 mg, 0.15 mmol) at RT for 18 h. Purified by catch and release chromatography (2 g SCX, MeOH followed by 3.5 M ammonia in MeOH) to provide the title compound (56 mg). LCMS (Method 15): 2.55 min, 736.3 [M+H]+. Intermediate 179: (R,Z)-N-(3-Bromo-5-methylbenzylidene)-2-methylpropane-2-sulfinamide

[0259] in an analogous manner to Intermediate 37 using 3-bromo-5- methylbenzaldehyde (10.6 g, 53.2 mmol, CAS 188813-04-9), (R)-2-methylpropane-2- sulfinamide (7.09 g, 58.5 mmol, CAS 196929-78-9) and titanium ethoxide (18.2 g, 79.7 mmol) in THF (86 mL) at 40 °C for 18 h, to provide the title compound (15.6 g). LCMS (Method 15): 2.26 min, 303.9 [M+H]+. Intermediate 180: Ethyl (S)-3-(3-bromo-5-methylphenyl)-3-(((R)-tert- butylsulfinyl)amino)propanoate

[0260] Prepared in an analogous manner to Intermediate 38 using zinc (5.41 g, 82.7 mmol), chlorotrimethylsilane (0.42 mL, 3.31 mmol) and ethyl bromoacetate (4.59 mL, 41.4 mmol) in THF (79 mL) at 60 °C for 1 h, then Intermediate 179 (5.0 g, 16.5 mmol) in THF (17 mL) at RT for 3 h. Purified by flash chromatography (120 g silica gel, 0-30% EtOAc in petroleum ether) to provide the title compound (2.4 g). LCMS (Method 15): 2.12 min, 392.0 [M+H]+. Intermediate 181: Ethyl (S)-3-amino-3-(3-bromo-5-methylphenyl)propanoate

[0261] A solution of Intermediate 180 (3.5 g, 8.52 mmol) in DCM (4.9 mL) and 4 M HCl in 1,4-dioxane (12.7 mL) was stirred at RT for 4 h. The mixture was basified with aqueous NaHCO3 and extracted with EtOAc. The organics were dried over Na2SO4, filtered and concentrated under reduced pressure, to provide the title compound (1.50 g). LCMS (Method 15): 1.82 min, 288.0 [M+H]+. Intermediate 182: Ethyl (S)-3-(3-bromo-5-methylphenyl)-3-((tert- butoxycarbonyl)amino)propanoate

[0262] Prepared in an analogous manner to Intermediate 20 using Intermediate 181 (1.5 g, 5.24 mmol), Boc anhydride (1.37 g, 6.29 mmol) and DIPEA (1.37 mL, 7.86 mmol) in DCM (12 mL) at RT for 2 h. Purified by flash chromatography (40 g silica gel, 0-40% EtOAc in petroleum ether) to provide the title compound (8.02 g). LCMS (Method 11): 2.24 min, 286.1 [M-Boc+H]+. Intermediate 183: Ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(4'-fluoro-2'-hydroxy-5,6'- dimethyl-[1,1'-biphenyl]-3-yl)propanoate

[0263] Prepared in an analogous manner to Intermediate 1 using Intermediate 182 (0.10 g, 0.25 mmol), Intermediate 191 (93 mg, 0.37 mmol), K3PO4 (0.16 g, 0.74 mmol), XPhosPdG2 (19 mg, 25 µmol) in 1,4-dioxane (4.1 mL) and water (1 mL) at 110 °C for 3 h. Purified by flash chromatography (12 g silica gel, 0-30% EtOAc in petroleum ether) to provide the title compound (45 mg). LCMS (Method 15): 2.25 min, 430.2 [M-H]-. Intermediate 184: Ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(4'-fluoro-2',5-dimethyl-6'- (((trifluoromethyl)sulfonyl)oxy)-[1,1'-biphenyl]-3-yl)propanoate

[0264] Prepared in anmanner to Intermediate 10 using Intermediate 183 (45 mg, 0.09 mmol), phenyl triflimide (32 mg, 0.09 mmol, CAS 37595-74-7) and Cs2CO3(35 mg, 0.11 mmol) in DCM (0.5 mL) at RT for 2 h. Purified by flash chromatography (12 g silica gel, 0–20% EtOAc in petroleum ether) to provide the title compound (33 mg). LCMS (Method 11): 2.54 min, 562.5 [M-H]-.Intermediate 185: Ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(4'-fluoro-2'-(hex-5-en-1-yl)- 5,6'-dimethyl-[1,1'-biphenyl]-3-yl)propanoate

[0265] Prepared in an analogous manner to Intermediate 1 using Intermediate 184 (0.68 g, 1.15 mmol), 5-hexenylboronic acid (0.20 g, 1.72 mmol, CAS 1072952-16-9), K2CO3(0.48 g, 3.44 mmol), palladium acetate (26 mg, 0.12 mmol) and RuPhos (80 mg, 0.17 mmol) in toluene (11 mL) and water (1.2 mL) at 100 °C for 1.5 h. Purified by flash chromatography (12 g silica gel, 0-20% EtOAc in petroleum ether) to provide the title compound (0.54 g). LCMS (Method 15): 2.88 min, 496.3 [M-H]-. Intermediate 186: Ethyl (S)-3-amino-3-(4'-fluoro-2'-(hex-5-en-1-yl)-5,6'-dimethyl-[1,1'- biphenyl]-3-yl)propanoate hydrochloride

[0266] A suspension of Intermediate 185 (0.74 g, 1.39 mmol) in 4 M HCl in 1,4- dioxane (3.5 mL) was stirred at RT for 1 h. The mixture was concentrated under reduced pressure to provide the title compound (0.81 g). LCMS (Method 15): 2.66 min, 398.2 [M+H]+. Intermediate 187: Ethyl (S)-3-(4'-fluoro-2'-(hex-5-en-1-yl)-5,6'-dimethyl-[1,1'-biphenyl]-3-yl)- 3-((R)-2-hydroxypent-4-enamido)propanoate

[0267] Prepared in an analogous manner to Intermediate 4 using Intermediate 186 (0.81 g, 1.39 mmol), (2R)-2-hydroxypent-4-enoic acid (0.26 g, 2.08 mmol, CAS 413622-10-3), DIPEA (0.74 mL, 4.16 mmol), HOBt (0.23 g, 1.39 mmol) and EDCI (0.32 g, 1.67 mmol) in MeCN (13 mL) at RT for 16 h. Purified by flash chromatography (24 g silica gel, 0-60% EtOAc in petroleum ether) to provide the title compound (0.51 g). LCMS (Method 15): 2.61 min, 496.2 [M+H]+. Intermediate 188: Ethyl (S)-3-(4'-fluoro-2'-(hex-5-en-1-yl)-5,6'-dimethyl-[1,1'-biphenyl]-3-yl)- 3-((R)-2-((methylsulfonyl)oxy)pent-4-enamido)propanoate

[0268] Prepared in an analogous manner to Intermediate 5 using Intermediate 187 (0.51 g, 0.90 mmol), triethylamine (0.25 mL, 1.79 mmol) and methanesulfonyl chloride (0.10 mL, 1.35 mmol) in DCM (8 mL) at RT for 1 h, to provide the title compound (0.70 g). LCMS (Method 15): 2.68 min, 574.3 [M+H]+. Intermediate 189: 5-Fluoro-2-iodo-1-(methoxymethoxy)-3-methylbenzene

[0269] To a solution of Intermediate 61 (4.24 g, 16.8 mmol) in DCM (73 mL) at RT was added DIPEA (7.33 mL, 42.0 mmol) and chloromethyl methyl ether (2.03 g, 1.92 mmol) then stirred at RT for 18 h. The mixture was washed with water, brine, dried over Na2SO4, filtered and concentrated under reduced pressure, to provide the title compound (5.3 g).1H NMR (400 MHz; CDCl3) δ: 6.72 – 6.68 (m, 2H), 5.22 (s, 2H), 3.51 (s, 3H), 2.46 (s, 3H).Intermediate 190: 2-(4-Fluoro-2-(methoxymethoxy)-6-methylphenyl)-4,4,5,5-tetramethyl- 1,3,2-dioxaborolane

[0270] Prepared in an analogous manner to Intermediate 33 using Intermediate 189 (2.65 g, 8.95 mmol), bis(pinacolato)diboron (2.73 g, 10.7 mmol), Cs2CO3(4.37 g, 13.4 mmol), tris(4-methoxyphenyl)phosphine (0.17 g, 0.49 mmol) and palladium acetate (0.10 g, 0.45 mmol) in EtOAc (90 mL) at 80 °C for 16 h. Purified by flash chromatography (40 g silica gel, 0-10% EtOAc in petroleum ether) to provide the title compound (2.59 g).1H NMR (400 MHz; CDCl3) δ: 6.58 (dd, 1H), 6.52 (dd, 1H), 5.11 (s, 2H), 3.46 (s, 3H), 2.34 (s, 3H), 1.38 (s, 12H). Intermediate 191: 5-Fluoro-3-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol

[0271] A suspension of Intermediate 190 (9.13 g, 29.6 mmol) in 4 M HCl in 1,4- dioxane (37 mL) was stirred at RT for 1.5 h. The mixture was concentrated under reduced pressure to provide the title compound (8.16 g).1H NMR (400 MHz; CDCl3) δ: 8.75 (d, 1H), 6.43-6.39 (m, 2H), 2.47 (s, 3H), 1.36 (s, 12H). Intermediate 192: Ethyl (S)-3-((S)-2-(3-chloro-6-oxo-4-(trifluoromethyl)pyridazin-1(6H)- yl)pent-4-enamido)-3-(4'-fluoro-2'-(hex-5-en-1-yl)-5,6'-dimethyl-[1,1'-biphenyl]-3- yl)propanoate

[0272] Prepared in an analogous manner to Intermediate 6 using Intermediate 188 (0.51 g, 0.90 mmol), Intermediate 50 (0.27 g, 1.34 mmol) and K2CO3 (0.37 g, 2.69 mmol) in MeCN (6.2 mL) at reflux for 2 h. Purified by flash chromatography (25 g silica gel, 0-30% EtOAc in petroleum ether) to provide the title compound (0.44 g). LCMS (Method 15): 2.86 min, 676.3 [M+H]+. Intermediate 193: Ethyl 2-((3S,6S)-6-(3-chloro-6-oxo-4-(trifluoromethyl)pyridazin-1(6H)-yl)- 14-fluoro-16,25-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphan-8-en-3- yl)acetate

[0273] Prepared in an analogous manner to Intermediate 7 using Intermediate 192 (0.44 g, 0.66 mmol) and Grubbs II (56 mg, 67 µmol) in DCE (0.34 L) at 50 °C for 2 h. Purified by flash chromatography (25 g silica gel, 0-100% EtOAc in petroleum ether) to provide the title compound (0.37 g). LCMS (Method 15): 2.75 min, 648.2 [M+H]+. Intermediate 194: Ethyl 2-((3S,6S)-6-(3-chloro-6-oxo-4-(trifluoromethyl)pyridazin-1(6H)-yl)- 14-fluoro-16,25-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3-yl)acetate

[0274] Prepared in an analogous manner to Intermediate 8 using Intermediate 193 (0.37 g, 0.45 mmol) and 10% palladium on carbon (53 mg) in EtOAc (22 mL) under a hydrogen atmosphere at RT for 14 h, to provide the title compound (0.29 g). LCMS (Method 15): 2.80 min, 650.3 [M+H]+.Intermediate 195: Ethyl 2-((3S,6S)-6-(3-(3-(dimethylamino)prop-1-yn-1-yl)-6-oxo-4- (trifluoromethyl)pyridazin-1(6H)-yl)-14-fluoro-16,25-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetate

[0275] Prepared in an analogous manner to Intermediate 17 using Intermediate 194 (0.15 g, 0.21 mmol), Pd(PPh3)2Cl2 (10 mg, 15 µmol), copper(I) iodide (2.8 mg, 15 µmol), triethylamine (0.21 mL, 1.47 mmol) and N,N-dimethylpropargylamine (0.16 mL, 1.47 mmol) in MeCN (2.0 mL) at 80 °C for 20 h. Purified by catch and release chromatography (2 g SCX, MeOH followed by 3.5 M ammonia in MeOH) to provide the title compound (82 mg). LCMS (Method 15): 2.72 min, 697.3 [M+H]+. Intermediate 196: Ethyl 2-((3S,6S)-6-(3-(3-(dimethylamino)propyl)-6-oxo-4- (trifluoromethyl)pyridazin-1(6H)-yl)-14-fluoro-16,25-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetate

[0276] Prepared in an analogous manner to Intermediate 8 using Intermediate 195 (82 mg, 0.10 mmol) and 10% palladium on carbon (11 mg) in IPA (14 mL) with AcOH (12 µL) under a hydrogen atmosphere at RT for 28 h, to provide the title compound (36 mg). LCMS (Method 27): 2.84 min, 701.4 [M+H]+. Intermediate 197: Ethyl 2-((3S,6S)-6-(3-(3-(dimethylamino)prop-1-yn-1-yl)-6-oxo-4- (trifluoromethyl)pyridazin-1(6H)-yl)-14,16,24-trifluoro-25-methyl-5-oxo-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetate

[0277] Prepared in an analogous manner to Intermediate 17 using Intermediate 146 (50 mg, 74 µmol), Pd(PPh3)2Cl2 (5.2 mg, 7 µmol), copper(I) iodide (2.8 mg, 15 µmol), triethylamine (0.10 mL, 0.74 mmol) and N,N-dimethylpropargylamine (74 µL, 0.74 mmol) in DMF (0.6 mL) at 110 °C for 6 h. Purified by catch and release chromatography (2 g SCX, MeOH followed by 3.5 M ammonia in MeOH) to provide the title compound (16 mg). LCMS (Method 15): 2.65 min, 719.3 [M+H]+. Intermediate 198: Ethyl 2-((3S,6S)-6-(3-(3-(dimethylamino)propyl)-6-oxo-4- (trifluoromethyl)pyridazin-1(6H)-yl)-14,16,24-trifluoro-25-methyl-5-oxo-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetate

[0278] Prepared in an analogous manner to Intermediate 8 using Intermediate 197 (33 mg, 34 µmol) and 10% palladium on carbon (3.7 mg) in IPA (5 mL) and EtOAc (5 mL) with AcOH (2 µL) under a hydrogen atmosphere at RT for 22 h, to provide the title compound (15 mg). LCMS (Method 15): 2.76 min, 723.3 [M+H]+. Intermediate 199: Ethyl (S)-3-((S)-2-(3-chloro-5-methyl-6-oxopyridazin-1(6H)-yl)pent-4- enamido)-3-(4,4'-difluoro-2'-(hex-5-en-1-yl)-5,6'-dimethyl-[1,1'-biphenyl]-3-yl)propanoate

[0279] Prepared in an analogous manner to Intermediate 6 using Intermediate 69 (2.28 g, 3.47 mmol), 3-chloro-5-methyl-1H-pyridazin-6-one (0.60 g, 4.61 mmol, CAS 1834-27- 1) and K2CO3(1.44 g, 10.4 mmol) in MeCN (39 mL) at reflux for 2 h. Purified by flash chromatography (40 g silica gel, 0-50% EtOAc in petroleum ether) to provide the title compound (1.72 g). LCMS (Method 15): 2.80 min, 640.3 [M+H]+. Intermediate 200: Ethyl 2-((3S,6S)-6-(3-chloro-5-methyl-6-oxopyridazin-1(6H)-yl)-14,24- difluoro-16,25-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphan-8-en-3- yl)acetate

[0280] Prepared in an analogous manner to Intermediate 7 using Intermediate 199 (1.72 g, 2.41 mmol) and Grubbs II (0.20 g, 0.24 mmol) in DCE (0.62 L) at 50 °C for 2 h. Purified by flash chromatography (40 g silica gel, 0-40% EtOAc in petroleum ether) to provide the title compound (1.27 g). LCMS (Method 15): 2.71 min, 612.2 [M+H]+. Intermediate 201: Ethyl 2-((3S,6S)-6-(3-chloro-5-methyl-6-oxopyridazin-1(6H)-yl)-14,24- difluoro-16,25-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3-yl)acetate

[0281] Prepared in an analogous manner to Intermediate 8 using Intermediate 200 (0.20 g, 0.27 mmol) and 10% palladium on carbon (29 mg) in EtOAc (12 mL) under a hydrogen atmosphere at RT for 22 h. Purified by flash chromatography (4 g silica gel, 0-30% EtOAc in petroleum ether) to provide the title compound (0.17 g). LCMS (Method 27): 2.22 min, 614.2 [M+H]+. Intermediate 202: Ethyl 2-((3S,6S)-6-(3-(3-(dimethylamino)prop-1-yn-1-yl)-5-methyl-6- oxopyridazin-1(6H)-yl)-14,24-difluoro-16,25-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetate

[0282] Prepared in an analogous manner to Intermediate 17 using Intermediate 201 (0.18 g, 0.26 mmol), Pd(PPh3)2Cl2 (13 mg, 18 µmol), copper(I) iodide (3.4 mg, 18 µmol), triethylamine (0.25 mL, 1.80 mmol) and N,N-dimethylpropargylamine (0.19 mL, 1.80 mmol) in MeCN (2.2 mL) at 75 °C for 41 h. Purified by catch and release chromatography (2 g SCX, MeOH followed by 3.5 M ammonia in MeOH) to provide the title compound (0.11 g). LCMS (Method 27): 2.04 min, 661.3 [M+H]+. Intermediate 203: Ethyl 2-((3S,6S)-6-(3-(3-(dimethylamino)propyl)-5-methyl-6-oxopyridazin- 1(6H)-yl)-14,24-difluoro-16,25-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetate

[0283] Prepared in an analogous manner to Intermediate 8 using Intermediate 202 (87 mg, 0.13 mmol) and 10% palladium on carbon (14 mg) in IPA (16 mL) with AcOH (15 µL) under a hydrogen atmosphere at RT for 1.5 h. Purified by catch and release chromatography(2 g SCX, MeOH followed by 3.5 M ammonia in MeOH) to provide the title compound (70 mg). LCMS (Method 15): 2.72 min, 665.4 [M+H]+. Intermediate 204: Ethyl (S)-3-(4,4'-difluoro-2'-(hex-4-en-1-yl)-5,6'-dimethyl-[1,1'-biphenyl]-3- yl)-3-((R)-2-hydroxy-4-methylpent-4-enamido)propanoate

[0284] Prepared in an analogous manner to Intermediate 4 using Intermediate 96 (1.40 g, 3.08 mmol), Intermediate 205 (0.19 g, 1.49 mmol), DIPEA (1.61 mL, 9.25 mmol), HOBt (0.57 g, 3.39 mmol) and EDCI (0.72 g, 4.63 mmol) in MeCN (21 mL) at RT for 18 h. Purified by flash chromatography (40 g silica gel, 0-60% EtOAc in petroleum ether) to provide the title compound (1.35 g). LCMS (Method 15): 2.34 min, 546.3 [M+H]+. Intermediate 205: (S)-2-Hydroxy-4-methylpent-4-enoic acid

[0285] To a solution of (2R)-2-amino-4-methyl-pent-4-enoic acid (1.22 g, 9.45 mmol, CAS 905929-81-9) in AcOH (15 mL) and water (39 mL) at 0 °C was added a solution of sodium nitrite (1.30 g, 18.9 mmol) in water (2 mL) dropwise, then the mixture was stirred at 0 °C for 1.5 h. Methylamine (2 M in THF, 9.65 mL) was added and the mixture stirred at 0 °C for 30 min. This was diluted with 2 M aqueous HCl and extracted with EtOAc. The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (80 g, silica gel, 0–10% MeOH in (1% AcOH in DCM)) to provide the title compound (0.33 g).1H NMR (500 MHz; CDCl3) δ: 4.96 (d, 1H), 4.87 (s, 1H), 4.41 – 4.38 (m, 1H), 2.66 – 2.61 (m, 1H), 2.42 (dd, 1H), 1.81 (s, 3H) – OH signals not observed. Intermediate 206: Ethyl (S)-3-((S)-2-(5-bromo-3-chloro-6-oxopyridazin-1(6H)-yl)pent-4- enamido)-3-(4,4'-difluoro-2'-(hex-5-en-1-yl)-5,6'-dimethyl-[1,1'-biphenyl]-

[0286] Prepared in an analogous manner to6 using Intermediate 69 (1.44 g, 2.43 mmol), 4-bromo-6-chloro-pyridazin-3-ol (0.51 g, 2.43 mmol, CAS 933041-13-5) and K2CO3 (0.78 g, 5.62 mmol) in MeCN (25 mL) at reflux for 18 h. Purified by flash chromatography (25 g silica gel, 0-40% EtOAc in petroleum ether) to provide the title compound (0.57 g). LCMS (Method 15): 2.84 min, 706.2 [M+H]+. Intermediate 207: Ethyl 2-((3S,6S)-6-(5-bromo-3-chloro-6-oxopyridazin-1(6H)-yl)-14,24- difluoro-16,25-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphan-8-en-3- yl)acetate

[0287] Prepared in an analogous manner to Intermediate 7 using Intermediate 206 (0.76 g, 0.96 mmol) and Grubbs II (82 mg, 96 µmol) in DCE (0.34 L) at 50 °C for 2 h. Purified by flash chromatography (24 g silica gel, 0-40% EtOAc in petroleum ether) to provide the title compound (0.57 g). LCMS (Method 15): 2.73 min, 678.1 [M+H]+.Intermediate 208: Ethyl 2-((3S,6S)-6-(3-chloro-5-cyclopropyl-6-oxopyridazin-1(6H)-yl)-14,24- difluoro-16,25-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphan-8-en-3- yl)acetate

[0288] Prepared in an analogous manner to Intermediate 1 using Intermediate 207 (0.45 g, 0.54 mmol), cyclopropaneboronic acid (51 mg, 0.59 mmol), Na2CO3 (0.11 g, 1.07 mmol), Pd(dppf)Cl2(44 mg, 53 µmol) in toluene (5.3 mL) and water (1.3 mL) at 95 °C for 5 h. Purified by flash chromatography (24 g silica gel, 0-40% EtOAc in petroleum ether) to provide the title compound (0.26 g). LCMS (Method 15): 2.78 min, 638.3 [M+H]+. Intermediate 209: Ethyl 2-((3S,6S)-6-(3-chloro-5-cyclopropyl-6-oxopyridazin-1(6H)-yl)-14,24- difluoro-16,25-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3-yl)acetate

[0289] Prepared in an analogous manner to Intermediate 8 using Intermediate 208 (0.26 g, 0.40 mmol) and 10% palladium on carbon (43 mg) in EtOAc (37 mL) under a hydrogen atmosphere at RT for 8 h. Purified by flash chromatography (12 g silica gel, 0-40% EtOAc in petroleum ether) to provide the title compound (0.24 g). LCMS (Method 15): 2.79 min, 640.3 [M+H]+. Intermediate 210: Ethyl 2-((3S,6S)-6-(5-cyclopropyl-3-((E)-2-ethoxyvinyl)-6-oxopyridazin- 1(6H)-yl)-14,24-difluoro-16,25-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetate

[0290] Prepared in an analogous manner to Intermediate 29 using Intermediate 209 (0.25 g, 0.40 mmol), trans-2-ethoxyvinylboronic acid pinacol ester (86 mg, 0.44 mmol, CAS 1201905-61-4), Pd(dppf)Cl2 (29 mg, 40 µmol) and Na2CO3 (84 mg, 0.79 mmol) in 1,4-dioxane (4.4 mL) and water (1.5 mL) at 90 °C for 1.5 h. Purified by flash chromatography (12 g silica gel, 0-40% EtOAc in petroleum ether), to provide the title compound (0.16 g). LCMS (Method 15): 2.84 min, 676.3 [M+H]+. Intermediate 211: Ethyl 2-((3S,6S)-6-(5-cyclopropyl-3-(2-(3-fluoroazetidin-1-yl)ethyl)-6- oxopyridazin-1(6H)-yl)-14,24-difluoro-16,25-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetate

[0291] Prepared in an analogous manner to Intermediate 46 using Intermediate 210 (82 mg, 0.12 mmol) in DCM (2.4 mL) and TFA (0.19 mL) at RT for 3 h. Then 3-fluoroazetidine hydrochloride (16 mg 0.15 mmol, CAS 617718-46-4), triethylamine (51 µL, 0.36 mmol) in DCM (2.4 mL) with 4 Å molecular sieves at RT for 1 h, followed by STAB (51 mg, 0.24 mmol) at RT for 18 h. Purified by catch and release chromatography (2 g SCX, MeOH followed by 3.5 M ammonia in MeOH) to provide the title compound (45 mg). LCMS (Method 15): 2.69 min, 707.4 [M+H]+.Intermediate 212: Ethyl (S)-3-(4,4'-difluoro-2'-(hex-4-en-1-yl)-5,6'-dimethyl-[1,1'-biphenyl]-3- yl)-3-((R)-4-methyl-2-((methylsulfonyl)oxy)pent-4-enamido)propanoate

[0292] Prepared in an analogous manner to Intermediate 5 using Intermediate 204 (0.57 g, 0.99 mmol), triethylamine (0.28 mL, 1.98 mmol) and methanesulfonyl chloride (0.12 mL, 1.49 mmol) in DCM (7 mL) at RT for 1 h, to provide the title compound (0.84 g). LCMS (Method 15): 2.74 min, 606.2 [M+H]+. Intermediate 213: Ethyl (S)-3-(4,4'-difluoro-2'-(hex-4-en-1-yl)-5,6'-dimethyl-[1,1'-biphenyl]-3- yl)-3-((S)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4- methylpent-4-enamido)propanoate

[0293] Prepared in an analogous manner to Intermediate 6 using Intermediate 212 (0.84 g, 1.09 mmol), 5-[2-(dimethylamino)ethyl]-4-(trifluoromethyl)-1H-pyridin-2-one (0.31 g, 1.30 mmol, CAS 2378705-10-1) and K2CO3 (0.45 g, 3.26 mmol) in MeCN (11 mL) at reflux for 20 h. Purified by flash chromatography (40 g silica gel, 0-3% (0.5% ammonia MeOH) in DCM) to provide the title compound (0.15 g). LCMS (Method 15): 2.90 min, 744.4 [M+H]+. Intermediate 214: Ethyl 2-((3S,6S)-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4- (trifluoromethyl)pyridin-1(2H)-yl)-14,24-difluoro-16,25,8-trimethyl-5-oxo-4-aza-1(1,2),2(1,3)- dibenzenacyclododecaphan-8-en-3-yl)acetate

[0294] Prepared in an analogous manner to Intermediate 7 using Intermediate 213 (0.15 g, 0.20 mmol) and Grubbs II (17 mg, 19 µmol) in toluene (61 mL) at 80 °C for 2 h. Purified by flash chromatography (12 g silica gel, 0-100% EtOAc in petroleum ether) to provide the title compound (0.13 g). LCMS (Method 15): 2.71 min, 702.3 [M+H]+. Intermediate 215: Ethyl 2-((3S,6S)-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4- (trifluoromethyl)pyridin-1(2H)-yl)-14,24-difluoro-16,25,8-trimethyl-5-oxo-4-aza-1(1,2),2(1,3)- dibenzenacyclododecaphane-3-yl)acetate

[0295] Prepared in an analogous manner to Intermediate 8 using Intermediate 214 (0.13 g, 0.18 mmol) and 10% palladium on carbon (19 mg) in ethanol (5.6 mL) under a hydrogen atmosphere at RT for 30 h. Purified by flash chromatography (40 g silica gel, 0-10% (0.5% ammonia MeOH) in DCM) to provide the title compound (67 mg). LCMS (Method 15): 2.76 min, 704.3 [M+H]+. Intermediate 216: Ethyl 2-((3S,6S)-6-(3-(2-(azetidin-1-yl)ethyl)-5-cyclopropyl-6- oxopyridazin-1(6H)-yl)-14,24-difluoro-16,25-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetate

[0296] Prepared in an analogous manner to Intermediate 46 using Intermediate 210 (0.11 g, 0.17 mmol) in DCM (3.4 mL) and TFA (0.26 mL) at RT for 1 h. Then azetidine (11 µL,0.17 mmol), triethylamine (71 µL, 0.51 mmol) in DCM (3.4 mL) with 4 Å molecular sieves at RT for 1 h, followed by STAB (72 mg, 0.34 mmol) at RT for 18 h. Purified by catch and release chromatography (2 g SCX, MeOH followed by 3.5 M ammonia in MeOH) to provide the title compound (56 mg). LCMS (Method 15): 3.06 min, 689.4 [M+H]+. Intermediate 220: Ethyl 2-((3S,6S)-6-(3-((E)-2-ethoxyvinyl)-5-methyl-6-oxopyridazin-1(6H)- yl)-14,24-difluoro-16,25-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3- yl)acetate

[0297] Prepared in an analogous manner to Intermediate 29 using Intermediate 201 (0.40 g, 0.65 mmol), trans-2-ethoxyvinylboronic acid pinacol ester (0.14 g, 0.72 mmol, CAS 1201905-61-4), Pd(dppf)Cl2 (48 mg, 65 µmol) and Na2CO3 (0.14 g, 1.30 mmol) in toluene (7.5 mL) and water (2.6 mL) at 90 °C for 28 h. Purified by flash chromatography (25 g silica gel, 0- 40% EtOAc in petroleum ether), to provide the title compound (0.12 g). LCMS (Method 15): 2.78 min, 650.3 [M+H]+. Intermediate 221: Ethyl 2-((3S,6S)-14,24-difluoro-6-(3-(2-(3-fluoroazetidin-1-yl)ethyl)-5- methyl-6-oxopyridazin-1(6H)-yl)-16,25-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetate

[0298] Prepared in an analogous manner to Intermediate 46 using Intermediate 220 (0.12 g, 0.17 mmol) in DCM (2.1 mL) and TFA (0.26 mL) at RT for 5 h. Then 3-fluoroazetidine hydrochloride (23 mg, 0.20 mmol, CAS 617718-46-4), triethylamine (94 µL, 0.67 mmol) in DCM (7.2 mL) with 4 Å molecular sieves at RT for 15 min, followed by STAB (71 mg, 0.34 mmol) at RT for 18 h. Purified by catch and release chromatography (5 g SCX, MeOH followed by 3.5 M ammonia in MeOH) to provide the title compound (16 mg). LCMS (Method 15): 2.63 min, 681.4 [M+H]+. Intermediate 222: Ethyl 2-((3S,6S)-6-(3-(2-(azetidin-1-yl)ethyl)-5-methyl-6-oxopyridazin- 1(6H)-yl)-14,24-difluoro-16,25-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetate

[0299] Prepared in an analogous manner to Intermediate 46 using Intermediate 220 (0.18 g, 0.25 mmol) in DCM (3.1 mL) and TFA (0.38 mL) at RT for 5 h. Then azetidine (20 µL, 0.29 mmol), triethylamine (0.14 mL, 0.98 mmol) in DCM (10 mL) with 4 Å molecular sieves at RT for 1 h, followed by STAB (0.10 g, 0.49 mmol) at RT for 18 h. Purified by catch and release chromatography (2 g SCX, MeOH followed by 3.5 M ammonia in MeOH) to provide the title compound (0.13 g). LCMS (Method 15): 2.78 min, 663.4 [M+H]+. Intermediate 223: (R,Z)-N-(3-Bromo-5-(trifluoromethyl)benzylidene)-2-methylpropane-2- sulfinamide

[0300] Prepared in an analogous manner to Intermediate 37 using 3-bromo-5- (trifluoromethyl)benzaldehyde (10.0 g, 43.6 mmol, CAS 477535-41-4), (R)-2-methylpropane- 2-sulfinamide (5.28 g, 43.6 mmol, CAS 196929-78-9) and titanium ethoxide (13.6 g, 59.5 mmol) in THF (72 mL) at 40 °C for 18 h, to provide the title compound (12.1 g).1H NMR (400 MHz; CDCl3) δ: 8.57 (s, 1H), 8.16 (s, 1H), 8.01 (s, 1H), 7.89 (s, 1H), 1.28 (s, 9H). Intermediate 224: Ethyl (S)-3-(3-bromo-5-(trifluoromethyl)phenyl)-3-(((R)-tert- butylsulfinyl)amino)propanoate

[0301] Prepared in an analogous manner to Intermediate 38 using zinc (6.98 g, 0.11 mol), chlorotrimethylsilane (0.54 mL, 4.27 mmol) and ethyl bromoacetate (5.92 mL, 53.5 mmol) in THF (0.10 L) at 65 °C for 1 h, then Intermediate 223 (7.60 g, 21.3 mmol) in THF (22 mL) at RT for 1 h. Purified by dry flash chromatography (1 kg silica gel, 0-30% EtOAc in petroleum ether) then flash chromatography (120 g silica gel, 0-30% EtOAc in petroleum ether) to provide the title compound (6.3 g). LCMS (Method 15): 2.22 min, 446.0 [M+H]+. Intermediate 225: Ethyl (S)-3-amino-3-(3-bromo-5-(trifluoromethyl)phenyl)propanoate

[0302] A solution of Intermediate 224 (9.6 g, 21.6 mmol) in DCM (12.5 mL) and 4 M HCl in 1,4-dioxane (32 mL) was stirred at RT for 2 h. The mixture concentrated under reduced pressure, diluted with water and washed with EtOAc. The aqueous was basified with aqueous NaHCO3 and extracted with EtOAc. The organics were dried over Na2SO4, filtered and concentrated under reduced pressure, to provide the title compound (2.0 g). LCMS (Method 15): 1.99 min, 342.0 [M+H]+. Intermediate 226: Ethyl (S)-3-(3-bromo-5-(trifluoromethyl)phenyl)-3-((tert- butoxycarbonyl)amino)propanoate

[0303] Prepared in an analogous manner to Intermediate 20 using Intermediate 225 (2.1 g, 6.17 mmol), Boc anhydride (1.62 g, 7.41 mmol) and DIPEA (1.61 mL, 9.26 mmol) in DCM (15 mL) at RT for 2 h. Purified by flash chromatography (40 g silica gel, 0-20% EtOAc in petroleum ether) to provide the title compound (2.40 g). LCMS (Method 4): 2.36 min, 341.9 [M-Boc+H]+. Intermediate 227: Ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(4'-fluoro-2'-hydroxy-6'-methyl- 5-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)propanoate

[0304] in an analogous manner to Intermediate 1 using Intermediate 226 (0.10 g, 0.22 mmol), Intermediate 191 (65 mg, 0.26 mmol), K3PO4(0.14 g, 0.65 mmol), XPhosPdG2 (17 mg, 22 µmol) in 1,4-dioxane (4.1 mL) and water (1 mL) at 110 °C for 3 h. Purified by flash chromatography (12 g silica gel, 0-30% EtOAc in petroleum ether) to provide the title compound (35 mg). LCMS (Method 15): 2.37 min, 484.2 [M-H]-.Intermediate 228: Ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(4'-fluoro-2'-methyl-5- (trifluoromethyl)-6'-((oxy)-[1,1'-biphenyl]-3-yl)propanoate

[0305] Prepared in an analogous manner to Intermediate 10 using Intermediate 227 (0.83 g, 1.64 mmol), phenyl triflimide (0.58 g, 1.63 mmol, CAS 37595-74-7) and Cs2CO3(0.64 g, 1.95 mmol) in DCM (8.2 mL) at RT for 20 h. Purified by flash chromatography (25 g silica gel, 0–30% EtOAc in petroleum ether) to provide the title compound (0.88 g). LCMS (Method 15): 2.65 min, 518.1 [M-Boc+H]+. Intermediate 229: Ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(4'-fluoro-2'-(hex-5-en-1-yl)-6'- methyl-5-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)propanoate

[0306] Prepared in an analogous manner to Intermediate 1 using Intermediate 228 (0.59 g, 0.91 mmol), 5-hexenylboronic acid (0.26 g, 2.29 mmol, CAS 1072952-16-9), K2CO3 (0.32 g, 2.29 mmol), RuPhosPdG3 (76 mg, 91 µmol) and RuPhos (43 mg, 91 µmol) in toluene (41 mL) and water (5 mL) at 95 °C for 1 h. Purified by flash chromatography (40 g silica gel, 0-30% EtOAc in petroleum ether) to provide the title compound (0.45 g). LCMS (Method 15): 2.77 min, 452.4 [M-Boc+H]+. Intermediate 230: Ethyl (S)-3-amino-3-(4'-fluoro-2'-(hex-5-en-1-yl)-6'-methyl-5- (trifluoromethyl)-[1,1'-biphenyl]-3-yl)propanoate

[0307] A suspension of Intermediate 229 (0.83 g, 1.29 mmol) in 4 M HCl in 1,4- dioxane (3.2 mL) was stirred at RT for 1 h. The mixture was concentrated under reduced pressure and purified by catch and release chromatography (10 g SCX, MeOH followed by 3.5 M ammonia in MeOH) to provide the title compound (0.58 g). LCMS (Method 15): 2.69 min, 452.1 [M+H]+. Intermediate 231: Ethyl (S)-3-(4'-fluoro-2'-(hex-5-en-1-yl)-6'-methyl-5-(trifluoromethyl)-[1,1'- biphenyl]-3-yl)-3-((R)-2-hydroxypent-4-enamido)propanoate

[0308] Prepared in an analogous manner to Intermediate 4 using Intermediate 230 (0.58 g, 1.17 mmol), (2R)-2-hydroxypent-4-enoic acid (0.23 g, 1.75 mmol, CAS 413622-10-3), DIPEA (0.62 mL, 3.50 mmol), HOBt (0.20 g, 1.17 mmol) and EDCI (0.27 g, 1.40 mmol) in MeCN (11 mL) at RT for 72 h. Purified by flash chromatography (24 g silica gel, 0-60% EtOAc in petroleum ether) to provide the title compound (0.52 g). LCMS (Method 15): 2.65 min, 550.2 [M+H]+. Intermediate 232: Ethyl (S)-3-(4'-fluoro-2'-(hex-5-en-1-yl)-6'-methyl-5-(trifluoromethyl)-[1,1'- biphenyl]-3-yl)-3-((R)-2-((methylsulfonyl)oxy)pent-4-enamido)propanoate

[0309] Prepared in an analogous manner to Intermediate 5 using Intermediate 231 (0.52 g, 0.95 mmol), triethylamine (0.26 mL, 1.90 mmol) and methanesulfonyl chloride (0.11 mL, 1.42 mmol) in DCM (6 mL) at RT for 1 h, to provide the title compound (0.70 g). LCMS (Method 15): 2.71 min, 628.3 [M+H]+. Intermediate 233: Ethyl (S)-3-((S)-2-(5-bromo-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)pent- 4-enamido)-3-(4'-fluoro-2'-(hex-5-en-1-yl)-6'-methyl-5-(trifluoromethyl)-[1,1'-biphenyl]-3- yl)propanoate

[0310] Prepared in an analogous manner to Intermediate 6 using Intermediate 232 (1.15 g, 1.83 mmol), 5-bromo-4-(trifluoromethyl)pyridin-2-ol (0.44 g, 1.83 mmol, CAS 109919- 32-6) and K2CO3 (0.76 g, 5.50 mmol) in MeCN (28 mL) at reflux for 18 h. Purified by flash chromatography (40 g silica gel, 0-30% EtOAc in petroleum ether) to provide the title compound (0.84 g). LCMS (Method 15): 2.90 min, 775.2 [M+H]+. Intermediate 234: Ethyl 2-((3S,6S)-6-(5-bromo-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-14- fluoro-16-methyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphan-8- en-3-yl)acetate

[0311] Prepared in an analogous manner to Intermediate 7 using Intermediate 233 (0.84 g, 1.08 mmol) and Grubbs II (92 mg, 0.11 mmol) in DCE (0.37 L) at 50 °C for 2 h. Purified by flash chromatography (24 g silica gel, 0-30% EtOAc in petroleum ether) to provide the title compound (0.60 g). LCMS (Method 15): 2.81 min, 747.2 [M+H]+. Intermediate 235: Ethyl 2-((3S,6S)-6-(5-(3-(dimethylamino)prop-1-yn-1-yl)-2-oxo-4- (trifluoromethyl)pyridin-1(2H)-yl)-14-fluoro-16-methyl-5-oxo-25-(trifluoromethyl)-4-aza- 1(1,2),2(1,3)-dibenzenacyclotridecaphan-8-en-3-yl)acetate

[0312] Prepared in an analogous manner to Intermediate 17 using Intermediate 234 (0.30 g, 0.41 mmol), Pd(PPh3)2Cl2 (20 mg, 28 µmol), copper(I) iodide (5.4 mg, 28 µmol), triethylamine (0.40 mL, 2.84 mmol) and N,N-dimethylpropargylamine (0.31 mL, 2.84 mmol) in MeCN (8 mL) at 80 °C for 16 h. Purified by catch and release chromatography (2 g SCX, MeOH followed by 3.5 M ammonia in MeOH) to provide the title compound (0.13 g). LCMS (Method 27): 2.73 min, 748.4 [M+H]+. Intermediate 236: Ethyl 2-((3S,6S)-6-(5-(3-(dimethylamino)propyl)-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)acetate

[0313] Prepared in an analogous manner to Intermediate 8 using Intermediate 235 (0.12 g, 0.16 mmol) and 10% palladium on carbon (18 mg) in ethanol (18 mL) under a hydrogen atmosphere at RT for 3 h. Purified by flash chromatography (4 g silica gel, 10%(0.5% ammonia MeOH) in DCM) to provide the title compound (79 mg). LCMS (Method 15): 2.85 min, 754.4 [M+H]+. Intermediate 237: Ethyl 2-((3S,6S)-6-(5-((E)-2-ethoxyvinyl)-2-oxo-4-(trifluoromethyl)pyridin- 1(2H)-yl)-14-fluoro-16-methyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphan-8-en-3-yl)acetate

[0314] Prepared in an analogous manner to Intermediate 29 using Intermediate 234 (0.30 g, 0.39 mmol), trans-2-ethoxyvinylboronic acid pinacol ester (82 mg, 0.41 mmol, CAS 1201905-61-4), Pd(dppf)Cl2 (29 mg, 39 µmol) and Na2CO3 (83 mg, 0.79 mmol) in 1,4-dioxane (8 mL) and water (2 mL) at 85 °C for 2 h. Purified by flash chromatography (25 g silica gel, 0- 40% EtOAc in petroleum ether), to provide the title compound (0.19 g). LCMS (Method 15): 2.83 min, 737.3 [M+H]+. Intermediate 238: Ethyl 2-((3S,6S)-14-fluoro-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)- dibenzenacyclotridecaphan-8-en-3-yl)acetate

[0315] Prepared in an analogous manner to Intermediate 46 using Intermediate 237 (0.19 g, 0.25 mmol) in DCM (6.2 mL) and TFA (0.40 mL) at RT for 2 h. Then 3- methoxyazetidine hydrochloride (38 mg, 0.31 mmol, CAS 148644-09-1), triethylamine (0.14 mL, 1.02 mmol) in DCM (12 mL) with 4 Å molecular sieves at RT for 15 min, followed by STAB (0.11 g, 0.51 mmol) at RT for 2 h. Purified by catch and release chromatography (2 g SCX, MeOH followed by 3.5 M ammonia in MeOH) to provide the title compound (95 mg). LCMS (Method 15): 2.67 min, 780.3 [M+H]+. Intermediate 239: Ethyl 2-((3S,6S)-14-fluoro-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)acetate

[0316] Prepared in an analogous manner to Intermediate 8 using Intermediate 238 (95 mg, 0.12 mmol) and 10% palladium on carbon (13 mg) in ethanol (11 mL) under a hydrogen atmosphere at RT for 3 h. Purified by flash chromatography (4 g silica gel, 10% (0.5% ammonia MeOH) in DCM) to provide the title compound (90 mg). LCMS (Method 15): 2.71 min, 782.4 [M+H]+. Intermediate 251: Ethyl (S)-3-((S)-2-(5-bromo-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)pent- 4-enamido)-3-(4,4'-difluoro-2'-(hex-5-en-1-yl)-6'-methyl-[1,1'-biphenyl]-3-yl)propanoate

[0317] Prepared in an analogous manner to6 using Intermediate 86 (1.76 g, 2.47 mmol), 5-bromo-4-(trifluoromethyl)pyridin-2-ol (0.88 g, 3.66 mmol, CAS 109919- 32-6) and K2CO3(1.01 g, 7.31 mmol) in MeCN (49 mL) at reflux for 18 h. Purified by flashchromatography (40 g silica gel, 0-40% EtOAc in petroleum ether) to provide the title compound (1.05 g). LCMS (Method 15): 2.83 min, 721.2 [M-H]-. Intermediate 252: Ethyl 2-((3S,6S)-6-(5-bromo-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)- 14,24-difluoro-16-methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphan-8-en-3- yl)acetate

[0318] Prepared in an analogous manner to Intermediate 7 using Intermediate 251 (1.05 g, 1.23 mmol) and Grubbs II (0.11 g, 0.12 mmol) in DCE (0.65 L) at 50 °C for 1 h. Purified by flash chromatography (40 g silica gel, 0-30% EtOAc in petroleum ether) to provide the title compound (0.66 g). LCMS (Method 15): 2.74 min, 697.2 [M+H]+. Intermediate 253: Ethyl 2-((3S,6S)-6-(5-bromo-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)acetate

[0319] Prepared in an analogous manner to Intermediate 8 using Intermediate 252 (0.66 g, 0.81 mmol) and 10% palladium on carbon (86 mg) in EtOAc (50 mL) under a hydrogen atmosphere at RT for 1 h, to provide the title compound (0.59 g). LCMS (Method 11): 2.68 min, 699.3 [M+H]+. Intermediate 254: Ethyl 2-((3S,6S)-6-(5-((E)-2-ethoxyvinyl)-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)acetate

[0320] Prepared in an analogous manner to Intermediate 29 using Intermediate 253 (0.33 g, 0.43 mmol), trans-2-ethoxyvinylboronic acid pinacol ester (89 mg, 0.45 mmol, CAS 1201905-61-4), Pd(dppf)Cl2 (31 mg, 43 µmol) and Na2CO3 (91 mg, 0.86 mmol) in 1,4-dioxane (9 mL) and water (2.5 mL) at 90 °C for 4 h. Purified by flash chromatography (25 g silica gel, 0-20% EtOAc in petroleum ether), to provide the title compound (0.12 g). LCMS (Method 15): 2.80 min, 689.2 [M+H]+. Intermediate 255: Ethyl 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-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetate

[0321] Prepared in an analogous manner to Intermediate 46 using Intermediate 254 (59 mg, 69 µmol) in DCM (3.1 mL) and TFA (0.34 mL) at RT for 2 h. Then 3-methoxyazetidine hydrochloride (10 mg, 82 µmol, CAS 148644-09-1), triethylamine (38 µL, 0.27 mmol) in DCM (0.7 mL) with 4 Å molecular sieves at RT for 1 h, followed by STAB (29 mg, 0.14 mmol) at RT for 18 h. Purified by catch and release chromatography (2 g SCX, MeOH followed by 3.5 M ammonia in MeOH) to provide the title compound (55 mg). LCMS (Method 15): 2.62 min, 732.3 [M+H]+.Intermediate 256: Ethyl 2-((3S,6S)-6-(5-(3-(dimethylamino)prop-1-yn-1-yl)-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)acetate

[0322] Prepared in an analogous manner to Intermediate 17 using Intermediate 253 (0.32 g, 0.26 mmol), Pd(PPh3)2Cl2 (23 mg, 33 µmol), copper(I) iodide (6 mg, 32 µmol), triethylamine (0.45 mL, 3.23 mmol) and N,N-dimethylpropargylamine (0.10 mL, 0.93 mmol) in MeCN (5 mL) at 80 °C for 40 h. Repeated conditions but in DMF (5 mL) at 110 °C for 10 h. Purified by catch and release chromatography (2 g SCX, MeOH followed by 3.5 M ammonia in MeOH) to provide the title compound (0.15 g). LCMS (Method 11): 2.60 min, 700.4 [M+H]+. Intermediate 257: Ethyl 2-((3S,6S)-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)acetate

[0323] Prepared in an analogous manner to Intermediate 8 using Intermediate 256 (0.12 g, 0.12 mmol) and 10% palladium on carbon (25 mg) in EtOAc (50 mL) under a hydrogen atmosphere at RT for 8 h. Purified by flash chromatography (25 g silica gel, 0-10% MeOH in DCM) to provide the title compound (85 mg). LCMS (Method 27): 2.28 min, 704.3 [M+H]+. Intermediate 278: 5-(2-(3-Methoxyazetidin-1-yl)ethyl)-4-methylpyrimidin-2(1H)-one

[0324] A solution of (E)-5-(2-ethoxyvinyl)-2-methoxy-4-methylpyrimidine (0.58 g, 2.68 mmol, CAS 2955527-94-1) in 33% HBr in AcOH (11.0 mL, 63.5 mmol) was stirred at 65 °C for 1 h. The mixture was cooled and concentrated under reduced pressure then dissolved in DCM (20 mL). To this was added 3-methoxyazetidine hydrochloride (0.50 g, 4.02 mmol), triethylamine (0.45 mL, 3.21 mmol) and 4 Å molecular sieves at RT for 10 min, followed by STAB (1.42 g, 6.70 mmol) at RT for 60 h. The mixture was filtered and washed with MeOH, then the filtrate concentrated under reduced pressure. The crude product was purified by catch and release chromatography (10 g SCX, MeOH followed by 1 M ammonia in MeOH) to provide the title compound (0.37 g).1H NMR (400 MHz; CD3OD) δ: 7.98 (s, 1H), 4.16 – 4.01 (m, 1H), 3.64 – 3.58 (m, 2H), 3.26 (s, 3H), 3.05 – 2.98 (m, 2H), 2.67 – 2.60 (m, 2H), 2.53 – 2.45 (m, 2H), 2.35 (s, 3H). Intermediate 409: Ethyl 2-((3S,6R)-14,24-difluoro-6-hydroxy-16-methyl-5-oxo-25- (trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphan-8-en-3-yl)acetate

[0325] Prepared in an analogous manner to Intermediate 7 using Intermediate 40 (0.40 g, 0.67 mmol) and Grubbs II (0.11 g, 0.13 mmol) in DCE (0.26 L) at 50 °C for 1 h. Purified by flash chromatography (25 g silica gel, 0-60% EtOAc in petroleum ether) to provide the title compound (0.45 g). LCMS (Method 11): 2.40 min, 540.3 [M+H]+.Intermediate 410: Ethyl 2-((3S,6R)-14,24-difluoro-6-hydroxy-16-methyl-5-oxo-25- (trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3-yl)acetate

[0326] Prepared in an analogous manner to Intermediate 8 using Intermediate 409 (0.45 g, 0.57 mmol) and 10% palladium on carbon (61 mg) in ethanol (25 mL) under a hydrogen atmosphere at RT for 2 h, to provide the title compound (0.34 g). LCMS (Method 11): 2.43 min, 542.3 [M+H]+. Intermediate 411: 3-(5-Methoxypyrazin-2-yl)-N,N-dimethylprop-2-yn-1-amine

[0327] Prepared in an analogous manner to Intermediate 17 using 2-bromo-5- methoxypyrazine (0.50 g, 2.65 mmol, CAS 143250-10-6), Pd(PPh3)2Cl2 (0.13 g, 0.19 mmol), copper(I) iodide (35 mg, 0.19 mmol), triethylamine (2.58 mL, 18.5 mmol) and N,N- dimethylpropargylamine (1.99 mL, 18.5 mmol) in MeCN (16 mL) at 80 °C for 16 h. Purified by flash chromatography (25 g silica gel, 0-10% MeOH in DCM) to provide the title compound (0.46 g). LCMS (Method 15): 1.40 min, 192.1 [M+H]+. Intermediate 412: 3-(5-Methoxypyrazin-2-yl)-N,N-dimethylpropan-1-amine

[0328] Prepared in an analogous manner to Intermediate 8 using Intermediate 411 (0.46 g, 2.41 mmol) and 10% palladium on carbon (0.13 g) in EtOAc (30 mL) and AcOH (0.28 mL) under a hydrogen atmosphere at RT for 2 h. Purified by catch and release chromatography (20 g SCX, MeOH followed by 1 M ammonia in MeOH) to provide the title compound (0.28 g). LCMS (Method 15): 1.41 min, 196.1 [M+H]+. Intermediate 413: 5-(3-(Dimethylamino)propyl)pyrazin-2(1H)-one

[0329] A solution of Intermediate 412 (0.25 g, 1.26 mmol) in 33% HBr in AcOH (4.35 mL, 25.1 mmol) was stirred at 65 °C for 1 h. The mixture was cooled and concentrated under reduced pressure. The crude product was purified by catch and release chromatography (5 g SCX, MeOH followed by 1 M ammonia in MeOH) to provide the title compound (0.23 g).1H NMR (400 MHz; CDCl3) δ: 8.16 (s, 1H), 7.10 (s, 1H), 2.60 (t, 2H), 2.38 – 2.32 (m, 2H), 2.24 (s, 6H), 1.92 – 1.78 (m, 2H). Intermediate 414: Ethyl 2-((3S,6R)-14,24-difluoro-16-methyl-6-((methylsulfonyl)oxy)-5-oxo- 25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3-yl)acetate

[0330] Prepared in an analogous manner to Intermediate 5 using Intermediate 410 (0.34 g, 0.57 mmol), triethylamine (0.16 mL, 1.15 mmol) and methanesulfonyl chloride (66 µL, 0.86 mmol) in DCM (6 mL) at RT for 1 h, to provide the title compound (0.40 g). LCMS (Method 11): 2.50 min, 620.3 [M+H]+.Intermediate 415: Ethyl 2-((3S,6S)-6-(5-(3-(dimethylamino)propyl)-2-oxopyrazin-1(2H)-yl)- 14,24-difluoro-16-methyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetate

[0331] Prepared in an analogous manner to Intermediate 6 using Intermediate 414 (0.30 g, 0.43 mmol), Intermediate 413 (93 mg, 0.51 mmol) and K2CO3 (0.18 g, 1.28 mmol) in MeCN (5 mL) at reflux for 5 h, to provide the title compound (0.27 g). LCMS (Method 15): 2.67 min, 705.3 [M+H]+. Intermediate 416: Ethyl (S)-3-(4,4'-difluoro-2'-(hex-5-en-1-yl)-6'-methyl-5-(trifluoromethyl)- [1,1'-biphenyl]-3-yl)-3-((S)-2-(5-(2-(dimethylamino)ethyl)-4-methyl-2-oxopyridin-1(2H)- yl)pent-4-enamido)propanoate

[0332] Prepared in an analogous manner to Intermediate 6 using Intermediate 41 (0.46 g, 0.71 mmol), 5-[2-(dimethylamino)ethyl]-4-methyl-1H-pyridin-2-one (0.18 g, 1.21 mmol, CAS 2378704-99-3) and K2CO3 (0.30 g, 2.17 mmol) in MeCN (20 mL) at reflux for 24 h. Purified by flash chromatography (25 g silica gel, 0-20% (0.5% ammonia MeOH) in DCM) to provide the title compound (0.28 g). LCMS (Method 31): 2.51 min, 730.5 [M+H]+. Intermediate 417: Ethyl 2-((3S,6S)-6-(5-(2-(dimethylamino)ethyl)-4-methyl-2-oxopyridin- 1(2H)-yl)-14,24-difluoro-16-methyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphan-8-en-3-yl)acetate

[0333] Prepared in an analogous manner to Intermediate 7 using Intermediate 416 (0.28 g, 0.29 mmol) and Grubbs II (25 mg, 29 µmol) in DCE (0.15 L) at 50 °C for 2.5 h. Purified by flash chromatography (25 g silica gel, 0-20% (0.5% ammonia MeOH) in DCM) to provide the title compound (0.15 g). LCMS (Method 27): 1.91 min, 702.3 [M+H]+. Intermediate 418: Ethyl 2-((3S,6S)-6-(5-(2-(dimethylamino)ethyl)-4-methyl-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)acetate

[0334] Prepared in an analogous manner to Intermediate 8 using Intermediate 417 (0.15 g, 0.15 mmol) and 10% palladium on carbon (60 mg) in ethanol (10 mL) under a hydrogen atmosphere at RT for 12 h, to provide the title compound (81 mg). LCMS (Method 27): 1.99 min, 704.3 [M+H]+. Intermediate 419: Ethyl (S)-3-((S)-2-(5-bromo-4-methyl-2-oxopyridin-1(2H)-yl)pent-4- enamido)-3-(4,4'-difluoro-2'-(hex-5-en-1-yl)-6'-methyl-5-(trifluoromethyl)-[1,1'-biphenyl]-3- yl)propanoate

[0335] Prepared in an analogous manner to Intermediate 6 using Intermediate 41 (1.09 g, 1.69 mmol), 5-bromo-4-methyl-1H-pyridin-2-one (0.35 g, 1.86 mmol, CAS 164513-38-6) and K2CO3(0.70 g, 5.06 mmol) in MeCN (27 mL) at reflux for 16 h. Purified by flash chromatography (80 g silica gel, 0-40% EtOAc in petroleum ether) to provide the title compound (0.59 g). LCMS (Method 15): 2.86 min, 739.3 [M+H]+. Intermediate 420: Ethyl 2-((3S,6S)-6-(5-bromo-4-methyl-2-oxopyridin-1(2H)-yl)-14,24- difluoro-16-methyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphan- 8-en-3-yl)acetate

[0336] Prepared in an analogous manner to Intermediate 7 using Intermediate 419 (0.59 g, 0.72 mmol) and Grubbs II (61 mg, 72 µmol) in DCE (0.36 L) at 50 °C for 1 h. Purified by flash chromatography (40 g silica gel, 0-50% EtOAc in petroleum ether) to provide the title compound (0.35 g). LCMS (Method 15): 2.77 min, 711.2 [M+H]+. Intermediate 421: Ethyl 2-((3S,6S)-6-(5-bromo-4-methyl-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)acetate

[0337] Prepared in an analogous manner to Intermediate 8 using Intermediate 420 (0.35 g, 0.49 mmol) and 10% palladium on carbon (78 mg) in EtOAc (50 mL) under a hydrogen atmosphere at RT for 1 h. Purified by flash chromatography (40 g silica gel, 0-50% EtOAc in petroleum ether) to provide the title compound (0.19 g). LCMS (Method 11): 2.63 min, 711.3 [M+H]+. Intermediate 422: Ethyl 2-((3S,6S)-6-(5-(3-(dimethylamino)prop-1-yn-1-yl)-4-methyl-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)acetate

[0338] Prepared in an analogous manner to Intermediate 17 using Intermediate 421 (0.19 g, 0.22 mmol), Pd(PPh3)2Cl2 (15 mg, 21 µmol), copper(I) iodide (5 mg, 26 µmol), triethylamine (0.30 mL, 2.15 mmol) and N,N-dimethylpropargylamine (0.25 mL, 2.32 mmol) in DMF (5 mL) at 80 °C for 18 h. Purified by flash chromatography (25 g silica gel, 0-20% (0.5% ammonia MeOH) in DCM) to provide the title compound (76 mg). LCMS (Method 31): 2.29 min, 714.5 [M+H]+. Intermediate 423: Ethyl 2-((3S,6S)-6-(5-(3-(dimethylamino)propyl)-4-methyl-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)acetate

[0339] Prepared in an analogous manner to Intermediate 8 using Intermediate 422 (76 mg, 79 µmol) and 10% palladium on carbon (20 mg) in ethanol (5 mL) under a hydrogen atmosphere at RT for 2.5 h. Purified by catch and release chromatography (5 g SCX, MeOHfollowed by 1 M ammonia in MeOH) to provide the title compound (58 mg). LCMS (Method 31): 2.57 min, 718.1 [M+H]+. Intermediate 424: (E)-5-(2-Ethoxyvinyl)-2-methoxy-4-(trifluoromethyl)pyridine

[0340] Prepared in an analogous manner to Intermediate 1 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, 0-20% 1 M ammonia MeOH in DCM) to provide the title compound (1.81 g). LCMS (Method 4): 1.72 min, 247.9 [M+H]+. Intermediate 425: 2-Methoxy-5-(2-(3-methoxyazetidin-1-yl)ethyl)-4-(trifluoromethyl)pyridine

[0341] Prepared in an analogous manner to Intermediate 46 using Intermediate 424 (2.05 g, 8.28 mmol) in TFA (10.2 mL) at RT for 6 h. Then 3-methoxyazetidine hydrochloride (0.75 g, 6.07 mmol), triethylamine (0.85 mL, 6.07 mmol) and 4 Å molecular sieves in DCM (25 mL) at RT for 16 h, then STAB (2.14 g, 10.1 mmol) at RT for 6 h. Purified by flash chromatography (12 g silica gel, 0-6% MeOH in DCM) then by reverse phase chromatography (20 g C18, 0–100% MeCN in 0.1 M aqueous ammonia) to provide the title compound (0.48 g). LCMS (Method 22): 1.41 min, 291.0 [M+H]+. Intermediate 426: 5-(2-(3-Methoxyazetidin-1-yl)ethyl)-4-(trifluoromethyl)pyridin-2(1H)-one

[0342] A suspension of sodium iodide (1.92 g, 12.8 mmol) and chlorotrimethylsilane (1.63 mL, 12.8 mmol) in MeCN (39 mL) was stirred at RT for 10 min then a solution of Intermediate 425 (0.74 g, 2.56 mmol) in MeCN (3.9 mL) was added and stirred at RT for 32 h. The mixture was directly purified by catch and release chromatography (20 g SCX, MeOH followed by 3.5 M ammonia in MeOH) to provide the title compound (0.51 g). LCMS (Method 15): 1.10 min, 277.1 [M+H]+. Intermediate 427: Ethyl (S)-3-(4-fluoro-2'-(hex-5-en-1-yl)-4',6'-dimethyl-5-(trifluoromethyl)- [1,1'-biphenyl]-3-yl)-3-((S)-2-(5-(2-(3-methoxyazetidin-1-yl)ethyl)-2-oxo-4- pyridin-1(2H)-yl)pent-4-enamido)propanoate

[0343] Prepared in an analogous manner to Intermediate 6 using ethyl (S)-3-(4- fluoro-2'-(hex-5-en-1-yl)-4',6'-dimethyl-5-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)-3-((R)-2- ((methylsulfonyl)oxy)pent-4-enamido)propanoate (0.25 g, 0.33 mmol, CAS 3055382-07-2), Intermediate 426 (0.12 g, 0.40 mmol) and K2CO3(0.14 g, 0.99 mmol) in MeCN (11 mL) at reflux for 16 h. Purified by flash chromatography (80 g silica gel, 0-10% MeOH in DCM) to provide the title compound (0.20 g). LCMS (Method 15): 2.89 min, 822.4 [M+H]+.Intermediate 428: Ethyl 2-((3S,6S)-24-fluoro-6-(5-(2-(3-methoxyazetidin-1-yl)ethyl)-2-oxo-4- (trifluoromethyl)pyridin-1(2H)-yl)-14,16-dimethyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphan-8-en-3-yl)acetate

[0344] Prepared in an analogous manner to Intermediate 7 using Intermediate 427 (0.20 g, 0.24 mmol) and Grubbs II (20 mg, 24 µmol) in DCE (80 mL) at 50 °C for 3 h. Purified by flash chromatography (40 g silica gel, 0-60% EtOAc in petroleum ether) to provide the title compound (0.14 g). LCMS (Method 15): 2.79 min, 794.4 [M+H]+. Intermediate 429: Ethyl 2-((3S,6S)-24-fluoro-6-(5-(2-(3-methoxyazetidin-1-yl)ethyl)-2-oxo-4- (trifluoromethyl)pyridin-1(2H)-yl)-14,16-dimethyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetate

[0345] Prepared in an analogous manner to Intermediate 8 using Intermediate 428 (50 mg, 63 µmol) and 10% palladium on carbon (7 mg) in ethanol (3 mL) under a hydrogen atmosphere at RT for 1 h, to provide the title compound (50 mg). LCMS (Method 27): 2.46 min, 796.4 [M+H]+. Intermediate 430: 5-(2-(3-(Difluoromethyl)azetidin-1-yl)ethyl)-4-(trifluoromethyl)pyridin- 2(1H)-one

[0346] Prepared in an analogous manner to Intermediate 426 using sodium iodide (1.17 g, 7.83 mmol), chlorotrimethylsilane (0.99 mL, 7.83 mmol) in MeCN (48 mL) at RT for 10 min then Intermediate 737 (0.49 g, 1.57 mmol) in MeCN (4.7 mL) at RT for 20 h. Purified by catch and release chromatography (20 g SCX, MeOH followed by 3.5 M ammonia in MeOH) to provide the title compound (0.44 g). LCMS (Method 15): 1.32 min, 297.0 [M+H]+. Intermediate 431: Ethyl (S)-3-(4,4'-difluoro-2'-(hex-5-en-1-yl)-6'-methyl-5-(trifluoromethyl)- [1,1'-biphenyl]-3-yl)-3-((S)-2-(5-(2-(3-(difluoromethyl)azetidin-1-yl)ethyl)-2-oxo-4- pyridin-1(2H)-yl)pent-4-enamido)propanoate

[0347] Prepared in an analogous manner to Intermediate 6 using Intermediate 41 (0.37 g, 0.58 mmol), Intermediate 430 (0.21 g, 0.64 mmol) and K2CO3 (0.24 g, 1.73 mmol) in MeCN (5.8 mL) at reflux for 18 h. Purified by flash chromatography (40 g silica gel, 50-100% EtOAc in petroleum ether) to provide the title compound (0.26 g). LCMS (Method 15): 2.83 min, 846.4 [M+H]+. Intermediate 432: Ethyl 2-((3S,6S)-6-(5-(2-(3-(difluoromethyl)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)-dibenzenacyclotridecaphan-8-en-3-yl)acetate

[0348] Prepared in an analogous manner to Intermediate 7 using Intermediate 431 (0.17 g, 0.18 mmol) and Grubbs II (15 mg, 18 µmol) in DCE (90 mL) at 50 °C for 1 h. Purifiedby flash chromatography (12 g silica gel, 0-10% (0.5% ammonia MeOH) in DCM) to provide the title compound (0.16 g). LCMS (Method 15): 2.75 min, 818.4 [M+H]+. Intermediate 433: Ethyl 2-((3S,6S)-6-(5-(2-(3-(difluoromethyl)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)acetate

[0349] Prepared in an analogous manner to Intermediate 8 using Intermediate 432 (0.16 g, 0.20 mmol) and 10% palladium on carbon (21 mg) in ethanol (12 mL) under a hydrogen atmosphere at RT for 6 h, to provide the title compound (0.16 g). LCMS (Method 15): 2.78 min, 820.4 [M+H]+. Intermediate 434: 3-(6-(Benzyloxy)-4-methylpyridin-3-yl)-2-methylpropanal

[0350] A stirred suspension of 2-benzyloxy-5-bromo-4-methylpyridine (1.85 g, 5.65 mmol, CAS 847349-87-5), 2-methylprop-2-en-1-ol (0.81 g, 11.3 mmol, CAS 513-42-8) and N,N-dicyclohexylmethylamine (1.33 mL, 6.21 mmol) in 1,4-dioxane (11 mL) were degassed with nitrogen for 10 min, then tri-tert-butylphosphonium tetrafluoroborate (0.16 g, 0.57 mmol) and Pd2(dba)3 (0.51 g, 0.44 mmol) were added. The mixture was heated at 100 °C for 3.5 h. The mixture was cooled, filtered, washed with EtOAc and concentrated under reduced pressure. The crude product was purified by flash chromatography (40 g silica gel, 0-10% EtOAc in petroleum ether) to provide the title compound (1.07 g). LCMS (Method 15): 2.13 min, 270.1 [M+H]+. Intermediate 435: 3-(6-(Benzyloxy)-4-methylpyridin-3-yl)-N,N,2-trimethylpropan-1-amine

[0351] Prepared in an analogous manner to Intermediate 31 using Intermediate 434 (1.20 g, 4.01 mmol), dimethylamine (2 M in THF, 2.40 mL, 4.80 mmol), MgSO4 and triethylamine (1.68 mL, 12.0 mmol) in DCM (10 mL) at RT for 1 h, followed by STAB (1.70 g, 8.01 mmol) at RT for 3 h. Purified by catch and release chromatography (10 g SCX, MeOH followed by 1 M ammonia in MeOH) to provide the title compound (0.99 g). LCMS (Method 15): 2.37 min, 299.2 [M+H]+. Intermediate 436: 5-(3-(Dimethylamino)-2-methylpropyl)-4-methylpyridin-2(1H)-one

[0352] Prepared in an analogous manner to Intermediate 8 using Intermediate 435 (0.74 g, 2.48 mmol) and 10% palladium on carbon (0.26 g) in ethanol (25 mL) under a hydrogen atmosphere at RT for 5 h, to provide the title compound (0.52 g). LCMS (Method 15): 1.24 min, 209.1 [M+H]+. Intermediate 437: Ethyl (3S)-3-(4,4'-difluoro-2'-(hex-5-en-1-yl)-6'-methyl-5-(trifluoromethyl)- [1,1'-biphenyl]-3-yl)-3-((2S)-2-(5-(3-(dimethylamino)-2-methylpropyl)-4-methyl-2-oxopyridin- 1(2H)-yl)pent-4-enamido)propanoate

[0353] Prepared in an analogous manner to Intermediate 6 using Intermediate 41 (0.51 g, 0.79 mmol), Intermediate 436 (0.19 g, 0.79 mmol) and K2CO3(0.33 g, 2.38 mmol) in MeCN (12 mL) at reflux for 16 h. Purified by flash chromatography (40 g silica gel, 50-100% EtOAc in petroleum ether) to provide the title compound (0.15 g). LCMS (Method 27): 2.70 min, 758.4 [M+H]+. Intermediate 438: Ethyl 2-((3S,6S)-6-(5-(3-(dimethylamino)-2-methylpropyl)-4-methyl-2- oxopyridin-1(2H)-yl)-14,24-difluoro-16-methyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphan-8-en-3-yl)acetate

[0354] Prepared in an analogous manner to Intermediate 7 using Intermediate 437 (0.15 g, 0.20 mmol) and Grubbs II (17 mg, 20 µmol) in DCE (99 mL) at 50 °C for 2 h. Purified by flash chromatography (12 g silica gel, 0-6% (0.5% ammonia MeOH) in DCM) to provide the title compound (0.10 g). LCMS (Method 27): 2.37 min, 730.3 [M+H]+. Intermediate 439: Ethyl 2-((3S,6S)-6-(5-(3-(dimethylamino)-2-methylpropyl)-4-methyl-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)acetate

[0355] Prepared in an analogous manner to Intermediate 8 using Intermediate 438 (0.10 g, 0.14 mmol) and 10% palladium on carbon (15 mg) in ethanol (9 mL) under a hydrogen atmosphere at RT for 6 h, to provide the title compound (76 mg). LCMS (Method 27): 2.49 min, 732.4 [M+H]+. Intermediate 440: 2-Methoxy-5-(2-(3-(methoxymethyl)azetidin-1-yl)ethyl)-4- (trifluoromethyl)pyridine

[0356] Prepared in an analogous manner to Intermediate 46 using Intermediate 424 (0.75 g, 3.03 mmol) in TFA (3.75 mL) at RT for 4 h. Then 3-(methoxymethyl)azetidine hydrochloride (0.33 g, 2.42 mmol, CAS 942308-06-7), triethylamine (0.85 mL, 6.06 mmol) and 4 Å molecular sieves in DCM (6.7 mL) at RT for 10 min, then STAB (0.86 g, 4.04 mmol) at RT for 18 h. Purified by catch and release chromatography (10 g SCX, MeOH followed by 3.5 M ammonia in MeOH) to provide the title compound (0.52 g). LCMS (Method 15): 1.87 min, 305.1 [M+H]+. Intermediate 441: 5-(2-(3-(Methoxymethyl)azetidin-1-yl)ethyl)-4-(trifluoromethyl)pyridin- 2(1H)-one

[0357] Prepared in an analogous manner to Intermediate 426 using sodium iodide (1.28 g, 8.56 mmol), chlorotrimethylsilane (1.09 mL, 8.56 mmol) in MeCN (52 mL) at RT for 10 min then Intermediate 440 (0.52 g, 1.71 mmol) in MeCN (5.2 mL) at RT for 18 h. Purifiedby catch and release chromatography (20 g SCX, MeOH followed by 3.5 M ammonia in MeOH) to provide the title compound (0.47 g). LCMS (Method 15): 1.23 min, 291.1 [M+H]+. Intermediate 442: Ethyl (S)-3-(4,4'-difluoro-2'-(hex-5-en-1-yl)-6'-methyl-5-(trifluoromethyl)- [1,1'-biphenyl]-3-yl)-3-((S)-2-(5-(2-(3-(methoxymethyl)azetidin-1-yl)ethyl)-2-oxo-4- (trifluoromethyl)pyridin-1(2H)-yl)pent-4-enamido)propanoate

[0358] Prepared in an analogous manner to Intermediate 6 using Intermediate 41 (0.37 g, 0.58 mmol), Intermediate 441 (0.21 g, 0.64 mmol) and K2CO3(0.24 g, 1.73 mmol) in MeCN (5.8 mL) at reflux for 18 h. Purified by flash chromatography (40 g silica gel, 50-100% EtOAc in petroleum ether then 10% MeOH in DCM) to provide the title compound (0.27 g). LCMS (Method 15): 2.84 min, 840.5 [M+H]+. Intermediate 443: Ethyl 2-((3S,6S)-14,24-difluoro-6-(5-(2-(3-(methoxymethyl)azetidin-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)-dibenzenacyclotridecaphan-8-en-3-yl)acetate

[0359] Prepared in an analogous manner to Intermediate 7 using Intermediate 442 (0.16 g, 0.19 mmol) and Grubbs II (16 mg, 19 µmol) in DCE (81 mL) at 50 °C for 2.5 h. Purified by flash chromatography (12 g silica gel, 0-10% (0.5% ammonia MeOH) in DCM) to provide the title compound (0.18 g). LCMS (Method 15): 2.74 min, 812.4 [M+H]+. Intermediate 444: Ethyl 2-((3S,6S)-14,24-difluoro-6-(5-(2-(3-(methoxymethyl)azetidin-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)acetate

[0360] Prepared in an analogous manner to Intermediate 8 using Intermediate 443 (0.15 g, 0.19 mmol) and 10% palladium on carbon (20 mg) in ethanol (11 mL) under a hydrogen atmosphere at RT for 11 h, to provide the title compound (0.19 g). LCMS (Method 15): 2.76 min, 814.5 [M+H]+. Intermediate 445: 2-Methoxy-4-(trifluoromethyl)-5-(2-(3-(trifluoromethyl)azetidin-1- yl)ethyl)pyridine

[0361] Prepared in an analogous manner to Intermediate 46 using Intermediate 424 (0.50 g, 2.02 mmol) in TFA (2.5 mL) at RT for 16 h. Then 3-(trifluoromethyl)azetidine hydrochloride (0.39 g, 2.43 mmol, CAS 1221272-90-7), triethylamine (0.85 mL, 6.06 mmol) and 4 Å molecular sieves in DCM (6.7 mL) at RT for 30 min, then STAB (0.86 g, 4.04 mmol) at RT for 4 h. Purified by catch and release chromatography (10 g SCX, MeOH followed by 3.5 M ammonia in MeOH) to provide the title compound (0.46 g). LCMS (Method 15): 2.17 min, 329.1 [M+H]+.Intermediate 446: 4-(Trifluoromethyl)-5-(2-(3-(trifluoromethyl)azetidin-1-yl)ethyl)pyridin- 2(1H)-one

[0362] Prepared in an analogous manner to Intermediate 426 using sodium iodide (1.05 g, 6.99 mmol), chlorotrimethylsilane (0.89 mL, 6.99 mmol) in MeCN (42 mL) at RT for 10 min then Intermediate 445 (0.46 g, 1.40 mmol) in MeCN (4.2 mL) at RT for 16 h. Purified by catch and release chromatography (10 g SCX, MeOH followed by 3.5 M ammonia in MeOH) to provide the title compound (0.28 g). LCMS (Method 15): 1.32 min, 315.0 [M+H]+. Intermediate 447: Ethyl (S)-3-(4,4'-difluoro-2'-(hex-5-en-1-yl)-6'-methyl-5-(trifluoromethyl)- [1,1'-biphenyl]-3-yl)-3-((S)-2-(2-oxo-4-(trifluoromethyl)-5-(2-(3-(trifluoromethyl)azetidin-1- pyridin-1(2H)-yl)pent-4-enamido)propanoate

[0363] Prepared in an analogous manner to Intermediate 6 using Intermediate 41 (0.42 g, 0.65 mmol), Intermediate 446 (0.25 g, 0.71 mmol) and K2CO3 (0.27 g, 1.94 mmol) in MeCN (6.5 mL) at reflux for 18 h. Purified by flash chromatography (24 g silica gel, 30-100% EtOAc in petroleum ether) to provide the title compound (0.37 g). LCMS (Method 15): 2.90 min, 864.4 [M+H]+. Intermediate 448: Ethyl 2-((3S,6S)-14,24-difluoro-16-methyl-5-oxo-6-(2-oxo-4- (trifluoromethyl)-5-(2-(3-(trifluoromethyl)azetidin-1-yl)ethyl)pyridin-1(2H)-yl)-25- (trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphan-8-en-3-yl)acetate

[0364] Prepared in an analogous manner to Intermediate 7 using Intermediate 447 (0.37 g, 0.43 mmol) and Grubbs II (36 mg, 42 µmol) in DCE (0.22 L) at 45 °C for 1.5 h. Purified by flash chromatography (12 g silica gel, 0-50% EtOAc in petroleum ether) to provide the title compound (0.33 g). LCMS (Method 15): 2.82 min, 836.4 [M+H]+. Intermediate 449: Ethyl 2-((3S,6S)-14,24-difluoro-16-methyl-5-oxo-6-(2-oxo-4- (trifluoromethyl)-5-(2-(3-(trifluoromethyl)azetidin-1-yl)ethyl)pyridin-1(2H)-yl)-25- (trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3-yl)acetate

[0365] Prepared in an analogous manner to Intermediate 8 using Intermediate 448 (0.33 g, 0.40 mmol) and 10% palladium on carbon (42 mg) in ethanol (24 mL) under a hydrogen atmosphere at RT for 9 h, to provide the title compound (0.22 g). LCMS (Method 15): 2.84 min, 838.4 [M+H]+. Intermediate 450: Ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(4,4'-difluoro-2'-hydroxy-6'- methyl-5-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)propanoate

[0366] Prepared in an analogous manner to Intermediate 1 using Intermediate 20 (3.0 g, 6.55 mmol), Intermediate 191 (2.48 g, 9.82 mmol), K3PO4(4.17 g, 19.6 mmol), XPhosPdG2 (0.52 g, 0.66 mmol) in 1,4-dioxane (0.10 L) and water (18 mL) at 110 °C for 2 h.Purified by flash chromatography (80 g silica gel, 0-100% EtOAc in petroleum ether) to provide the title compound (3.36 g). LCMS (Method 22): 1.85 min, 502.2 [M-H]-. Intermediate 451: Ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(4,4'-difluoro-2'-methyl-5- (trifluoromethyl)-6'-(((trifluoromethyl)sulfonyl)oxy)-[1,1'-biphenyl]-3-yl)propanoate

[0367] Prepared in an analogous manner to Intermediate 10 using Intermediate 450 (1.67 g, 3.02 mmol), phenyl triflimide (1.08 g, 3.02 mmol, CAS 37595-74-7) and Cs2CO3(1.18 g, 3.62 mmol) in DCM (15 mL) at RT for 16 h. Purified by flash chromatography (25 g silica gel, 0–20% EtOAc in petroleum ether) to provide the title compound (1.95 g). LCMS (Method 22): 2.06 min, 634.2 [M-H]-. Intermediate 452: Ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(4,4'-difluoro-2'-methyl-6'- (pent-4-en-1-yl)-5-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)propanoate

[0368] Prepared in an analogous manner to Intermediate 1 using Intermediate 451 (1.01 g, 1.48 mmol), 4,4,5,5-tetramethyl-2-(pent-4-en-1-yl)-1,3,2-dioxaborolane (0.43 g, 2.21 mmol, CAS 157735-10-9), K2CO3 (0.61 g, 4.43 mmol), RuPhosPdG3 (0.12 g, 0.15 mmol) and RuPhos (69 mg, 0.15 mmol) in toluene (17 mL) and water (2 mL) at 95 °C for 1.5 h. Purified by flash chromatography (40 g silica gel, 0-20% EtOAc in petroleum ether) to provide the title compound (1.25 g). LCMS (Method 22): 2.17 min, 554.3 [M-H]-. Intermediate 453: Ethyl (S)-3-amino-3-(4,4'-difluoro-2'-methyl-6'-(pent-4-en-1-yl)-5- (trifluoromethyl)-[1,1'-biphenyl]-3-yl)propanoate hydrochloride

[0369] A suspension of Intermediate 452 (0.88 g, 1.44 mmol) in 4 M HCl in 1,4- dioxane (3.6 mL) was stirred at RT for 3 h. The mixture was concentrated under reduced pressure to provide the title compound (0.85 g). LCMS (Method 22): 2.04 min, 456.2 [M+H]+. Intermediate 454: Ethyl (S)-3-(4,4'-difluoro-2'-methyl-6'-(pent-4-en-1-yl)-5-(trifluoromethyl)- [1,1'-biphenyl]-3-yl)-3-((R)-2-hydroxy-4-methylpent-4-enamido)propanoate Prepared in an analogous manner to Intermediate 4 using Intermediate 453 (3.50 g, 7.12 mmol), Intermediate 205 (1.30 g, 9.96 mmol), DIPEA (3.72 mL, 21.3 mmol), HOBt (1.20 g, 7.83 mmol) and EDCI (1.66 g, 10.7 mmol) in MeCN (0.11 L) at RT for 16 h. Purified by flash chromatography (80 g silica gel, 0-50% EtOAc in petroleum ether) to provide the title compound (2.86 g). LCMS (Method 15): 2.68 min, 563.3 [M+H]+. Intermediate 455: Ethyl (S)-3-(4,4'-difluoro-2'-methyl-6'-(pent-4-en-1-yl)-5-(trifluoromethyl)- [1,1'-biphenyl]-3-yl)-3-((R)-4-methyl-2-((methylsulfonyl)oxy)pent-4-enamido)propanoate

[0371] Prepared in an analogous manner to Intermediate 5 using Intermediate 454 (1.22 g, 2.15 mmol), triethylamine (0.60 mL, 4.30 mmol) and methanesulfonyl chloride (0.25mL, 3.22 mmol) in DCM (8.8 mL) at RT for 1.5 h, to provide the title compound (0.51 g). LCMS (Method 15): 2.68 min, 646.2 [M+H]+. Intermediate 457: Ethyl (S)-3-((S)-2-(5-bromo-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4- methylpent-4-enamido)-3-(4,4'-difluoro-2'-methyl-6'-(pent-4-en-1-yl)-5-(trifluoromethyl)-[1,1'- biphenyl]-3-yl)propanoate

[0372] Prepared in an analogous manner to Intermediate 6 using Intermediate 455 (1.41 g, 2.05 mmol), 5-bromo-4-(trifluoromethyl)-1H-pyridin-2-one (0.54 g, 2.25 mmol, CAS 109919-32-6) and K2CO3 (0.85 g, 6.14 mmol) in MeCN (28 mL) at reflux for 20 h. Purified by flash chromatography (40 g silica gel, 0-20% EtOAc in petroleum ether) to provide the title compound (0.82 g). LCMS (Method 15): 2.89 min, 791.2 [M+H]+. Intermediate 458: Ethyl 2-((3S,6S)-6-(5-bromo-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)- dibenzenacyclododecaphan-8-en-3-yl)acetate

[0373] Prepared in an analogous manner to Intermediate 7 using Intermediate 457 (0.82 g, 1.03 mmol) and Grubbs II (88 mg, 0.10 mmol) in toluene (0.58 L) at 50 °C for 2 h. Purified by flash chromatography (40 g silica gel, 0-30% EtOAc in petroleum ether) to provide the title compound (0.55 g). LCMS (Method 15): 2.81 min, 765.2 [M+H]+. Intermediate 459: Ethyl 2-((3S,6S)-6-(5-((E)-2-ethoxyvinyl)-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)- dibenzenacyclododecaphan-8-en-3-yl)acetate

[0374] Prepared in an analogous manner to Intermediate 29 using Intermediate 458 (0.33 g, 0.43 mmol), trans-2-ethoxyvinylboronic acid pinacol ester (89 mg, 0.45 mmol, CAS 1201905-61-4), Pd(dppf)Cl2 (31 mg, 43 µmol) and Na2CO3 (90 mg, 0.85 mmol) in 1,4-dioxane (3.9 mL) and water (1.3 mL) at 85 °C for 6 h. Purified by flash chromatography (25 g silica gel, 0-100% EtOAc in petroleum ether), to provide the title compound (0.11 g). LCMS (Method 15): 2.82 min, 755.3 [M+H]+. Intermediate 460: Ethyl 2-((3S,6S)-14,24-difluoro-6-(5-(2-(3-methoxyazetidin-1-yl)ethyl)-2- oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-16,8-dimethyl-5-oxo-25-(trifluoromethyl)-4-aza- 1(1,2),2(1,3)-dibenzenacyclododecaphan-8-en-3-yl)acetate

[0375] Prepared in an analogous manner to Intermediate 46 using Intermediate 459 (0.11 g, 0.12 mmol) in DCM (3 mL) and TFA (0.18 mL) at RT for 2 h. Then 3-methoxyazetidine hydrochloride (29 mg, 0.23 mmol, CAS 148644-09-1), triethylamine (49 µL, 0.35 mmol) and 4 Å molecular sieves in DCM (10 mL) at RT for 15 min, then STAB (50 g, 0.23 mmol) at RT for 18 h. Purified by catch and release chromatography (2 g SCX, MeOH followed by 3.5 Mammonia in MeOH) to provide the title compound (56 mg). LCMS (Method 15): 2.68 min, 798.4 [M+H]+. Intermediate 461: Ethyl 2-((3S,6S)-14,24-difluoro-6-(5-(2-(3-methoxyazetidin-1-yl)ethyl)-2- oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-16,8-dimethyl-5-oxo-25-(trifluoromethyl)-4-aza- 1(1,2),2(1,3)-dibenzenacyclododecaphane-3-yl)acetate

[0376] Prepared in an analogous manner to Intermediate 8 using Intermediate 460 (56 mg, 65 µmol) and 10% palladium on carbon (21 mg) in ethanol (4 mL) under a hydrogen atmosphere at RT for 88 h. The crude produce was dissolved in DCM (4 mL) followed by the addition of manganese dioxide (57 mg, 0.65 mmol) and the mixture was stirred at RT for 16 h. The mixture was filtered and the filtrate concentrated under reduced pressure. This was purified by flash chromatography (12 g silica gel, 0-20% (0.5% ammonia MeOH) in DCM) to provide the title compound (30 mg). LCMS (Method 27): 2.20 min, 800.4 [M+H]+. Intermediate 462: 5-(2-(3-Ethoxyazetidin-1-yl)ethyl)-2-methoxy-4-(trifluoromethyl)pyridine

[0377] Prepared in an analogous manner to Intermediate 46 using Intermediate 424 (0.50 g, 2.02 mmol) in TFA (2.5 mL) at RT for 16 h. Then 3-ethoxyazetidine hydrochloride (0.33 g, 2.42 mmol, CAS 535924-73-3), triethylamine (0.85 mL, 6.06 mmol) and 4 Å molecular sieves in DCM (6.7 mL) at RT for 10 min, then STAB (0.86 g, 4.04 mmol) at RT for 18 h. Purified by catch and release chromatography (5 g SCX, MeOH followed by 3.5 M ammonia in MeOH) to provide the title compound (0.32 g). LCMS (Method 15): 1.95 min, 305.1 [M+H]+. Intermediate 463: 5-(2-(3-Ethoxyazetidin-1-yl)ethyl)-4-(trifluoromethyl)pyridin-2(1H)-one

[0378] Prepared in an analogous manner to Intermediate 426 usingiodide (0.78 g, 5.21 mmol), chlorotrimethylsilane (0.66 mL, 5.21 mmol) in MeCN (32 mL) at RT for 10 min then Intermediate 462 (0.32 g, 1.04 mmol) in MeCN (3.2 mL) at RT for 16 h. Purified by catch and release chromatography (20 g SCX, MeOH followed by 3.5 M ammonia in MeOH) to provide the title compound (0.31 g). LCMS (Method 15): 1.17 min, 291.1 [M+H]+. Intermediate 464: Ethyl (S)-3-(4,4'-difluoro-2'-(hex-5-en-1-yl)-6'-methyl-5-(trifluoromethyl)- [1,1'-biphenyl]-3-yl)-3-((S)-2-(5-(2-(3-ethoxyazetidin-1-yl)ethyl)-2-oxo-4- pyridin-1(2H)-yl)pent-4-enamido)propanoate

[0379] Prepared in an analogous manner to Intermediate 6 using Intermediate 41 (0.40 g, 0.62 mmol), Intermediate 463 (0.21 g, 0.68 mmol) and K2CO3(0.26 g, 1.85 mmol) in MeCN (6.2 mL) at reflux for 18 h. Purified by flash chromatography (40 g silica gel, 0-100% EtOAc in petroleum ether) to provide the title compound (0.18 g). LCMS (Method 15): 2.86 min, 840.5 [M+H]+.Intermediate 465: Ethyl 2-((3S,6S)-6-(5-(2-(3-ethoxyazetidin-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)-dibenzenacyclotridecaphan-8-en-3-yl)acetate

[0380] Prepared in an analogous manner to Intermediate 7 using Intermediate 464 (0.18 g, 0.21 mmol) and Grubbs II (18 mg, 21 µmol) in DCE (90 mL) at 50 °C for 2.5 h. Purified by flash chromatography (12 g silica gel, 0-100% EtOAc in petroleum ether) to provide the title compound (0.12 g). LCMS (Method 15): 2.76 min, 812.4 [M+H]+. Intermediate 466: Ethyl 2-((3S,6S)-6-(5-(2-(3-ethoxyazetidin-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)acetate

[0381] Prepared in an analogous manner to Intermediate 8 using Intermediate 465 (0.12 g, 0.14 mmol) and 10% palladium on carbon (15 mg) in ethanol (8 mL) under a hydrogen atmosphere at RT for 8 h, to provide the title compound (0.13 g). LCMS (Method 27): 2.78 min, 814.4 [M+H]+. Intermediate 467: Ethyl 2-((3S,6S)-6-(5-(3-(dimethylamino)prop-1-yn-1-yl)-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)-dibenzenacyclododecaphan-8-en-3-yl)acetate

[0382] Prepared in an analogous manner to Intermediate 17 using Intermediate 458 (0.23 g, 0.30 mmol), Pd(PPh3)2Cl2 (15 mg, 21 µmol), copper(I) iodide (4 mg, 21 µmol), triethylamine (0.29 mL, 2.06 mmol) and N,N-dimethylpropargylamine (0.22 mL, 2.06 mmol) in MeCN (3 mL) at 80 °C for 18 h. Purified by flash chromatography (25 g silica gel, 0-10% MeOH in DCM) followed by catch and release chromatography (SCX, MeOH followed by 3.5 M ammonia in MeOH) to provide the title compound (0.23 g). LCMS (Method 15): 2.73 min, 766.3 [M+H]+. Intermediate 468: Ethyl 2-((3S,6S)-6-(5-(3-(dimethylamino)propyl)-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)acetate

[0383] Prepared in an analogous manner to Intermediate 461 using Intermediate 467 (0.19 g, 0.25 mmol) and 10% palladium on carbon (79 mg) in ethanol (17 mL) and AcOH (14 µL, 0.25 mmol) under a hydrogen atmosphere at RT for 88 h, followed by manganese dioxide (0.22 g, 2.48 mmol) in DCM (5 mL) at RT for 16 h, to provide the title compound (16 mg). LCMS (Method 27): 2.54 min, 772.4 [M+H]+. Intermediate 469: Ethyl 2-(5-bromo-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2-cyanoacetate

[0384] A mixture of 5-bromo-3-iodo-1-methylpyridin-2-one (2.05 g, 6.53 mmol, CAS 1643367-68-3), ethyl cyanoacetate (1.46 mL, 13.7 mmol), copper(I) iodide (0.12 g, 0.65 mmol), pyridine-2-carboxylic acid (0.16 g, 1.31 mmol) and Cs2CO3(4.67 g, 3.36 mmol) in DMF (28 mL) was stirred at 100 °C for 40 min. The mixture was diluted with water and extracted into EtOAc. The organic layer was washed with water, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (80 g silica gel, 0-10% MeOH in DCM) to provide the title compound (1.19 g). LCMS (Method 15): 0.92 min, 298.9 [M+H]+. Intermediate 470: 2-(5-Bromo-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)acetic acid

[0385] A solution of Intermediate 469 (1.19 g, 3.82 mmol) in 37% aqueous HCl (8.3 mL, 84.5 mmol) was stirred at 100 °C for 5 h. The mixture was concentrated under reduced pressure to provide the title compound (1.30 g). LCMS (Method 30): 0.22 min, 247.9 [M+H]+. Intermediate 471: Ethyl 2-(5-bromo-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)acetate

[0386] A solution of Intermediate 470 (1.30 g, 3.82 mmol) in ethanol (0.22 L) and 4 M HCl in dioxane (4.49 mL) was stirred at RT for 22 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, 0-10% MeOH in DCM) to provide the title compound (0.86 g). LCMS (Method 15): 1.39 min, 275.9 [M+H]+. Intermediate 472: Ethyl 2-(5-bromo-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)pent-4-enoate

[0387] Prepared in an analogous manner to Intermediate 6 using Intermediate 471 (0.86 g, 3.12 mmol), allyl bromide (0.40 mL, 4.68 mmol) and Cs2CO3 (1.52 g, 4.68 mmol) in DMF (6.2 mL) at RT for 5 h. Purified by reverse phase chromatography (35 g C18, 0–55% MeCN in 0.1 M aqueous ammonia) to provide the title compound (0.55 g). LCMS (Method 15): 1.78 min, 316.0 [M+H]+. Intermediate 473: 2-(5-Bromo-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)pent-4-enoic acid

[0388] Prepared in an analogous manner to Example 1 using Intermediate 472 (0.55 g, 1.75 mmol) and lithium hydroxide (96 mg, 4.01 mmol) in THF (2.4 mL), MeOH (0.6 mL) and water (1.2 mL) at RT for 5 h, to provide the title compound (0.44 g). LCMS (Method 30): 0.22 min, 288.0 [M+H]+. Intermediate 475: Ethyl (3S)-3-(2-(5-bromo-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)pent-4- enamido)-3-(4,4'-difluoro-5-en-1-yl)-6'-methyl-5-(trifluoromethyl)-[1,1'-biphenyl]-3- yl)propanoate – Diastereomer 2

[0389] Prepared in an analogous manner to Intermediate 4 using Intermediate 39 (0.60 g, 1.07 mmol), Intermediate 473 (0.44 g, 1.49 mmol), DIPEA (0.56 mL, 3.20 mmol), HOBt (0.20 g, 1.17 mmol) and EDCI (0.25 g, 1.60 mmol) in MeCN (8 mL) at RT for 2 h. Purified by flash chromatography (80 g silica gel, 0-30% EtOAc in petroleum ether) to provide the title compound (0.39 g – Peak 2). Note: Diastereomer 1 decomposed. LCMS (Method 15): 2.81 min, 739.2 [M+H]+. Intermediate 476: Ethyl 2-((3S)-6-(5-bromo-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-14,24- difluoro-16-methyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphan- 8-en-3-yl)acetate - Diastereomer 2

[0390] Prepared in an analogous manner to Intermediate 7 using Intermediate 475 (0.39 g, 0.53 mmol) and Grubbs II (45 mg, 53 µmol) in DCE (0.28 L) at 50 °C for 2 h. Purified by flash chromatography (40 g silica gel, 0-60% EtOAc in petroleum ether) to provide the title compound (0.27 g). LCMS (Method 15): 2.70 min, 711.2 [M+H]+. Intermediate 477: Ethyl 2-((3S)-6-(5-((E)-2-ethoxyvinyl)-1-methyl-2-oxo-1,2-dihydropyridin- 3-yl)-14,24-difluoro-16-methyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphan-8-en-3-yl)acetate - Diastereomer 2

[0391] Prepared in an analogous manner to Intermediate 29 using Intermediate 476 (0.22 g, 0.28 mmol), trans-2-ethoxyvinylboronic acid pinacol ester (59 mg, 0.30 mmol, CAS 1201905-61-4), Pd(dppf)Cl2 (21 mg, 28 µmol) and Na2CO3 (60 mg, 0.57 mmol) in 1,4-dioxane (5.3 mL) and water (1.5 mL) at 85 °C for 1 h. Purified by flash chromatography (25 g silica gel, 0-50% EtOAc in petroleum ether), followed by reverse phase chromatography (55 g C18, 5– 65% MeCN in 0.1 M aqueous ammonia) to provide the title compound (80 mg). LCMS (Method 15): 2.72 min, 701.3 [M+H]+. Intermediate 478: Ethyl 2-((3S)-6-(5-(2-(dimethylamino)ethyl)-1-methyl-2-oxo-1,2- dihydropyridin-3-yl)-14,24-difluoro-16-methyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphan-8-en-3-yl)acetate - Diastereomer 2

[0392] Prepared in an analogous manner to Intermediate 46 using Intermediate 477 (80 mg, 0.11 mmol) in DCM (3.2 mL) and TFA (0.17 mL) at RT for 2 h. Then dimethylamine (2 M in THF, 81 µL, 0.16 mmol), triethylamine (60 µL, 0.43 mmol) and 4 Å molecular sieves in DCM (9 mL) at RT for 15 min, then STAB (46 mg, 0.43 mmol) at RT for 18 h. Purified by catch and release chromatography (2 g SCX, MeOH followed by 3.5 M ammonia in MeOH) to provide the title compound (45 mg). LCMS (Method 15): 2.60 min, 702.4 [M+H]+.Intermediate 479: Ethyl 2-((3S)-6-(5-(2-(dimethylamino)ethyl)-1-methyl-2-oxo-1,2- dihydropyridin-3-yl)-14,24-difluoro-16-methyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetate - Diastereomer 2

[0393] Prepared in an analogous manner to Intermediate 8 using Intermediate 478 (45 mg, 61 µmol) and 10% palladium on carbon (6.5 mg) in ethanol (1.8 mL) under a hydrogen atmosphere at RT for 6 h, to provide the title compound (40 mg). LCMS (Method 27): 2.67 min, 704.4 [M+H]+. Intermediate 480: Ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(5-chloro-3-cyclobutyl-2- fluorophenyl)propanoate

[0394] Prepared in an analogous manner to Intermediate 1 using Intermediate 107 (30.0 g, 45.9 mmol), cyclobutylboronic acid (36.7 g, 0.37 mol, CAS 849052-26-2), Cs2CO3 (74.8 g, 0.23 mol), RuPhos (77 mg, 0.12 mmol) and Pd(dppf)Cl2.DCM (3.75 g, 4.59 mmol) in toluene (0.13 L) and water (10 mL) at 90 °C for 16 h. Purified by reverse phase chromatography 320 g C18, 0-100% MeCN in water) to provide the title compound (8.7 g). LCMS (Method 34): 1.68 min, 300.5 [M-Boc+H]+. Intermediate 481: Ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(5-cyclobutyl-4,4'-difluoro-2'- hydroxy-6'-methyl-[1,1'-biphenyl]-3-yl)propanoate

[0395] Prepared in an analogous manner to Intermediate 1 using Intermediate 480 (7.0 g, 13.3 mmol), Intermediate 191 (4.0 g, 53.2 mmol), Cs2CO3 (13.0 g, 39.9 mmol), XPhosPdG3 (0.90 g, 1.06 mmol) in 1,4-dioxane (7.0 mL) and water (0.5 mL) at 90 °C for 16 h. Purified by flash chromatography (120 g silica gel, 0-10% EtOAc in hexane) to provide the title compound (1.0 g). LCMS (Method 34): 1.67 min, 390.6 [M-Boc+H]+. Intermediate 482: Ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(5-cyclobutyl-4,4'-difluoro-2'- methyl-6'-(((trifluoromethyl)sulfonyl)oxy)-[1,1'-biphenyl]-3-yl)propanoate

[0396] Prepared in an analogous manner to Intermediate 10 using Intermediate 481 (1.0 g, 1.59 mmol), phenyl triflimide (0.63 g, 1.75 mmol, CAS 37595-74-7) and Cs2CO3 (0.62 g, 1.91 mmol) in DCM (12 mL) at RT for 2 h. Purified by flash chromatography (40 g silica gel, 0–10% EtOAc in petroleum ether) to provide the title compound (1.0 g). LCMS (Method 35): 1.30 min, 522.4 [M-Boc+H]+. Intermediate 483: Ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(5-cyclobutyl-4,4'-difluoro-2'- (hex-5-en-1-yl)-6'-methyl-[1,1'-biphenyl]-3-yl)propanoate

[0397] Preparedmanner to Intermediate 1 using Intermediate 482 (1.0 g, 1.40 mmol), 5-hexenylboronic acid (0.45 g, 3.50 mmol, CAS 1072952-16-9), K2CO3(0.77 g, 5.60 mmol), RuPhos (0.13 g, 0.28 mmol) and palladium(II) acetate (31 mg, 0.14 mmol)in toluene (15 mL) and water (1.5 mL) at 125 °C for 3 h. Purified by flash chromatography (40 g silica gel, 0-10% EtOAc in petroleum ether) to provide the title compound (0.85 g). LCMS (Method 35): 1.42 min, 456.5 [M-Boc+H]+. Intermediate 484: Ethyl (S)-3-amino-3-(5-cyclobutyl-4,4'-difluoro-2'-(hex-5-en-1-yl)-6'- methyl-[1,1'-biphenyl]-3-yl)propanoate hydrochloride

[0398] A solution of Intermediate 483 (0.85 g, 1.30 mmol) in DCM (2.2 mL) and 4 M HCl in dioxane (7.4 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 (0.62 g). LCMS (Method 35): 0.87 min, 456.6 [M+H]+. Intermediate 485: Ethyl (S)-3-(5-cyclobutyl-4,4'-difluoro-2'-(hex-5-en-1-yl)-6'-methyl-[1,1'- biphenyl]-3-yl)-3-((R)-2-hydroxypent-4-enamido)propanoate

[0399] Prepared in an analogous manner to Intermediate 4 using Intermediate 484 (0.62 g, 1.18 mmol), (2R)-2-hydroxypent-4-enoic acid (0.17 g, 1.42 mmol, CAS 413622-10-3), DIPEA (1.03 mL, 5.92 mmol), and HATU (0.68 g, 1.78 mmol) in DMF (11 mL) at RT for 16 h. Purified by flash chromatography (silica gel, 0-30% EtOAc in petroleum ether) to provide the title compound (0.57 g). LCMS (Method 35): 1.30 min, 554.6 [M+H]+. Intermediate 486: Ethyl (S)-3-(5-cyclobutyl-4,4'-difluoro-2'-(hex-5-en-1-yl)-6'-methyl-[1,1'- biphenyl]-3-yl)-3-((R)-2-((methylsulfonyl)oxy)pent-4-enamido)propanoate

[0400] Prepared in an analogous manner to Intermediate 5 using Intermediate 485 (0.57 g, 0.77 mmol), triethylamine (0.32 mL, 2.32 mmol) and methanesulfonyl chloride (90 µL, 1.16 mmol) in DCM (9.1 mL) at RT for 3 h. Purified by flash chromatography (silica gel, 0-30% EtOAc in petroleum ether) to provide the title compound (0.53 g). LCMS (Method 35): 1.32 min, 630.6 [M-H]-. Intermediate 487: Ethyl (S)-3-(5-cyclobutyl-4,4'-difluoro-2'-(hex-5-en-1-yl)-6'-methyl-[1,1'- biphenyl]-3-yl)-3-((S)-2-(5-(2-(3-methoxyazetidin-1-yl)ethyl)-4-methyl-2-oxopyrimidin-- yl)pent-4-enamido)propanoate

[0401] Prepared in an analogous manner to Intermediate 6 using Intermediate 486 (0.25 g, 0.35 mmol), Intermediate 278 (0.17 g, 0.53 mmol) and K2CO3(0.15 g, 1.06 mmol) in MeCN (3.7 mL) at reflux for 18 h. Purified by flash chromatography (40 g silica gel, 0-10% MeOH in DCM) to provide the title compound (0.15 g). LCMS (Method 36): 3.92 min, 757.5 [M-H]-. Intermediate 488: Ethyl 2-((3S,6S)-25-cyclobutyl-14,24-difluoro-6-(5-(2-(3-methoxyazetidin-1- yl)ethyl)-4-methyl-2-oxopyrimidin-1(2H)-yl)-16-methyl-5-oxo-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphan-8-en-3-

[0402] Prepared in an analogous manner to Intermediate 7 using Intermediate 487 (0.15 g, 0.13 mmol) and Grubbs II (2.3 mg, 3 µmol) in DCE (15 mL) at 40 °C for 16 h. Purified by flash chromatography (40 g silica gel, 0-10% MeOH in DCM) to provide the title compound (0.11 g). LCMS (Method 36): 3.74 min, 731.5 [M+H]+. Intermediate 489: Ethyl 2-((3S,6S)-25-cyclobutyl-14,24-difluoro-6-(5-(2-(3-methoxyazetidin-1- yl)ethyl)-4-methyl-2-oxopyrimidin-1(2H)-yl)-16-methyl-5-oxo-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetate

[0403] Prepared in an analogous manner to Intermediate 461 using Intermediate 488 (0.11 g, 93 µmol) and 10% palladium on carbon (50 mg) in ethanol (5 mL) and EtOAc (5 mL) under a hydrogen atmosphere at 40 psi and RT for 2 h, followed by manganese dioxide (81 mg, 0.93 mmol) in DCM (5 mL) at RT for 16 h, to provide the title compound (0.10 g). LCMS (Method 27): 3.80 min, 733.5 [M+H]+. Intermediate 490: 3-(6-Methoxy-4-(trifluoromethyl)pyridin-3-yl)propanal

[0404] Prepared in an analogous manner to Intermediate 434 using 5-bromo-2- methoxy-4-(trifluoromethyl)pyridine (1.0 g, 3.91 mmol, CAS 847349-87-5), prop-2-en-1-ol (0.85 g, 7.81 mmol, CAS 107-18-6), N,N-dicyclohexylmethylamine (0.50 mL, 2.34 mmol), tri- tert-butylphosphonium tetrafluoroborate (0.11 g, 0.39 mmol), DIPEA (0.41 mL, 2.34 mmol) and Pd2(dba)3 (0.18 g, 0.20 mmol) in 1,4-dioxane (7.8 mL) at 50 °C for 16 h. Purified by flash chromatography (25 g silica gel, 0-10% EtOAc in petroleum ether) to provide the title compound (0.65 g).1H NMR (400 MHz; CDCl3) δ: 9.82 (t, 1H), 8.16 (s, 1H), 6.97 (s, 1H), 3.95 (s, 3H), 3.04 (t, 2H), 2.77 (td, 2H). Intermediate 491: 2-Methoxy-5-(3-(3-methoxyazetidin-1-yl)propyl)-4- (trifluoromethyl)pyridine

[0405] Prepared in an analogous manner to Intermediate 31 using Intermediate 490 (0.78 g, 3.32 mmol), 3-methoxyazetidine hydrochoride (0.49 g, 3.99 mmol), MgSO4 and triethylamine (1.39 mL, 9.97 mmol) in DCM (11 mL) at RT for 1 h, followed by STAB (1.41 g, 6.65 mmol) at RT for 3 h. Purified by catch and release chromatography (20 g SCX, MeOH followed by 1 M ammonia in MeOH) to provide the title compound (0.82 g). LCMS (Method 15): 1.88 min, 305.3 [M+H]+. Intermediate 492: 5-(3-(3-Methoxyazetidin-1-yl)propyl)-4-(trifluoromethyl)pyridin-2(1H)-one

[0406] Prepared in an analogous manner to Intermediate 426 using sodium iodide (1.92 g, 12.8 mmol), chlorotrimethylsilane (1.61 mL, 12.8 mmol) in MeCN (65 mL) at RT for 10 min then Intermediate 491 (0.82 g, 2.65 mmol) in MeCN (6.5 mL) at RT for 16 h. Purifiedby catch and release chromatography (20 g SCX, MeOH followed by 3.5 M ammonia in MeOH) to provide the title compound (0.68 g). LCMS (Method 15): 1.26 min, 291.1 [M+H]+. Intermediate 493: Ethyl (S)-3-(4,4'-difluoro-2'-(hex-5-en-1-yl)-6'-methyl-5-(trifluoromethyl)- [1,1'-biphenyl]-3-yl)-3-((S)-2-(5-(3-(3-methoxyazetidin-1-yl)propyl)-2-oxo-4- (trifluoromethyl)pyridin-1(2H)-yl)pent-4-enamido)propanoate

[0407] Prepared in an analogous manner to Intermediate 6 using Intermediate 41 (0.51 g, 0.79 mmol), Intermediate 492 (0.24 g, 0.79 mmol) and K2CO3(0.33 g, 2.38 mmol) in MeCN (12 mL) at reflux for 18 h. Purified by flash chromatography (40 g silica gel, 0-3% 0.5% ammonia MeOH) in DCM) to provide the title compound (0.21 g). LCMS (Method 27): 2.59 min, 840.5 [M+H]+. Intermediate 494: Ethyl 2-((3S,6S)-14,24-difluoro-6-(5-(3-(3-methoxyazetidin-1-yl)propyl)-2- oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-16-methyl-5-oxo-25-(trifluoromethyl)-4-aza- 1(1,2),2(1,3)-dibenzenacyclotridecaphan-8-en-3-yl)acetate

[0408] Prepared in an analogous manner to Intermediate 7 using Intermediate 493 (0.21 g, 0.22 mmol) and Grubbs II (19 mg, 22 µmol) in DCE (0.14 L) at 50 °C for 2 h. Purified by flash chromatography (40 g silica gel, 0-3% (0.5% ammonia MeOH) in DCM) to provide the title compound (0.15 g). LCMS (Method 27): 2.27 min, 812.4 [M+H]+. Intermediate 495: Ethyl 2-((3S,6S)-14,24-difluoro-6-(5-(3-(3-methoxyazetidin-1-yl)propyl)-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)acetate

[0409] Prepared in an analogous manner to Intermediate 8 using Intermediate 494 (0.15 g, 0.19 mmol) and 10% palladium on carbon (20 mg) in ethanol (11 mL) under a hydrogen atmosphere at RT for 6 h. Purified by flash chromatography (12 g silica gel, 0-3% (0.5% ammonia MeOH) in DCM) to provide the title compound (0.12 g). LCMS (Method 27): 2.34 min, 814.4 [M+H]+. Intermediate 496: (R,Z)-N-(5-Bromo-3-chloro-2-fluorobenzylidene)-2-methylpropane-2- sulfinamide

[0410] Prepared in an analogous manner to Intermediate 37 using 5-bromo-3-chloro- 2-fluorobenzaldehyde (10.1 g, 42.6 mmol, CAS 1280786-80-2), (R)-2-methylpropane-2- sulfinamide (5.68 g, 46.9 mmol, CAS 196929-78-9) and titanium ethoxide (14.6 g, 63.9 mmol) in THF (69 mL) at 40 °C for 18 h, to provide the title compound (13.6 g). LCMS (Method 15): 2.33 min, 341.9 [M+H]+. Intermediate 497: Ethyl (S)-3-(5-bromo-3-chloro-2-fluorophenyl)-3-(((R)-tert- butylsulfinyl)amino)propanoate

[0411] Prepared in an analogous manner to Intermediate 38 using zinc (9.03 g, 0.14 mol), chlorotrimethylsilane (0.70 mL, 5.52 mmol) and ethyl bromoacetate (7.65 mL, 69.0 mmol) in THF (85 mL) at 60 °C for 1 h, then Intermediate 496 (9.50 g, 27.6 mmol) in THF (25 mL) at RT for 40 min. Purified by dry flash chromatography (silica gel, 0-30% EtOAc in petroleum ether) to provide the title compound (3.3 g). LCMS (Method 15): 2.19 min, 428.0 [M-H]-. Intermediate 498: Ethyl (S)-3-amino-3-(5-bromo-3-chloro-2-fluorophenyl)propanoate

[0412] A suspension of Intermediate 497 (6.0 g, 12.9 mmol) in 4 M HCl in 1,4-dioxane (32 mL) was stirred at RT for 5 h. The mixture was concentrated under reduced pressure, quenched with saturated aqueous sodium bicarbonate and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by catch and release chromatography (20 g SCX, MeOH followed by 3.5 M ammonia in MeOH) to provide the title compound (4.06 g). LCMS (Method 15): 1.94 min, 325.9 [M+H]+. Intermediate 499: Ethyl (S)-3-(5-bromo-3-chloro-2-fluorophenyl)-3-((tert- butoxycarbonyl)amino)propanoate

[0413] Prepared in an analogous manner to Intermediate 20 using Intermediate 498 (3.12 g, 9.61 mmol), Boc anhydride (2.31 g, 10.6 mmol) and triethylamine (2.01 mL, 14.4 mmol) in DCM (63 mL) at RT for 16 h. Purified by flash chromatography (40 g silica gel, 0- 10% EtOAc in petroleum ether) to provide the title compound (3.36 g). LCMS (Method 15): 2.38 min, 424.1 [M-H]-. Intermediate 500: Ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(5-chloro-4,4'-difluoro-2'- hydroxy-6'-methyl-[1,1'-biphenyl]-3-yl)propanoate

[0414] in an analogous manner to Intermediate 1 using Intermediate 499 (2.36 g, 5.56 mmol), Intermediate 191 (2.10 g, 8.33 mmol), K3PO4 (3.54 g, 16.7 mmol), XPhosPdG2 (0.44 g, 0.56 mmol) in 1,4-dioxane (0.10 L) and water (25 mL) at 100 °C for 0.5 h. Purified by flash chromatography (120 g silica gel, 0-10% EtOAc in hexane) to provide the title compound (1.0 g). LCMS (Method 15): 2.35 min, 370.1 [M-Boc+H]+. Intermediate 501: Ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(5-chloro-4,4'-difluoro-2'- methyl-6'-(((trifluoromethyl)-[1,1'-biphenyl]-3-yl)propanoate

[0415] Prepared in an analogousto Intermediate 10 using Intermediate 500 (3.88 g, 8.26 mmol), phenyl triflimide (2.95 g, 8.26 mmol, CAS 37595-74-7) and Cs2CO3(3.23 g, 9.91 mmol) in DCM (66 mL) at RT for 16 h. Purified by flash chromatography (40 g silicagel, 0–20% EtOAc in petroleum ether) to provide the title compound (3.53 g). LCMS (Method 15): 2.66 min, 502.1 [M-Boc+H]+. Intermediate 502: Ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(5-chloro-4,4'-difluoro-2'-(hex- 5-en-1-yl)-6'-methyl-[1,1'-biphenyl]-3-yl)propanoate

[0416] Prepared in an analogous manner to Intermediate 1 using Intermediate 501 (3.53 g, 5.40 mmol), 5-hexenylboronic acid (0.69 g, 5.40 mmol, CAS 1072952-16-9), K2CO3(2.24 g, 16.2 mmol), RuPhos (0.38 g, 0.81 mmol) and palladium(II) acetate (0.12 g, 0.54 mmol) in toluene (34 mL) and water (5 mL) at 100 °C for 1 h. Purified by flash chromatography (120 g silica gel, 0-10% EtOAc in petroleum ether) to provide the title compound (1.77 g). LCMS (Method 15): 2.89 min, 436.2 [M-Boc+H]+. Intermediate 503: Ethyl (S)-3-amino-3-(5-chloro-4,4'-difluoro-2'-(hex-5-en-1-yl)-6'-methyl- [1,1'-biphenyl]-3-yl)propanoate hydrochloride A suspension of Intermediate 502 (1.77 g, 3.04 mmol) in 4 M HCl in 1,4- dioxane (8 mL) was stirred at RT for 3 h. The mixture was concentrated under reduced pressure to provide the title compound (1.52 g). LCMS (Method 11): 2.62 min, 436.4 [M+H]+. Intermediate 504: Ethyl (S)-3-(5-chloro-4,4'-difluoro-2'-(hex-5-en-1-yl)-6'-methyl-[1,1'- biphenyl]-3-yl)-3-((R)-2-hydroxypent-4-enamido)propanoate

[0418] Prepared in an analogous manner to Intermediate 4 using (2R)-2- hydroxypent-4-enoic acid (0.53 g, 4.49 mmol, CAS 413622-10-3), Intermediate 503 (1.52 g, 2.99 mmol), DIPEA (1.60 mL, 9.17 mmol), HOBt (0.40 g, 2.99 mmol) and EDCI (0.69 g, 3.59 mmol) in MeCN (7.4 mL) at RT for 18 h. Purified by flash chromatography (25 g silica gel, 0- 40% EtOAc in petroleum ether) to provide the title compound (1.37 g). LCMS (Method 11): 2.57 min, 532.7 [M+H]+. Intermediate 505: Ethyl (S)-3-(5-chloro-4,4'-difluoro-2'-(hex-5-en-1-yl)-6'-methyl-[1,1'- biphenyl]-3-yl)-3-((R)-2-((methylsulfonyl)oxy)pent-4-enamido)propanoate

[0419] Prepared in an analogous manner to Intermediate 5 using Intermediate 504 (1.13 g, 2.01 mmol), triethylamine (0.56 mL, 4.02 mmol) and methanesulfonyl chloride (0.23 mL, 3.02 mmol) in DCM (20 mL) at RT for 1 h, to provide the title compound (1.45 g). LCMS (Method 15): 2.71 min, 610.2 [M-H]-. Intermediate 506: Ethyl (S)-3-(5-chloro-4,4'-difluoro-2'-(hex-5-en-1-yl)-6'-methyl-[1,1'- biphenyl]-3-yl)-3-((S)-2-(5-(2-(3-methoxyazetidin-1-yl)ethyl)-2-oxo-4-1(2H)-yl)pent-4-enamido)propanoate

[0420] Prepared in an analogous manner to Intermediate 6 using Intermediate 505 (0.50 g, 0.74 mmol), Intermediate 426 (0.25 g, 0.89 mmol) and K2CO3(0.31 g, 2.23 mmol) in MeCN (22 mL) at reflux for 16 h. Purified by flash chromatography (40 g silica gel, 0-5% (0.5% ammonia MeOH) in DCM) to provide the title compound (0.57 g). LCMS (Method 15): 2.80 min, 792.4 [M+H]+. Intermediate 507: Ethyl 2-((3S,6S)-25-chloro-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)- dibenzenacyclotridecaphan-8-en-3-yl)acetate

[0421] Prepared in an analogous manner to Intermediate 7 using Intermediate 506 (0.57 g, 0.39 mmol) and Grubbs II (33 mg, 39 µmol) in DCE (0.20 L) at 50 °C for 1 h. Purified by flash chromatography (40 g silica gel, 0-8% MeOH in DCM) to provide the title compound (0.44 g). LCMS (Method 27): 2.13 min, 764.3 [M+H]+. Intermediate 508: Ethyl 2-((3S,6S)-25-chloro-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)acetate

[0422] Prepared in an analogous manner to Intermediate 8 using Intermediate 507 (0.44 g, 0.26 mmol) and 10% palladium on carbon (28 mg) in EtOAc (20 mL) under a hydrogen atmosphere at RT for 7.5 h. Purified by flash chromatography (12 g silica gel, 40-100% EtOAc in petroleum ether) to provide the title compound (0.17 g). LCMS (Method 27): 2.39 min, 766.5 [M+H]+. Intermediate 509: 3-(6-Methoxy-4-(trifluoromethyl)pyridin-3-yl)-N,N-dimethylprop-2-yn-1- amine

[0423] Prepared in an analogous manner to Intermediate 17 using 5-bromo-4- trifluoromethyl-2-methoxypyridine (3.0 g, 11.7 mmol, CAS 688047-09-8), Pd(PPh3)2Cl2 (0.58 g, 0.82 mmol), copper(I) iodide (0.16 g, 0.82 mmol), triethylamine (11.4 mL, 82.0 mmol) and N,N-dimethylpropargylamine (4.42 mL, 41.0 mmol) in MeCN (85 mL) at 80 °C for 18 h. Purified by flash chromatography (80 g silica gel, 0-10% (0.5% ammonia MeOH) in DCM) followed by catch and release chromatography (50 g SCX, MeOH followed by 3.5 M ammonia in MeOH) to provide the title compound (2.39 g). LCMS (Method 15): 1.98 min, 259.2 [M+H]+. Intermediate 510: 3-(6-Methoxy-4-(trifluoromethyl)pyridin-3-yl)-N,N-dimethylpropan-1-amine

[0424] Prepared in an analogous manner to Intermediate 8 using Intermediate 509 (2.39 g, 9.26 mmol) and 10% palladium on carbon (0.49 g) in EtOAc (16 mL) under a hydrogen atmosphere at RT for 2 h. Purified by catch and release chromatography (20 g SCX, MeOHfollowed by 3.5 M ammonia in MeOH), to provide the title compound (1.96 g). LCMS (Method 15): 2.03 min, 263.2 [M+H]+. Intermediate 511: 5-(3-(Dimethylamino)propyl)-4-(trifluoromethyl)pyridin-2(1H)-one

[0425] A solution of Intermediate 510 (1.96 g, 7.25 mmol) in 33% HBr in AcOH (25 mL, 0.14 mol) was stirred at 65 °C for 6 h. The mixture was cooled and concentrated under reduced pressure. The crude product was purified by catch and release chromatography (5 g SCX, MeOH followed by 3.5 M ammonia in MeOH) to provide the title compound (1.57 g). LCMS (Method 15): 1.20 min, 249.1 [M+H]+. Intermediate 512: Ethyl (S)-3-(5-chloro-4,4'-difluoro-2'-(hex-5-en-1-yl)-6'-methyl-[1,1'- biphenyl]-3-yl)-3-((S)-2-(5-(3-(dimethylamino)propyl)-2-oxo-4-(trifluoromethyl)- yl)pent-4-enamido)propanoate

[0426] Prepared in an analogous manner to Intermediate 6 using Intermediate 505 (0.46 g, 0.69 mmol), Intermediate 511 (0.21 g, 0.83 mmol) and K2CO3 (0.29 g, 2.08 mmol) in MeCN (20 mL) at reflux for 16 h. Purified by flash chromatography (12 g silica gel, 0-10% MeOH in DCM) to provide the title compound (0.40 g). LCMS (Method 15): 2.92 min, 764.4 [M+H]+. Intermediate 513: Ethyl 2-((3S,6S)-25-chloro-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)- dibenzenacyclotridecaphan-8-en-3-yl)acetate

[0427] Prepared in an analogous manner to Intermediate 7 using Intermediate 512 (0.40 g, 0.38 mmol) and Grubbs II (33 mg, 38 µmol) in DCE (0.19 L) at 50 °C for 1.5 h. Purified by flash chromatography (25 g silica gel, 0-10% MeOH in DCM) to provide the title compound (0.30 g). LCMS (Method 15): 2.84 min, 736.4 [M+H]+. Intermediate 514: Ethyl 2-((3S,6S)-25-chloro-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)acetate

[0428] Prepared in an analogous manner to Intermediate 8 using Intermediate 513 (0.30 g, 0.25 mmol) and 10% palladium on carbon (27 mg) in EtOAc (15 mL) under a hydrogen atmosphere at RT for 16 h. Purified by flash chromatography (12 g silica gel, 40-100% EtOAc in petroleum ether) to provide the title compound (0.12 g). LCMS (Method 15): 2.88 min, 738.3 [M+H]+. Intermediate 515: 5-(2-(3-Fluoroazetidin-1-yl)ethyl)-2-methoxy-4-(trifluoromethyl)pyridine

[0429] Prepared in an analogous manner to Intermediate 46 using Intermediate 424 (2.50 g, 10.1 mmol) in TFA (23 mL) at RT for 4 h. Then 3-fluoroazetidine hydrochloride (0.75 g, 6.07 mmol, CAS 617718-46-4), triethylamine (4.23 mL, 30.3 mmol) and 4 Å molecular sieves in DCM (50 mL) at RT for 10 min, then STAB (5.36 g, 25.3 mmol) at RT for 18 h. Purified by catch and release chromatography (20 g SCX, MeOH followed by 3.5 M ammonia in MeOH) to provide the title compound (2.46 g). LCMS (Method 11): 1.86 min, 279.2 [M+H]+. Intermediate 516: 5-(2-(3-Fluoroazetidin-1-yl)ethyl)-4-(trifluoromethyl)pyridin-2(1H)-one

[0430] A solution of Intermediate 515 (2.46 g, 7.96 mmol) in 33% HBr in AcOH (14 mL, 79.6 mmol) was stirred at 50 °C for 4.5 h. The mixture was cooled and concentrated under reduced pressure. The crude product was purified by catch and release chromatography (50 g SCX, MeOH followed by 3.5 M ammonia in MeOH) to provide the title compound (1.36 g). LCMS (Method 11): 1.15 min, 265.2 [M+H]+. Intermediate 517: Ethyl (S)-3-(5-chloro-4,4'-difluoro-2'-(hex-5-en-1-yl)-6'-methyl-[1,1'- biphenyl]-3-yl)-3-((S)-2-(5-(2-(3-fluoroazetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)1(2H)-yl)pent-4-enamido)propanoate

[0431] Prepared in an analogous manner to Intermediate 6 using Intermediate 505 (0.48 g, 0.71 mmol), Intermediate 516 (0.21 g, 0.78 mmol) and K2CO3 (0.29 g, 2.12 mmol) in MeCN (10 mL) at reflux for 16 h. Purified by flash chromatography (40 g silica gel, 0-60% EtOAc in petroleum ether) to provide the title compound (0.22 g). LCMS (Method 15): 2.82 min, 780.3 [M+H]+. Intermediate 518: Ethyl 2-((3S,6S)-25-chloro-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)- dibenzenacyclotridecaphan-8-en-3-yl)acetate

[0432] Prepared in an analogous manner to Intermediate 7 using Intermediate 517 (0.22 g, 0.28 mmol) and Grubbs II (24 mg, 28 µmol) in DCE (0.14 L) at 50 °C for 2 h. Purified by flash chromatography (25 g silica gel, 0-60% EtOAc in petroleum ether) to provide the title compound (0.17 g). LCMS (Method 15): 2.73 min, 752.3 [M+H]+. Intermediate 519: Ethyl 2-((3S,6S)-25-chloro-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)acetate

[0433] Prepared in an analogous manner to Intermediate 8 using Intermediate 518 (0.17 g, 0.22 mmol) and 10% palladium on carbon (23 mg) in EtOAc (16 mL) under a hydrogen atmosphere at RT for 6 h. Purified by flash chromatography (12 g silica gel, 0-60% EtOAc inpetroleum ether) to provide the title compound (0.15 g). LCMS (Method 15): 2.75 min, 754.4 [M+H]+. Intermediate 520: Ethyl (S)-3-(4,4'-difluoro-2'-(hex-5-en-1-yl)-5,6'-dimethyl-[1,1'-biphenyl]-3- yl)-3-((S)-2-(5-(3-(3-methoxyazetidin-1-yl)propyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)- yl)pent-4-enamido)propanoate

[0434] Prepared in an analogous manner to Intermediate 6 using Intermediate 69 (0.49 g, 0.83 mmol), Intermediate 492 (0.25 g, 0.83 mmol) and K2CO3(0.34 g, 2.49 mmol) in MeCN (11 mL) at reflux for 7 h. Purified by flash chromatography (12 g silica gel, 0-3% (0.5% ammonia MeOH) in DCM) to provide the title compound (0.23 g). LCMS (Method 15): 2.82 min, 786.5 [M+H]+. Intermediate 521: Ethyl 2-((3S,6S)-14,24-difluoro-6-(5-(3-(3-methoxyazetidin-1-yl)propyl)-2- oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-16,25-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphan-8-en-3-yl)acetate

[0435] Prepared in an analogous manner to Intermediate 7 using Intermediate 520 (0.23 g, 0.30 mmol) and Grubbs II (25 mg, 30 µmol) in DCE (98 mL) at 40 °C for 2 h. Purified by flash chromatography (12 g silica gel, 0-5% (0.5% ammonia MeOH) in DCM) to provide the title compound (0.15 g). LCMS (Method 15): 2.73 min, 758.4 [M+H]+. Intermediate 522: Ethyl 2-((3S,6S)-14,24-difluoro-6-(5-(3-(3-methoxyazetidin-1-yl)propyl)-2- oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-16,25-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetate

[0436] Prepared in an analogous manner to Intermediate 8 using Intermediate 521 (0.15 g, 0.16 mmol) and 10% palladium on carbon (17 mg) in ethanol (10 mL) under a hydrogen atmosphere at RT for 7 h. Purified by flash chromatography (12 g silica gel, 0-5% (0.5% ammonia MeOH) in DCM) to provide the title compound (0.12 g). LCMS (Method 27): 2.26 min, 760.4 [M+H]+. Intermediate 523: Ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(4-fluoro-2'-hydroxy-6'-methyl- 4',5-bis(trifluoromethyl)-[1,1'-biphenyl]-3-yl)propanoate

[0437] Prepared in an analogous manner to Intermediate 1 using Intermediate 20 (0.60 g, 1.30 mmol), 3-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5- (trifluoromethyl)phenol (0.49 g, 1.62 mmol, CAS 2557358-38-8), K3PO4(0.83 g, 3.90 mmol), XPhosPdG2 (0.10 g, 0.13 mmol) in 1,4-dioxane (23 mL) and water (6 mL) at 100 °C for 0.5 h. Purified by flash chromatography (40 g silica gel, 0-20% EtOAc in petroleum ether) to provide the title compound (0.70 g). LCMS (Method 11): 2.21 min, 454.1 [M-Boc+H]+.Intermediate 524: Ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(4-fluoro-2'-methyl-4',5- bis(trifluoromethyl)-6'-((sulfonyl)oxy)-[1,1'-biphenyl]-3-yl)propanoate

[0438] Prepared in an analogous manner to Intermediate 10 using Intermediate 523 (0.69 g, 1.16 mmol), phenyl triflimide (0.41 g, 1.16 mmol, CAS 37595-74-7) and Cs2CO3(0.45 g, 1.39 mmol) in DCM (10 mL) at RT for 16 h. Purified by flash chromatography (25 g silica gel, 0–20% EtOAc in petroleum ether) to provide the title compound (0.83 g). LCMS (Method 15): 2.73 min, 586.1 [M-Boc+H]+. Intermediate 525: Ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(4-fluoro-2'-(hex-5-en-1-yl)-6'- methyl-4',5-bis(trifluoromethyl)-[1,1'-biphenyl]-3-yl)propanoate

[0439] Prepared in an analogous manner to Intermediate 1 using Intermediate 524 (0.62 g, 0.85 mmol), 5-hexenylboronic acid (0.11 g, 0.85 mmol, CAS 1072952-16-9), K2CO3 (0.35 g, 2.56 mmol), RuPhos (60 mg, 0.13 mmol) and palladium(II) acetate (19 mg, 85 µmol) in toluene (13 mL) and water (2.5 mL) at 100 °C for 3 h. Conditions repeated with fresh reagents at 100 °C for 1 h. Purified by flash chromatography (25 g silica gel, 0-10% EtOAc in petroleum ether) to provide the title compound (0.49 g). LCMS (Method 15): 2.94 min, 520.2 [M-Boc+H]+. Intermediate 526: Ethyl (S)-3-amino-3-(4-fluoro-2'-(hex-5-en-1-yl)-6'-methyl-4',5- bis(trifluoromethyl)-[1,1'-biphenyl]-3-yl)propanoate hydrochloride

[0440] A suspension of Intermediate 525 (0.58 g, 0.93 mmol) in 4 M HCl in 1,4- dioxane (2.5 mL) was stirred at RT for 1 h. The mixture was concentrated under reduced pressure to provide the title compound (0.49 g). LCMS (Method 15): 2.78 min, 520.2 [M+H]+. Intermediate 527: Ethyl (S)-3-(4-fluoro-2'-(hex-5-en-1-yl)-6'-methyl-4',5-bis(trifluoromethyl)- [1,1'-biphenyl]-3-yl)-3-((R)-2-hydroxypent-4-enamido)propanoate Prepared in an analogous manner to Intermediate 4 using (2R)-2- hydroxypent-4-enoic acid (0.15 g, 1.26 mmol, CAS 413622-10-3), Intermediate 526 (0.49 g, 0.84 mmol), DIPEA (0.45 mL, 2.58 mmol), HOBt (0.11 g, 0.84 mmol) and EDCI (0.19 g, 1.01 mmol) in MeCN (5 mL) at RT for 18 h. Purified by flash chromatography (25 g silica gel, 0- 40% EtOAc in petroleum ether) to provide the title compound (0.45 g). LCMS (Method 11): 2.74 min, 618.3 [M+H]+. Intermediate 528: Ethyl (S)-3-(4-fluoro-2'-(hex-5-en-1-yl)-6'-methyl-4',5-bis(trifluoromethyl)- [1,1'-biphenyl]-3-yl)-3-((R)-2-((methylsulfonyl)oxy)pent-4-enamido)propanoate Prepared in an analogous manner to Intermediate 5 using Intermediate 527 (0.45 g, 0.68 mmol), triethylamine (0.19 mL, 1.36 mmol) and methanesulfonyl chloride (79 µL,1.02 mmol) in DCM (6.8 mL) at RT for 1 h, to provide the title compound (0.47 g). LCMS (Method 15): 2.71 min, 694.2 [M-H]-. Intermediate 529: Ethyl (S)-3-(4-fluoro-2'-(hex-5-en-1-yl)-6'-methyl-4',5-bis(trifluoromethyl)- [1,1'-biphenyl]-3-yl)-3-((S)-2-(5-(2-(3-fluoroazetidin-1-yl)ethyl)-2-oxo-4- (trifluoromethyl)pyridin-1(2H)-yl)pent-4-enamido)propanoate

[0443] Prepared in an analogous manner to Intermediate 6 using Intermediate 528 (0.47 g, 0.68 mmol), Intermediate 516 (0.19 g, 0.70 mmol) and K2CO3(0.28 g, 2.03 mmol) in MeCN (15 mL) at reflux for 16 h. Purified by flash chromatography (25 g silica gel, 0-100% EtOAc in petroleum ether) to provide the title compound (0.25 g). LCMS (Method 15): 2.87 min, 864.4 [M+H]+. Intermediate 530: Ethyl 2-((3S,6S)-24-fluoro-6-(5-(2-(3-fluoroazetidin-1-yl)ethyl)-2-oxo-4- (trifluoromethyl)pyridin-1(2H)-yl)-16-methyl-5-oxo-14,25-bis(trifluoromethyl)-4-aza- 1(1,2),2(1,3)-dibenzenacyclotridecaphan-8-en-3-yl)acetate

[0444] Prepared in an analogous manner to Intermediate 7 using Intermediate 529 (0.25 g, 0.29 mmol) and Grubbs II (24 mg, 28 µmol) in DCE (0.14 L) at 50 °C for 1.5 h. Purified by flash chromatography (25 g silica gel, 0-100% EtOAc in petroleum ether) to provide the title compound (0.19 g). LCMS (Method 15): 2.80 min, 836.4 [M+H]+. Intermediate 531: Ethyl 2-((3S,6S)-24-fluoro-6-(5-(2-(3-fluoroazetidin-1-yl)ethyl)-2-oxo-4- (trifluoromethyl)pyridin-1(2H)-yl)-16-methyl-5-oxo-14,25-bis(trifluoromethyl)-4-aza- 1(1,2),2(1,3)-dibenzenacyclotridecaphane-3-yl)acetate

[0445] Prepared in an analogous manner to Intermediate 8 using Intermediate 530 (0.19 g, 0.20 mmol) and 10% palladium on carbon (21 mg) in ethanol (12 mL) under a hydrogen atmosphere at RT for 2.5 h. Purified by flash chromatography (12 g silica gel, 0-10% MeOH in DCM) to provide the title compound (0.16 g). LCMS (Method 15): 2.82 min, 838.4 [M+H]+. Intermediate 532: (E)-4-(Difluoromethyl)-5-(2-ethoxyvinyl)-2-methoxypyridine

[0446] Prepared in an analogous manner to Intermediate 29 using 5-bromo-4- (difluoromethyl)-2-methoxypyridine (1.03 g, 4.33 mmol, CAS 1806764-22-6), trans-2- ethoxyvinylboronic acid pinacol ester (0.94 g, 4.76 mmol, CAS 1201905-61-4), Pd(PPh3)4(0.25 g, 0.22 mmol) and K2CO3(1.79 g, 13.0 mmol) in 1,4-dioxane (12 mL) and water (2.4 mL) at 100 °C for 18 h. Purified by flash chromatography (25 g silica gel, 0-30% EtOAc in petroleum ether) to provide the title compound (0.81 g). LCMS (Method 15): 1.99 min, 230.1 [M+H]+. Intermediate 533: 2-(4-(Difluoromethyl)-6-methoxypyridin-3-yl)acetaldehyde

[0447] A solution of Intermediate 532 (0.71 g, 3.11 mmol) in TFA (12 mL) was stirred at RT for 5.5 h. The mixture was concentrated under reduced pressure to provide the title compound (0.70 g). LCMS (Method 15): 1.34 min, 202.0 [M+H]+. Intermediate 534: 4-(Difluoromethyl)-2-methoxy-5-(2-(3-methoxyazetidin-1-yl)ethyl)pyridine

[0448] Prepared in an analogous manner to Intermediate 31 using Intermediate 533 (0.62 g, 3.10 mmol), 3-methoxyazetidine hydrochloride (0.46 g, 3.72 mmol, CAS 148644-09- 1) and triethylamine (1.30 mL, 9.30 mmol) in DCM (9.5 mL) at RT for 0.5 h, followed by STAB (1.31 g, 6.20 mmol) at RT for 16 h. Purified by flash chromatography (24 g silica gel, 0-10% (0.5% ammonia MeOH) in DCM) to provide the title compound (0.26 g). LCMS (Method 15): 1.58 min, 273.3 [M+H]+. Intermediate 535: 4-(Difluoromethyl)-5-(2-(3-methoxyazetidin-1-yl)ethyl)pyridin-2(1H)-one

[0449] Prepared in an analogous manner to Intermediate 426 using sodium iodide (0.65 g, 4.33 mmol), chlorotrimethylsilane (1.10 mL, 8.65 mmol) in MeCN (10 mL) at RT for 15 min then Intermediate 534 (0.26 g, 0.87 mmol) in MeCN (2 mL) at RT for 16 h. Purified by catch and release chromatography (5 g SCX, MeOH followed by 3.5 M ammonia in MeOH) to provide the title compound (0.16 g). LCMS (Method 15): 1.15 min, 259.0 [M+H]+. Intermediate 536: Ethyl (S)-3-(4,4'-difluoro-2'-(hex-5-en-1-yl)-6'-methyl-5-(trifluoromethyl)- [1,1'-biphenyl]-3-yl)-3-((S)-2-(4-(difluoromethyl)-5-(2-(3-methoxyazetidin-1-yl)ethyl)-2- 1(2H)-yl)pent-4-enamido)propanoate

[0450] Prepared in an analogous manner to Intermediate 6 using Intermediate 41 (0.35 g, 0.55 mmol), Intermediate 535 (0.20 g, 0.71 mmol) and K2CO3 (0.23 g, 1.65 mmol) in MeCN (24 mL) at reflux for 16 h. Purified by flash chromatography (40 g silica gel, 0-5% (0.5% ammonia MeOH) in DCM) to provide the title compound (0.17 g). LCMS (Method 15): 2.72 min, 808.4 [M+H]+. Intermediate 537: Ethyl 2-((3S,6S)-6-(4-(difluoromethyl)-5-(2-(3-methoxyazetidin-1-yl)ethyl)- 2-oxopyridin-1(2H)-yl)-14,24-difluoro-16-methyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphan-8-en-3-yl)acetate

[0451] Prepared in an analogous manner to Intermediate 7 using Intermediate 536 (0.17 g, 0.19 mmol) and Grubbs II (16 mg, 19 µmol) in DCE (0.13 L) at 50 °C for 3 h. Purified by flash chromatography (12 g silica gel, 0-10% (0.5% ammonia MeOH) in DCM) to provide the title compound (0.14 g). LCMS (Method 15): 2.62 min, 780.4 [M+H]+. Intermediate 538: Ethyl 2-((3S,6S)-6-(4-(difluoromethyl)-5-(2-(3-methoxyazetidin-1-yl)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)acetate

[0452] Prepared in an analogous manner to Intermediate 8 using Intermediate 537 (0.14 g, 0.16 mmol) and 10% palladium on carbon (35 mg) in ethanol (15 mL) under a hydrogen atmosphere at RT for 9 h. Purified by flash chromatography (12 g silica gel, 0-10% MeOH in DCM) to provide the title compound (0.16 g). LCMS (Method 15): 2.64 min, 782.4 [M+H]+. Intermediate 539: Ethyl (S)-3-((S)-2-(5-bromo-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)pent- 4-enamido)-3-(5-chloro-4,4'-difluoro-2'-(hex-5-en-1-yl)-6'-methyl-[1,1'-biphenyl]-3- yl)propanoate

[0453] Prepared in an analogous manner to Intermediate 6 using Intermediate 505 (0.25 g, 0.40 mmol), 5-bromo-4-(trifluoromethyl)-1H-pyridin-2-one (0.15 g, 0.60 mmol) and K2CO3 (0.17 g, 1.21 mmol) in MeCN (10 mL) at reflux for 16 h. Purified by flash chromatography (25 g silica gel, 0-20% EtOAc in petroleum ether) to provide the title compound (0.16 g). LCMS (Method 15): 2.91 min, 759.3 [M+H]+. Intermediate 540: Ethyl 2-((3S,6S)-6-(5-bromo-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-25- chloro-14,24-difluoro-16-methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphan-8-en-3- yl)acetate

[0454] Prepared in an analogous manner to Intermediate 7 using Intermediate 539 (0.16 g, 0.18 mmol) and Grubbs II (15.5 mg, 18 µmol) in DCE (0.10 L) at 50 °C for 40 min. Purified by flash chromatography (25 g silica gel, 0-20% EtOAc in petroleum ether) to provide the title compound (0.11 g). LCMS (Method 27): 2.57 min, 731.2 [M+H]+. Intermediate 541: Ethyl 2-((3S,6S)-6-(5-bromo-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-25- chloro-14,24-difluoro-16-methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3- yl)acetate

[0455] Prepared in an analogous manner to Intermediate 8 using Intermediate 540 (0.11 g, 0.15 mmol) and 10% palladium on carbon (15 mg) in EtOAc (10 mL) under a hydrogen atmosphere at RT for 2.5 h, to provide the title compound (0.12 g). LCMS (Method 15): 2.87 min, 733.2 [M+H]+. Intermediate 542: Ethyl 2-((3S,6S)-25-chloro-14,24-difluoro-16-methyl-5-oxo-6-(2-oxo-5-(3- oxopropyl)-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetate

[0456] Prepared in an analogous manner to Intermediate 434 using Intermediate 541 (98 mg, 0.12 mmol), prop-2-en-1-ol (21 mg, 0.36 mmol, CAS 107-18-6), N,N- dicyclohexylmethylamine (32 µL, 0.15 mmol), tri-tert-butylphosphonium tetrafluoroborate (3.5 mg, 12 µmol), and Pd2(dba)3(5.5 mg, 6.0 µmol) in 1,4-dioxane (6.6 mL) at 50 °C for 2 h.Purified by flash chromatography (12 g silica gel, 0-30% EtOAc in petroleum ether) to provide the title compound (48 mg). LCMS (Method 15): 2.70 min, 709.3 [M+H]+. Intermediate 543: Ethyl 2-((3S,6S)-6-(5-(3-(azetidin-1-yl)propyl)-2-oxo-4- (trifluoromethyl)pyridin-1(2H)-yl)-25-chloro-14,24-difluoro-16-methyl-5-oxo-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetate

[0457] Prepared in an analogous manner to Intermediate 31 using Intermediate 542 (48 mg, 63 µmol), azetidine (12.7 µL, 0.19 mmol) and triethylamine (26 µL, 0.19 mmol) in DCM (2.2 mL) at RT for 10 min, followed by STAB (40 mg, 0.19 mmol) at RT for 18 h. Purified by catch and release chromatography (2 g SCX, MeOH followed by 3.5 M ammonia in MeOH) to provide the title compound (49 mg). LCMS (Method 15): 2.97 min, 750.4 [M+H]+. Intermediate 544: 3-(4-(Difluoromethyl)-6-methoxypyridin-3-yl)propanal

[0458] Prepared in an analogous manner to Intermediate 434 using 5-bromo-4- (difluoromethyl)-2-methoxypyridine (2.27 g, 9.54 mmol, CAS 1806764-22-6), prop-2-en-1-ol (1.11 g, 19.1 mmol, CAS 107-18-6), N,N-dicyclohexylmethylamine (2.25 mL, 10.5 mmol), tri- tert-butylphosphonium tetrafluoroborate (0.28 g, 0.95 mmol), and Pd2(dba)3 (0.44 g, 0.48 mmol) in 1,4-dioxane (18 mL) at 50 °C for 16 h. Purified by flash chromatography (12 g silica gel, 0-10% EtOAc in petroleum ether) to provide the title compound (1.51 g). LCMS (Method 15): 1.53 min, 216.1 [M+H]+. Intermediate 545: 3-(4-(Difluoromethyl)-6-methoxypyridin-3-yl)-N,N-dimethylpropan-1- amine

[0459] Prepared in an analogous manner to Intermediate 31 using Intermediate 544 (0.91 g, 4.22 mmol), dimethylamine (2 M in THF, 2.53 mL) and triethylamine (1.29 mL, 9.27 mmol) in DCM (13 mL) at RT for 30 min, followed by STAB (1.79 g, 8.43 mmol) at RT for 16 h. Purified by flash chromatography (12 g silica gel, 0-10% MeOH in DCM) to provide the title compound (0.39 g). LCMS (Method 15): 1.78 min, 245.1 [M+H]+. Intermediate 546: 4-(Difluoromethyl)-5-(3-(dimethylamino)propyl)pyridin-2(1H)-one

[0460] Prepared in an analogous manner to Intermediate 426 using sodium iodide (1.18 g, 7.88 mmol), chlorotrimethylsilane (1.0 mL, 7.88 mmol) in MeCN (35 mL) at RT for 20 min then Intermediate 545 (0.39 g, 1.58 mmol) in MeCN (3.5 mL) at RT for 16 h. Purified by catch and release chromatography (10 g SCX, MeOH followed by 3.5 M ammonia in MeOH) to provide the title compound (0.22 g). LCMS (Method 15): 1.16 min, 231.1 [M+H]+. Intermediate 547: Ethyl (S)-3-(4,4'-difluoro-2'-(hex-5-en-1-yl)-6'-methyl-5-(trifluoromethyl)- [1,1'-biphenyl]-3-yl)-3-((S)-2-(4-(difluoromethyl)-5-(3-(dimethylamino)propyl)-2-oxopyridin- -yl)pent-4-enamido)propanoate

[0461] Prepared in an analogous manner to Intermediate 6 using Intermediate 41 (0.36 g, 0.56 mmol), Intermediate 546 (0.13 g, 0.56 mmol) and K2CO3(0.23 g, 1.67 mmol) in MeCN (5.6 mL) at reflux for 18 h. Purified by flash chromatography (24 g silica gel, 0-6% (0.5% ammonia MeOH) in DCM) to provide the title compound (0.22 g). LCMS (Method 15): 2.84 min, 780.4 [M+H]+. Intermediate 548: Ethyl 2-((3S,6S)-6-(4-(difluoromethyl)-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)- dibenzenacyclotridecaphan-8-en-3-yl)acetate

[0462] Prepared in an analogous manner to Intermediate 7 using Intermediate 547 (0.22 g, 0.25 mmol) and Grubbs II (21 mg, 25 µmol) in DCE (0.13 L) at 45 °C for 1.5 h. Purified by flash chromatography (12 g silica gel, 0-5% (0.5% ammonia MeOH) in DCM) to provide the title compound (0.21 g). LCMS (Method 15): 2.75 min, 752.4 [M+H]+. Intermediate 549: Ethyl 2-((3S,6S)-6-(4-(difluoromethyl)-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)acetate

[0463] Prepared in an analogous manner to Intermediate 8 using Intermediate 548 (0.21 g, 0.23 mmol) and 10% palladium on carbon (25 mg) in EtOAc (15 mL) under a hydrogen atmosphere at RT for 4 h. Purified by flash chromatography (12 g silica gel, 2-6% (0.5% ammonia MeOH) in DCM) to provide the title compound (0.17 g). LCMS (Method 15): 2.79 min, 754.4 [M+H]+. Intermediate 550: Ethyl (S)-3-((S)-2-(5-(3-(3-methoxyazetidin-1-yl)propyl)-2-oxo-4- (trifluoromethyl)pyridin-1(2H)-yl)pent-4-enamido)-3-(2',4,4'-trifluoro-6'-(hex-5-en-1-yl)-5- (trifluoromethyl)-[1,1'-biphenyl]-3-yl)propanoate

[0464] Prepared in an analogous manner to Intermediate 6 using Intermediate 25 (0.32 g, 0.49 mmol), Intermediate 492 (0.15 g, 0.49 mmol) and K2CO3 (0.20 g, 1.48 mmol) in MeCN (7 mL) at reflux for 18 h. Purified by flash chromatography (40 g silica gel, 0-100% EtOAc in petroleum ether then 0-3% (0.5% ammonia MeOH) in DCM) to provide the title compound (0.15 g). LCMS (Method 27): 2.42 min, 844.5 [M+H]+. Intermediate 551: Ethyl 2-((3S,6S)-14,16,24-trifluoro-6-(5-(3-(3-methoxyazetidin-1-yl)propyl)- 2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphan-8-en-3-yl)acetate

[0465] Prepared in an analogous manner to Intermediate 7 using Intermediate 550 (0.15 g, 0.18 mmol) and Grubbs II (15 mg, 18 µmol) in DCE (64 mL) at 50 °C for 1.5 h. Purifiedby flash chromatography (12 g silica gel, 0-10% (0.5% ammonia MeOH) in DCM) to provide the title compound (59 mg). LCMS (Method 27): 2.07 min, 816.5 [M+H]+. Intermediate 552: Ethyl 2-((3S,6S)-14,16,24-trifluoro-6-(5-(3-(3-methoxyazetidin-1-yl)propyl)- 2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetate

[0466] Prepared in an analogous manner to Intermediate 8 using Intermediate 551 (59 mg, 72 µmol) and 10% palladium on carbon (7.6 mg) in ethanol (4.8 mL) under a hydrogen atmosphere at RT for 9 h, to provide the title compound (58 mg). LCMS (Method 27): 2.16 min, 818.4 [M+H]+. Intermediate 553: (E)-1-Benzyl-5-(2-ethoxyvinyl)-3-methylpyrimidine-2,4(1H,3H)-dione

[0467] Prepared in an analogous manner to Intermediate 29 using 1-benzyl-5-bromo- 3-methylpyrimidine-2,4(1H,3H)-dione (2.21 g, 7.49 mmol, CAS 57712-74-0), trans-2- ethoxyvinylboronic acid pinacol ester (1.63 g, 8.23 mmol, CAS 1201905-61-4), Pd(dppf)Cl2 (0.31 g, 0.37 mmol) and Na2CO3 (1.59 g, 15.0 mmol) in 1,4-dioxane (32 mL) and water (5.4 mL) at 100 °C for 16 h. Purified by flash chromatography (80 g silica gel, 0-50% EtOAc in petroleum ether) to provide the title compound (1.56 g). LCMS (Method 15): 1.82 min, 287.0 [M+H]+. Intermediate 554: 1-Benzyl-5-(2-(dimethylamino)ethyl)-3-methylpyrimidine-2,4(1H,3H)- dione

[0468] Prepared in an analogous manner to Intermediate 46 using Intermediate 553 (1.46 g, 4.84 mmol) in 4 M HCl in 1,4-dioxane (36 mL) at RT for 1.5 h. Then dimethylamine (2 M in THF, 2.9 mL), triethylamine (2.02 mL, 14.5 mmol) and 4 Å molecular sieves in DCM (45 mL) at RT for 10 min, then STAB (2.05 g, 9.68 mmol) at RT for 2 h. Purified by catch and release chromatography (20 g SCX, MeOH followed by 3.5 M ammonia in MeOH) to provide the title compound (0.79 g). LCMS (Method 15): 1.53 min, 288.2 [M+H]+. Intermediate 555: 5-(2-(Dimethylamino)ethyl)-3-methylpyrimidine-2,4(1H,3H)-dione

[0469] To a solution of Intermediate 554 (1.51 g, 5.26 mmol) in ethanol (0.25 L) was added palladium(II) hydroxide (0.74 g, 1.05 mmol) and ammonium formate (6.64 g, 0.11 mol) and the mixture stirred at 80 °C for 20 h. The cooled mixture was filtered and washed with methanol, then concentrated under reduced pressure. The crude product was purified by catch and release chromatography (20 g SCX, MeOH followed by 3.5 M ammonia in MeOH) to provide the title compound (1.83 g). LCMS (Method 15): 0.87 min, 198.1 [M+H]+.Intermediate 556: Ethyl (S)-3-(4,4'-difluoro-2'-(hex-5-en-1-yl)-6'-methyl-5-(trifluoromethyl)- [1,1'-biphenyl]-3-yl)-3-((S)-2-(5-(2-(dimethylamino)ethyl)-3-methyl-2,4-dioxo-3,4- 1(2H)-yl)pent-4-enamido)propanoate

[0470] Prepared in an analogous manner to Intermediate 6 using Intermediate 41 (0.65 g, 1.00 mmol), Intermediate 555 (0.22 g, 1.00 mmol) and K2CO3 (0.42 g, 3.01 mmol) in MeCN (15 mL) at reflux for 16 h. Purified by flash chromatography (40 g silica gel, 0-6% (0.5% ammonia MeOH) in DCM) to provide the title compound (0.36 g). LCMS (Method 27): 2.29 min, 747.4 [M+H]+. Intermediate 557: Ethyl 2-((3S,6S)-6-(5-(2-(dimethylamino)ethyl)-3-methyl-2,4-dioxo-3,4- dihydropyrimidin-1(2H)-yl)-14,24-difluoro-16-methyl-5-oxo-25-(trifluoromethyl)-4-aza- 1(1,2),2(1,3)-dibenzenacyclotridecaphan-8-en-3-yl)acetate

[0471] Prepared in an analogous manner to Intermediate 7 using Intermediate 556 (0.36 g, 0.39 mmol) and Grubbs II (33 mg, 39 µmol) in DCE (0.23 L) at 50 °C for 5 h. Purified by flash chromatography (40 g silica gel, 0-6% (0.5% ammonia MeOH) in DCM) to provide the title compound (0.13 g). LCMS (Method 27): 1.97 min, 719.4 [M+H]+. Intermediate 558: Ethyl 2-((3S,6S)-6-(5-(2-(dimethylamino)ethyl)-3-methyl-2,4-dioxo-3,4- dihydropyrimidin-1(2H)-yl)-14,24-difluoro-16-methyl-5-oxo-25-(trifluoromethyl)-4-aza- 1(1,2),2(1,3)-dibenzenacyclotridecaphane-3-yl)acetate

[0472] Prepared in an analogous manner to Intermediate 8 using Intermediate 557 (0.13 g, 0.10 mmol) and 10% palladium on carbon (11 mg) in ethanol (6.7 mL) under a hydrogen atmosphere at RT for 9 h. Purified by flash chromatography (25 g silica gel, 0-10% (0.5% ammonia MeOH) in DCM) to provide the title compound (58 mg). LCMS (Method 27): 2.04 min, 721.4 [M+H]+. Intermediate 559: Ethyl 2-((3S,6S)-14,16,24-trifluoro-5-oxo-6-(2-oxo-5-(3-oxopropyl)-4- (trifluoromethyl)pyridin-1(2H)-yl)-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetate

[0473] Prepared in an analogous manner to Intermediate 434 using Intermediate 28 (0.20 g, 0.21 mmol), prop-2-en-1-ol (43 µL, 0.63 mmol, CAS 107-18-6), N,N- dicyclohexylmethylamine (56 µL, 0.25 mmol), tri-tert-butylphosphonium tetrafluoroborate (6.1 mg, 21 µmol), and Pd2(dba)3(9.6 mg, 11 µmol) in 1,4-dioxane (12 mL) at 70 °C for 18 h. Purified by flash chromatography (12 g silica gel, 0-50% EtOAc in petroleum ether) to provide the title compound (0.10 g). LCMS (Method 15): 2.64 min, 747.3 [M+H]+.Intermediate 560: Ethyl 2-((3S,6S)-6-(5-(3-(azetidin-1-yl)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)acetate

[0474] Prepared in an analogous manner to Intermediate 31 using Intermediate 559 (0.10 g, 0.13 mmol), azetidine (25 µL, 0.37 mmol) and triethylamine (52 µL, 0.37 mmol) in DCM (4.6 mL) at RT for 10 min, followed by STAB (79 mg, 0.37 mmol) at RT for 62 h. Purified by catch and release chromatography (5 g SCX, MeOH followed by 3.5 M ammonia in MeOH) to provide the title compound (78 mg). LCMS (Method 15): 2.89 min, 788.4 [M+H]+. Intermediate 561: 5-(3-(3-Fluoroazetidin-1-yl)propyl)-2-methoxy-4-(trifluoromethyl)pyridine

[0475] Prepared in an analogous manner to Intermediate 31 using Intermediate 490 (1.27 g, 5.17 mmol), 3-fluoroazetidine hydrochloride (0.58 g, 5.17 mmol, CAS 617718-46-4) and triethylamine (0.87 mL, 6.21 mmol) in DCM (55 mL) at RT for 10 min, followed by STAB (2.74 g, 12.9 mmol) at RT for 1.5 h. Purified by flash chromatography (40 g silica gel, 0-10% (0.5% ammonia MeOH) in DCM) to provide the title compound (1.33 g). LCMS (Method 15): 1.96 min, 293.3 [M+H]+. Intermediate 562: 5-(3-(3-Fluoroazetidin-1-yl)propyl)-4-(trifluoromethyl)pyridin-2(1H)-one

[0476] A solution of Intermediate 561 (1.03 g, 2.93 mmol) in 33% HBr(10 mL, 57.1 mmol) was stirred at 50 °C for 11 h. The mixture was cooled and concentrated under reduced pressure, dissolved in MeCN (10 mL) and 2 M aqueous sodium hydroxide (5.85 mL) and heated at 50 °C for 18 h. The mixture was acidified with 4 M HCl in 1,4-dioxane (2.92 mL) then concentrated under reduced pressure. The crude product was purified by catch and release chromatography (20 g SCX, MeOH followed by 3.5 M ammonia in MeOH) to provide the title compound (0.56 g). LCMS (Method 11): 1.30 min, 279.2 [M+H]+. Intermediate 563: Ethyl (S)-3-(4,4'-difluoro-2'-(hex-5-en-1-yl)-5,6'-dimethyl-[1,1'-biphenyl]-3- yl)-3-((S)-2-(5-(3-(3-fluoroazetidin-1-yl)propyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)pent- 4-enamido)propanoate

[0477] Prepared in an analogous manner to Intermediate 6 using Intermediate 69 (0.31 g, 0.53 mmol), Intermediate 562 (0.22 g, 0.69 mmol) and K2CO3(0.22 g, 1.60 mmol) in MeCN (14 mL) at reflux for 18 h. Purified by flash chromatography (25 g silica gel, 0-100% EtOAc in petroleum ether) to provide the title compound (0.15 g). LCMS (Method 15): 2.84 min, 774.4 [M+H]+. Intermediate 564: Ethyl 2-((3S,6S)-14,24-difluoro-6-(5-(3-(3-fluoroazetidin-1-yl)propyl)-2-oxo- 4-(trifluoromethyl)pyridin-1(2H)-yl)-16,25-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphan-8-en-3-yl)acetate

[0478] Prepared in an analogous manner to Intermediate 7 using Intermediate 563 (0.17 g, 0.20 mmol) and Grubbs II (17 mg, 20 µmol) in DCE (0.10 L) at 50 °C for 1 h. Purified by flash chromatography (12 g silica gel, 0-100% EtOAc in petroleum ether) to provide the title compound (0.15 g). LCMS (Method 15): 2.74 min, 746.4 [M+H]+. Intermediate 565: Ethyl 2-((3S,6S)-14,24-difluoro-6-(5-(3-(3-fluoroazetidin-1-yl)propyl)-2-oxo- 4-(trifluoromethyl)pyridin-1(2H)-yl)-16,25-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetate

[0479] Prepared in an analogous manner to Intermediate 8 using Intermediate 564 (0.15 g, 0.17 mmol) and 10% palladium on carbon (18 mg) in ethanol (10 mL) under a hydrogen atmosphere at RT for 8 h, to provide the title compound (0.15 g). LCMS (Method 15): 2.77 min, 748.4 [M+H]+. Intermediate 566: 5-Bromo-3-(difluoromethyl)-2-fluorobenzaldehyde

[0480] To a stirred solution of 4-bromo-2-(difluoromethyl)-1-fluorobenzene (5.0 g, 22.2 mmol, CAS 445303-69-5) and in THF (26 mL) at -70 °C was added LDA (2 M in THF / heptane / ethylbenzene, 16.7 mL) dropwise and the mixture was stirred at -70 °C for 1 h. DMF (8.1 mL, 0.11 mol) was added slowly then stirring continued at -70 °C for 1 h before warming to RT.1 M aqueous HCl (20 mL) was added and extracted with EtOAc. The organics were washed with water, brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (80 g silica gel, 0-10% EtOAc in petroleum ether) to provide the title compound (4.10 g). LCMS (Method 15): 1.86 min, 250.9 [M-H]-. Intermediate 567: (R,Z)-N-(5-Bromo-3-(difluoromethyl)-2-fluorobenzylidene)-2- methylpropane-2-sulfinamide

[0481] Prepared in an analogous manner to Intermediate 37 using Intermediate 566 (4.10 g, 16.2 mmol), (R)-2-methylpropane-2-sulfinamide (2.16 g, 17.8 mmol, CAS 196929-78- 9) and titanium ethoxide (5.54 g, 24.3 mmol) in THF (44 mL) at 40 °C for 5 h, to provide the title compound (5.80 g). LCMS (Method 15): 2.26 min, 354.0 [M-H]-. Intermediate 568: Ethyl (S)-3-(5-bromo-3-(difluoromethyl)-2-fluorophenyl)-3-(((R)-tert- butylsulfinyl)amino)propanoate

[0482] Prepared in an analogous manner to Intermediate 38 using zinc (4.19 g, 64.0 mmol), chlorotrimethylsilane (0.33 mL, 2.56 mmol) and ethyl bromoacetate (3.55 mL, 32.0 mmol) in THF (60 mL) at 65 °C for 1 h, then Intermediate 567 (4.80 g, 12.8 mmol) in THF (37 mL) at RT for 1 h. Purified by dry flash chromatography (silica gel, 0-50% EtOAc in petroleum ether) to provide the title compound (3.3 g). LCMS (Method 15): 2.09 min, 446.0 [M+H]+.Intermediate 569: Ethyl (S)-3-amino-3-(5-bromo-3-(difluoromethyl)-2- fluorophenyl)propanoate

[0483] A suspension of Intermediate 568 (3.95 g, 8.71 mmol) in 4 M HCl in 1,4- dioxane (13 mL) was stirred at RT for 2 h. The mixture was concentrated under reduced pressure, quenched with saturated aqueous sodium bicarbonate and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by catch and release chromatography (10 g SCX, MeOH followed by 3.5 M ammonia in MeOH) to provide the title compound (2.40 g). LCMS (Method 15): 1.85 min, 342.0 [M+H]+. Intermediate 570: Ethyl (S)-3-(5-bromo-3-(difluoromethyl)-2-fluorophenyl)-3-((tert- butoxycarbonyl)amino)propanoate

[0484] Prepared in an analogous manner to Intermediate 20 using Intermediate 569 (2.40 g, 7.06 mmol), Boc anhydride (1.85 g, 8.47 mmol) and DIPEA (1.84 mL, 10.6 mmol) in DCM (25 mL) at RT for 7 h. Purified by flash chromatography (40 g silica gel, 0-20% EtOAc in petroleum ether) to provide the title compound (2.90 g). LCMS (Method 15): 2.27 min, 438.0 [M-H]-. Intermediate 571: Ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(5-(difluoromethyl)-4,4'- difluoro-2'-hydroxy-6'-methyl-[1,1'-biphenyl]-3-yl)propanoate

[0485] Prepared in an analogous manner to Intermediate 1 using Intermediate 570 (2.40 g, 5.18 mmol), Intermediate 191 (1.64 g, 6.16 mmol), K3PO4 (3.32 g, 15.6 mmol), XPhosPdG2 (0.20 g, 0.26 mmol) in 1,4-dioxane (20 mL) and water (6.6 mL) at 110 °C for 1.5 h. Purified by flash chromatography (24 g silica gel, 0-30% EtOAc in petroleum ether) to provide the title compound (1.63 g). LCMS (Method 15): 2.22 min, 484.2 [M-H]-. Intermediate 572: Ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(5-(difluoromethyl)-4,4'- difluoro-2'-methyl-6'-(((trifluoromethyl)sulfonyl)oxy)-[1,1'-biphenyl]-3-yl)propanoate

[0486] Prepared in an analogous manner to10 using Intermediate 571 (1.94 g, 3.68 mmol), phenyl triflimide (1.31 g, 3.67 mmol, CAS 37595-74-7) and Cs2CO3 (1.44 g, 4.42 mmol) in DCM (37 mL) at RT for 3 h. Purified by flash chromatography (40 g silica gel, 0–30% EtOAc in petroleum ether) to provide the title compound (2.10 g). LCMS (Method 15): 2.55 min, 616.2 [M-H]-. Intermediate 573: Ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(5-(difluoromethyl)-4,4'- difluoro-2'-(hex-5-en-1-yl)-6'-methyl-[1,1'-biphenyl]-3-yl)propanoate

[0487] Prepared in an analogous manner to Intermediate 1 using Intermediate 572 (1.50 g, 2.31 mmol), 5-hexenylboronic acid (0.44 g, 3.46 mmol, CAS 1072952-16-9), K2CO3(0.96 g, 6.92 mmol), RuPhos (0.16 g, 0.35 mmol) and palladium(II) acetate (52 mg, 0.23 mmol) in toluene (20 mL) and water (3.3 mL) at 95 °C for 0.5 h. Purified by flash chromatography (40 g silica gel, 0-10% EtOAc in petroleum ether) to pr...

Claims

Claims 1. A compound selected from: 2-((3S,6S)-6-(5-(2-(Dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-14,16-difluoro-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-fluoro-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)- 14,16,24-trifluoro-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-14,16,24-Trifluoro-6-(5-(2-(3-methoxyazetidin-1-yl)ethyl)-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)-14,24-Difluoro-6-(5-(2-(3-fluoro-3-methylazetidin-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-(Dimethylamino)ethyl)-2-oxopyridin-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-(3-(3-(Dimethylamino)propyl)-6-oxo-4-(trifluoromethyl)pyridazin-1(6H)-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)-6-(5-(2-(Dimethylamino)ethyl)-3-methyl-2-oxopyrazin-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-(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)-14,16,24-Trifluoro-6-(5-(2-(3-fluoroazetidin-1-yl)ethyl)-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-(Dimethylamino)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-((10S,13S)-10-(5-(2-(Azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-15- cyclopropyl-14,24-difluoro-26-methyl-11-oxo-3-oxa-12-aza-1(1,3),2(1,2)-dibenzenacyclotridecaphane-13-yl)acetic acid; 2-((3S,6S)-6-(3-(2-(Dimethylamino)ethyl)-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)-14,24-Difluoro-6-(3-(2-(3-fluoro-3-methylazetidin-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)-6-(5-(2-(Dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)- 14,16,24-trifluoro-25-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-oxopyridazin-1(6H)-yl)-14-fluoro-16- methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-14,16,24-Trifluoro-6-(3-(2-(3-methoxyazetidin-1-yl)ethyl)-6-oxo-4- (trifluoromethyl)pyridazin-1(6H)-yl)-25-methyl-5-oxo-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-6-(5-(2-(Dimethylamino)ethyl)-3-methyl-2-oxopyrazin-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)-16,25-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)-3-methyl-2-oxopyrazin- 1(2H)-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-(2-(dimethylamino)ethyl)-2-oxo-4- (trifluoromethyl)pyridin-1(2H)-yl)-14,16,24-trifluoro-5-oxo-12-oxa-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-fluoro-16,25-dimethyl-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)- 14,16,24-trifluoro-25-methyl-5-oxo-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-16,25-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)- 14,24-difluoro-16,25,8-trimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclododecaphane- 3-yl)acetic acid; 2-((3S,6S)-6-(5-Cyclopropyl-3-(2-(3-fluoroazetidin-1-yl)ethyl)-6-oxopyridazin-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)-6-(3-(2-(Azetidin-1-yl)ethyl)-5-cyclopropyl-6-oxopyridazin-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)-14,24-Difluoro-6-(3-(2-(3-fluoroazetidin-1-yl)ethyl)-5-methyl-6-oxopyridazin- 1(6H)-yl)-16,25-dimethyl-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)-5-methyl-6-oxopyridazin-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)-6-(5-(3-(Dimethylamino)propyl)-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)-14-Fluoro-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)-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)-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)-6-(5-(3-(Dimethylamino)propyl)-2-oxopyrazin-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)-4-methyl-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-(3-(Dimethylamino)propyl)-4-methyl-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)-24-Fluoro-6-(5-(2-(3-methoxyazetidin-1-yl)ethyl)-2-oxo-4- (trifluoromethyl)pyridin-1(2H)-yl)-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-(3-(Difluoromethyl)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-(3-(Dimethylamino)-2-methylpropyl)-4-methyl-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)-14,24-Difluoro-6-(5-(2-(3-(methoxymethyl)azetidin-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)-14,24-Difluoro-16-methyl-5-oxo-6-(2-oxo-4-(trifluoromethyl)-5-(2-(3- (trifluoromethyl)azetidin-1-yl)ethyl)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-6-(5-(2-(3-methoxyazetidin-1-yl)ethyl)-2-oxo-4- (trifluoromethyl)pyridin-1(2H)-yl)-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-(3-Ethoxyazetidin-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-(3-(Dimethylamino)propyl)-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)-6-(5-(2-(Dimethylamino)ethyl)-1-methyl-2-oxo-1,2-dihydropyridin-3-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-Cyclobutyl-14,24-difluoro-6-(5-(2-(3-methoxyazetidin-1-yl)ethyl)-4-methyl- 2-oxopyrimidin-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-(5-(3-(3-methoxyazetidin-1-yl)propyl)-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)-25-Chloro-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-Chloro-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-Chloro-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)-14,24-Difluoro-6-(5-(3-(3-methoxyazetidin-1-yl)propyl)-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)-24-Fluoro-6-(5-(2-(3-fluoroazetidin-1-yl)ethyl)-2-oxo-4- (trifluoromethyl)pyridin-1(2H)-yl)-16-methyl-5-oxo-14,25-bis(trifluoromethyl)-4-aza- 1(1,2),2(1,3)-dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-6-(4-(Difluoromethyl)-5-(2-(3-methoxyazetidin-1-yl)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-(3-(Azetidin-1-yl)propyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-25- chloro-14,24-difluoro-16-methyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane- 3-yl)acetic acid; 2-((3S,6S)-6-(4-(Difluoromethyl)-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)-14,16,24-trifluoro-6-(5-(3-(3-methoxyazetidin-1-yl)propyl)-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)-3-methyl-2,4-dioxo-3,4-dihydropyrimidin- 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)- 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-Difluoro-6-(5-(3-(3-fluoroazetidin-1-yl)propyl)-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)-25-(Difluoromethyl)-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-(Difluoromethyl)-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)-6-(5-(3-(Azetidin-1-yl)propyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-25- (difluoromethyl)-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-(3-(Azetidin-1-yl)propyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)- 14,16,24-trifluoro-25-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)-4-(difluoromethyl)-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)-14,24-Difluoro-16,25-dimethyl-6-(5-((1-methylazetidin-3-yl)methyl)-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)-14,24-Difluoro-16,25-dimethyl-6-(5-((1-methylpiperidin-4-yl)methyl)-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)-25-Chloro-6-(5-(3-(dimethylamino)-2-methylpropyl)-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-(3-(Dimethylamino)-2-methylpropyl)-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)-2-methylpropyl)-2-oxo-4-(trifluoromethyl)pyridin- 1(2H)-yl)-14,16,24-trifluoro-25-methyl-5-oxo-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-25-(Difluoromethyl)-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)-6-(5-(3-(Dimethylamino)-2-methylpropyl)-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)-14,16,24-Trifluoro-6-(5-(2-(3-fluoroazetidin-1-yl)ethyl)-2-oxo-4- (trifluoromethyl)pyridin-1(2H)-yl)-25-methyl-5-oxo-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-24-Fluoro-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-(3-(Dimethylamino)propyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-24- fluoro-16-methyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-25-Chloro-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)-25-Cyclopropyl-14-fluoro-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)-14,24-Difluoro-6-(5-(3-(3-fluoroazetidin-1-yl)propyl)-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)-14-Cyano-24-fluoro-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-(2-(Dimethylamino)ethyl)-3-methyl-2,4-dioxo-3,4-dihydropyrimidin- 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)-3-methyl-2,4-dioxo-3,4-dihydropyrimidin- 1(2H)-yl)-14,24-difluoro-16,9-dimethyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacycloundecaphane-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)-16,25,9-trimethyl-5-oxo-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphan-9-en-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)-16,25,9-trimethyl-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)-16,25,8-trimethyl-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)-3-methyl-2,4-dioxo-3,4- dihydropyrimidin-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-(Dimethylamino)ethyl)-3-methyl-2,4-dioxo-3,4-dihydropyrimidin- 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-(3-(Dimethylamino)-2-methylpropyl)-3-methyl-2,4-dioxo-3,4- dihydropyrimidin-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-16,9-dimethyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacycloundecaphane-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)- dibenzenacycloundecaphane-3-yl)acetic acid; 2-((3S,6S)-6-(5-(3-(Dimethylamino)propyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)- 14,16,24-trifluoro-8-methyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacycloundecaphane-3-yl)acetic acid; 2-((9S,12S)-9-(5-(2-(Dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-24-fluoro-26-methyl- 10-oxo-3-oxa-11-aza-1(1,3),2(1,2)-dibenzenacyclododecaphane-12-yl)acetic acid; 2-((11S,14S)-11-(5-(2-(Dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-24-fluoro-26- methyl-12-oxo-3-oxa-13-aza-1(1,3),2(1,2)-dibenzenacyclotetradecaphane-14-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)-16,9-dimethyl-5-oxo-25-(trifluoromethyl)-4-aza- 1(1,2),2(1,3)-dibenzenacycloundecaphane-3-yl)acetic acid; 2-((9S,12S)-9-(5-(2-(Dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-26-methyl-10-oxo-3- oxa-11-aza-1(1,3),2(1,2)-dibenzenacyclododecaphane-12-yl)acetic acid; and 2-((11S,14S)-11-(5-(2-(Dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-26-methyl-12-oxo- 3-oxa-13-aza-1(1,3),2(1,2)-dibenzenacyclotetradecaphane-14-yl)acetic acid, or a pharmaceutically acceptable salt thereof.

2. A pharmaceutical composition comprising a compound according to claim 1, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

3. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 2, for use in therapy.

4. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 2, for use in the treatment of diseases or disorders mediated by α4β7.

5. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 2, for use in the treatment of an inflammatory bowel disease.

6. The compound or the pharmaceutical composition for the use according to claim 5, wherein the inflammatory bowel disease is selected from ulcerative colitis and Crohn’s disease.

7. The compound or the pharmaceutical composition for the use according to claim 5 or claim 6, in combination with one or more additional therapeutic agents.

8. 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 according to claim 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 2.

9. A method of treating an inflammatory bowel disease, said method comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 2.

10. The method according to claim 9, wherein the inflammatory bowel disease is selected from ulcerative colitis and Crohn’s disease.

11. The method according to claim 9 or claim 10, wherein the compound or the pharmaceutical composition is administered in combination with a therapeutically effective amount of one or more additional therapeutic agents.

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